Science.gov

Sample records for kidney injury molecule-1

  1. Kidney injury molecule-1 (KIM-1) mediates renal epithelial cell repair via ERK MAPK signaling pathway

    PubMed Central

    Zhang, Zhiwei; Cai, Cindy X

    2016-01-01

    The expression of kidney injury molecule-1 (KIM-1), a very promising sensitive and specific urinary biomarker for acute renal injury, is markedly upregulated in injured and regenerating renal proximal tubular epithelial cells following ischemic or toxic insults, suggesting a possible role for this molecule in renal repair process. In the present study we report that expression of KIM-1 facilitates renal tubular epithelial cell repair by promoting cell migration and proliferation. KIM-1 expression also enhances ERK MAPK activation, and the modulatory effect of KIM-1 on cellular repair process is likely mediated via ERK MAPK signaling pathway. PMID:27084535

  2. Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1.

    PubMed

    Cárdenas-González, M; Osorio-Yáñez, C; Gaspar-Ramírez, O; Pavković, M; Ochoa-Martínez, A; López-Ventura, D; Medeiros, M; Barbier, O C; Pérez-Maldonado, I N; Sabbisetti, V S; Bonventre, J V; Vaidya, V S

    2016-10-01

    Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5-12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples had levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6ppb) and chromium (61.7ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467pg/mL; T3: 615pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents. PMID:27431456

  3. Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1.

    PubMed

    Cárdenas-González, M; Osorio-Yáñez, C; Gaspar-Ramírez, O; Pavković, M; Ochoa-Martínez, A; López-Ventura, D; Medeiros, M; Barbier, O C; Pérez-Maldonado, I N; Sabbisetti, V S; Bonventre, J V; Vaidya, V S

    2016-10-01

    Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5-12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples had levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6ppb) and chromium (61.7ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467pg/mL; T3: 615pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents.

  4. Kidney Injury Molecule-1 and Cardiovascular Diseases: From Basic Science to Clinical Practice

    PubMed Central

    Medić, Branislava; Rovčanin, Branislav; Basta Jovanović, Gordana; Radojević-Škodrić, Sanja; Prostran, Milica

    2015-01-01

    Despite the recent findings concerning pathogenesis and novel therapeutic strategies, cardiovascular disease (CVD) still stays the leading cause of morbidity and mortality in patients with renal dysfunction, especially acute kidney injury (AKI). Early detection of patients with impaired renal function with cardiovascular risk may help ensure more aggressive treatment and improve clinical outcome. Kidney injury molecule-1 (KIM-1) is a new, promising marker of kidney damage which is currently the focus of countless studies worldwide. Some recent animal and human studies established KIM-1 as an important marker of acute tubular necrosis (ATN) and reliable predictor of development and prognosis of AKI. Food and Drug Administration (FDA) in USA acclaimed KIM-1 as an AKI biomarker for preclinical drug development. Recent data suggest the importance of monitoring of KIM-1 for early diagnosis and clinical course not only in patients with various forms of AKI and other renal diseases but also in patients with cardiorenal syndrome, heart failure, cardiopulmonary bypass, cardiothoracic surgical interventions in the pediatric emergency setting, and so forth. The aim of this review article is to summarize the literature data concerning KIM-1 as a potential novel marker in the early diagnosis and prediction of clinical outcome of certain cardiovascular diseases. PMID:26697493

  5. Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

    PubMed Central

    Ismail, Ola Z.; Zhang, Xizhong; Wei, Junjun; Haig, Aaron; Denker, Bradley M.; Suri, Rita S.; Sener, Alp; Gunaratnam, Lakshman

    2016-01-01

    Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein α12 (Gα12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits Gα12 activation and protects mice against renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular Gα12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to Gα12. Compared with Kim-1+/+ mice, Kim-1−/− mice exhibited greater Gα12 and downstream Src activation both in primary tubular epithelial cells after in vitro stimulation with H2O2 and in whole kidneys after unilateral renal artery clamping. Finally, we show that Kim-1–deficient mice had more severe kidney dysfunction and tissue damage after bilateral renal artery clamping, compared with wild-type mice. Our results suggest that KIM-1 is an endogenous protective mechanism against renal ischemia-reperfusion injury through inhibition of Gα12. PMID:25759266

  6. Kidney injury molecule-1 expression is closely associated with renal allograft damage.

    PubMed

    Song, Lianlian; Xue, Lijuan; Yu, Jinyu; Zhao, Jun; Zhang, Wenlan; Fu, Yaowen

    2013-08-01

    The aim of our study was to investigate the expression of kidney injury molecule-1 (KIM-1) in renal allograft biopsy samples and assess the clinical significance of its use as a biomarker for tissue damage. A total of 69 renal allograft biopsy samples from 17 patients with normal serum creatinine and 52 cases of increased serum creatinine were collected. They were divided into different groups according to the Banff 2007 diagnostic criteria. KIM-1 expression was detected by immunohistochemical methods and the association of KIM-1 and blood biochemical indexes was analyzed. KIM-1 expression increased as Banff 2007 classification grade increased and was positively correlated with tubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1 expression was strongly positive in the chronic active antibody-mediated rejection group. Interestingly, KIM-1 was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group, 27.3% (3/11) of the cases with normal serum creatinine level showed weakly positive KIM-1 expression in their renal tissues. KIM-1 expression level is positively correlated with renal allograft damage and tubular cell injury. KIM-1 is expressed in tubular epithelial cells before blood biochemical indexes become elevated and morphological changes occur. KIM-1 expression is an early, sensitive, and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue.

  7. Tissue Kidney Injury Molecule-1 Expression in the Prediction of Renal Function for Several Years after Kidney Biopsy

    PubMed Central

    Simic Ogrizovic, Sanja; Basta-Jovanovic, Gordana; Radojevic, Sanja; Pavlovic, Jelena; Kotur Stevuljevic, Jelena; Dopsaj, Violeta; Naumovic, Radomir

    2013-01-01

    Objectives. Retrospective study was designed to examine the importance of tissue kidney injury molecule-1 (KIM-1) expression in predicting kidney function in sixty patients (27 males) aged 34.15 ± 12.23 years with different kidney diseases over three years after kidney biopsy. Materials and Methods. Tissue KIM-1 expression was determined immunohistochemically and KIM-1 staining was scored semiquantitatively, as well as tubulointerstitialis (TIN), inflammation, atrophy, and fibrosis. Kidney function (MDRD formula) and proteinuria/day were evaluated at the time of biopsy (GFR0) and 6, 12, 24, and 36 months later. Results. Significantly positive correlations between tissue KIM-1 expression and age (r = 0.313), TIN inflammation (r = 0.456), fibrosis (r = 0.317), and proteinuria at 6 months (r = 0.394) as well as negative correlations with GFR0 (r = −0.572), GFR6 (r = −0.442), GFR24 (r = −0.398), and GFR36 (r = −0.412) were found. Meanwhile, TIN inflammation was the best predictor of all measured kidney functions during three years, while tissue KIM-1 expression (P = 0.016) was a predictor only at 6 months after biopsy. Conclusion. Tissue KIM-1 expression significantly predicts kidney function solely at 6 months after biopsy, when the effects of immune and nonimmune treatments are the strongest. PMID:24282337

  8. Anti-interleukin-33 Reduces Ovalbumin-Induced Nephrotoxicity and Expression of Kidney Injury Molecule-1

    PubMed Central

    2016-01-01

    Purpose: To evaluate the effect of anti-interleukin-33 (anti-IL-33) on a mouse model of ovalbumin (OVA)-induced acute kidney injury (AKI). Methods: Twenty-four female BALB/c mice were assigned to 4 groups: group A (control, n=6) was administered sterile saline intraperitoneally (i.p.) and intranasally (i.n.); group B (allergic, n=6) was administered i.p./i.n. OVA challenge; group C (null treatment, n=6) was administered control IgG i.p. before OVA challenge; and group D (anti-IL-33, n=6) was pretreated with 3.6 µg of anti-IL-33 i.p. before every OVA challenge. The following were evaluated after sacrifice: serum blood urea nitrogen and creatinine levels, Kidney injury molecule-1 gene (Kim-1) and protein (KIM-1) expression in renal parenchyma, and expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phosphorylated endothelial NOS (p-eNOS), and phosphorylated AMP kinase (p-AMPK) proteins in renal parenchyma. Results: After OVA injection and intranasal challenge, mice in groups B and C showed significant increases in the expression of Kim-1 at both the mRNA and protein levels. After anti-IL-33 treatment, mice in group D showed significant Kim-1 down-regulation at the mRNA and protein levels. Group D also showed significantly lower COX-2 protein expression, marginally lesser iNOS expression than groups B and C, and p-eNOS and p-AMPK expression at baseline levels. Conclusions: Kim-1 could be a useful marker for detecting early-stage renal injury in mouse models of OVA-induced AKI. Further, anti-IL-33 might have beneficial effects on these mouse models. PMID:27377943

  9. Electrical detection of kidney injury molecule-1 with AlGaN /GaN high electron mobility transistors

    NASA Astrophysics Data System (ADS)

    Wang, H. T.; Kang, B. S.; Ren, F.; Pearton, S. J.; Johnson, J. W.; Rajagopal, P.; Roberts, J. C.; Piner, E. L.; Linthicum, K. J.

    2007-11-01

    AlGaN /GaN high electron mobility transistors (HEMTs) were used to detect kidney injury molecule-1 (KIM-1), an important biomarker for early kidney injury detection. The gate region consisted of 5nm gold deposited onto the AlGaN surface. The gold was conjugated to highly specific KIM-1 antibodies through a self-assembled monolayer of thioglycolic acid. The HEMT source-drain current showed a clear dependence on the KIM-1 concentration in phosphate-buffered saline solution. The limit of detection was 1ng/ml using a 20×50μm2 gate sensing area. This approach shows potential for both preclinical and clinical kidney injury diagnosis with accurate, rapid, noninvasive, and high throughput capabilities.

  10. Electrical detection of kidney injury molecule-1 with AlGaN/GaN high electron mobility transistors

    SciTech Connect

    Wang, H. T.; Kang, B. S.; Ren, F.; Pearton, S. J.; Johnson, J. W.; Rajagopal, P.; Roberts, J. C.; Piner, E. L.; Linthicum, K. J.

    2007-11-26

    AlGaN/GaN high electron mobility transistors (HEMTs) were used to detect kidney injury molecule-1 (KIM-1), an important biomarker for early kidney injury detection. The gate region consisted of 5 nm gold deposited onto the AlGaN surface. The gold was conjugated to highly specific KIM-1 antibodies through a self-assembled monolayer of thioglycolic acid. The HEMT source-drain current showed a clear dependence on the KIM-1 concentration in phosphate-buffered saline solution. The limit of detection was 1 ng/ml using a 20x50 {mu}m{sup 2} gate sensing area. This approach shows potential for both preclinical and clinical kidney injury diagnosis with accurate, rapid, noninvasive, and high throughput capabilities.

  11. Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.

    PubMed

    Sabbisetti, Venkata S; Waikar, Sushrut S; Antoine, Daniel J; Smiles, Adam; Wang, Chang; Ravisankar, Abinaya; Ito, Kazumi; Sharma, Sahil; Ramadesikan, Swetha; Lee, Michelle; Briskin, Rebeccah; De Jager, Philip L; Ngo, Thanh Thu; Radlinski, Mark; Dear, James W; Park, Kevin B; Betensky, Rebecca; Krolewski, Andrzej S; Bonventre, Joseph V

    2014-10-01

    Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.

  12. A Bioinformatics Approach Identifies Signal Transducer and Activator of Transcription-3 and Checkpoint Kinase 1 as Upstream Regulators of Kidney Injury Molecule-1 after Kidney Injury

    PubMed Central

    Ajay, Amrendra Kumar; Kim, Tae-Min; Ramirez-Gonzalez, Victoria; Park, Peter J.; Frank, David A.

    2014-01-01

    Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention. PMID:24158981

  13. Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease

    PubMed Central

    Gauer, Stefan; Urbschat, Anja; Gretz, Norbert; Hoffmann, Sigrid C.; Kränzlin, Bettina; Geiger, Helmut; Obermüller, Nicholas

    2016-01-01

    Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an established model for autosomal dominant polycystic kidney disease, with chronic, mainly proximal tubulointerstitial alterations. For immunohistochemistry or Western blot analysis, kidneys of male adult heterozygously-affected (cy/+) and unaffected (+/+) littermates were perfusion-fixed or directly removed. Kim-1 expression was determined using peroxidase- or fluorescence-linked immunohistochemistry (alone or in combination with markers for tubule segments or differentiation). Compared to (+/+), only in (cy/+) kidneys, a chronic expression of Kim-1 could be detected by Western blot analysis, which was histologically confined to an apical cellular localization in areas of cystically-transformed proximal tubules with varying size and morphology, but not in distal tubular segments. Kim-1 was expressed by cystic epithelia exhibiting varying extents of dedifferentiation, as shown by double labeling with aquaporin-1, vimentin or osteopontin, yielding partial cellular coexpression. In this model, in contrast to other known molecules indicating renal injury and/or repair mechanisms, the chronic renal expression of Kim-1 is strictly confined to proximal cysts. Its exact role in interfering with tubulo-interstitial alterations in polycystic kidney disease warrants future investigations. PMID:27231899

  14. Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease.

    PubMed

    Gauer, Stefan; Urbschat, Anja; Gretz, Norbert; Hoffmann, Sigrid C; Kränzlin, Bettina; Geiger, Helmut; Obermüller, Nicholas

    2016-01-01

    Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an established model for autosomal dominant polycystic kidney disease, with chronic, mainly proximal tubulointerstitial alterations. For immunohistochemistry or Western blot analysis, kidneys of male adult heterozygously-affected (cy/+) and unaffected (+/+) littermates were perfusion-fixed or directly removed. Kim-1 expression was determined using peroxidase- or fluorescence-linked immunohistochemistry (alone or in combination with markers for tubule segments or differentiation). Compared to (+/+), only in (cy/+) kidneys, a chronic expression of Kim-1 could be detected by Western blot analysis, which was histologically confined to an apical cellular localization in areas of cystically-transformed proximal tubules with varying size and morphology, but not in distal tubular segments. Kim-1 was expressed by cystic epithelia exhibiting varying extents of dedifferentiation, as shown by double labeling with aquaporin-1, vimentin or osteopontin, yielding partial cellular coexpression. In this model, in contrast to other known molecules indicating renal injury and/or repair mechanisms, the chronic renal expression of Kim-1 is strictly confined to proximal cysts. Its exact role in interfering with tubulo-interstitial alterations in polycystic kidney disease warrants future investigations. PMID:27231899

  15. Increased plasma Kidney Injury Molecule-1 suggests early progressive renal decline in non-proteinuric patients with Type 1 diabetes

    PubMed Central

    Nowak, Natalia; Skupien, Jan; Niewczas, Monika A.; Yamanouchi, Masayuki; Major, Melissa; Croall, Stephanie; Smiles, Adam; Warram, James H.; Bonventre, Joseph V.; Krolewski, Andrzej S.

    2015-01-01

    Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D. PMID:26509588

  16. Urinary biomarkers in hexachloro-1:3-butadiene-induced acute kidney injury in the female Hanover Wistar rat; correlation of α-glutathione S-transferase, albumin and kidney injury molecule-1 with histopathology and gene expression.

    PubMed

    Swain, Aubrey; Turton, John; Scudamore, Cheryl L; Pereira, Ines; Viswanathan, Neeti; Smyth, Rosemary; Munday, Michael; McClure, Fiona; Gandhi, Mitul; Sondh, Surjit; York, Malcolm

    2011-05-01

    Hexachloro-1:3-butadiene (HCBD) causes kidney injury specific to the pars recta of the proximal tubule. In the present studies, injury to the nephron was characterized at 24 h following a single dose of HCBD, using a range of quantitative urinary measurements, renal histopathology and gene expression. Multiplexed renal biomarker measurements were performed using both the Meso Scale Discovery (MSD) and Rules Based Medicine platforms. In a second study, rats were treated with a single nephrotoxic dose of HCBD and the time course release of a range of traditional and newer urinary biomarkers was followed over a 25 day period. Urinary albumin (a marker of both proximal tubular function and glomerular integrity) and α-glutathione S-transferase (α-GST, a proximal tubular cell marker of cytoplasmic leakage) showed the largest fold change at 24 h (day 1) after dosing. Most other markers measured on either the MSD or RBM platforms peaked on day 1 or 2 post-dosing, whereas levels of kidney injury molecule-1 (KIM-1), a marker of tubular regeneration, peaked on day 3/4. Therefore, in rat proximal tubular nephrotoxicity, the measurement of urinary albumin, α-GST and KIM-1 is recommended as they potentially provide useful information about the function, degree of damage and repair of the proximal tubule. Gene expression data provided useful confirmatory information regarding exposure of the kidney and liver to HCBD, and the response of these tissues to HCBD in terms of metabolism, oxidative stress, inflammation, and regeneration and repair.

  17. Expression of kidney injury molecule-1 (Kim-1) in relation to necrosis and apoptosis during the early stages of Cd-induced proximal tubule injury

    SciTech Connect

    Prozialeck, Walter C. Edwards, Joshua R.; Lamar, Peter C.; Liu, Jie; Vaidya, Vishal S.; Bonventre, Joseph V.

    2009-08-01

    Cadmium (Cd) is a nephrotoxic industrial and environmental pollutant that causes a generalized dysfunction of the proximal tubule. Kim-1 is a transmembrane glycoprotein that is normally not detectable in non-injured kidney, but is up-regulated and shed into the urine during the early stages of Cd-induced proximal tubule injury. The objective of the present study was to examine the relationship between the Cd-induced increase in Kim-1 expression and the onset of necrotic and apoptotic cell death in the proximal tubule. Adult male Sprague-Dawley rats were treated with 0.6 mg (5.36 {mu}mol) Cd/kg, subcutaneously, 5 days per week for up to 12 weeks. Urine samples were analyzed for levels of Kim-1 and the enzymatic markers of cell death, lactate dehydrogenase (LDH) and alpha-glutathione-S-transferase ({alpha}-GST). In addition, necrotic cells were specifically labeled by perfusing the kidneys in situ with ethidium homodimer using a procedure that has been recently developed and validated in the Prozialeck laboratory. Cryosections of the kidneys were also processed for the immunofluorescent visualization of Kim-1 and the identification of apoptotic cells by TUNEL labeling. Results showed that significant levels of Kim-1 began to appear in the urine after 6 weeks of Cd treatment, whereas the levels of total protein, {alpha}-GST and LDH were not increased until 8-12 weeks. Results of immunofluorescence labeling studies showed that after 6 weeks and 12 weeks, Kim-1 was expressed in the epithelial cells of the proximal tubule, but that there was no increase in the number of necrotic cells, and only a modest increase in the number of apoptotic cells at 12 weeks. These results indicate that the Cd-induced increase in Kim-1 expression occurs before the onset of necrosis and at a point where there is only a modest level of apoptosis in the proximal tubule.

  18. Effect of Renin-Angiotensin-Aldosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease: A Post Hoc Analysis of a Randomized Controlled Trial

    PubMed Central

    Waanders, Femke; Vaidya, Vishal S.; van Goor, Harry; Leuvenink, Henri; Damman, Kevin; Hamming, Inge; Bonventre, Joseph V.; Vogt, Liffert; Navis, Gerjan

    2012-01-01

    Background Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. Study Design Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. Setting & Participants 34 proteinuric patients without diabetes from our outpatient renal clinic. Intervention Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. Outcomes & Measurements Urinary excretion of KIM-1, total protein, and N-acetyl-β-D-glucosaminidase (NAG) as a positive control for tubular injury. Results Mean baseline urine protein level was 3.8 ± 0.4 (SE) g/d, and KIM-1 level was 1,706 ± 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 ± 388 ng/d; P = 0.04), losartan/high sodium (1,184 ± 296 ng/d; P = 0.09), losartan/LS (921 ± 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 ± 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 ± 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. Limitations Post hoc analysis. Conclusions Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with

  19. Peroxisomes and Kidney Injury

    PubMed Central

    2016-01-01

    Abstract Significance: Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than fifty enzymes and fulfill a multitude of biological tasks. They actively participate in apoptosis, innate immunity, and inflammation. In recent years, a considerable amount of evidence has been collected to support the involvement of peroxisomes in the pathogenesis of kidney injury. Recent Advances: The nature of the two most important peroxisomal tasks, beta-oxidation of fatty acids and hydrogen peroxide turnover, functionally relates peroxisomes to mitochondria. Further support for their communication and cooperation is furnished by the evidence that both organelles share the components of their division machinery. Until recently, the majority of studies on the molecular mechanisms of kidney injury focused primarily on mitochondria and neglected peroxisomes. Critical Issues: The aim of this concise review is to introduce the reader to the field of peroxisome biology and to provide an overview of the evidence about the contribution of peroxisomes to the development and progression of kidney injury. The topics of renal ischemia–reperfusion injury, endotoxin-induced kidney injury, diabetic nephropathy, and tubulointerstitial fibrosis, as well as the potential therapeutic implications of peroxisome activation, are addressed in this review. Future Directions: Despite recent progress, further studies are needed to elucidate the molecular mechanisms induced by dysfunctional peroxisomes and the role of the dysregulated mitochondria–peroxisome axis in the pathogenesis of renal injury. Antioxid. Redox Signal. 25, 217–231. PMID:26972522

  20. Closed kidney injury.

    PubMed

    Viola, Tracey A

    2013-04-01

    The purpose of this article is to discuss the prevalence of blunt renal trauma and the nature of the problem, including the risk of renal injury with sports participation and epidemiology. Patient history of mechanism of injury, as well as examination findings, will risk-stratify patients to determine who needs immediate surgical intervention, who requires imaging, and what patients do not need further imaging. Computed tomography is readily available, fast, and accurate in the diagnosis of renal injury. Discussion of the athlete with congenital renal disease and the solitary kidney concludes this article.

  1. Acute Kidney Injury.

    PubMed

    Zuk, Anna; Bonventre, Joseph V

    2016-01-01

    Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).

  2. Kidney injury associated with telavancin dosing regimen in an animal model.

    PubMed

    Tam, Vincent H; Ledesma, Kimberly R; Bowers, Dana R; Zhou, Jian; Truong, Luan D

    2015-05-01

    The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.

  3. Acute kidney injury in children.

    PubMed

    Merouani, A; Flechelles, O; Jouvet, P

    2012-04-01

    Acute kidney injury (AKI) affects 5% of critically ill hospitalized children and is a risk factor for increased morbidity and mortality. The current review focuses on new definitions of acute kidney injury, standardized to reflect the entire spectrum of the disease, as well as on ongoing research to identify early biomarkers of kidney injury. Its also provides an overview of current practice and available therapies, with emphasis on new strategies for the prevention and pharmacological treatment of diarrhea-associated hemolytic uremic syndrome. Furthermore, a decision-making algorithm is presented for the use of renal replacement therapies in critically ill children with AKI. PMID:22495187

  4. [Ascites and acute kidney injury].

    PubMed

    Piano, Salvatore; Tonon, Marta; Angeli, Paolo

    2016-07-01

    Ascites is the most common complication of cirrhosis. Ascites develops as a consequence of an abnormal splanchnic vasodilation with reduction of effecting circulating volume and activation of endogenous vasoconstrictors system causing salt and water retention. Patients with ascites have a high risk to develop further complications of cirrhosis such as hyponatremia, spontaneous bacterial peritonitis and acute kidney injury resulting in a poor survival. In recent years, new studies helped a better understanding of the pathophysiology of ascites and acute kidney injury in cirrhosis. Furthermore, new diagnostic criteria have been proposed for acute kidney injury and hepatorenal syndrome and a new algorithm for their management has been recommended with the aim of an early diagnosis and treatment. Herein we will review the current knowledge on the pathophysiology, diagnosis and treatment of ascites and acute kidney injury in patients with cirrhosis and we will identify the unmet needs that should be clarified in the next years. PMID:27571467

  5. [Ascites and acute kidney injury].

    PubMed

    Piano, Salvatore; Tonon, Marta; Angeli, Paolo

    2016-07-01

    Ascites is the most common complication of cirrhosis. Ascites develops as a consequence of an abnormal splanchnic vasodilation with reduction of effecting circulating volume and activation of endogenous vasoconstrictors system causing salt and water retention. Patients with ascites have a high risk to develop further complications of cirrhosis such as hyponatremia, spontaneous bacterial peritonitis and acute kidney injury resulting in a poor survival. In recent years, new studies helped a better understanding of the pathophysiology of ascites and acute kidney injury in cirrhosis. Furthermore, new diagnostic criteria have been proposed for acute kidney injury and hepatorenal syndrome and a new algorithm for their management has been recommended with the aim of an early diagnosis and treatment. Herein we will review the current knowledge on the pathophysiology, diagnosis and treatment of ascites and acute kidney injury in patients with cirrhosis and we will identify the unmet needs that should be clarified in the next years.

  6. Perioperative acute kidney injury.

    PubMed

    Goren, O; Matot, I

    2015-12-01

    Perioperative acute kidney injury (AKI) is not uncommon and is associated with considerable morbidity and mortality. Recently, several definition systems for AKI were proposed, incorporating both small changes of serum creatinine and urinary output reduction as diagnostic criteria. Novel biomarkers are under investigation as fast and accurate predictors of AKI. Several special considerations regarding the risk of AKI are of note in the surgical patient. Co-morbidities are important risk factors for AKI. The surgery in itself, especially emergency and major surgery in the critically ill, is associated with a high incidence of AKI. Certain types of surgeries, such as cardiac and transplantation surgeries, require special attention because they carry higher risk of AKI. Nephrotoxic drugs, contrast dye, and diuretics are commonly used in the perioperative period and are responsible for a significant amount of in-hospital AKI. Before surgery, the anaesthetist is required to identify patients at risk of AKI, optimize anaemia, and treat hypovolaemia. During surgery, normovolaemia is of utmost importance. Additionally, the surgical and anaesthesia team is advised to use measures to reduce blood loss and avoid unnecessary blood transfusion. Hypotension should be avoided because even short periods of mean arterial pressure <55-60 mm Hg carry a risk of postoperative AKI. Higher blood pressures are probably required for hypertensive patients. Urine output can be reduced significantly during surgery and is unrelated to perioperative renal function. Thus, fluids should not be given in excess for the sole purpose of avoiding or treating oliguria. Use of hydroxyethyl starch needs to be reconsidered. Recent evidence indicates a beneficial effect of administering low-chloride solutions. PMID:26658199

  7. Acute kidney injury after pediatric cardiac surgery.

    PubMed

    Singh, Sarvesh Pal

    2016-01-01

    Acute kidney injury is a common complication after pediatric cardiac surgery. The definition, staging, risk factors, biomarkers and management of acute kidney injury in children is detailed in the following review article. PMID:27052074

  8. The cell cycle and acute kidney injury.

    PubMed

    Price, Peter M; Safirstein, Robert L; Megyesi, Judit

    2009-09-01

    Acute kidney injury (AKI) activates pathways of cell death and cell proliferation. Although seemingly discrete and unrelated mechanisms, these pathways can now be shown to be connected and even to be controlled by similar pathways. The dependence of the severity of renal-cell injury on cell cycle pathways can be used to control and perhaps to prevent acute kidney injury. This review is written to address the correlation between cellular life and death in kidney tubules, especially in acute kidney injury.

  9. Epigenetics in acute kidney injury

    PubMed Central

    Tang, Jinhua; Zhuang, Shougang

    2015-01-01

    Purpose of review Recent advances in epigenetics indicate the involvement of several epigenetic modifications in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to summarize our understanding of recent advances in epigenetic regulation of AKI and provide mechanistic insight into the role of acetylation, methylation, and microRNA expression in the pathological processes of AKI. Recent findings Enhancement of protein acetylation by pharmacological inhibition of histone deacetylases (HDACs) leads to more severe tubular injury and impairment of renal structural and functional recovery. The changes in promoter DNA methylation occur in the kidney with ischemia/reperfusion. microRNA expression is associated with regulation of both renal injury and regeneration after AKI. Summary Recent studies on epigenetic regulation indicate that acetylation, methylation, and microRNA expression are critically implicated in the pathogenesis of AKI. Strategies targeting epigenetic processes may hold a therapeutic potential for patients with AKI. PMID:26050122

  10. Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

    PubMed Central

    Ledesma, Kimberly R.; Bowers, Dana R.; Zhou, Jian; Truong, Luan D.

    2015-01-01

    The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted. PMID:25712358

  11. Acute Kidney Injury in the Elderly

    PubMed Central

    Abdel-Kader, Khaled; Palevsky, Paul

    2009-01-01

    Synopsis The aging kidney undergoes a number of important anatomic and physiologic changes that increase the risk of acute kidney injury (formerly acute renal failure) in the elderly. This article reviews these changes and discusses the diagnoses frequently encountered in the elderly patient with acute kidney injury. The incidence, staging, evaluation, management, and prognosis of acute kidney injury are also examined with special focus given to older adults. PMID:19765485

  12. Pathophysiology of Acute Kidney Injury

    PubMed Central

    Basile, David P.; Anderson, Melissa D.; Sutton, Timothy A.

    2014-01-01

    Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future. PMID:23798302

  13. Apoptosis and acute kidney injury

    PubMed Central

    Havasi, Andrea; Borkan, Steven C.

    2015-01-01

    Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the ‘perfect storm’ for outer mitochondrial membrane injury to release its cellular ‘executioners’. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI. PMID:21562469

  14. Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

    PubMed

    Cowgill, Larry D; Polzin, David J; Elliott, Jonathan; Nabity, Mary B; Segev, Gilad; Grauer, Gregory F; Brown, Scott; Langston, Cathy; van Dongen, Astrid M

    2016-11-01

    International Renal Interest Society chronic kidney disease Stage 1 and acute kidney injury Grade I categorizations of kidney disease are often confused or ignored because patients are nonazotemic and generally asymptomatic. Recent evidence suggests these seemingly disparate conditions may be mechanistically linked and interrelated. Active kidney injury biomarkers have the potential to establish a new understanding for traditional views of chronic kidney disease, including its early identification and possible mediators of its progression, which, if validated, would establish a new and sophisticated paradigm for the understanding and approach to the diagnostic evaluation, and treatment of urinary disease in dogs and cats.

  15. Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

    PubMed

    Cowgill, Larry D; Polzin, David J; Elliott, Jonathan; Nabity, Mary B; Segev, Gilad; Grauer, Gregory F; Brown, Scott; Langston, Cathy; van Dongen, Astrid M

    2016-11-01

    International Renal Interest Society chronic kidney disease Stage 1 and acute kidney injury Grade I categorizations of kidney disease are often confused or ignored because patients are nonazotemic and generally asymptomatic. Recent evidence suggests these seemingly disparate conditions may be mechanistically linked and interrelated. Active kidney injury biomarkers have the potential to establish a new understanding for traditional views of chronic kidney disease, including its early identification and possible mediators of its progression, which, if validated, would establish a new and sophisticated paradigm for the understanding and approach to the diagnostic evaluation, and treatment of urinary disease in dogs and cats. PMID:27593574

  16. Targeting Iron Homeostasis in Acute Kidney Injury.

    PubMed

    Walker, Vyvyca J; Agarwal, Anupam

    2016-01-01

    Iron is an essential metal involved in several major cellular processes required to maintain life. Because of iron's ability to cause oxidative damage, its transport, metabolism, and storage is strictly controlled in the body, especially in the small intestine, liver, and kidney. Iron plays a major role in acute kidney injury and has been a target for therapeutic intervention. However, the therapies that have been effective in animal models of acute kidney injury have not been successful in human beings. Targeting iron trafficking via ferritin, ferroportin, or hepcidin may offer new insights. This review focuses on the biology of iron, particularly in the kidney, and its implications in acute kidney injury. PMID:27085736

  17. Role of Intercellular Adhesion Molecule-1 in Radiation-Induced Brain Injury

    SciTech Connect

    Wu, K.-L.; Tu Ba; Li Yuqing; Wong, C. Shun

    2010-01-15

    Purpose: To determine the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of brain injury after irradiation (IR). Methods and Materials: We assessed the expression of ICAM-1 in mouse brain after cranial IR and determined the histopathologic and behavioral changes in mice that were either wildtype (+/+) or knockout (-/-) of the ICAM-1 gene after IR. Results: There was an early dose-dependent increase in ICAM-1 mRNA and protein expression after IR. Increased ICAM-1 immunoreactivity was observed in endothelia and glia of ICAM-1+/+ mice up to 8 months after IR. ICAM-1-/- mice showed no expression. ICAM-1+/+ and ICAM-1-/- mice showed similar vascular abnormalities at 2 months after 10-17 Gy, and there was evidence for demyelination and inhibition of hippocampal neurogenesis at 8 months after 10 Gy. After 10 Gy, irradiated ICAM-1+/+ and ICAM-1-/- mice showed similar behavioral changes at 2-6 months in open field, light-dark chamber, and T-maze compared with age-matched genotype controls. Conclusion: There is early and late upregulation of ICAM-1 in the vasculature and glia of mouse brain after IR. ICAM-1, however, does not have a causative role in the histopathologic injury and behavioral dysfunction after moderate single doses of cranial IR.

  18. Nephrology Update: Acute Kidney Injury.

    PubMed

    Sarabu, Nagaraju; Rahman, Mahboob

    2016-05-01

    Acute kidney injury (AKI) refers to any acute decrease in glomerular filtration rate, regardless of etiology. Staging of AKI has been recommended to stratify AKI patients according to severity of the condition, based on serum creatinine level and urine output. Classification of AKI into prerenal, intrinsic renal, and postrenal etiologies is helpful in differential diagnosis and management. AKI in hospitalized patients typically occurs due to decreased renal perfusion. Drug-induced, contrast-associated, postoperative, and sepsis-associated AKI also can occur. Clinical assessment of a patient with AKI involves a medical record review, thorough history and physical examination, urinary and blood tests, renal imaging, and, in some instances, renal biopsy. Contrast-induced nephropathy is a common iatrogenic etiology of AKI associated with administration of intravenous iodinated contrast media. Measures to prevent AKI should be taken before administration of intravenous iodinated contrast. AKI can result in many short- and long-term complications, including chronic kidney disease and end-stage renal disease. Appropriate treatment of AKI patients involves management of the underlying etiology, when possible, and use of nondialytic and dialytic therapies. PMID:27163760

  19. Macrophage-Mediated Injury and Repair After Ischemic Kidney Injury

    PubMed Central

    Huen, Sarah C.; Cantley, Lloyd G.

    2016-01-01

    Acute ischemic kidney injury is a common complication in hospitalized patients. Currently no treatment is available for augmenting kidney repair or preventing progressive kidney fibrosis. Animal models of acute kidney injury demonstrate that activation of the innate immune system plays a major role in the systemic response to ischemia/reperfusion injury. Macrophage depletion studies suggest that macrophages, key participants in the innate immune response, augment the initial injury after reperfusion, but also promote tubular repair and contribute to long-term kidney fibrosis after ischemic injury. The distinct functional outcomes seen following macrophage depletion at different time points after ischemia/reperfusion injury suggest heterogeneity in macrophage activation states. Identifying the pathways that regulate the transitions of macrophage activation is thus critical for understanding the mechanisms that govern both macrophage-mediated injury and repair in the post-ischemic kidney. This review examines our current understanding of the complex and intricately controlled pathways that determine monocyte recruitment, macrophage activation, and macrophage effector functions after renal ischemia/reperfusion injury. Careful delineation of repair and resolution pathways could provide therapeutic targets for the development of effective treatments to offer patients with acute kidney injury. PMID:24442822

  20. KIM-1-mediated phagocytosis reduces acute injury to the kidney.

    PubMed

    Yang, Li; Brooks, Craig R; Xiao, Sheng; Sabbisetti, Venkata; Yeung, Melissa Y; Hsiao, Li-Li; Ichimura, Takaharu; Kuchroo, Vijay; Bonventre, Joseph V

    2015-04-01

    Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.

  1. Acute kidney injury due to decompression illness

    PubMed Central

    Viecelli, Andrea; Jamboti, Jagadish; Waring, Andrew; Banham, Neil; Ferrari, Paolo

    2014-01-01

    Decompression illness is a rare but serious complication of diving caused by intravascular or extravascular gas bubble formation. We report the first case of acute kidney injury in a 27-year-old diver following three rapid ascents. He presented with transient neurological symptoms and abdominal pain followed by rapidly progressive acute kidney injury (creatinine peak 1210 µmol/L) due to arterial air emboli. He received supportive care and 100% oxygen followed by hyperbaric therapy and recovered fully. Arterial air emboli caused by rapid decompression can affect multiple organs including the kidneys. Early transfer to a hyperbaric unit is important as complications may present delayed. PMID:25852912

  2. Spectroscopic Monitoring of Kidney Tissue Ischemic Injury

    SciTech Connect

    Demos, S G; Fitzgerald, J T; Michalopoulou, A P; Troppmann, C

    2004-03-11

    Noninvasive evaluation of tissue viability of donor kidneys used for transplantation is an issue that current technology is not able to address. In this work, we explore optical spectroscopy for its potential to assess the degree of ischemic damage in kidney tissue. We hypothesized that ischemic damage to kidney tissue will give rise to changes in its optical properties which in turn may be used to asses the degree of tissue injury. The experimental results demonstrate that the autofluorescence intensity of the injured kidney is decreasing as a function of time exposed to ischemic injury. Changes were also observed in the NIR light scattering intensities most probably arising from changes due to injury and death of the tissue.

  3. Contrast-associated Acute Kidney Injury.

    PubMed

    Weisbord, Steven D; Palevsky, Paul M

    2015-10-01

    Contrast-associated acute kidney injury (CAAKI) is a common iatrogenic condition. The principal risk factors for CAAKI are underlying renal impairment; diabetes in the setting of kidney disease; and intravascular volume depletion, effective or absolute. CAAKI is associated with serious adverse short-term and long-term outcomes, including mortality and more rapidly progressive chronic kidney disease, although the causal nature of these associations remains unproved. Patients with chronic kidney disease and other risk factors for CAAKI who present with acute coronary syndrome should undergo indicated angiographic procedures.

  4. MRL/MpJ mice show unique pathological features after experimental kidney injury.

    PubMed

    Shiozuru, Daichi; Ichii, Osamu; Kimura, Junpei; Nakamura, Teppei; Elewa, Yaser Hosny Ali; Otsuka-Kanazawa, Saori; Kon, Yasuhiro

    2016-02-01

    Clarification of the renal repair process is crucial for developing novel therapeutic strategies for kidney injury. MRL/MpJ mice have a unique repair process characterized by low scar formation. The pathological features of experimentally injured MRL/MpJ and C57BL/6 mouse kidneys were compared to examine the renal repair process. The dilation and atrophy of renal tubules were observed in folic acid (FA)-induced acute kidney injury (AKI) in both strains, and the histopathological injury scores and number of interleukin (IL)-1F6-positive damaged distal tubules and kidney injury molecule 1 (KIM-1)-positive damaged proximal tubules drastically increased 1 day after AKI induction. However, KIM-1-positive tubules and the elevation of serum renal function markers were significantly fewer and lower, respectively, in MRL/MpJ mice at days 2 and 7 after AKI. After traumatic kidney injury (TKI) via needle puncture, severe tubular necrotic lesions in the punctured area and fibrosis progressed in both strains. Indices for fibrosis such as aniline blue-positive area, number of alpha smooth muscle actin-positive myofibroblasts, and messenger RNA expression levels of Tgfb1 and Mmp2 indicated lower fibrotic activity in MRL/MpJ kidneys. Characteristically, only MRL/MpJ kidneys manifested remarkable calcification around the punctured area beginning 7 days after TKI. The pathological features of injured MRL/MpJ and C57BL/6 kidneys differed, especially those of kidneys with mild proximal tubular injuries after FA-induced AKI. Lower fibrotic activity and increased calcification after TKI were observed in MRL/MpJ kidneys. These findings clarified the unique pathological characteristics of MRL/MpJ mouse kidneys and contribute to understanding of the renal repair process after kidney injury.

  5. Acute Kidney Injury Associated with Linagliptin.

    PubMed

    Nandikanti, Deepak K; Gosmanova, Elvira O; Gosmanov, Aidar R

    2016-01-01

    Linagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that is approved for the treatment of type 2 diabetes mellitus. About 5% of linagliptin is eliminated by the kidneys and no dose adjustment is recommended in kidney impairment. We report a first case of linagliptin-associated acute kidney injury (AKI) in a patient with preexisting chronic kidney disease (CKD). We hypothesize that AKI was due to renal hypoperfusion from linagliptin-induced natriuresis and intravascular volume contraction in the setting of concomitant lisinopril use, which is known to impair autoregulation and potentiate hypotension-induced AKI. It may be prudent to exert caution and closely monitor kidney function when initiating linagliptin in combination with ACE-inhibitors in CKD patients. PMID:26981294

  6. Decreased pulmonary inflammation after ethanol exposure and burn injury in intercellular adhesion molecule-1 knockout mice.

    PubMed

    Bird, Melanie D; Morgan, Michelle O; Ramirez, Luis; Yong, Sherri; Kovacs, Elizabeth J

    2010-01-01

    Clinical and laboratory evidence suggests that alcohol consumption dysregulates immune function. Burn patients who consume alcohol before their injuries demonstrate higher rates of morbidity and mortality, including acute respiratory distress syndrome, than patients without alcohol at the time of injury. Our laboratory observed higher levels of proinflammatory cytokines and leukocyte infiltration in the lungs of mice after ethanol exposure and burn injury than with either insult alone. To understand the mechanism of the increased pulmonary inflammatory response in mice treated with ethanol and burn injury, we investigated the role of intercellular adhesion molecule (ICAM)-1. Wild-type and ICAM-1 knockout (KO) mice were treated with vehicle or ethanol and subsequently given a sham or burn injury. Twenty-four hours postinjury, lungs were harvested and analyzed for indices of inflammation. Higher numbers of neutrophils were observed in the lungs of wild-type mice after burn and burn with ethanol treatment. This increase in pulmonary inflammatory cell accumulation was significantly lower in the KO mice. In addition, levels of KC, interleukin-1beta, and interleukin-6 in the lung were decreased in the ICAM-1 KO mice after ethanol exposure and burn injury. Interestingly, no differences were observed in serum or lung tissue content of soluble ICAM-1 24 hours postinjury. These data suggest that upregulation of adhesion molecules such as ICAM-1 on the vascular endothelium may play a critical role in the excessive inflammation seen after ethanol exposure and burn injury.

  7. Acute kidney injury with hypoxic respiratory failure

    PubMed Central

    Neubert, Zachary; Hoffmann, Paul; Owshalimpur, David

    2014-01-01

    A 27-year-old Caucasian man was transferred from a remote clinic with acute kidney injury for the prior 7–10 days preceded by gastroenteritis. His kidney biopsy showed non-specific mesangiopathic glomerular changes, minimal tubulointerstitial disease without sclerosis, crescents, nor evidence of vasculitis. On his third hospital day, he developed acute hypoxic respiratory failure requiring intubation and mechanical ventilation. Pulmonary renal syndromes ranked highest on his differential diagnosis. He was extubated after 2 days of mechanical ventilation and after pulse dose steroids. His lung biopsy showed pulmonary capillaritis. Our case describes a patient with clinically appearing renopulmonary syndrome, but found to have pulmonary capillaritis, a rare form of lung disease that may also cause acute kidney injury. PMID:25246473

  8. A SCUBA diver with acute kidney injury.

    PubMed

    Gleeson, Patrick James; Kelly, Yvelynne; Ni Sheaghdha, Eadaoin; Lappin, David

    2015-01-01

    An otherwise healthy young man was transferred to our hospital after a diving incident. He had made an uncontrolled ascent from 10 m. On arrival he appeared well. No hypotensive episodes occurred during the transfer. He denied having arthralgias, back pain, dyspnoea or neurological symptoms. Laboratory investigations revealed acutely elevated creatinine (170 µmol/L) and creatine kinase (909 U/L). Radiology was consistent with a focus of pulmonary barotrauma and intrinsic renal disease. Creatine kinase is a marker of arterial gas embolism (AGE). We determined that our patient suffered acute kidney injury as a result of gas embolisation to his renal vasculature from an area of pulmonary barotrauma. Creatinine fell the following day in response to aggressive intravenous fluids. This is the first reported case of acute kidney injury secondary to AGE. Biochemical studies should be part of the routine assessment of patients involved in diving incidents. PMID:25948841

  9. A SCUBA diver with acute kidney injury.

    PubMed

    Gleeson, Patrick James; Kelly, Yvelynne; Ni Sheaghdha, Eadaoin; Lappin, David

    2015-01-01

    An otherwise healthy young man was transferred to our hospital after a diving incident. He had made an uncontrolled ascent from 10 m. On arrival he appeared well. No hypotensive episodes occurred during the transfer. He denied having arthralgias, back pain, dyspnoea or neurological symptoms. Laboratory investigations revealed acutely elevated creatinine (170 µmol/L) and creatine kinase (909 U/L). Radiology was consistent with a focus of pulmonary barotrauma and intrinsic renal disease. Creatine kinase is a marker of arterial gas embolism (AGE). We determined that our patient suffered acute kidney injury as a result of gas embolisation to his renal vasculature from an area of pulmonary barotrauma. Creatinine fell the following day in response to aggressive intravenous fluids. This is the first reported case of acute kidney injury secondary to AGE. Biochemical studies should be part of the routine assessment of patients involved in diving incidents.

  10. Dengue-associated acute kidney injury

    PubMed Central

    Oliveira, João Fernando Picollo; Burdmann, Emmanuel A.

    2015-01-01

    Dengue is presently the most relevant viral infection transmitted by a mosquito bite that represents a major threat to public health worldwide. Acute kidney injury (AKI) is a serious and potentially lethal complication of this disease, and the actual incidence is unknown. In this review, we will assess the most relevant epidemiological and clinical data regarding dengue and the available evidence on the frequency, etiopathogenesis, outcomes and treatment of dengue-associated AKI. PMID:26613023

  11. [Drug-induced acute kidney injury].

    PubMed

    Derungs, Adrian

    2015-12-01

    Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related injuries. This article provides an overview of the pathophysiological mechanisms involved in nephrotoxicity, the most common nephrotoxic drugs, and the risk factors for the occurrence of drug-induced acute kidney injuries. NSAIDs, diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs} are the most frequent prerenal causes of an acute elevation in creatinine levels. Primary vascular damage arises from thrombotic microangiopathy (e. g. due to cic/osporin, tacrolimus, muromonab-CD3, mitomycin C, quinine, ticlopidine, clopidogrel}. Anticoagulants and thrombolytic medications lead to secondary blood vessel damage by cholesterol emboli, embolism of thrombus material into the periphery or bleeding. Tubulopathies can be observed on treatment with ifosfamide and cisplatin (rarely with cyclophosphamide or carboplatin), aminoglycosides, vancomycin, and radiocontrast agents. Immunological mechanisms underlie interstitial nephritides, which are induced by drugs in about 85% of cases. In drug-induced glomerulopathies;- renal biopsy allows closer identification of the triggering medication. Drug-induced systemic lupus erythematosus (SLE} represents a special form of immune complex glomerulonephritis and can be triggered by procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine, and propylthiouracil. Crystal-induced kidney injury is caused by precipitation of drugs (e. g. aciclovir, sulfonamide antibiotics, methotrexate, indinavir) in the renal tubules and the urine-conducting organs with consecutive obstruction thereof. PMID:26654816

  12. [Perioperative acute kidney injury and failure].

    PubMed

    Chhor, Vibol; Journois, Didier

    2014-04-01

    Perioperative period is very likely to lead to acute renal failure because of anesthesia (general or perimedullary) and/or surgery which can cause acute kidney injury. Characterization of acute renal failure is based on serum creatinine level which is imprecise during and following surgery. Studies are based on various definitions of acute renal failure with different thresholds which skewed their comparisons. The RIFLE classification (risk, injury, failure, loss, end stage kidney disease) allows clinicians to distinguish in a similar manner between different stages of acute kidney injury rather than using a unique definition of acute renal failure. Acute renal failure during the perioperative period can mainly be explained by iatrogenic, hemodynamic or surgical causes and can result in an increased morbi-mortality. Prevention of this complication requires hemodynamic optimization (venous return, cardiac output, vascular resistance), discontinuation of nephrotoxic drugs but also knowledge of the different steps of the surgery to avoid further degradation of renal perfusion. Diuretics do not prevent acute renal failure and may even push it forward especially during the perioperative period when venous retourn is already reduced. Edema or weight gain following surgery are not correlated with the vascular compartment volume, much less with renal perfusion. Treatment of perioperative acute renal failure is similar to other acute renal failure. Renal replacement therapy must be mastered to prevent any additional risk of hemodynamic instability or hydro-electrolytic imbalance.

  13. The role of the complement system in acute kidney injury.

    PubMed

    McCullough, James W; Renner, Brandon; Thurman, Joshua M

    2013-11-01

    Acute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury.

  14. Acute kidney injury due to rhabdomyolysis.

    PubMed

    Lima, Rafael Siqueira Athayde; da Silva Junior, Geraldo Bezerra; Liborio, Alexandre Braga; Daher, Elizabeth De Francesco

    2008-09-01

    Rhabdomyolysis is a clinical and biochemical syndrome that occurs when skeletal muscle cells disrupt and release creatine phosphokinase (CK), lactate dehydrogenase (LDH), and myoglobin into the interstitial space and plasma. The main causes of rhabdomyolysis include direct muscular injury, strenuous exercise, drugs, toxins, infections, hyperthermia, seizures, meta-bolic and/or electrolyte abnormalities, and endocrinopathies. Acute kidney injury (AKI) occurs in 33-50% of patients with rhabdomyolysis. The main pathophysiological mechanisms of renal injury are renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity. Rhabdo-myolysis can be asymptomatic, present with mild symptoms such as elevation of muscular en-zymes, or manifest as a severe syndrome with AKI and high mortality. Serum CK five times higher than the normal value usually confirms rhabdomyolysis. Early diagnosis and saline volume expansion may reduce the risk of AKI. Further studies are necessary to establish the importance of bicarbonate and mannitol in the prevention of AKI due to rhabdomyolysis. PMID:18711286

  15. Cardiac surgery-associated acute kidney injury.

    PubMed

    Mao, Huijuan; Katz, Nevin; Ariyanon, Wassawon; Blanca-Martos, Lourdes; Adýbelli, Zelal; Giuliani, Anna; Danesi, Tommaso Hinna; Kim, Jeong Chul; Nayak, Akash; Neri, Mauro; Virzi, Grazia Maria; Brocca, Alessandra; Scalzotto, Elisa; Salvador, Loris; Ronco, Claudio

    2013-10-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy. PMID:24454314

  16. Programmed necrosis in acute kidney injury.

    PubMed

    Linkermann, Andreas; De Zen, Federica; Weinberg, Joel; Kunzendorf, Ulrich; Krautwald, Stefan

    2012-09-01

    Programmed cell death (PCD) had been widely used synonymously to caspase-mediated apoptosis until caspase-independent cell death was described. Identification of necrosis as a regulated process in ischaemic conditions has recently changed our understanding of PCD. At least three pathways of programmed necrosis (PN) have been identified. First, receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis causes organ failure following stroke, myocardial infarction and renal ischaemia/reperfusion injury. Necroptosis can be mediated either by a large intracellular caspase-8-containing signalling complex called the ripoptosome or by the RIP1-/RIP3-containing necroptosome and is controlled by a caspase-8/FLICE inhibitory protein(long) heterodimer at least in the latter case. Second, mitochondrial permeability transition mediates apoptotic or necrotic stimuli and depends on the mitochondrial protein cyclophilin D. The third PN pathway involves the poly(ADP-ribose) polymerase-calpain axis that contributes to acute kidney injury (AKI). Preclinical interference with the PN pathways therefore raises expectations for the future treatment of ischaemic conditions. In this brief review, we aim to summarize the clinically relevant PCD pathways and to transfer the basic science data to settings of AKI. We conclude that pathologists were quite right to refer to ischaemic kidney injury as 'acute tubular necrosis'. PMID:22942173

  17. Acute kidney injury: A rare cause.

    PubMed

    Mendonca, Satish; Barki, Satish; Mishra, Mayank; Kumar, R S V; Gupta, Devika; Gupta, Pooja

    2015-09-01

    We present a young lady who consumed hair dye, which contained paraphenylene diamine (PPD), as a means of deliberate self-harm. This resulted in severe angio-neurotic edema for which she had to be ventilated, and thereafter developed rhabdomyolysis leading to acute kidney injury (AKI). The unusual aspect was that the patient continued to have flaccid quadriparesis and inability to regain kidney function. Renal biopsy performed 10 weeks after the dye consumption revealed severe acute tubular necrosis with myoglobin pigment casts. This suggests that PPD has a long-term effect leading to ongoing myoglobinuria, causing flaccid paralysis to persist and preventing the recovery of AKI. In such instances, timely treatment to prevent AKI in the form alkalinization of urine should be initiated promptly. Secondly, because PPD is a nondialyzable toxin, and its long-term effect necessitates its speedy removal, hemoperfusion might be helpful and is worth considering. PMID:26354573

  18. Sepsis-induced acute kidney injury.

    PubMed

    Majumdar, Arghya

    2010-01-01

    Acute kidney injury (AKI) is a common sequel of sepsis in the intensive care unit. It is being suggested that sepsis-induced AKI may have a distinct pathophysiology and identity. Availability of biomarkers now enable us to detect AKI as early as four hours after it's inception and may even help us to delineate sepsis-induced AKI. Protective strategies such as preferential use of vasopressin or prevention of intra-abdominal hypertension may help, in addition to the other global management strategies of sepsis. Pharmacologic interventions have had limited success, may be due to their delayed usage. Newer developments in extracorporeal blood purification techniques may proffer effects beyond simple replacement of renal function, such as metabolic functions of the kidney or modulation of the sepsis cascade.

  19. Acute Kidney Injury in Pediatric Heart Failure.

    PubMed

    Riley, Alyssa; Gebhard, Daniel J; Akcan-Arikan, Ayse

    2016-01-01

    Acute kidney injury (AKI) is very common in pediatric medical and surgical cardiac patients. Not only is it an independent risk factor for increased morbidity and mortality in the short run, but repeated episodes of AKI lead to chronic kidney disease (CKD) especially in the most vulnerable hosts with multiple risk factors, such as heart transplant recipients. The cardiorenal syndrome, a term coined to emphasize the bidirectional nature of simultaneous or sequential cardiac-renal dysfunction both in acute and chronic settings, has been recently described in adults but scarcely reported in children. Despite the common occurrence and clinical and financial impact, AKI in pediatric heart failure outside of cardiac surgery populations remains poorly studied and there are no large-scale pediatric specific preventive or therapeutic studies to date. This article will review pediatric aspects of the cardiorenal syndrome in terms of pathophysiology, clinical impact and treatment options.

  20. Does orlistat cause acute kidney injury?

    PubMed

    Beyea, Michael M; Garg, Amit X; Weir, Matthew A

    2012-04-01

    Orlistat is an inhibitor of gastric and pancreatic lipase with proven efficacy in the augmentation and maintenance of weight loss. Although its use has been limited by troublesome but benign gastrointestinal side effects, it has more recently been associated with acute kidney injury (AKI). In this review, we summarize orlistat's benefits and drawbacks and discuss the body of evidence supporting its role as a cause of AKI. Although we cannot yet draw an unequivocal causal link between orlistat and AKI, there is enough evidence to include orlistat exposure in the clinical assessment of patients with AKI. PMID:25083225

  1. Contrast-Induced Acute Kidney Injury.

    PubMed

    McCullough, Peter A; Choi, James P; Feghali, Georges A; Schussler, Jeffrey M; Stoler, Robert M; Vallabahn, Ravi C; Mehta, Ankit

    2016-09-27

    Coronary angiography and percutaneous intervention rely on the use of iodinated intravascular contrast for vessel and chamber imaging. Despite advancements in imaging and interventional techniques, iodinated contrast continues to pose a risk of contrast-induced acute kidney injury (CI-AKI) for a subgroup of patients at risk for this complication. There has been a consistent and graded signal of risk for associated outcomes including need for renal replacement therapy, rehospitalization, and death, according to the incidence and severity of CI-AKI. This paper reviews the epidemiology, pathophysiology, prognosis, and management of CI-AKI as it applies to the cardiac catheterization laboratory. PMID:27659469

  2. [Mechanism of Platinum Derivatives Induced Kidney Injury].

    PubMed

    Yan, Feifei; Duan, Jianchun; Wang, Jie

    2015-09-20

    Platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors, lung cancer, and colorectal cancer. Two major problems exist, however, in the clinic use of platinum derivatives. One is the development of tumor resistance to the drug during therapy, leading to treatment failure. The other is the drug's toxicity such as the cisplatin's nephrotoxicity, which limits the dose that can be administered. This paper describes the mechanism of platinum derivatives induced kidney injury.

  3. Does orlistat cause acute kidney injury?

    PubMed Central

    Beyea, Michael M.; Garg, Amit X.

    2012-01-01

    Orlistat is an inhibitor of gastric and pancreatic lipase with proven efficacy in the augmentation and maintenance of weight loss. Although its use has been limited by troublesome but benign gastrointestinal side effects, it has more recently been associated with acute kidney injury (AKI). In this review, we summarize orlistat’s benefits and drawbacks and discuss the body of evidence supporting its role as a cause of AKI. Although we cannot yet draw an unequivocal causal link between orlistat and AKI, there is enough evidence to include orlistat exposure in the clinical assessment of patients with AKI. PMID:25083225

  4. Late intervention with the small molecule BB3 mitigates postischemic kidney injury.

    PubMed

    Narayan, Prakash; Duan, Bin; Jiang, Kai; Li, Jingsong; Paka, Latha; Yamin, Michael A; Friedman, Scott L; Weir, Matthew R; Goldberg, Itzhak D

    2016-08-01

    Ischemia-reperfusion-mediated acute kidney injury can necessitate renal replacement therapy and is a major cause of morbidity and mortality. We have identified BB3, a small molecule, which when first administered at 24 h after renal ischemia in rats, improved survival, augmented urine output, and reduced the increase in serum creatinine and blood urea nitrogen. Compared with control kidneys, the kidneys of BB3-treated animals exhibited reduced levels of kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and reduced tubular apoptosis and acute tubular necrosis but enhanced tubular regeneration. Consistent with its hepatocyte growth factor-like mode of action, BB3 treatment promoted phosphorylation of renal cMet and Akt and upregulated renal expression of the survival protein Bcl-2. These data suggest that the kidney is amenable to pharmacotherapy even 24 h after ischemia-reperfusion and that activation of the hepatocyte growth factor signaling pathway with the small molecule BB3 confers interventional benefits late into ischemia-reperfusion injury. These data formed, in part, the basis for the use of BB3 in a clinical trial in kidney recipients presenting with delayed graft function.

  5. Laboratory Test Surveillance following Acute Kidney Injury

    PubMed Central

    Matheny, Michael E.; Peterson, Josh F.; Eden, Svetlana K.; Hung, Adriana M.; Speroff, Theodore; Abdel-Kader, Khaled; Parr, Sharidan K.; Ikizler, T. Alp; Siew, Edward D.

    2014-01-01

    Background Patients with hospitalized acute kidney injury (AKI) are at increased risk for accelerated loss of kidney function, morbidity, and mortality. We sought to inform efforts at improving post-AKI outcomes by describing the receipt of renal-specific laboratory test surveillance among a large high-risk cohort. Methods We acquired clinical data from the Electronic health record (EHR) of 5 Veterans Affairs (VA) hospitals to identify patients hospitalized with AKI from January 1st, 2002 to December 31st, 2009, and followed these patients for 1 year or until death, enrollment in palliative care, or improvement in renal function to estimated GFR (eGFR) ≥60 L/min/1.73 m2. Using demographic data, administrative codes, and laboratory test data, we evaluated the receipt and timing of outpatient testing for serum concentrations of creatinine and any as well as quantitative proteinuria recommended for CKD risk stratification. Additionally, we reported the rate of phosphorus and parathyroid hormone (PTH) monitoring recommended for chronic kidney disease (CKD) patients. Results A total of 10,955 patients admitted with AKI were discharged with an eGFR<60 mL/min/1.73 m2. During outpatient follow-up at 90 and 365 days, respectively, creatinine was measured on 69% and 85% of patients, quantitative proteinuria was measured on 6% and 12% of patients, PTH or phosphorus was measured on 10% and 15% of patients. Conclusions Measurement of creatinine was common among all patients following AKI. However, patients with AKI were infrequently monitored with assessments of quantitative proteinuria or mineral metabolism disorder, even for patients with baseline kidney disease. PMID:25117447

  6. Suramin protects from cisplatin-induced acute kidney injury.

    PubMed

    Dupre, Tess V; Doll, Mark A; Shah, Parag P; Sharp, Cierra N; Kiefer, Alex; Scherzer, Michael T; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G; Beverly, Levi J; Siskind, Leah J

    2016-02-01

    Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.

  7. The relationship between platelet endothelial cell adhesion molecule-1 and paraquat-induced lung injury in rabbits

    PubMed Central

    Shi, Jing; Hu, Chun-lin; Gao, Yu-feng; Liao, Xiao-xing; Xu, Hope

    2012-01-01

    BACKGROUND: Platelet endothelial cell adhesion molecule-1 (PECAM-1), also known as CD31, is mainly distributed in vascular endothelial cells. Studies have shown that PECAM-1 is a very significant indicator of angiogenesis, and has been used as an indicator for vascular endothelial cells. The present study aimed to explore the relationship between the expression of PECAM-1 and the degree of acute lung injury (ALI) and fibrosis in paraquat (PQ) induced lung injury in rabbits. METHODS: Thirty-six adult New Zealand rabbits were randomly divided into three groups (12 rabbits in each group) according to PQ dosage: 8 mg/kg (group A), 16 mg/kg (group B), and 32 mg/kg (group C). After PQ infusion, the rabbits were monitored for 7 days and then euthanized. The lungs were removed for histological evaluation. Masson staining was used to determine the degree of lung fibrosis (LF), and semi-quantitative immune-histochemistry analysis to determine the expression of PECAM-1. Pearson’s product-moment correlation analysis was performed to evaluate the relationship between the expression of PECAM-1 and the extent of lung injuries expressed by ALI score and degree of LF. RESULTS: Rabbits in the three groups showed apparent poisoning. The rabbits survived longer in group A than in groups B and C (6.47±0.99 days vs. 6.09±1.04 days vs. 4.77±2.04 days) (P<0.05). ALI score was lower in group A than in groups B and C (8.33±1.03 vs. 9.83±1.17 vs. 11.50±1.38) (P<0.05), and there was statistically significant difference between group B and group C (P=0.03). LF was slighter in group A than in groups B and C (31.09%±2.05 % vs. 34.37%±1.62 % vs. 36.54%±0.44%) (P<0.05), and there was statistically significant difference between group B and group C (P=0.026). The PEACAM-1 expression was higher in group A than in groups B and C (20.31%±0.70% vs. 19.34%±0.68% vs. 18.37%±0.46%) (P<0.05), and there was statistically significant difference between group B and group C (P=0.017). Pearson

  8. Mechanisms of kidney cell injury from metals.

    PubMed

    Fowler, B A

    1993-04-01

    The most environmentally abundant toxic metals/metalloids (arsenic, cadmium, lead, and mercury) are each known to produce cell injury in the kidney but the molecular mechanisms underlying these events are now being elucidated. It is clear that the nephrotoxicity of these agents is due, in part, to the fact that urinary elimination is a major route of excretion from the body. The role(s) of molecular factors such as metal-binding proteins, inclusion bodies, and cell-specific receptorlike proteins that appear to influence renal tubule cell expression, have attracted increased interest as determinants that modulate cell populations as special risk for toxicity and renal cancer. The future of mechanistic toxicology studies with regard to how and why only certain renal cell populations become targets for toxicity from these metals/metalloids and other less common inorganic nephrotoxicants must focus on the molecular handling of these agents by target cell populations.

  9. Delayed kidney injury following coronary angiography

    PubMed Central

    WANG, FENG; PENG, CHENG; ZHANG, GUANGYUAN; ZHAO, QING; XUAN, CHANGYOU; WEI, MENG; WANG, NIANSONG

    2016-01-01

    It is occasionally observed that patients without contrast-induced nephropathy (CIN) develop kidney injury within 1–6 months after coronary angiography (CAG), termed delayed CIN or delayed kidney injury (DKI) following CAG. The present study aimed to investigate the associated risk factors of delayed CIN and its possible pathogenesis. Subjects with CAG or coronary stenting from January 2008 to December 2009 were studied. A retrospective survey on DKI after CAG was conducted and the risk factors were analyzed. There were 436 cases receiving CAG with complete medical records enrolled in the present cohort, in which the DKI incidence was 7.1% (31/436). Patients with DKI after CAG exhibited lower hemoglobin (121.2±17.3 vs. 133.8±18.6 g/l), estimated glomerular filtration rate (eGFR; 66.4±30.2 vs. 71.9±28.6 ml/min), higher serum creatinine (110.9±43.2 vs. 91.7±37.6 µmol/l), higher rate of heart failure (22.6 vs. 5.4%) and 300 mg aspirin therapy (29 vs. 5.7%) compared with non-DKI patients (all P<0.05). However, no differences were observed in morbidities of diabetes, hypertension, hyperlipidemia and proteinuria, or in the treatments with angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor-1 blockers (ARBs), diuretics, statins and other anti-platelets between the two groups (P>0.05). Logistic regression revealed that anemia, heart failure and 300 mg aspirin intake were risk factors of DKI (P<0.05), while the contrast level, isotonic contrast, diabetes, ACE inhibitors/ARBs, eGFR and other factors were not associated with DKI (P>0.05). Heart dysfunction and 300 mg aspirin therapy may contribute to DKI after CAG, and iodinated contrast media administration is not a risk factor. PMID:27347090

  10. Molecular determinants of acute kidney injury

    PubMed Central

    Husi, Holger; Human, Christin

    2015-01-01

    Abstract: Background: Acute kidney injury (AKI) is a condition that leads to a rapid deterioration of renal function associated with impairment to maintain electrolyte and acid balance, and, if left untreated, ultimately irreversible kidney damage and renal necrosis. There are a number of causes that can trigger AKI, ranging from underlying conditions as well as trauma and surgery. Specifically, the global rise in surgical procedures led to a substantial increase of AKI incidence rates, which in turn impacts on mortality rates, quality of life and economic costs to the healthcare system. However, no effective therapy for AKI exists. Current approaches, such as pharmacological intervention, help in alleviating symptoms in slowing down the progression, but do not prevent or reverse AKI-induced organ damage. Methods: An in-depth understanding of the molecular machinery involved in and modulated by AKI induction and progression is necessary to specifically pharmacologically target key molecules. A major hurdle to devise a successful strategy is the multifactorial and complex nature of the disorder itself, whereby the activation of a number of seemingly independent molecular pathways in the kidney leads to apoptotic and necrotic events. Results: The renin-angiotensin-aldosterone-system (RAAS) axis appears to be a common element, leading to downstream events such as triggers of immune responses via the NFB pathway. Other pathways intricately linked with AKI-induction and progression are the tumor necrosis factor alpha (TNF α) and transforming growth factor beta (TGF β) signaling cascades, as well as a number of other modulators. Surprisingly, it has been shown that the involvement of the glutamatergic axis, believed to be mainly a component of the neurological system, is also a major contributor. Conclusions: Here we address the current understanding of the molecular pathways evoked in AKI, their interplay, and the potential to pharmacologically intervene in the

  11. Reflex anuria: a rare cause of acute kidney injury

    PubMed Central

    Adediran, Samuel; Dhakarwal, Pradeep

    2014-01-01

    Background Acute Kidney Injury results from pre renal, post renal or intrinsic renal causes. Reflex anuria is a very rare cause of renal impairment which happens due to irritation or trauma to one kidney or ureter, or severely painful stimuli to other nearby organs. Case Presentation Here we present a case of acute kidney injury secondary to reflex anuria in a patient who underwent extensive gynecological surgery along with ureteral manipulation which recovered spontaneously. Conclusion Reflex Anuria is a rare and often not considered as cause of acute kidney injury. This case illustrates that this should be kept as a differential in potential cause of acute kidney injury in patient undergoing urogenital or gynecological surgeries. PMID:24765255

  12. Clinical trial endpoints in acute kidney injury.

    PubMed

    Billings, Frederic T; Shaw, Andrew D

    2014-01-01

    The development and use of consensus criteria for acute kidney injury (AKI) diagnosis and the inclusion of recently identified markers of renal parenchymal damage as endpoints in clinical trials have improved the ability of physicians to compare the incidence and severity of AKI across patient populations, provided targets for testing new treatments, and may increase insight into the mechanisms of AKI. To date, these markers have not consistently translated into important clinical outcomes. Is that because these markers of renal injury/dysfunction are measurements of process of care (and not indicative of persistently impaired renal function), or is it because patients do actually recover from AKI? Physicians currently have limited ability to measure renal function reserve, and the ultimate consequence of a case of AKI on long-term morbidity remains unclear. There is little doubt that groups of patients who develop AKI have worse outcomes than groups of patients who do not, but investigators are now realizing the value of measuring clinically meaningful renal endpoints in all subjects enrolled in AKI clinical trials. Important examples of these outcomes include persistently impaired renal function, new hemodialysis, and death. We propose that these major adverse kidney events (MAKE) be included in all effectiveness clinical trials. Adaptation of the MAKE composite assessed 30, 60, or 90 days following AKI (i.e., MAKE30 or MAKE90) will improve our capacity to understand and treat AKI and may also provide a consensus composite to allow comparison of different interventions. Primary endpoints for phase I and II clinical trials, on the other hand, should continue to use continuous markers of renal injury/dysfunction as well as 'hard' clinical outcomes in order to generate meaningful data with limited subject exposure to untested treatments. By doing so, investigators may assess safety without requiring large sample sizes, demonstrate treatment effect of an unknown

  13. Acute kidney injury by arsine poisoning: the ultrastructural pathology of the kidney.

    PubMed

    Lee, Jun Young; Eom, Minseob; Yang, Jae Won; Han, Byoung Geun; Choi, Seung Ok; Kim, Jae Seok

    2013-01-01

    Arsenic is a terribly poisonous material. There have been many reports of arsine poisoning in workers, and a few have discussed acute kidney injury by arsine. But literatures which investigated the pathologic findings are uncommon, and especially, the ones describing ultrastructural findings are rare. Here, we report an incident of acute arsine poisoning complicated by acute kidney injury and suggest the characteristics of the renal pathology in arsine-induced renal injury, especially the ultrastructural findings.

  14. Recent advances in the understanding of acute kidney injury

    PubMed Central

    Tögel, Florian

    2014-01-01

    Acute kidney injury (AKI) is a common clinical entity associated with high morbidity and mortality and clinical costs. The pathophysiology is multifaceted and involves inflammation, tubular injury, and vascular damage. Recently identified components include necroptosis, a special form of cell death, and autophagy. Most of the pathophysiological knowledge is obtained from animal models but these do not directly reflect the reality of the clinical situation. Tubular cells have a remarkable capacity to regenerate, and the role of stem/progenitor cells is discussed. Acute kidney injury is frequently associated with chronic kidney disease, and the implications are widespread. PMID:25343040

  15. Acute Kidney Injury Predicts Mortality after Charcoal Burning Suicide

    PubMed Central

    Chen, Yu-Chin; Tseng, Yi-Chia; Huang, Wen-Hung; Hsu, Ching-Wei; Weng, Cheng-Hao; Liu, Shou-Hsuan; Yang, Huang-Yu; Chen, Kuan-Hsin; Chen, Hui-Ling; Fu, Jen-Fen; Lin, Wey-Ran; Wang, I-Kuan; Yen, Tzung-Hai

    2016-01-01

    A paucity of literature exists on risk factors for mortality in charcoal burning suicide. In this observational study, we analyzed the data of 126 patients with charcoal burning suicide that seen between 2002 and 2013. Patients were grouped according to status of renal damage as acute kidney injury (N = 49) or non-acute kidney injury (N = 77). It was found that patients with acute kidney injury suffered severer complications such as respiratory failure (P = 0.002), myocardial injury (P = 0.049), hepatic injury (P < 0.001), rhabdomyolysis (P = 0.045) and out-of-hospital cardiac arrest (P = 0.028) than patients without acute kidney injury. Moreover, patients with acute kidney injury suffered longer hospitalization duration (16.9 ± 18.3 versus 10.7 ± 10.9, P = 0.002) and had higher mortality rate (8.2% versus 0%, P = 0.011) than patients without injury. In a multivariate Cox regression model, it was demonstrated that serum creatinine level (P = 0.019) and heart rate (P = 0.022) were significant risk factors for mortality. Finally, Kaplan-Meier analysis revealed that patients with acute kidney injury suffered lower cumulative survival than without injury (P = 0.016). In summary, the overall mortality rate of charcoal burning suicide population was 3.2%, and acute kidney injury was a powerful predictor of mortality. Further studies are warranted. PMID:27430168

  16. Acute Kidney Injury Predicts Mortality after Charcoal Burning Suicide.

    PubMed

    Chen, Yu-Chin; Tseng, Yi-Chia; Huang, Wen-Hung; Hsu, Ching-Wei; Weng, Cheng-Hao; Liu, Shou-Hsuan; Yang, Huang-Yu; Chen, Kuan-Hsin; Chen, Hui-Ling; Fu, Jen-Fen; Lin, Wey-Ran; Wang, I-Kuan; Yen, Tzung-Hai

    2016-01-01

    A paucity of literature exists on risk factors for mortality in charcoal burning suicide. In this observational study, we analyzed the data of 126 patients with charcoal burning suicide that seen between 2002 and 2013. Patients were grouped according to status of renal damage as acute kidney injury (N = 49) or non-acute kidney injury (N = 77). It was found that patients with acute kidney injury suffered severer complications such as respiratory failure (P = 0.002), myocardial injury (P = 0.049), hepatic injury (P < 0.001), rhabdomyolysis (P = 0.045) and out-of-hospital cardiac arrest (P = 0.028) than patients without acute kidney injury. Moreover, patients with acute kidney injury suffered longer hospitalization duration (16.9 ± 18.3 versus 10.7 ± 10.9, P = 0.002) and had higher mortality rate (8.2% versus 0%, P = 0.011) than patients without injury. In a multivariate Cox regression model, it was demonstrated that serum creatinine level (P = 0.019) and heart rate (P = 0.022) were significant risk factors for mortality. Finally, Kaplan-Meier analysis revealed that patients with acute kidney injury suffered lower cumulative survival than without injury (P = 0.016). In summary, the overall mortality rate of charcoal burning suicide population was 3.2%, and acute kidney injury was a powerful predictor of mortality. Further studies are warranted. PMID:27430168

  17. Urinary levels of early kidney injury molecules in children with vitamin B12 deficiency.

    PubMed

    Güneş, Ali; Aktar, Fesih; Tan, İlhan; Söker, Murat; Uluca, Ünal; Balık, Hasan; Mete, Nuriye

    2016-10-01

    The aim of this study was to investigate urine early kidney injury molecules, including human kidney injury molecule-1 (KIM-1), liver-type fatty-acid binding protein (L-FABP), N-acetyl-b-D-glucosaminidase A (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in children with vitamin B12 (cobalamin) deficiency (CD). Twelve children with vitamin B12 deficiency and 20 healthy matched controls were included. Hematologic parameters, serum urea, creatinine (Cr), electrolytes, B12 and folate levels were recorded. Estimated glomerular filtration rate (eGFR) was calculated. Urine protein, electrolytes, andurinary early markers were measured. Patients with CD had significantly higher urine electrolyte/Cr ratios (p <0.05). Significantly higher urinary KIM-1/Cr, L-FABP/Cr, NAG/Cr and NGAL/Cr were found in CD group (p <0.05). Significant negative correlations were found between levels of serum B12 and urinary markers in the patients (p <0.05). Increased urinary kidney injury molecules and electrolytes in children with B12 deficiency suggest a possible subclinical renal dysfunction, which cannot be determined by conventional kidney function tests.

  18. Urinary levels of early kidney injury molecules in children with vitamin B12 deficiency.

    PubMed

    Güneş, Ali; Aktar, Fesih; Tan, İlhan; Söker, Murat; Uluca, Ünal; Balık, Hasan; Mete, Nuriye

    2016-10-01

    The aim of this study was to investigate urine early kidney injury molecules, including human kidney injury molecule-1 (KIM-1), liver-type fatty-acid binding protein (L-FABP), N-acetyl-b-D-glucosaminidase A (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in children with vitamin B12 (cobalamin) deficiency (CD). Twelve children with vitamin B12 deficiency and 20 healthy matched controls were included. Hematologic parameters, serum urea, creatinine (Cr), electrolytes, B12 and folate levels were recorded. Estimated glomerular filtration rate (eGFR) was calculated. Urine protein, electrolytes, andurinary early markers were measured. Patients with CD had significantly higher urine electrolyte/Cr ratios (p <0.05). Significantly higher urinary KIM-1/Cr, L-FABP/Cr, NAG/Cr and NGAL/Cr were found in CD group (p <0.05). Significant negative correlations were found between levels of serum B12 and urinary markers in the patients (p <0.05). Increased urinary kidney injury molecules and electrolytes in children with B12 deficiency suggest a possible subclinical renal dysfunction, which cannot be determined by conventional kidney function tests. PMID:27606644

  19. Ouabain Contributes to Kidney Damage in a Rat Model of Renal Ischemia-Reperfusion Injury

    PubMed Central

    Villa, Luca; Buono, Roberta; Ferrandi, Mara; Molinari, Isabella; Benigni, Fabio; Bettiga, Arianna; Colciago, Giorgia; Ikehata, Masami; Messaggio, Elisabetta; Rastaldi, Maria Pia; Montorsi, Francesco; Salonia, Andrea; Manunta, Paolo

    2016-01-01

    Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and renal EO variations and markers of glomerular and tubular damage (nephrin, KIM-1, Kidney-Injury-Molecule-1, α1 Na-K ATPase) and the protective effect of the ouabain inhibitor, rostafuroxin. We studied five groups of rats: (1) normal; (2) infused for eight weeks with ouabain (30 µg/kg/day, OHR) or (3) saline; (4) ouabain; or (5) saline-infused rats orally treated with 100 µg/kg/day rostafuroxin for four weeks. In group 1, 2–3 h after IRI, EO increased in ischemic kidneys while decreased in plasma. Nephrin progressively decreased and KIM-1 mRNA increased starting from 24 h. Ouabain infusion (group 2) increased blood pressure (from 111.7 to 153.4 mmHg) and ouabain levels in plasma and kidneys. In OHR ischemic kidneys at 120 h from IRI, nephrin, and KIM-1 changes were greater than those detected in the controls infused with saline (group 3). All these changes were blunted by rostafuroxin treatment (groups 4 and 5). These findings support the role of EO in IRI and suggest that rostafuroxin pre-treatment of patients before partial nephrectomy with warm ischemia may reduce IRI, particularly in those with high EO. PMID:27754425

  20. The potential use of biomarkers in predicting contrast-induced acute kidney injury

    PubMed Central

    Andreucci, Michele; Faga, Teresa; Riccio, Eleonora; Sabbatini, Massimo; Pisani, Antonio; Michael, Ashour

    2016-01-01

    Contrast-induced acute kidney injury (CI-AKI) is a problem associated with the use of iodinated contrast media, causing kidney dysfunction in patients with preexisting renal failure. It accounts for 12% of all hospital-acquired kidney failure and increases the length of hospitalization, a situation that is worsening with increasing numbers of patients with comorbidities, including those requiring cardiovascular interventional procedures. So far, its diagnosis has relied upon the rise in creatinine levels, which is a late marker of kidney damage and is believed to be inadequate. Therefore, there is an urgent need for biomarkers that can detect CI-AKI sooner and more reliably. In recent years, many new biomarkers have been characterized for AKI, and these are discussed particularly with their use in known CI-AKI models and studies and include neutrophil gelatinase-associated lipocalin, cystatin C (Cys-C), kidney injury molecule-1, interleukin-18, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein (L-FABP). The potential of miRNA and metabolomic technology is also mentioned. Early detection of CI-AKI may lead to early intervention and therefore improve patient outcome, and in future any one or a combination of several of these markers together with development in technology for their analysis may prove effective in this respect.

  1. The potential use of biomarkers in predicting contrast-induced acute kidney injury.

    PubMed

    Andreucci, Michele; Faga, Teresa; Riccio, Eleonora; Sabbatini, Massimo; Pisani, Antonio; Michael, Ashour

    2016-01-01

    Contrast-induced acute kidney injury (CI-AKI) is a problem associated with the use of iodinated contrast media, causing kidney dysfunction in patients with preexisting renal failure. It accounts for 12% of all hospital-acquired kidney failure and increases the length of hospitalization, a situation that is worsening with increasing numbers of patients with comorbidities, including those requiring cardiovascular interventional procedures. So far, its diagnosis has relied upon the rise in creatinine levels, which is a late marker of kidney damage and is believed to be inadequate. Therefore, there is an urgent need for biomarkers that can detect CI-AKI sooner and more reliably. In recent years, many new biomarkers have been characterized for AKI, and these are discussed particularly with their use in known CI-AKI models and studies and include neutrophil gelatinase-associated lipocalin, cystatin C (Cys-C), kidney injury molecule-1, interleukin-18, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein (L-FABP). The potential of miRNA and metabolomic technology is also mentioned. Early detection of CI-AKI may lead to early intervention and therefore improve patient outcome, and in future any one or a combination of several of these markers together with development in technology for their analysis may prove effective in this respect. PMID:27672338

  2. The potential use of biomarkers in predicting contrast-induced acute kidney injury

    PubMed Central

    Andreucci, Michele; Faga, Teresa; Riccio, Eleonora; Sabbatini, Massimo; Pisani, Antonio; Michael, Ashour

    2016-01-01

    Contrast-induced acute kidney injury (CI-AKI) is a problem associated with the use of iodinated contrast media, causing kidney dysfunction in patients with preexisting renal failure. It accounts for 12% of all hospital-acquired kidney failure and increases the length of hospitalization, a situation that is worsening with increasing numbers of patients with comorbidities, including those requiring cardiovascular interventional procedures. So far, its diagnosis has relied upon the rise in creatinine levels, which is a late marker of kidney damage and is believed to be inadequate. Therefore, there is an urgent need for biomarkers that can detect CI-AKI sooner and more reliably. In recent years, many new biomarkers have been characterized for AKI, and these are discussed particularly with their use in known CI-AKI models and studies and include neutrophil gelatinase-associated lipocalin, cystatin C (Cys-C), kidney injury molecule-1, interleukin-18, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein (L-FABP). The potential of miRNA and metabolomic technology is also mentioned. Early detection of CI-AKI may lead to early intervention and therefore improve patient outcome, and in future any one or a combination of several of these markers together with development in technology for their analysis may prove effective in this respect. PMID:27672338

  3. A case of acute kidney injury by near-drowning.

    PubMed

    Amir, A; Lee, Y L

    2013-01-01

    Acute kidney injury following immersion or near-drowning is rarely described and no data from Malaysia have been found. We report a case of acute kidney injury following a near-drowning event. A 20-year-old man who recovered from near-drowning in a swimming pool 5 days earlier presented to our clinic with abdominal pain, anorexia, nausea and polyuria. Dipstick urinalysis showed a trace of blood. The serum creatinine level was 10-fold higher than the normal range. A bedside ultrasound showed features suggestive of acute tubular necrosis. He is then referred to the hospital with the diagnosis of acute kidney injury with the possibility of acute tubular necrosis secondary to near-drowning. We suggest that any patient presenting after immersion or near-drowning to be should assessed for potential acute kidney injury.

  4. Challenges of targeting vascular stability in acute kidney injury.

    PubMed

    Basile, David P

    2008-08-01

    Acute kidney injury following folate administration is characterized by a vascular remodeling that is initially proliferative but subsequently results in vascular endothelial loss. Interventions directed toward promoting endothelial growth may preserve vascular structure and therefore renal function. However, angiopoietin-1 therapy in the setting of folate-induced acute kidney injury resulted in an expanded fibrotic response despite apparent preservation of the vasculature, indicating that renal repair responses are complex and vascular-directed therapies should be approached with caution.

  5. Cardiac surgery-associated acute kidney injury

    PubMed Central

    Ortega-Loubon, Christian; Fernández-Molina, Manuel; Carrascal-Hinojal, Yolanda; Fulquet-Carreras, Enrique

    2016-01-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-recognized complication resulting with the higher morbid-mortality after cardiac surgery. In its most severe form, it increases the odds ratio of operative mortality 3–8-fold, length of stay in the Intensive Care Unit and hospital, and costs of care. Early diagnosis is critical for an optimal treatment of this complication. Just as the identification and correction of preoperative risk factors, the use of prophylactic measures during and after surgery to optimize renal function is essential to improve postoperative morbidity and mortality of these patients. Cardiopulmonary bypass produces an increased in tubular damage markers. Their measurement may be the most sensitive means of early detection of AKI because serum creatinine changes occur 48 h to 7 days after the original insult. Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 are most promising as an early diagnostic tool. However, the ideal noninvasive, specific, sensitive, reproducible biomarker for the detection of AKI within 24 h is still not found. This article provides a review of the different perspectives of the CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment. We searched the electronic databases, MEDLINE, PubMed, EMBASE using search terms relevant including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment, in order to provide an exhaustive review of the different perspectives of the CSA-AKI. PMID:27716701

  6. MicroRNAs in acute kidney injury.

    PubMed

    Fan, Pei-Chun; Chen, Chia-Chun; Chen, Yung-Chang; Chang, Yu-Sun; Chu, Pao-Hsien

    2016-01-01

    Acute kidney injury (AKI) is an important clinical issue that is associated with significant morbidity and mortality. Despite research advances over the past decades, the complex pathophysiology of AKI is not fully understood. The regulatory mechanisms underlying post-AKI repair and fibrosis have not been clarified either. Furthermore, there is no definitively effective treatment for AKI. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs of 19~23 nucleotides that have been shown to be crucial to the post-transcriptional regulation of various cellular biological functions, including proliferation, differentiation, metabolism, and apoptosis. In addition to being fundamental to normal development and physiology, miRNAs also play important roles in various human diseases. In AKI, some miRNAs appear to act pathogenically by promoting inflammation, apoptosis, and fibrosis, while others may act protectively by exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenic effects. Thus, miRNAs have not only emerged as novel biomarkers for AKI; they also hold promise to be potential therapeutic targets. PMID:27608623

  7. Acute kidney injury in the tropics

    PubMed Central

    Mathew, Ashish Jacob; George, Jacob

    2011-01-01

    Acute kidney injury (AKI) is one of the most challenging problems faced by clinicians in the tropics owing to its fast-changing burden. AKI in the tropics is strikingly different from that in the developed world in terms of etiology and presentation. In addition, there is a stark contrast between well-developed and poor areas in the tropics. The true epidemiological picture of AKI in the tropics is not well understood due to the late presentation of patients to tertiary centers. Infections remain the major culprit in most cases of AKI, with high mortality rates in the tropics. Human immunodeficiency virus–related AKI, related to nephrotoxicity due to antiretroviral therapy, is on the rise. Acute tubular necrosis and thrombotic microangiopathy are the most common mechanisms of AKI. A notable problem in the tropics is the scarcity of resources in health centers to support patients who require critical care due to AKI. This article reviews the unique and contrasting nature of AKI in the tropics and describes its management in each situation. PMID:21911980

  8. Histone lysine crotonylation during acute kidney injury in mice

    PubMed Central

    Ruiz-Andres, Olga; Sanchez-Niño, Maria Dolores; Cannata-Ortiz, Pablo; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto; Sanz, Ana Belen

    2016-01-01

    ABSTRACT Acute kidney injury (AKI) is a potentially lethal condition for which no therapy is available beyond replacement of renal function. Post-translational histone modifications modulate gene expression and kidney injury. Histone crotonylation is a recently described post-translational modification. We hypothesized that histone crotonylation might modulate kidney injury. Histone crotonylation was studied in cultured murine proximal tubular cells and in kidneys from mice with AKI induced by folic acid or cisplatin. Histone lysine crotonylation was observed in tubular cells from healthy murine and human kidney tissue. Kidney tissue histone crotonylation increased during AKI. This was reproduced by exposure to the protein TWEAK in cultured tubular cells. Specifically, ChIP-seq revealed enrichment of histone crotonylation at the genes encoding the mitochondrial biogenesis regulator PGC-1α and the sirtuin-3 decrotonylase in both TWEAK-stimulated tubular cells and in AKI kidney tissue. To assess the role of crotonylation in kidney injury, crotonate was used to increase histone crotonylation in cultured tubular cells or in the kidneys in vivo. Crotonate increased the expression of PGC-1α and sirtuin-3, and decreased CCL2 expression in cultured tubular cells and healthy kidneys. Systemic crotonate administration protected from experimental AKI, preventing the decrease in renal function and in kidney PGC-1α and sirtuin-3 levels as well as the increase in CCL2 expression. For the first time, we have identified factors such as cell stress and crotonate availability that increase histone crotonylation in vivo. Overall, increasing histone crotonylation might have a beneficial effect on AKI. This is the first observation of the in vivo potential of the therapeutic manipulation of histone crotonylation in a disease state. PMID:27125278

  9. Biomarkers in acute kidney injury: Evidence or paradigm?

    PubMed

    Lombi, Fernando; Muryan, Alexis; Canzonieri, Romina; Trimarchi, Hernán

    2016-01-01

    Acute kidney injury in the critically ill represents an independent risk factor of morbidity and mortality in the short and long terms, with significant economic impacts in terms of public health costs. Currently its diagnosis is still based on the presence of oliguria and/or a gradual increase in serum creatinine, which make the diagnosis a delayed event and to detriment of the so-called 'therapeutic window'. The appearance of new biomarkers of acute kidney injury could potentially improve this situation, contributing to the detection of 'subclinical acute kidney injury', which could allow the precocious employment of multiple treatment strategies in order to preserve kidney function. However these new biomarkers display sensitive features that may threaten their full capacity of action, which focus specifically on their additional contribution in the early approach of the situation, given the lack of specific validated treatments for acute kidney injury. This review aims to analyze the strengths and weaknesses of these new tools in the early management of acute kidney injury.

  10. Autophagy is activated to protect against endotoxic acute kidney injury

    PubMed Central

    Mei, Shuqin; Livingston, Man; Hao, Jielu; li, Lin; Mei, Changlin; Dong, Zheng

    2016-01-01

    Endotoxemia in sepsis, characterized by systemic inflammation, is a major cause of acute kidney injury (AKI) in hospitalized patients, especially in intensive care unit; however the underlying pathogenesis is poorly understood. Autophagy is a conserved, cellular catabolic pathway that plays crucial roles in cellular homeostasis including the maintenance of cellular function and viability. The regulation and role of autophagy in septic or endotoxic AKI remains unclear. Here we show that autophagy was induced in kidney tubular cells in mice by the endotoxin lipopolysaccharide (LPS). Pharmacological inhibition of autophagy with chloroquine enhanced LPS-induced AKI. Moreover, specific ablation of autophagy gene 7 (Atg7) from kidney proximal tubules worsened LPS-induced AKI. Together, the results demonstrate convincing evidence of autophagy activation in endotoxic kidney injury and support a renoprotective role of autophagy in kidney tubules. PMID:26916346

  11. Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers.

    PubMed

    Wunnapuk, Klintean; Gobe, Glenda; Endre, Zoltan; Peake, Philip; Grice, Jeffrey E; Roberts, Michael S; Buckley, Nicholas A; Liu, Xin

    2014-02-10

    Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup(®), leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup(®) intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 h after dosing. Biomarkers were quantified by absolute concentration; by normalising to urine creatinine; and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8h (best cut-off point>0.00029 μg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point>0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.

  12. Severe but reversible acute kidney injury resulting from Amanita punctata poisoning

    PubMed Central

    Kang, Eunjung; Cheong, Ka-Young; Lee, Min-Jeong; Kim, Seirhan; Shin, Gyu-Tae; Kim, Heungsoo; Park, In-Whee

    2015-01-01

    Mushroom-related poisoning can cause acute kidney injury. Here we report a case of acute kidney injury after ingestion of Amanita punctata, which is considered an edible mushroom. Gastrointestinal symptoms occurred within 24 hours from the mushroom intake and were followed by an asymptomatic period, acute kidney injury, and elevation of liver and pancreatic enzymes. Kidney function recovered with supportive care. Nephrotoxic mushroom poisoning should be considered as a cause of acute kidney injury. PMID:26779427

  13. Renoprotective mechanisms of morin in cisplatin-induced kidney injury.

    PubMed

    Wei, Zhengkai; He, Xuexiu; Kou, Jinhua; Wang, Jingjing; Chen, Libin; Yao, Minjun; Zhou, Ershun; Fu, Yunhe; Guo, Changming; Yang, Zhengtao

    2015-09-01

    In this study, we investigated the renoprotective effects of morin on cisplatin-induced kidney injury in mice. Serum creatinine and blood urea nitrogen (BUN) levels, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) activities were determined according to the corresponding kits. The mRNA levels of TNF-α and IL-1β in kidney tissues were measured by quantitative real-time PCR (qRT-PCR). The activities of cytochrome P450 2E1 (CYP2E1), nuclear factor kappa B (NF-κB) p65, P38 mitogen-activated protein kinase (MAPK), Bax, p53 and cleaved caspase 3 were evaluated by western blotting. The results showed that the model of cisplatin-induced kidney injury was successfully replicated, and morin significantly attenuated histopathological changes and decreased the levels of TNF-α and IL-1β in the kidneys. In addition, morin attenuated the activation of CYP2E1, phospho-NF-κB p65, phospho-P38 MAPK, Bax, phospho-p53 and cleaved caspase 3 in CP-induced kidney injury. In conclusion, these results indicated that the renoprotective mechanisms of morin may be attributed to the suppression of oxidative stress, inflammation and apoptosis in CP-induced kidney injury.

  14. Molecular mediators of favism-induced acute kidney injury.

    PubMed

    García-Camín, Rosa María; Goma, Montserrat; Osuna, Rosa García; Rubio-Navarro, Alfonso; Buendía, Irene; Ortiz, Alberto; Egido, Jesús; Manzarbeitia, Félix; Chevarria, Julio Leonel; Gluksmann, María Constanza; Moreno, Juan Antonio

    2014-03-01

    Intolerance to fava beans in subjects with glucose-6-phosphate-dehydrogenase deficiency (favism) may lead to severe hemolytic crises and decreased renal function. Renal biopsy findings exploring the molecular mechanisms of renal damage in favism have not been previously reported. We report a case of favism-associated acute kidney injury in which renal biopsy showed acute tubular necrosis and massive iron deposits in tubular cells. Interestingly, iron deposit areas were characterized by the presence of oxidative stress markers (NADPH-p22 phox and heme-oxigenase-1) and macrophages expressing the hemoglobin scavenger receptor CD163. In addition, iron deposits, NADPH-p22 phox, hemeoxigenase- 1 and CD163 positive cells were observed in some glomeruli. These results identify both glomerular and tubular involvement in favism-associated acute kidney injury and suggest novel therapeutic targets to prevent or accelerate recovery from acute kidney injury.

  15. Molecular mediators of favism-induced acute kidney injury.

    PubMed

    García-Camín, Rosa María; Goma, Montserrat; Osuna, Rosa García; Rubio-Navarro, Alfonso; Buendía, Irene; Ortiz, Alberto; Egido, Jesús; Manzarbeitia, Félix; Chevarria, Julio Leonel; Gluksmann, María Constanza; Moreno, Juan Antonio

    2014-03-01

    Intolerance to fava beans in subjects with glucose-6-phosphate-dehydrogenase deficiency (favism) may lead to severe hemolytic crises and decreased renal function. Renal biopsy findings exploring the molecular mechanisms of renal damage in favism have not been previously reported. We report a case of favism-associated acute kidney injury in which renal biopsy showed acute tubular necrosis and massive iron deposits in tubular cells. Interestingly, iron deposit areas were characterized by the presence of oxidative stress markers (NADPH-p22 phox and heme-oxigenase-1) and macrophages expressing the hemoglobin scavenger receptor CD163. In addition, iron deposits, NADPH-p22 phox, hemeoxigenase- 1 and CD163 positive cells were observed in some glomeruli. These results identify both glomerular and tubular involvement in favism-associated acute kidney injury and suggest novel therapeutic targets to prevent or accelerate recovery from acute kidney injury. PMID:23006341

  16. Fructose induces tubulointerstitial injury in the kidney of mice.

    PubMed

    Aoyama, Masahiro; Isshiki, Keiji; Kume, Shinji; Chin-Kanasaki, Masami; Araki, Hisazumi; Araki, Shin-Ichi; Koya, Daisuke; Haneda, Masakazu; Kashiwagi, Atsunori; Maegawa, Hiroshi; Uzu, Takashi

    2012-03-01

    Fructose induces several kinds of human metabolic disorders; however, information regarding fructose-induced kidney injury is still limited. This study examined fructose-induced kidney injury in mice and clarified the differential susceptibility of three mouse strains: C57Bl/6J, CBA/JN and DBA/2N. In this study all mice were fed with an equal calorie count for sixteen weeks to remove the influence of total energy intake from metabolic effects by fructose-feeding. Only DBA/2N mice, but not C57Bl/6J and CBA/JN mice, fed with fructose displayed tubulointerstitial fibrosis localized on the outer cortex of the kidney together with the increase of mRNA expression of Kim1 and Ngal in the absence of distinct glomerular lesions and albuminuria - decidedly different from diabetic nephropathy. In time-course study of DBA/2N mice fed with fructose diet, the inflammation and fibrosis in the outer cortex of the kidney were enhancing after eight weeks, in parallel with the accumulation of oxidative stress. This progression of renal damage in DBA/2N mice was accompanied with increasing mRNA expression of GLUT5. These results suggest that the responsiveness of GLUT5 expression to fructose at the kidney is one of pivotal roles for the progression of fructose-induced kidney injury.

  17. Alpinetin inhibits lipopolysaccharide-induced acute kidney injury in mice.

    PubMed

    Huang, Yi; Zhou, Li-shan; Yan, Li; Ren, Juan; Zhou, Dai-xing; Li, Shu-Sheng

    2015-10-01

    Alpinetin, a novel plant flavonoid isolated from Alpinia katsumadai Hayata, has been demonstrated to have anti-inflammatory and antioxidant effects. However, the effects of alpinetin on lipopolysaccharide (LPS)-induced acute kidney injury have not been reported. In the present study, we investigated the protective effects and the underlying mechanism of alpinetin against LPS-induced acute kidney injury in mice. The results showed that alpinetin inhibited LPS-induced kidney histopathologic changes, blood urea nitrogen (BUN) and creatinine levels. Alpinetin also inhibited LPS-induced ROS, MDA, and inflammatory cytokines TNF-α, IL-6 and IL-1β production in kidney tissues. Meanwhile, Western blot analysis showed that alpinetin suppressed LPS-induced TLR4 expression and NF-κB activation in kidney tissues. In addition, alpinetin was found to up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner. In conclusion, alpinetin protected LPS-induced kidney injury through activating Nrf2 and inhibiting TLR4 expression.

  18. Synthetic marijuana and acute kidney injury: an unforeseen association

    PubMed Central

    Kazory, Amir; Aiyer, Ravi

    2013-01-01

    Synthetic cannabinoids (SCs) have emerged as drugs of abuse with increasing popularity among young adults. The potential renal complication related to the abuse of SC was not recognized until recently. Here, we present a case of severe acute kidney injury (AKI) that developed after inhalation of SC in an otherwise healthy young patient. A kidney biopsy revealed severe acute tubular necrosis, and supportive management resulted in the recovery of the kidney function. Herein, we briefly summarize the only two previous reports (a total of 21 cases) on the association between SC abuse and renal dysfunction and identify the common aspects in all observations. PMID:26064495

  19. Acute kidney injury after using contrast during cardiac catheterization in children with heart disease.

    PubMed

    Hwang, Young Ju; Hyun, Myung Chul; Choi, Bong Seok; Chun, So Young; Cho, Min Hyun

    2014-08-01

    Acute kidney injury (AKI) is closely associated with the mortality of hospitalized patients and long-term development of chronic kidney disease, especially in children. The purpose of our study was to assess the evidence of contrast-induced AKI after cardiac catheterization in children with heart disease and evaluate the clinical usefulness of candidate biomarkers in AKI. A total of 26 children undergoing cardiac catheterization due to various heart diseases were selected and urine and blood samples were taken at 0 hr, 6 hr, 24 hr, and 48 hr after cardiac catheterization. Until 48 hr after cardiac catheterization, there was no significant increase in serum creatinine level in all patients. Unlike urine kidney injury molecule-1, IL-18 and neutrophil gelatinase-associated lipocalin, urine liver-type fatty acid-binding protein (L-FABP) level showed biphasic pattern and the significant difference in the levels of urine L-FABP between 24 and 48 hr. We suggest that urine L-FABP can be one of the useful biomarkers to detect subclinical AKI developed by the contrast before cardiac surgery.

  20. Ammonium dichromate poisoning: A rare cause of acute kidney injury

    PubMed Central

    Radhakrishnan, H.; Gopi, M.; Arumugam, A.

    2014-01-01

    Ammonium dichromate is an inorganic compound frequently used in screen and color printing. Being a strong oxidizing agent, it causes oxygen free radical injury resulting in organ failure. We report a 25-year-old female who presented with acute kidney injury after consumption of ammonium dichromate. She was managed successfully with hemodialysis and supportive measures. This case is reported to highlight the toxicity of ammonium dichromate. PMID:25484533

  1. APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV

    PubMed Central

    Jotwani, Vasantha; Shlipak, Michael G.; Scherzer, Rebecca; Parekh, Rulan S.; Kao, W.H. Linda; Bennett, Michael; Cohen, Mardge H.; Nowicki, Marek; Sharma, Anjali; Young, Mary; Tien, Phyllis C.; Parikh, Chirag R.; Estrella, Michelle M.

    2015-01-01

    Background APOL1 genotype is associated with advanced kidney disease in African-Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury, and with kidney function decline, were evaluated. Study Design Observational study. Setting & Participants 431 HIV-infected African-American women enrolled in Women's Interagency HIV Study (WIHS). Predictor APOL1 genotype. Outcomes Albumin-creatinine ratio (ACR), four tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [α1m]), and kidney function estimated using the CKD-EPI cystatin C equation. Measurements Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarker levels were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-up. Results At baseline, ACR levels were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs. 11 mg/g; p < 0.001). Compared to women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACR (95% CI, 29-223 mg/g) and 2-fold greater risk of ACR > 30 mg/g (95% CI, 1.17-3.44) after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr, KIM-1:Cr, and NGAL:Cr (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to 1%], and 10% [95% CI, -26% to 64%], respectively), or detectable urine α1m (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared to women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, -2.2 to -0.2) ml/min/1.73 m2 per year, and had 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1-2.5) and 10% annual eGFR decline (95% CI, 1.7-6.7), respectively, with minimal attenuation

  2. Lutein protects against ischemia/reperfusion injury in rat kidneys.

    PubMed

    Liu, Zhen-Guo; Qi, Zong-Cai; Liu, Wei-Liang; Wang, Wei-Zhi

    2015-03-01

    Ischemia‑reperfusion (I/R) injury has a major impact on renal dysfunction during transplantation. The present study investigated the role of lutein against I/R injury‑induced oxidative stress in rat kidneys. Biochemical analysis and oxidative stress parameters demonstrated that lutein protected the rat kidney significantly from I/R injury. Pretreatment with lutein significantly increased the total antioxidant capacity with a concomitant decline in the total oxidant status. Rats with I/R injury showed a significant increase in oxidative stress. The results revealed significant increases in the levels of lipid peroxidation and protein carbonyl content with concomitant decreases in enzymic and non‑enzymic antioxidants. The activity of these enzymes was reversed and demonstrated a significant increase following lutein pre‑treatment compared with the rats subjected to I/R injury alone. Furthermore, lutein protected the renal tissue from I/R injury by maintaining normal kidney architecture and led to a reduction in the levels of the renal markers urea and creatinine in the serum. These results demonstrated clear evidence that lutein offered a significant protective effect against I/R injury by enhancing antioxidant defense mechanisms.

  3. Relationships among injury, fibrosis, and time in human kidney transplants

    PubMed Central

    Venner, Jeffery M.; Famulski, Konrad S.; Reeve, Jeff; Chang, Jessica; Halloran, Philip F.

    2016-01-01

    BACKGROUND. Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression. METHODS. Expression microarrays from 681 kidney transplant indication biopsies taken either early (n = 282, <1 year) or late (n = 399, >1 year) after transplant were used to analyze the molecular landscape of fibrosis in relationship to histologic fibrosis and diseases. RESULTS. Fibrosis was absent at transplantation but was present in some early biopsies by 4 months after transplant, apparently as a self-limited response to donation implantation injury not associated with progression to failure. The molecular phenotype of early biopsies represented the time sequence of the response to wounding: immediate expression of acute kidney injury transcripts, followed by fibrillar collagen transcripts after several weeks, then by the appearance of immunoglobulin and mast cell transcripts after several months as fibrosis appeared. Fibrosis in late biopsies correlated with injury, fibrillar collagen, immunoglobulin, and mast cell transcripts, but these were independent of time. Pathway analysis revealed epithelial response-to-wounding pathways such as Wnt/β-catenin. CONCLUSION. Fibrosis in late biopsies had different associations because many kidneys had potentially progressive diseases and subsequently failed. Molecular correlations with fibrosis in late biopsies were independent of time, probably because ongoing injury obscured the response-to-wounding time sequence. The results indicate that fibrosis in kidney transplants is driven by nephron injury and that progression to failure reflects continuing injury, not autonomous fibrogenesis. TRIAL REGISTRATION. INTERCOM study (www.clinicalTrials.gov; NCT01299168). FUNDING. Canada Foundation for Innovation and Genome Canada. PMID:27699214

  4. Relationships among injury, fibrosis, and time in human kidney transplants

    PubMed Central

    Venner, Jeffery M.; Famulski, Konrad S.; Reeve, Jeff; Chang, Jessica; Halloran, Philip F.

    2016-01-01

    BACKGROUND. Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression. METHODS. Expression microarrays from 681 kidney transplant indication biopsies taken either early (n = 282, <1 year) or late (n = 399, >1 year) after transplant were used to analyze the molecular landscape of fibrosis in relationship to histologic fibrosis and diseases. RESULTS. Fibrosis was absent at transplantation but was present in some early biopsies by 4 months after transplant, apparently as a self-limited response to donation implantation injury not associated with progression to failure. The molecular phenotype of early biopsies represented the time sequence of the response to wounding: immediate expression of acute kidney injury transcripts, followed by fibrillar collagen transcripts after several weeks, then by the appearance of immunoglobulin and mast cell transcripts after several months as fibrosis appeared. Fibrosis in late biopsies correlated with injury, fibrillar collagen, immunoglobulin, and mast cell transcripts, but these were independent of time. Pathway analysis revealed epithelial response-to-wounding pathways such as Wnt/β-catenin. CONCLUSION. Fibrosis in late biopsies had different associations because many kidneys had potentially progressive diseases and subsequently failed. Molecular correlations with fibrosis in late biopsies were independent of time, probably because ongoing injury obscured the response-to-wounding time sequence. The results indicate that fibrosis in kidney transplants is driven by nephron injury and that progression to failure reflects continuing injury, not autonomous fibrogenesis. TRIAL REGISTRATION. INTERCOM study (www.clinicalTrials.gov; NCT01299168). FUNDING. Canada Foundation for Innovation and Genome Canada.

  5. Acute kidney injury in dengue fever using Acute Kidney Injury Network criteria: incidence and risk factors.

    PubMed

    Mehra, Nikita; Patel, Amish; Abraham, Georgi; Reddy, Yogesh N V; Reddy, Yuvaram N V

    2012-07-01

    The aim of this study was to assess incidence and risk factors for acute kidney injury (AKI) in patients with dengue fever (DF). A total of 223 patients (males, 130; females, 93; mean age, 26.2 ± 18.2 years) from a tertiary care centre in southern India were retrospectively analysed. Acute renal failure (ARF) developed in 24 (10.8%) patients. Based on the Acute Kidney Injury Network (AKIN) criteria, the results revealed that: 12 (5.4%) had mild AKI; seven (3.1%) had moderate AKI; and five (2.2%) had severe AKI. A further 54 (24%) were diagnosed with dengue haemorrhagic fever (DHF); 11 (5%) were co-infected with leptospirosis; thrombocytopenia was present in 157 (70%); and 64 (29%) were hypotensive. Patients were divided into either group A (with AKI) or group B (without AKI), and group A was divided into mild (A1), moderate (A2) and severe (A3) subgroups. We recorded: a higher total white count (A = 9824; B = 6706; P = 0.01); serum glutamic pyruvic transaminase (SGPT; A = 450; B = 144; P = 0.001); alkaline phosphatase (ALP) levels (A = 207; B = 42; P = 0.001); lower albumin (A = 2.65; B = 3.09; P < 0.001); and serum bicarbonate (A = 20.57; B = 23.21; P = 0.009). Hypotension (P = 0.01), coexisting viral hepatitis (P < 0.001), sepsis (P < 0.001), multiple organ dysfunction syndrome (MODS; P < 0.001) and the need for inotropes (P < 0.001) were associated with DF. Total white count (P = 0.038), glomerular filtration rate (GFR) on discharge (P = 0.034), specific gravity of urine (P = 0.006), ALP (P = 0.013), SGPT (P = 0.042), MODS (P = 0.05) and use of platelet fresh frozen plasma (FFP; P = 0.007) were significantly different between mild, moderate and severe AKI subgroups. Twenty-two (9%) died. AKI is associated with an increased mortality in DF (P = 0.005).

  6. Urinary Kidney Injury Molecules in Children with Iron-Deficiency Anemia

    PubMed Central

    Güneş, Ali; Ece, Aydın; Aktar, Fesih; Tan, İlhan; Söker, Murat; Karabel, Duran; Balık, Hasan; Uluca, Ünal; Şen, Velat; Yolbaş, İlyas

    2015-01-01

    Background The aim of this study was to investigate the urine levels of human kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG), and liver-type fatty acid-binding protein (L-FABP) in children with iron-deficiency anemia (IDA). Material/Methods Thirty-five children with IDA and 32 matched healthy controls were recruited. We assessed complete blood count, serum iron, iron-binding capacity, ferritin, serum levels of urea, creatinine (Cr), sodium (Na), potassium (K), calcium (Ca), and glucose levels. Estimated glomerular filtration rate (eGFR) was calculated. Urinary NAG, NGAL, KIM-1, and L-FABP were measured and divided by urine creatinine for comparisons. Results There were no significant differences in serum urea, Cr, or eGFR between the IDA group and the control group (p>0.05, for all). IDA patients had significantly higher urine NGAL/Cr, L-FABP/Cr, KIM-1/Cr, and NAG/Cr compared with the control group (p<0.05). There were significant negative correlations between hemoglobin, hematocrit, red blood cell count, and urine NGAL/Cr, NAG/Cr, L-FABP/Cr, KIM-1/Cr levels (p<0.05). Conclusions Higher urinary kidney injury molecule levels in IDA patients suggest a possible subclinical renal injury in pediatric IDA patients whose renal functions and serum electrolytes were normal. PMID:26697893

  7. Emerging Biomarkers and Metabolomics for Assessing Toxic Nephropathy and Acute Kidney Injury (AKI) in Neonatology

    PubMed Central

    Mussap, M.; Noto, A.; Fanos, V.; Van Den Anker, J. N.

    2014-01-01

    Identification of novel drug-induced toxic nephropathy and acute kidney injury (AKI) biomarkers has been designated as a top priority by the American Society of Nephrology. Increasing knowledge in the science of biology and medicine is leading to the discovery of still more new biomarkers and of their roles in molecular pathways triggered by physiological and pathological conditions. Concomitantly, the development of the so-called “omics” allows the progressive clinical utilization of a multitude of information, from those related to the human genome (genomics) and proteome (proteomics), including the emerging epigenomics, to those related to metabolites (metabolomics). In preterm newborns, one of the most important factors causing the pathogenesis and the progression of AKI is the interaction between the individual genetic code, the environment, the gestational age, and the disease. By analyzing a small urine sample, metabolomics allows to identify instantly any change in phenotype, including changes due to genetic modifications. The role of liquid chromatography-mass spectrometry (LC-MS), proton nuclear magnetic resonance (1H NMR), and other emerging technologies is strategic, contributing basically to the sudden development of new biochemical and molecular tests. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are closely correlated with the severity of kidney injury, representing noninvasive sensitive surrogate biomarkers for diagnosing, monitoring, and quantifying kidney damage. To become routine tests, uNGAL and KIM-1 should be carefully tested in multicenter clinical trials and should be measured in biological fluids by robust, standardized analytical methods. PMID:25013791

  8. Arterial Stiffness: A Novel Risk Factor for Kidney Injury Progression?

    PubMed

    Georgianos, Panagiotis I; Sarafidis, Pantelis A; Liakopoulos, Vassilios

    2015-08-01

    Arterial stiffness is typical feature of vascular remodeling in chronic kidney disease (CKD). Increased arterial stiffness raises flow and pressure pulsatility and is considered the principle pathogenic mechanism of isolated systolic hypertension, left ventricular hypertrophy, and congestive heart failure. Apart from the impact of arterial stiffness on left ventricular afterload, downstream transmission of pressure pulsatility to the level of microcirculation is suggested to promote injury of other susceptible organs. This may be of particular importance for kidney injury progression, since passive renal perfusion along with low resistance and input impedance in renal microvessels make kidneys particularly vulnerable to the damaging effect of systemic pulsatile pressure. Recent studies have provided evidence that arterial stiffness culminates in elevated pulsatility and resistance in renal microvasculature, promoting structural damage of small intra-renal arterioles. Further, prospective observational studies have shown that reduced aortic compliance is closely associated with the annual rate of renal function decline and represents independent predictor of kidney injury progression to end-stage renal disease among patients with CKD. This article provides insights into the cross-talk between macrocirculation and renal microcirculation and summarizes the currently available clinical evidence linking increased arterial stiffness with kidney disease progression.

  9. Acute kidney injury and dermonecrosis after Loxosceles reclusa envenomation

    PubMed Central

    Nag, A.; Datta, J.; Das, A.; Agarwal, A. K.; Sinha, D.; Mondal, S.; Ete, T.; Chakraborty, A.; Ghosh, S.

    2014-01-01

    Spiders of the Loxosceles species can cause dermonecrosis and acute kidney injury (AKI). Hemolysis, rhabdomyolysis and direct toxin-mediated renal damage have been postulated. There are very few reports of Loxoscelism from India. We report a case of AKI, hemolysis and a “gravitational” pattern of ulceration following the bite of the brown recluse spider (Loxosceles spp). PMID:25097339

  10. Pathophysiology of cisplatin-induced acute kidney injury.

    PubMed

    Ozkok, Abdullah; Edelstein, Charles L

    2014-01-01

    Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality. PMID:25165721

  11. Acute kidney injury: changing lexicography, definitions, and epidemiology.

    PubMed

    Himmelfarb, J; Ikizler, T A

    2007-05-01

    In recent years, there have been numerous advances in understanding the molecular determinants of functional kidney injury after ischemic and/or toxic exposure. However, translation of successful novel therapies designed to attenuate kidney functional injury from animal models to the clinical sphere has had modest results. This lack of translatability is at least in part due to lack of sufficient standardization in definitions and classification of cases of acute kidney injury (AKI), an incomplete understanding of the natural history of human AKI, and a limited understanding of how kidney injury interacts with other organ system failure in the context of systemic metabolic abnormalities. A concerted effort is now being made by nephrologists and intensivists to arrive at standardized terminology and classification of AKI. There have also been dramatic advances in our understanding of the epidemiology and natural history of AKI, particularly in the hospital and intensive care unit setting. Promising strategies are now being developed which may ultimately lead to improved outcomes for patients at risk for or who have developed AKI, which should be readily testable in the coming decade.

  12. Cocaine and kidney injury: a kaleidoscope of pathology

    PubMed Central

    Goel, Narender; Pullman, James M.; Coco, Maria

    2014-01-01

    Cocaine is abused worldwide as a recreational drug. It is a potent activator of the sympathetic nervous system leading to intense vasoconstriction, endothelial dysfunction, oxidative stress, platelet activation and decrease in prostaglandins E2 and prostacyclin. Cocaine can lead to widespread systemic adverse effects such as stroke, myocardial infarction, arterial dissection, vascular thrombosis and rhabdomyolysis. In human and rat kidneys, cocaine has been associated with glomerular, tubular, vascular and interstitial injury. It is not uncommon to diagnose cocaine-related acute kidney injury (AKI), malignant hypertension and chronic kidney disease. Cocaine abuse can lead to AKI by rhabdomyolysis, vasculitis, infarction, thrombotic microangiopathy and malignant hypertension. It is reported that 50–60% of people who use both cocaine and heroin are at increased risk of HIV, hepatitis and additional risk factors that can cause kidney diseases. While acute interstitial nephritis (AIN) is a known cause of AKI, an association of AIN with cocaine is unusual and seldom reported. We describe a patient with diabetes mellitus, hypertension and chronic hepatitis C, who presented with AKI. Urine toxicology was positive for cocaine and a kidney biopsy was consistent with AIN. Illicit drugs such as cocaine or contaminants may have caused AIN in this case and should be considered in the differential diagnosis of causes of AKI in a patient with substance abuse. We review the many ways that cocaine adversely impacts on kidney function. PMID:25859366

  13. Nephrotoxin Microinjection in Zebrafish to Model Acute Kidney Injury.

    PubMed

    McKee, Robert A; Wingert, Rebecca A

    2016-01-01

    The kidneys are susceptible to harm from exposure to chemicals they filter from the bloodstream. This can lead to organ injury associated with a rapid decline in renal function and development of the clinical syndrome known as acute kidney injury (AKI). Pharmacological agents used to treat medical circumstances ranging from bacterial infection to cancer, when administered individually or in combination with other drugs, can initiate AKI. Zebrafish are a useful animal model to study the chemical effects on renal function in vivo, as they form an embryonic kidney comprised of nephron functional units that are conserved with higher vertebrates, including humans. Further, zebrafish can be utilized to perform genetic and chemical screens, which provide opportunities to elucidate the cellular and molecular facets of AKI and develop therapeutic strategies such as the identification of nephroprotective molecules. Here, we demonstrate how microinjection into the zebrafish embryo can be utilized as a paradigm for nephrotoxin studies. PMID:27500823

  14. Associations between Deceased-Donor Urine Injury Biomarkers and Kidney Transplant Outcomes.

    PubMed

    Reese, Peter P; Hall, Isaac E; Weng, Francis L; Schröppel, Bernd; Doshi, Mona D; Hasz, Rick D; Thiessen-Philbrook, Heather; Ficek, Joseph; Rao, Veena; Murray, Patrick; Lin, Haiqun; Parikh, Chirag R

    2016-05-01

    Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m(2) In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant. PMID:26374609

  15. Toll-like receptor 4 contributes to acute kidney injury after cardiopulmonary resuscitation in mice

    PubMed Central

    Zhang, Qingsong; Li, Gang; Xu, Li; Li, Qian; Wang, Qianyan; Zhang, Yue; Zhang, Qing; Sun, Peng

    2016-01-01

    Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild-type (C3H/HeN) and TLR4-mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) and growth-regulated oncogene-β (GRO-β) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM-1, GRO-β and MPO in a CA-duration dependent manner. However, there was decreased expression of ICAM-1, GRO-β and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM-1 and GRO-β may be important in mediating inflammatory responses to renal injury after CPR. PMID:27510583

  16. The Serum Changes of Neuron-Specific Enolase and Intercellular Adhesion Molecule-1 in Patients With Diffuse Axonal Injury Following Progesterone Administration: A Randomized Clinical Trial

    PubMed Central

    Shahrokhi, Nader; Soltani, Zahra; Khaksari, Mohammad; Karamouzian, Saeid; Mofid, Behshad; Asadikaram, Gholamreza

    2016-01-01

    Background Improvement of neurologic outcome in progesterone-administered patients with diffuse axonal injury (DAI) has been found in a recent study. Also, there has been interest in the importance of serum parameters as predictors of outcome in traumatic brain injury. Objectives The aim of this study was to examine the effect of progesterone administration on serum levels of neuron-specific enolase (NSE), and intercellular adhesion molecule-1 (ICAM-1) in clinical DAI. Patients and Methods In this study, the serum levels of ICAM-1 and NSE of 32 male DAI patients (18 - 60 years of age, a Glasgow coma scale of 12 or less, and admitted within 4 hours after injury) who were randomized for a controlled phase II trial of progesterone were analyzed. The analysis was performed between the control and progesterone groups at admission time, and 24 hours and six days after DAI, respectively. Results A reduction in the serum level of ICAM-1 was noticed in the progesterone group 24 hours after the injury (P < 0.05). There was no significant difference in the serum level of NSE between the study groups during evaluation. At 24 hours after the injury, the level of ICAM-1 in the control group was higher than that at admission time (P < 0.05). The lowest level of NSE in the two groups was seen six days after DAI (P < 0.01). Conclusions In summary, progesterone administration reduced serum ICAM-1, and whereby may attenuate blood brain barrier disruption, the latter needs further investigation for confirmation. PMID:27800469

  17. Comparison of Plasma and Urine Biomarker Performance in Acute Kidney Injury

    PubMed Central

    Schley, Gunnar; Köberle, Carmen; Manuilova, Ekaterina; Rutz, Sandra; Forster, Christian; Weyand, Michael; Formentini, Ivan; Kientsch-Engel, Rosemarie; Eckardt, Kai-Uwe; Willam, Carsten

    2015-01-01

    Background New renal biomarkers measured in urine promise to increase specificity for risk stratification and early diagnosis of acute kidney injury (AKI) but concomitantly may be altered by urine concentration effects and chronic renal insufficiency. This study therefore directly compared the performance of AKI biomarkers in urine and plasma. Methods This single-center, prospective cohort study included 110 unselected adults undergoing cardiac surgery with cardiopulmonary bypass between 2009 and 2010. Plasma and/or urine concentrations of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), kidney injury molecule 1 (KIM1), and albumin as well as 15 additional biomarkers in plasma and urine were measured during the perioperative period. The primary outcome was AKI defined by AKIN serum creatinine criteria within 72 hours after surgery. Results Biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24h after surgery) detection of AKI than urine biomarkers. Discriminative power of urine biomarkers improved when concentrations were normalized to urinary creatinine, but urine biomarkers had still lower AUC values than plasma biomarkers. Best diagnostic performance 4h after surgery had plasma NGAL (AUC 0.83), cystatin C (0.76), MIG (0.74), and L-FAPB (0.73). Combinations of multiple biomarkers did not improve their diagnostic power. Preoperative clinical scoring systems (EuroSCORE and Cleveland Clinic Foundation Score) predicted the risk for AKI (AUC 0.76 and 0.71) and were not inferior to biomarkers. Preexisting chronic kidney disease limited the diagnostic performance of both plasma and urine biomarkers. Conclusions In our cohort plasma biomarkers had higher discriminative power for risk stratification and early diagnosis of AKI than urine biomarkers. For preoperative risk stratification of AKI clinical models showed

  18. Advances in acute kidney injury associated with cardiac surgery: the unfolding revolution in early detection.

    PubMed

    Wyckoff, Tygh; Augoustides, John G T

    2012-04-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is important because it remains common and serious. A major limitation in the management of CSA-AKI has been ongoing delayed diagnosis by standard clinical approaches, including serum creatinine and calculated glomerular filtration rate. Recent advances in the understanding of CSA-AKI have highlighted the utility of novel biomarkers that diagnose CSA-AKI within the first 24 hours. The biomarkers that have been evaluated in clinical trials include neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule 1 and interleukin-18. The biomarker with the greatest clinical promise is NGAL. Although it has multiple advantages over serum creatinine, it is still not the ideal biomarker for CSA-AKI. It is likely that a panel of early biomarkers will be developed to facilitate rapid and reliable detection of CSA-AKI, combining their different characteristics to optimize patient management. Future clinical trials likely will focus on whether these biomarkers predict adverse outcomes independent of serum creatinine fluctuations and whether therapies guided by biomarker profiles improve renal salvage and overall clinical outcomes. Given their clinical utility, these novel biomarkers have been evaluated beyond cardiac surgery for AKI in multiple clinical environments, including the emergency department, the operating room, the cardiac catheterization laboratory, and the intensive care unit. Their integration into clinical practice seems likely in the near future.

  19. Associations between urinary kidney injury biomarkers and cardiovascular mortality risk in elderly men with diabetes

    PubMed Central

    Tonkonogi, Aleksandra; Carlsson, Axel C.; Helmersson-Karlqvist, Johanna; Larsson, Anders; Ärnlöv, Johan

    2016-01-01

    Aim Three urinary biomarkers, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C, have been suggested as clinically relevant highly specific biomarkers of acute kidney tubular damage. Yet, the utility of these biomarkers in the prognostication of diabetic nephropathy has been less studied. Therefore, we aimed to investigate the longitudinal association between these urinary biomarkers and cardiovascular mortality in patients with diabetes. Methods The study sample consisted of participants with diabetes in the community-based Uppsala Longitudinal Study of Adult Men (n = 91; mean age 77.8 years). During follow-up (median 8.3 years, interval 0.7–13.4 years), 33 participants died of cardiovascular causes. Results In a multivariable Cox regression model adjusting for age, glomerular filtration rate, and urinary albumin/creatinine ratio, higher urinary KIM-1/creatinine was associated with an increased risk for cardiovascular mortality (HR per SD increase 1.51, 95% confidence intervals 1.03–2.24, P = 0.03). Neither urinary NGAL/creatinine nor urinary cystatin C/creatinine were independently associated with an increased cardiovascular mortality risk. Conclusion In elderly men with diabetes, higher urinary KIM-1/creatinine was associated with an increased long-term risk of cardiovascular mortality independently of established markers of diabetic nephropathy. Our data provide support for kidney tubular damage as an important aspect of diabetic nephropathy that merits further investigation. PMID:27321055

  20. Nestin(+) kidney resident mesenchymal stem cells for the treatment of acute kidney ischemia injury.

    PubMed

    Jiang, Mei Hua; Li, Guilan; Liu, Junfeng; Liu, Longshan; Wu, Bingyuan; Huang, Weijun; He, Wen; Deng, Chunhua; Wang, Dong; Li, Chunling; Lahn, Bruce T; Shi, Chenggang; Xiang, Andy Peng

    2015-05-01

    Renal resident mesenchymal stem cells (MSCs) are important regulators of kidney homeostasis, repair or regeneration. However, natural distribution and the starting population properties of these cells remain elusive because of the lack of specific markers. Here, we identified post-natal kidney derived Nestin(+) cells that fulfilled all of the criteria as a mesenchymal stem cell. These isolated Nestin(+) cells expressed the typical cell-surface marker of MSC, including Sca-1, CD44, CD106, NG2 and PDGFR-α. They were capable of self-renewal, possessed high clonogenic potential and extensive proliferation for more than 30 passages. Under appropriate differentiation conditions, these cells could differentiate into adipocytes, osteocytes, chondrocytes and podocytes. After intravenous injection into acute kidney injury mice, Nestin(+) cells contributed to functional improvement by significantly decreasing the peak level of serum creatinine and BUN, and reducing the damaged cell apoptosis. Furthermore, conditioned medium from Nestin(+) cells could protect against ischemic acute renal failure partially through paracrine factor VEGF. Taken together, our findings indicate that renal resident Nestin(+) MSCs can be derived, propagated, differentiated, and repair the acute kidney injury, which may shed new light on understanding MSCs biology and developing cell replacement therapies for kidney disease.

  1. Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury.

    PubMed

    Nakagawa, Shunsaku; Nishihara, Kumiko; Inui, Ken-ichi; Masuda, Satohiro

    2012-12-01

    Inhibitors of mammalian target of rapamycin (mTOR) have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Using cells from normal kidney epithelial cell lines, we found that the antiproliferative effects of mTOR inhibitor everolimus accompanied the accumulation of a marker for cellular autophagic activity, the phosphatidylethanolamine-conjugated form of microtubule-associated protein 1 light chain 3 (LC3-II) in cells. We also showed that the primary autophagy factor UNC-51-like kinase 1 was involved in the antiproliferative effects of everolimus. Levels of LC3-II decreased in the kidneys of rats treated with ischemia-reperfusion or cisplatin; however, renal LC3-II levels increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment. Simultaneously, increased signals for kidney injury molecule-1 and single-stranded DNA and decreased signals for Ki-67 in the proximal tubules were observed after treatment with everolimus, indicating that everolimus diminished renal function after acute tubular injury. We also found leakage of LC3 protein into rat urine after treatment with everolimus, and urinary LC3 protein was successfully measured between 0.1 and 500ng/mL by using an enzyme-linked immunosorbent assay. Urinary LC3 levels were increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment, suggesting that renal LC3-II and urinary LC3 protein are new biomarkers for autophagy in acute kidney injury. Taken together, our results demonstrated that the induction of autophagy by everolimus aggravates tubular dysfunction during recovery from kidney injury. PMID:23022334

  2. Diagnostic Criteria for Acute Kidney Injury: Present and Future

    PubMed Central

    Kellum, John A.

    2015-01-01

    Synopsis Acute kidney injury in a clinical diagnosis guided by standard criteria based on changes in serum creatinine, urine output or both. Severity of acute kidney injury is determined by the magnitude of increase in serum creatinine or decrease in urine output. Patients manifesting both oliguria and azotemia and those in which these impairments are persistent are more likely to have worse disease and worse outcomes. Both short- and long-term outcomes are worse when patients have some stage of AKI by both criteria. Duration of AKI was also a significant predictor of long-term outcomes irrespective of severity. New biomarkers for AKI may substantially aid in the risk assessment and evaluation of patients at risk for AKI. PMID:26410133

  3. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.

    PubMed

    White, Laura E; Santora, Rachel J; Cui, Yan; Moore, Frederick A; Hassoun, Heitham T

    2012-09-01

    Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

  4. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury

    PubMed Central

    White, Laura E.; Santora, Rachel J.; Cui, Yan; Moore, Frederick A.

    2012-01-01

    Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1−/− mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets. PMID:22728466

  5. [Uncaria tomentosa and acute ischemic kidney injury in rats].

    PubMed

    de Fátima Fernandes Vattimo, Maria; da Silva, Natalia Oliveira

    2011-03-01

    The objective of this study was to evaluate the renoprotective effects of Uncaria Tomentosa (cat's claw) on ischemic acute kidney injury induced by renal clamping in rats. The hypoxia and hypoperfusion increase the production of reactive species already present in the inflammatory process. Results showed that the renal function evaluated by creatinine clearance, the urinary excretion of peroxides and malondealdehyde indexes demonstrated that UT induced renoprotection, probably related to its antioxidant activities.

  6. Acute kidney injury in sepsis: transient or intrinsic?

    PubMed

    Jörres, Achim

    2013-11-20

    The negative prediction of intrinsic versus transient acute kidney injury (AKI) in septic patients may be facilitated by combined assessment of fractional excretion of sodium and urea. If both excretions are high this would signal the presence of transient AKI and suggest that successful restoration of diuresis by conservative therapy is likely, thus supporting a wait-and-watch approach regarding the initiation of acute renal replacement therapy.

  7. Gender Related Differences in Kidney Injury Induced by Mercury

    PubMed Central

    Hazelhoff, María H.; Bulacio, Romina P.; Torres, Adriana M.

    2012-01-01

    The aim of this study was to determine if there are sex-related differences in the acute kidney injury induced by HgCl2 since female rats express lower levels of renal Oat1 and Oat3 (transporters involved in renal uptake of mercury) as compared with males. Control males and females and Hg-treated male and female Wistar rats were employed. Animals were treated with HgCl2 (4 mg/kg body weight (b.w.), intraperitoneal (i.p.)) 18 h before the experiments. HgCl2 induced renal impairment both in male and female rats. However, female rats showed a lower renal impairment than male rats. The observed increase in kidney weight/body weight ratio seen in male and female rats following HgCl2 treatment was less in the female rats. Urine volume and creatinine clearance decreased and Oat5 urinary excretion increased in both males and females, but to a lesser degree in the latter. Urinary alkaline phosphatase (AP) activity and histological parameters were modified in male but not in female rats after HgCl2 administration. These results indicate that the lower Oat1 and Oat3 expression in the kidney of females restricts Hg uptake into renal cells protecting them from this metal toxicity. These gender differences in renal injury induced by mercury are striking and also indicate that Oat1 and Oat3 are among the main transporters responsible for HgCl2-induced renal injury. PMID:22949877

  8. Oxygen deprivation-induced injury to isolated rabbit kidney tubules.

    PubMed Central

    Weinberg, J M

    1985-01-01

    The utility of freshly isolated suspensions of rabbit tubules enriched in proximal segments for studying the pathogenesis of oxygen deprivation-induced renal tubular cell injury was evaluated. Oxygenated control preparations exhibited very good stability of critical cell injury-related metabolic parameters including oxygen consumption, cell cation homeostasis, and adenine nucleotide metabolism for periods in excess of 2 h. Highly reproducible models of oxygen deprivation-induced injury and recovery were developed and alterations of injury-related metabolic parameters in these models were characterized in detail. When oxygen deprivation was produced under hypoxic conditions, tubules sustained widespread lethal cell injury and associated metabolic alterations within 15-30 min. However, when oxygen deprivation was produced under simulated ischemic conditions, tubules tolerated 30-60 min with only moderate amounts of lethal cell injury occurring, a situation similar to that seen with ischemia in vivo. Like ischemia in vivo, simulated ischemia in vitro was characterized by a fall in pH during oxygen deprivation. No such fall in pH occurred in the hypoxic model. To test whether this fall in pH could contribute to the protection seen during simulated ischemia in vitro, tubules were subjected to hypoxia at medium pHs ranging from 7.45 to 6.41. Striking protection from hypoxic injury was seen as pH was reduced with maximal protection occurring in tubules made hypoxic at pHs below 7.0. Measurements of injury-associated metabolic parameters suggested that the protective effect of reduced pH may be mediated by pH-induced alterations of tubule cell Ca++ metabolism. This study has, thus, defined and characterized in detail a new and extremely versatile model system for the study of oxygen deprivation-induced cell injury in the kidney and has established that pH alterations play a major role in modulating such injury. PMID:4044830

  9. Kidney Disease and the Nexus of Chronic Kidney Disease and Acute Kidney Injury: The Role of Novel Biomarkers as Early and Accurate Diagnostics.

    PubMed

    Yerramilli, Murthy; Farace, Giosi; Quinn, John; Yerramilli, Maha

    2016-11-01

    Chronic kidney disease (CKD) and acute kidney injury (AKI) are interconnected and the presence of one is a risk for the other. CKD is an important predictor of AKI after exposure to nephrotoxic drugs or major surgery, whereas persistent or repetitive injury could result in the progression of CKD. This brings new perspectives to the diagnosis and monitoring of kidney diseases highlighting the need for a panel of kidney-specific biomarkers that reflect functional as well as structural damage and recovery, predict potential risk and provide prognosis. This article discusses the kidney-specific biomarkers, symmetric dimethylarginine (SDMA), clusterin, cystatin B, and inosine.

  10. Kidney Disease and the Nexus of Chronic Kidney Disease and Acute Kidney Injury: The Role of Novel Biomarkers as Early and Accurate Diagnostics.

    PubMed

    Yerramilli, Murthy; Farace, Giosi; Quinn, John; Yerramilli, Maha

    2016-11-01

    Chronic kidney disease (CKD) and acute kidney injury (AKI) are interconnected and the presence of one is a risk for the other. CKD is an important predictor of AKI after exposure to nephrotoxic drugs or major surgery, whereas persistent or repetitive injury could result in the progression of CKD. This brings new perspectives to the diagnosis and monitoring of kidney diseases highlighting the need for a panel of kidney-specific biomarkers that reflect functional as well as structural damage and recovery, predict potential risk and provide prognosis. This article discusses the kidney-specific biomarkers, symmetric dimethylarginine (SDMA), clusterin, cystatin B, and inosine. PMID:27485279

  11. Pathophysiology and Clinical Work-Up of Acute Kidney Injury.

    PubMed

    Meola, Mario; Nalesso, Federico; Petrucci, Ilaria; Samoni, Sara; Ronco, Claudio

    2016-01-01

    Acute kidney injury (AKI), also known in the past as acute renal failure, is a syndrome characterized by the rapid loss of kidney excretory function. It is usually diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output or both. AKI is the clinical consequence of several disorders that acutely affect the kidney, causing electrolytes and acid-base imbalance, hyperhydration and loss of depurative function. AKI is common in critical care patients in whom it is often secondary to extrarenal events. No specific therapies can attenuate AKI or accelerate renal function recovery; thus, the only treatment is supportive. New diagnostic techniques such as renal biomarkers might improve early diagnosis. Also ultrasonography helps nephrologists in AKI diagnosis, in order to describe and follow kidney alterations and find possible causes of AKI. Renal replacement therapy is a life-saving treatment if AKI is severe. If patients survive to AKI, and did not have previous chronic kidney disease (CKD), they typically recover to dialysis independence. However, evidence suggests that patients who have had AKI are at increased risk of subsequent CKD. PMID:27169469

  12. Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice

    PubMed Central

    Skrypnyk, Nataliya I.; Harris, Raymond C.; de Caestecker, Mark P.

    2013-01-01

    Ischemia-reperfusion induced acute kidney injury (IR-AKI) is widely used as a model of AKI in mice, but results are often quite variable with high, often unreported mortality rates that may confound analyses. Bilateral renal pedicle clamping is commonly used to induce IR-AKI, but differences between effective clamp pressures and/or renal responses to ischemia between kidneys often lead to more variable results. In addition, shorter clamp times are known to induce more variable tubular injury, and while mice undergoing bilateral injury with longer clamp times develop more consistent tubular injury, they often die within the first 3 days after injury due to severe renal insufficiency. To improve post-injury survival and obtain more consistent and predictable results, we have developed two models of unilateral ischemia-reperfusion injury followed by contralateral nephrectomy. Both surgeries are performed using a dorsal approach, reducing surgical stress resulting from ventral laparotomy, commonly used for mouse IR-AKI surgeries. For induction of moderate injury BALB/c mice undergo unilateral clamping of the renal pedicle for 26 min and also undergo simultaneous contralateral nephrectomy. Using this approach, 50-60% of mice develop moderate AKI 24 hr after injury but 90-100% of mice survive. To induce more severe AKI, BALB/c mice undergo renal pedicle clamping for 30 min followed by contralateral nephrectomy 8 days after injury. This allows functional assessment of renal recovery after injury with 90-100% survival. Early post-injury tubular damage as well as post injury fibrosis are highly consistent using this model. PMID:23963468

  13. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation.

    PubMed

    Malyszko, Jolanta; Lukaszyk, Ewelina; Glowinska, Irena; Durlik, Magdalena

    2015-01-01

    Renal transplantation ensures distinct advantages for patients with end-stage kidney disease. However, in some cases early complications can lead to allograft dysfunction and consequently graft loss. One of the most common early complications after kidney transplantation is delayed graft function (DGF). Unfortunately there is no effective treatment for DGF, however early diagnosis of DGF and therapeutic intervention (eg modification of immunosuppression) may improve outcome. Therefore, markers of acute kidney injury are required. Creatinine is a poor biomarker for kidney injury due principally to its inability to help diagnose early acute renal failure and complete inability to help differentiate among its various causes. Different urinary and serum proteins have been intensively investigated as possible biomarkers in this setting. There are promising candidate biomarkers with the ability to detect DGF. We focused on emerging biomarkers of DGF with NGAL is being the most studied followed by KIM-1, L-FABP, IL-18, and others. However, large randomized studies are needed to establish the value of new, promising biomarkers, in DGF diagnosis, prognosis and its cost-effectiveness. PMID:26175216

  14. Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury

    PubMed Central

    Cheng, Shun-Yang; Chou, Yu-Hsiang; Liao, Fang-Ling; Lin, Chi-Chun; Chang, Fan-Chi; Liu, Chia-Hao; Huang, Tao-Min; Lai, Chun-Fu; Lin, Yu-Feng; Wu, Vin-Cent; Chu, Tzong-Shinn; Wu, Ming-Shiou; Lin, Shuei-Liong

    2016-01-01

    Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal ischemia-reperfusion injury. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter mice manifested increase of blood pressure, albuminuria and azotemia progressively. Drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5-month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrate that losartan can reduce ensuing CKD and mortality after functional recovery from AKI. PMID:27677327

  15. Paneth cell-mediated multiorgan dysfunction after acute kidney injury

    PubMed Central

    Park, Sang Won; Kim, Mihwa; Kim, Joo Yun; Ham, Ahrom; Brown, Kevin M.; Mori-Akiyama, Yuko; Ouellette, André J.; D’Agati, Vivette D.; Lee, H. Thomas

    2012-01-01

    Acute kidney injury (AKI) is frequently complicated by extra-renal multi-organ injury including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of pro-inflammatory mediators drives multi-organ injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage depleted mice decreased markedly, and intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI. PMID:23109723

  16. Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury.

    PubMed

    Won, A Jin; Kim, Siwon; Kim, Yoon Gyoon; Kim, Kyu-Bong; Choi, Wahn Soo; Kacew, Sam; Kim, Kyeong Seok; Jung, Jee H; Lee, Byung Mu; Kim, Suhkmann; Kim, Hyung Sik

    2016-01-01

    The discovery of new biomarkers for early detection of drug-induced acute kidney injury (AKI) is clinically important. In this study, sensitive metabolomic biomarkers identified in the urine of rats were used to detect cisplatin-induced AKI. Cisplatin (10 mg kg(-1), i.p.) was administered to Sprague-Dawley rats, which were subsequently euthanized after 1, 3 or 5 days. In cisplatin-treated rats, mild histopathological alterations were noted at day 1, and these changes were severe at days 3 and 5. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at days 3 and 5. The levels of new urinary protein-based biomarkers, including kidney injury molecule-1 (KIM-1), glutathione S-transferase-α (GST-α), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, neutrophil, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, were significantly elevated at days 3 and 5. Among urinary metabolites, trigonelline and 3-indoxylsulfate (3-IS) levels were significantly decreased in urine collected from cisplatin-treated rats prior to histological kidney damage. However, carbon tetrachloride (CCl4), a hepatotoxicant, did not affect these urinary biomarkers. Trigonelline is closely associated with GSH depletion and results in insufficient antioxidant capacity against cisplatin-induced AKI. The predominant cisplatin-induced AKI marker appeared to be reduced in urinary 3-IS levels. Because 3-IS is predominantly excreted via active secretion in proximal tubules, a decrease is indicative of tubular damage. Further, urinary excretion of 3-IS levels was markedly reduced in patients with AKI compared to normal subjects. The area under the curve receiver operating characteristics (AUC-ROC) for 3-IS was higher than for SCr, BUN, lactate dehydrogenase (LDH), total protein, and glucose. Therefore, low urinary or high serum 3-IS levels may be more useful for early detection of AKI than

  17. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

    PubMed

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M; Perocchi, Fabiana; Brooks, Craig R; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K; Bonventre, Joseph V

    2015-09-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo. PMID:26501107

  18. Meclizine Preconditioning Protects the Kidney Against Ischemia–Reperfusion Injury

    PubMed Central

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M.; Perocchi, Fabiana; Brooks, Craig R.; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K.; Bonventre, Joseph V.

    2015-01-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a ‘nutrient-sensitized’ chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo. PMID:26501107

  19. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

    PubMed

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M; Perocchi, Fabiana; Brooks, Craig R; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K; Bonventre, Joseph V

    2015-09-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.

  20. Hepatic Sulfotransferase as a Nephropreventing Target by Suppression of the Uremic Toxin Indoxyl Sulfate Accumulation in Ischemic Acute Kidney Injury

    PubMed Central

    Saito, Hideyuki; Yoshimura, Misato; Saigo, Chika; Komori, Megumi; Nomura, Yui; Yamamoto, Yuko; Sagata, Masataka; Wakida, Ayaka; Chuman, Erina; Nishi, Kazuhiko; Jono, Hirofumi

    2014-01-01

    Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is evoked by diverse pathophysiological conditions and/or surgical procedures. Here, we evaluated the nephropreventive effect of sulfotransferase (SULT) inhibitors, quercetin, and resveratrol, which hamper hepatic indoxyl sulfate (IS) production. I/R of the kidney caused severe renal injury with marked accumulation of serum and renal IS and urinary excretion of kidney injury molecule-1. Oral administration of AST-120 resulted in a significant restoration of kidney injury, suggesting that uremic toxins, which can be suppressed or adsorbed by AST-120 in the intestine, contribute to the progression or development of I/R-induced AKI. Oral administration of resveratrol or quercetin, SULT inhibitors, suppressed IS accumulation, accompanied by significant amelioration of renal dysfunction. The expression of nuclear factor E2-related factor 2 (Nrf2) in the renal nuclear fractions was markedly elevated by renal I/R, but suppressed by treatment with SULT inhibitors. IS is primarily taken up by HK-2 cells derived from human proximal tubular cells via organic anion transporters, which then evokes activation of Nrf2, most likely due to intracellular oxidative stress. Renal basolateral organic anion transporters OAT1 and OAT3, which mediate renal tubular uptake of IS in basolateral membrane, were markedly downregulated by renal I/R, but restored by SULT inhibitors. Our results suggest that renal accumulation of IS in ischemic AKI induces oxidative stress and downregulation of organic anion transporters resulting in kidney damage, which could be restored to some extent by inhibiting hepatic SULT activity as a nephropreventive target. PMID:24958931

  1. Acute kidney injury in pregnancy-current status.

    PubMed

    Acharya, Anjali; Santos, Jolina; Linde, Brian; Anis, Kisra

    2013-05-01

    Pregnancy-related acute kidney injury (PR-AKI) causes significant maternal and fetal morbidity and mortality. Management of PR-AKI warrants a thorough understanding of the physiologic adaptations in the kidney and the urinary tract. Categorization of etiologies of PR-AKI is similar to that of acute kidney injury (AKI) in the nonpregnant population. The causes differ between developed and developing countries, with thrombotic microangiopathies (TMAs) being common in the former and septic abortion and puerperal sepsis in the latter. The incidence of PR-AKI is reported to be on a decline, but there is no consensus on the exact definition of the condition. The physiologic changes in pregnancy make diagnosis of PR-AKI difficult. Newer biomarkers are being studied extensively but are not yet available for clinical use. Early and accurate diagnosis is necessary to improve maternal and fetal outcomes. Timely identification of "at-risk" individuals and treatment of underlying conditions such as sepsis, preeclampsia, and TMAs remain the cornerstone of management. Questions regarding renal replacement therapy such as modality, optimal prescription, and timing of initiation in PR-AKI remain unclear. There is a need to systematically explore these variables to improve care of women with PR-AKI. PMID:23928385

  2. Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury.

    PubMed

    Parr, Sharidan K; Clark, Amanda J; Bian, Aihua; Shintani, Ayumi K; Wickersham, Nancy E; Ware, Lorraine B; Ikizler, T Alp; Siew, Edward D

    2015-03-01

    Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

  3. Acute kidney injury in acute on chronic liver failure.

    PubMed

    Maiwall, Rakhi; Sarin, S K; Moreau, Richard

    2016-03-01

    Acute on chronic liver failure (ACLF) is a distinct clinical entity; however, there is still debate in the way it is defined in the East as compared to the West, especially with respect to incorporation of kidney dysfunction or failure in the definition of ACLF. Kidney dysfunction is defined as serum creatinine between 1.5 and 1.9 mg/dl and kidney failure as serum creatinine of more than 2 mg/dl or requirement of renal replacement therapy according to the EASL-CLIF Consortium. Kidney dysfunction or failure is universally present in patients with ACLF according to the definition by the EASL-CLIF Consortium while on the contrary the APASL definition of ACLF does not incorporate kidney dysfunction or failure in its definition. Recently, both the diagnosis and management of renal failure in patients with cirrhosis has changed with the advent of the acute kidney injury (AKI) criteria defined as an abrupt decline in renal functions, characterized by an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or an increase of more than 50 % from baseline, which is known or presumed to have occurred in the previous 7 days. Further, recent studies in patients with cirrhosis have shown the utility of biomarkers for the diagnosis of AKI. The present review covers the pathogenetic mechanisms, diagnosis, prognosis as well as management of AKI in patients with ACLF from both a Western as well as an Eastern perspective. The review identifies an unmet need to diagnose AKI and prevent this ominous complication in patients with ACLF.

  4. Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery

    PubMed Central

    Schaub, Jennifer A.; Garg, Amit X.; Coca, Steven G.; Testani, Jeffrey M.; Shlipak, Michael G.; Eikelboom, John; Kavsak, Peter; McArthur, Eric; Shortt, Colleen; Whitlock, Richard; Parikh, Chirag R.

    2015-01-01

    Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery. PMID:25830762

  5. Biomarkers of acute kidney injury and associations with short- and long-term outcomes

    PubMed Central

    Schaub, Jennifer A.; Parikh, Chirag R.

    2016-01-01

    Acute kidney injury is strongly associated with increased mortality and other adverse outcomes. Medical researchers have intensively investigated novel biomarkers to predict short- and long-term outcomes of acute kidney injury in many patient care settings, such as cardiac surgery, intensive care units, heart failure, and transplant. Future research should focus on leveraging this relationship to improve enrollment for clinical trials of acute kidney injury. PMID:27239295

  6. Outpatient nephrology referral rates after acute kidney injury.

    PubMed

    Siew, Edward D; Peterson, Josh F; Eden, Svetlana K; Hung, Adriana M; Speroff, Theodore; Ikizler, T Alp; Matheny, Michael E

    2012-02-01

    AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) <60 ml/min per 1.73 m(2) 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR ≥60 ml/min per 1.73 m(2)), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR <60 ml/min per 1.73 m(2)) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.

  7. Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury.

    PubMed

    Khan, Abdul Hye; Falck, John R; Manthati, Vijaya L; Campbell, William B; Imig, John D

    2014-01-01

    Epoxyeicosatrienoic acids (EETs) contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II)-induced hypertension. EET-B was administered in drinking water for 14 days (10 mg/kg/d) and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

  8. A case of life-threatening acute kidney injury with toxic encephalopathy caused by Dioscorea quinqueloba.

    PubMed

    Kang, Kyung-Sik; Heo, Sang Taek

    2015-01-01

    Some herbal medications induce acute kidney injury. The acute kidney injuries caused by herbal medications are mild and commonly treated by palliative care. A 51-years-old man who drank the juice squeezed from the raw tubers of Dioscorea quinqueloba (D. quinqueloba) was admitted with nausea, vomiting and chilling. He developed a seizure with decreased level of consciousness. He was diagnosed with acute kidney injury, which was cured by continuous venovenous hemodialfiltration. Non-detoxified D. quinqueloba can cause severe acute kidney injury with toxic encephalopathy. It is critical to inform possible adverse effects of the medicinal herbs and to implement more strict regulation of these products.

  9. Hyperglycemia and acute kidney injury in critically ill children

    PubMed Central

    Gordillo, Roberto; Ahluwalia, Tania; Woroniecki, Robert

    2016-01-01

    Background Hyperglycemia and acute kidney injury (AKI) are common in critically ill children and have been associated with higher morbidity and mortality. The incidence of AKI in children is difficult to estimate because of the lack of a standard definition for AKI. The pediatric RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria can be used to define AKI in children. Various biomarkers in urine and blood have been studied to detect AKI in critically ill children. However, it is not clear whether hyperglycemia is associated with AKI. Our objective was to evaluate the effect of hyperglycemia on kidney function and its effect on neutrophil gelatinase-associated lipocalin (NGAL) in children. Methods We studied retrospective and prospective cohorts of pediatric critically ill subjects admitted to the pediatric intensive care unit (PICU). We analyzed data from admission that included estimated glomerular filtration rate, plasma and urine NGAL, serum glucose and peak glycemia (highest glycemia during PICU admission), and length of hospital and PICU stay from two different institutions. Results We found that the prevalence of hyperglycemia was 89% in the retrospective cohort and 86% in the prospective cohort, P=0.99. AKI was associated with peak glycemia, P=0.03. There was a statistically significant correlation between peak glycemia and hospital and PICU stays, P=<0.001 and P<0.001, respectively. Urine NGAL and plasma NGAL were not statistically different in subjects with and without hyperglycemia, P=0.99 and P=0.85, respectively. Subjects on vasopressors had lower estimated glomerular filtration rate and higher glycemia, P=0.01 and P=0.04, respectively. Conclusion We conclude that in critically ill children, hyperglycemia is associated with AKI and longer PICU stays. PMID:27601931

  10. Associations of deceased donor kidney injury with kidney discard and function after transplantation

    PubMed Central

    Hall, Isaac E.; Schröppel, Bernd; Doshi, Mona D.; Ficek, Joseph; Weng, Francis L.; Hasz, Rick D.; Thiessen-Philbrook, Heather; Reese, Peter P.; Parikh, Chirag R.

    2015-01-01

    Deceased-donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing admission-to-terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08–1.52), 1.82 (1.45–2.30) and 2.74 (2.0–3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09–1.49), 1.70 (1.37–2.12) and 2.25 (1.74–2.91), respectively. Six-month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 [interquartile range: 31–61] vs. 58 [45–75] ml/min/1.73m2 for no DGF, P<0.001). There was significant favorable interaction between donor AKI and DGF such that 6-month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 [29–60], 49 [32–64], 52 [36–59] and 58 [39–71] ml/min/1.73m2 for no AKI, stage 1, 2 and 3, respectively; interaction P=0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6-month allograft function, clinicians should consider cautious expansion into this donor pool. PMID:25762442

  11. Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

    PubMed Central

    Krishnamoorthy, Aparna; Ajay, Amrendra Kumar; Hoffmann, Dana; Kim, Tae-Min; Ramirez, Victoria; Campanholle, Gabriela; Bobadilla, Norma A.; Waikar, Sushrut S.

    2011-01-01

    Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease. PMID:21685370

  12. Adrenal insufficiency presenting as hypercalcemia and acute kidney injury

    PubMed Central

    Ahn, Seung Won; Kim, Tong Yoon; Lee, Sangmin; Jeong, Jeong Yeon; Shim, Hojoon; Han, Yu min; Choi, Kyu Eun; Shin, Seok Joon; Yoon, Hye Eun

    2016-01-01

    Adrenal insufficiency is an uncommon cause of hypercalcemia and not easily considered as an etiology of adrenal insufficiency in clinical practice, as not all cases of adrenal insufficiency manifest as hypercalcemia. We report a case of secondary adrenal insufficiency presenting as hypercalcemia and acute kidney injury in a 66-year-old female. The patient was admitted to the emergency department with general weakness and poor oral intake. Hypercalcemia (11.5 mg/dL) and moderate renal dysfunction (serum creatinine 4.9 mg/dL) were shown in her initial laboratory findings. Studies for malignancy and hyperparathyroidism showed negative results. Basal cortisol and adrenocorticotropic hormone levels and adrenocorticotropic hormone stimulation test confirmed the diagnosis of adrenal insufficiency. With the administration of oral hydrocortisone, hypercalcemia was dramatically resolved within 3 days. This case shows that adrenal insufficiency may manifest as hypercalcemia and acute kidney injury, which implicates that adrenal insufficiency should be considered a cause of hypercalcemia in clinical practice. PMID:27536162

  13. Effect of melatonin on kidney cold ischemic preservation injury

    PubMed Central

    Aslaner, Arif; Gunal, Omer; Turgut, Hamdi Taner; Celik, Erdal; Yildirim, Umran; Demirci, Rojbin Karakoyun; Gunduz, Umut Riza; Calis, Hasan; Dogan, Sami

    2013-01-01

    Melatonin is a potent free radical scavenger of reactive oxygen species, nitric oxide synthase inhibitor and a well-known antioxidant secreted from pineal gland. This hormone has been reported to protect tissue from oxidative damage. In this study, we aim to investigate the effect of melatonin on kidney cold ischemia time when added to preservation solution. Thirty male Wistar albino rats were divided equally into three groups; Ringer Lactate (RL) solution, University of Wisconsin (UW) solution with and without melatonin. The serum Lactate Dehydrogenase (LDH) activities of the preservation solutions at 2nd, 24th, 36th, and 48th hours were determined. Tissue malondialdehyde (MDA) levels were also measured and a histological examination was performed at 48th hour. Melatonin that added to preservation solution prevented enzyme elevation and decreased lipid peroxidation in preservation solution when compared to the control group (p<0.05). The histological examination revealed that UW solution containing melatonin significantly prevented the kidney from pathological injury (p<0.05). Melatonin added to preservation solutions such as UW solution seemed to protect the tissue preserved effectively from cold ischemic injury for up to 48 hour. PMID:24179573

  14. Acute Kidney Injury by Radiographic Contrast Media: Pathogenesis and Prevention

    PubMed Central

    Faga, Teresa; Pisani, Antonio; Michael, Ashour

    2014-01-01

    It is well known that iodinated radiographic contrast media may cause kidney dysfunction, particularly in patients with preexisting renal impairment associated with diabetes. This dysfunction, when severe, will cause acute renal failure (ARF). We may define contrast-induced Acute Kidney Injury (AKI) as ARF occurring within 24–72 hrs after the intravascular injection of iodinated radiographic contrast media that cannot be attributed to other causes. The mechanisms underlying contrast media nephrotoxicity have not been fully elucidated and may be due to several factors, including renal ischaemia, particularly in the renal medulla, the formation of reactive oxygen species (ROS), reduction of nitric oxide (NO) production, and tubular epithelial and vascular endothelial injury. However, contrast-induced AKI can be prevented, but in order to do so, we need to know the risk factors. We have reviewed the risk factors for contrast-induced AKI and measures for its prevention, providing a long list of references enabling readers to deeply evaluate them both. PMID:25197639

  15. APOL1 nephropathy: from gene to mechanisms of kidney injury.

    PubMed

    Kruzel-Davila, Etty; Wasser, Walter G; Aviram, Sharon; Skorecki, Karl

    2016-03-01

    The contribution of African ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein L1 (APOL1). The APOL1 variants appear at a high allele frequency in populations of West African ancestry as a result of apparent adaptive selection of the heterozygous state. Heterozygosity protects from infection with Trypanosoma brucei rhodesiense. This review will describe the role of the approaches in population genetics for the description of APOL1-associated nephropathies and draw inferences as to the biologic mechanisms from genetic epidemiology findings to date. Modifier loci can influence APOL1 risk for the development of kidney disease. 'Second hits', both viral and non-viral, may explain the discrepancy between the remarkably high odds ratios and the low lifetime risks of kidney disease in two allele carriers of APOL1 risk variants. Therapeutic strategies for APOL1-associated nephropathies will require the prevention and treatment of these 'second hits' and the development of drugs to protect the APOL1 downstream renal injury pathways.

  16. Acute kidney injury in critically ill cancer patients: an update.

    PubMed

    Lameire, Norbert; Vanholder, Raymond; Van Biesen, Wim; Benoit, Dominique

    2016-01-01

    Patients with cancer represent a growing group among actual ICU admissions (up to 20 %). Due to their increased susceptibility to infectious and noninfectious complications related to the underlying cancer itself or its treatment, these patients frequently develop acute kidney injury (AKI). A wide variety of definitions for AKI are still used in the cancer literature, despite existing guidelines on definitions and staging of AKI. Alternative diagnostic investigations such as Cystatin C and urinary biomarkers are discussed briefly. This review summarizes the literature between 2010 and 2015 on epidemiology and prognosis of AKI in this population. Overall, the causes of AKI in the setting of malignancy are similar to those in other clinical settings, including preexisting chronic kidney disease. In addition, nephrotoxicity induced by the anticancer treatments including the more recently introduced targeted therapies is increasingly observed. However, data are sometimes difficult to interpret because they are often presented from the oncological rather than from the nephrological point of view. Because the development of the acute tumor lysis syndrome is one of the major causes of AKI in patients with a high tumor burden or a high cell turnover, the diagnosis, risk factors, and preventive measures of the syndrome will be discussed. Finally, we will briefly discuss renal replacement therapy modalities and the emergence of chronic kidney disease in the growing subgroup of critically ill post-AKI survivors. PMID:27480256

  17. Early detection of acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Jefferies, John Lynn; Devarajan, Prasad

    2016-01-01

    Acute kidney injury (AKI) is increasingly recognized as a common problem in children undergoing cardiac surgery, with well documented increases in morbidity and mortality in both the short and the long term. Traditional approaches to the identification of AKI such as changes in serum creatinine have revealed a large incidence in this population with significant negative impact on clinical outcomes. However, the traditional diagnostic approaches to AKI diagnosis have inherent limitations that may lead to under-diagnosis of this pathologic process. There is a dearth of randomized controlled trials for the prevention and treatment of AKI associated with cardiac surgery, at least in part due to the paucity of early predictive biomarkers. Novel non-invasive biomarkers have ushered in a new era that allows for earlier detection of AKI. With these new diagnostic tools, a more consistent approach can be employed across centers that may facilitate a more accurate representation of the actual prevalence of AKI and more importantly, clinical investigation that may minimize the occurrence of AKI following pediatric cardiac surgery. A thoughtful management approach is necessary to mitigate the effects of AKI after cardiac surgery, which is best accomplished in close collaboration with pediatric nephrologists. Long-term surveillance for improvement in kidney function and potential development of chronic kidney disease should also be a part of the comprehensive management strategy. PMID:27429538

  18. Novel Assays for Detection of Urinary KIM-1 in Mouse Models of Kidney Injury

    PubMed Central

    Sabbisetti, Venkata S.

    2013-01-01

    Kidney injury molecule-1 (KIM-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a urinary biomarker to monitor preclinical nephrotoxicity in rats and on a case-by-case basis for the translation of potentially nephrotoxic drugs into first-in human studies. Although mouse models are widely employed in preclinical studies, few urinary biomarker studies have been performed in mice due to limited urine availability and lack of sensitive assays. Here, we report the development and validation of two different assays for quantitative assessment of mouse urinary KIM-1 (uKIM-1) and compare the sensitivity of KIM-1 relative to other standard markers in ischemia reperfusion and aristolochic acid (AA)–induced kidney injury in mice. A sensitive, reproducible, and quantitative microbead-based KIM-1 ELISA was established, which requires only 10 μl urine for triplicate determination with an assay range of 12.21 pg/ml to 50ng/ml. The second assay is a laminar flow dipstick assay, which has an assay range of 195 pg/ml to 50ng/ml and provides quantitative assessment of KIM-1 in 15min. uKIM-1 levels increased with increasing time of ischemia or time after AA administration. After only 10-min ischemia followed by 24-h reperfusion, uKIM-1 was significantly elevated by 13-fold, whereas serum creatinine (sCr), blood urea nitrogen, N-acetyl-β-glucosaminidase (NAG), and proteinuria levels did not change. After AA administration, uKIM-1 levels were significantly upregulated by greater than threefold within 12h, whereas sCr and NAG levels were unchanged. Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at −80°C. PMID:23019274

  19. The liver X receptor agonist TO901317 protects mice against cisplatin-induced kidney injury

    PubMed Central

    Yang, Meng; Wang, Rong; Sun, Jing; Yu, Kezhou; Chen, Bing; Xu, Liang; Zhao, Bing

    2015-01-01

    Liver X receptors are in the nuclear receptor superfamily and are contained in the regulation of lipid and cholesterol metabolism. Besides, liver X receptors are considered crucial regulators of the inflammatory response and innate immunity. The current study evaluates the in vivo effects that the synthetic liver X receptor agonist TO901317 protects against cisplatin-induced kidney injury in mice. Mice received cisplatin administration through a single intraperitoneal injection (20 mg/kg in saline). And then the mice were treated with the TO901317 by daily gavage (10 mg/kg/day) 12 h postcisplatin administration, and cisplatin nephrotoxicity was evaluated. At 72 h after cisplatin treatment, elevated plasma urea and creatinine levels (P < 0.05) were evidenced which indicates the renal dysfunction of the vehicle-treated mice, consistent with tubular necrosis, protein cast, dilation of renal tubules, and desquamation of epithelial cells in renal tubules. In contrast, the severity of renal dysfunction and histological damage was reduced in TO901317 treated mice (P < 0.05). In accordance, circulating tumor necrosis factor alpha levels, renal tumor necrosis factor alpha, p47phox, gp91phox, and protein expression levels and COX-2 mRNA, renal monocyte chemoattractant protein 1, VACAM-1 mRNA and intercellular adhesion molecule-1 contents, and renal prostaglandin E2 amounts, were higher in samples from cisplatin-treated mice in comparison with controls (P < 0.05) but attenuated in the TO901317 treatment group (P < 0.05). Taken together, treatment with the liver X receptor agonist TO901317 ameliorated the inflammatory response and oxidative stress in cisplatin-induced kidney injury in mice. PMID:26062799

  20. Outpatient Nephrology Referral Rates after Acute Kidney Injury

    PubMed Central

    Siew, Edward D.; Peterson, Josh F.; Eden, Svetlana K.; Hung, Adriana M.; Speroff, Theodore; Ikizler, T. Alp

    2012-01-01

    AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) <60 ml/min per 1.73 m2 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR ≥60 ml/min per 1.73 m2), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62–79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR <60 ml/min per 1.73 m2) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6–9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions. PMID:22158435

  1. Neuroimmune Control of Acute Kidney Injury and Inflammation

    PubMed Central

    Inoue, Tsuyoshi; Okusa, Mark D.

    2015-01-01

    Despite major advances in identifying pathophysiological mechanisms of acute kidney injury (AKI), no definitive therapeutic or preventive modalities have been developed with the exception of dialysis. One possible approach is the control of inflammation and AKI through activation of the neuro-immune axis. The cholinergic anti-inflammatory pathway is thought to contribute to the homeostatic response to inflammation-related disorders and forms the basis for recent approaches to therapeutic intervention. The concept is based on the emerging understanding of the interface between the nervous and immune systems. In the cholinergic anti-inflammatory pathway, the efferent vagus nerve indirectly stimulates the CD4+ T cells in the spleen. The CD4+ T cells produce acetylcholine, which stimulates alpha 7 nicotinic receptors (α7nAch) on macrophages. Activation of the α7nAch receptors on macrophages activates NF-κβ and elicits an anti-inflammatory response. Recently we demonstrated the effect of a non-pharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury and sepsis-induced AKI in mice. Our data suggest that ultrasound-induced tissue protection is mediated through the activation of the cholinergic anti-inflammatory pathway. In addition, nicotinic receptor agonists and ghrelin, a neuropeptide, were reported to prevent AKI possibly through a mechanism closely linked with vagus nerve stimulation. Based on the studies focusing on inflammation and the observations regarding kidney injury, we believe that activating the cholinergic anti-inflammatory pathway will be a new modality for the prevention and treatment of AKI. PMID:26376049

  2. Bilateral renal lymphoma: rapid recovery from an acute kidney injury after open renal biopsy.

    PubMed

    Mitome, Taku; Furuya, Kazuhiro; Imano, Masashi; Osaka, Kimito; Yokomizo, Yumiko; Hayashi, Narihiko; Nakaigawa, Noboru; Yamanaka, Shoji; Yao, Masahiro

    2016-01-01

    Renal lymphoma as an initial lesion is relatively rare. Bilateral renal lymphoma frequently presents as acute kidney injury. With systematic chemotherapy for the lymphoma, patients usually recover their kidney function. However, in the case we describe here, the patient's kidney function recovered greatly after an open renal biopsy. Here, we review and discuss this unique case.

  3. Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion.

    PubMed

    Mohamed, Fahim; Buckley, Nicholas A; Jayamanne, Shaluka; Pickering, John W; Peake, Philip; Palangasinghe, Chathura; Wijerathna, Thilini; Ratnayake, Indira; Shihana, Fathima; Endre, Zoltan H

    2015-09-01

    Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine samples from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)]; 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning. PMID:26071311

  4. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  5. Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury.

    PubMed

    Sekine, Michiko; Monkawa, Toshiaki; Morizane, Ryuji; Matsuoka, Kunie; Taya, Choji; Akita, Yoshiko; Joh, Kensuke; Itoh, Hiroshi; Hayashi, Matsuhiko; Kikkawa, Yoshiaki; Kohno, Kenji; Suzuki, Akemi; Yonekawa, Hiromichi

    2012-02-01

    The proximal straight tubule (S3 segment) of the kidney is highly susceptible to ischemia and toxic insults but has a remarkable capacity to repair its structure and function. In response to such injuries, complex processes take place to regenerate the epithelial cells of the S3 segment; however, the precise molecular mechanisms of this regeneration are still being investigated. By applying the "toxin receptor mediated cell knockout" method under the control of the S3 segment-specific promoter/enhancer, Gsl5, which drives core 2 β-1,6-N-acetylglucosaminyltransferase gene expression, we established a transgenic mouse line expressing the human diphtheria toxin (DT) receptor only in the S3 segment. The administration of DT to these transgenic mice caused the selective ablation of S3 segment cells in a dose-dependent manner, and transgenic mice exhibited polyuria containing serum albumin and subsequently developed oliguria. An increase in the concentration of blood urea nitrogen was also observed, and the peak BUN levels occurred 3-7 days after DT administration. Histological analysis revealed that the most severe injury occurred in the S3 segments of the proximal tubule, in which tubular cells were exfoliated into the tubular lumen. In addition, aquaporin 7, which is localized exclusively to the S3 segment, was diminished. These results indicate that this transgenic mouse can suffer acute kidney injury (AKI) caused by S3 segment-specific damage after DT administration. This transgenic line offers an excellent model to uncover the mechanisms of AKI and its rapid recovery.

  6. Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

    PubMed

    Zhao, Shi-Lei; Wei, Shi-Yao; Wang, Yu-Xiao; Diao, Tian-Tian; Li, Jian-Si; He, Yi-Xin; Yu, Jing; Jiang, Xi-Yue; Cao, Yang; Mao, Xin-Yue; Wei, Qiu-Ju; Wang, Yu; Li, Bing

    2016-01-01

    Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury. PMID:27600466

  7. Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury

    PubMed Central

    Zhao, Shi-Lei; Wei, Shi-Yao; Wang, Yu-Xiao; Diao, Tian-Tian; Li, Jian-Si; He, Yi-Xin; Yu, Jing; Jiang, Xi-Yue; Cao, Yang; Mao, Xin-Yue; Wei, Qiu-Ju; Wang, Yu; Li, Bing

    2016-01-01

    Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury. PMID:27600466

  8. Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

    PubMed

    Zhao, Shi-Lei; Wei, Shi-Yao; Wang, Yu-Xiao; Diao, Tian-Tian; Li, Jian-Si; He, Yi-Xin; Yu, Jing; Jiang, Xi-Yue; Cao, Yang; Mao, Xin-Yue; Wei, Qiu-Ju; Wang, Yu; Li, Bing

    2016-01-01

    Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

  9. [Epidemiology of acute kidney injury in hospitalized patients in China].

    PubMed

    Lang, Xiabing; Yang, Yi; Chen, Jianghua

    2016-03-01

    Acute kidney injury (AKI) is a disease spectrum ranging from minimal elevation of serum creatinine to complete renal failure. It is significantly associated with increased mortality, length of hospital stay and medical care cost. With the increasing awareness of the importance of AKI, several high quality and multicenter epidemiological studies have been published recently in China. However, the results differ a lot due to the differences in regional economic development, the selection of target population and testing indicators, the disease definition and study strategies. The reported incidence of AKI in China is much lower than that in the developed countries. This article will analyze the current status and the problems facing AKI epidemiological studies of hospitalized patients with our own data and those from literature. The article intends to clarify the burden of AKI,to increase the awareness of AKI among clinicians and policy makers for achieving the goal of "zero by 2025" in China. PMID:27273996

  10. Acute kidney injury after massive attack of Africanised bees

    PubMed Central

    Bridi, Ramaiane A; Balbi, Andre Luis; Neves, Precil M; Ponce, Daniela

    2014-01-01

    Acute kidney injury (AKI) is a well-documented complication of massive attack by Africanised bees and can be observed 48–72 h after the accident. We report a case of Africanised bees attack followed by severe and lethal AKI. A 56-year-old man was admitted to emergency department after a massive attack of Africanised bees (>1000 bee stings). He was unconscious, presenting with hypotension and tachycardia. Mechanical ventilation, volume expansion and care for anaphylaxis were instituted. The patient was transferred to the intensive care unit (ICU) and after 48 h he developed rhabdomyolysis, oliguria, increased creatinine levels, hyperkalaemia and refractory acidosis. A diagnosis of AKI secondary to rhabdomyolysis and shock was made. The patient was treated with a prolonged course of haemodialysis. However, he progressed to refractory shock and died 5 days after admission. PMID:24618864

  11. Acute kidney injury in acute liver failure: a review.

    PubMed

    Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

    2013-11-01

    Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

  12. Severe acute kidney injury as presentation of Burkitt's lymphoma.

    PubMed

    ter Haar, Eva; Labarque, Veerle; Tousseyn, Thomas; Mekahli, Djalila

    2016-01-01

    We discuss a case of acute kidney injury (AKI) at a very young age caused by primary lymphomatous renal infiltration due to Burkitt's lymphoma and analyse the literature on this rare condition. At presentation, clinical examination showed impressive bilateral nephromegaly and hypertension. Blood analysis indicated severe AKI, mild anaemia and normal serum electrolytes. There were no signs of tumour lysis syndrome. Urine sediment was normal, with neither haematuria nor proteinuria. Abdominal ultrasound demonstrated bilateral renal enlargement (+12 SD), with increased corticomedullar differentiation. MRI demonstrated the presence of a homogenous renal enlargement with features of an infiltrative lesion. Ultimately, microscopic and immunohistochemical analysis of the renal biopsy confirmed the diagnosis of Burkitt's lymphoma. Early and aggressive therapy is the key to ensure a good outcome. PMID:27118748

  13. Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury

    PubMed Central

    Alidori, Simone; Akhavein, Nima; Thorek, Daniel L. J.; Behling, Katja; Romin, Yevgeniy; Queen, Dawn; Beattie, Bradley J.; Manova-Todorova, Katia; Bergkvist, Magnus; Scheinberg, David A.; McDevitt, Michael R.

    2016-01-01

    RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)–mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, including Trp53, Mep1b, Ctr1, and EGFP. A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1b and fCNT/siTrp53 significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention. PMID:27009268

  14. Acute Kidney Injury Increases Risk of ESRD among Elderly

    PubMed Central

    Ishani, Areef; Xue, Jay L.; Himmelfarb, Jonathan; Eggers, Paul W.; Kimmel, Paul L.; Molitoris, Bruce A.; Collins, Allan J.

    2009-01-01

    Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged ≥67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for ≥2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease. PMID:19020007

  15. Acute kidney injury increases risk of ESRD among elderly.

    PubMed

    Ishani, Areef; Xue, Jay L; Himmelfarb, Jonathan; Eggers, Paul W; Kimmel, Paul L; Molitoris, Bruce A; Collins, Allan J

    2009-01-01

    Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged > or = 67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for > or = 2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease.

  16. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury

    PubMed Central

    Duann, Pu; Lianos, Elias A.; Ma, Jianjie; Lin, Pei-Hui

    2016-01-01

    Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed. PMID:27153058

  17. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury.

    PubMed

    Duann, Pu; Lianos, Elias A; Ma, Jianjie; Lin, Pei-Hui

    2016-01-01

    Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed. PMID:27153058

  18. Lithium-Induced Minimal Change Disease and Acute Kidney Injury

    PubMed Central

    Tandon, Parul; Wong, Natalie; Zaltzman, Jeffrey S

    2015-01-01

    Context: Lithium carbonate is a psychiatric medication commonly used in the treatment of bipolar disorder. It has been implicated in inducing nephrogenic diabetes inspidus, chronic tubulointerstitial nephropathy, and acute tubular necrosis. We describe a case of lithium-induced minimal change disease (MCD) and acute kidney injury (AKI). Case Report: A 32-year-old female with a medical history of bipolar disorder treated with chronic lithium therapy presented with anasarca, fatigue, and tremors. Work-up revealed supra-therapeutic lithium levels, hypoalbuminemia, and significant proteinuria. The patient was treated conservatively with fluids and discontinuation of lithium therapy. Subsequently, she developed significant AKI and persistent proteinuria. She underwent a renal biopsy that demonstrated effacement of podocyte foot processes consistent with lithium-induced MCD. This was treated with corticosteroids, which decreased the proteinuria and resolved all the patient's symptoms. Conclusion: Lithium-induced MCD is a rare disease that affects patients of all ages. It is often associated with therapeutic lithium and is typically resolved with discontinuation of lithium. In some cases, concurrent AKI may result due to vascular obstruction from hyperalbuminuria and associated renal interstitial edema. Corticosteroids may be needed to reduce the proteinuria and prevent progression to chronic kidney disease. As such, patients on lithium therapy may benefit from monitoring of glomerular function via urinalysis to prevent the onset of nephrotic syndrome. PMID:26258081

  19. Contrast-Induced Acute Kidney Injury: Definition, Epidemiology, and Outcome

    PubMed Central

    Meinel, Felix G.; De Cecco, Carlo N.; Schoepf, U. Joseph

    2014-01-01

    Contrast-induced acute kidney injury (CI-AKI) is commonly defined as a decline in kidney function occurring in a narrow time window after administration of iodinated contrast material. The incidence of AKI after contrast material administration greatly depends on the specific definition and cutoff values used. Although self-limiting in most cases, postcontrast AKI carries a risk of more permanent renal insufficiency, dialysis, and death. The risk of AKI from contrast material, in particular when administered intravenously for contrast-enhanced CT, has been exaggerated by older, noncontrolled studies due to background fluctuations in renal function. More recent evidence from controlled studies suggests that the risk is likely nonexistent in patients with normal renal function, but there may be a risk in patients with renal insufficiency. However, even in this patient population, the risk of CI-AKI is probably much smaller than traditionally assumed. Since volume expansion is the only preventive strategy with a convincing evidence base, liberal hydration should be encouraged to further minimize the risk. The benefits of the diagnostic information gained from contrast-enhanced examinations will still need to be balanced with the potential risk of CI-AKI for the individual patient and clinical scenario. PMID:24734250

  20. Functional Magnetic Resonance Imaging in Acute Kidney Injury: Present Status

    PubMed Central

    Zhou, Hai Ying; Chen, Tian Wu; Zhang, Xiao Ming

    2016-01-01

    Acute kidney injury (AKI) is a common complication of hospitalization that is characterized by a sudden loss of renal excretory function and associated with the subsequent development of chronic kidney disease, poor prognosis, and increased mortality. Although the pathophysiology of renal functional impairment in the setting of AKI remains poorly understood, previous studies have identified changes in renal hemodynamics, perfusion, and oxygenation as key factors in the development and progression of AKI. The early assessment of these changes remains a challenge. Many established approaches are not applicable to humans because of their invasiveness. Functional renal magnetic resonance (MR) imaging offers an alternative assessment tool that could be used to evaluate renal morphology and function noninvasively and simultaneously. Thus, the purpose of this review is to illustrate the principle, application, and role of the techniques of functional renal MR imaging, including blood oxygen level-dependent imaging, arterial spin labeling, and diffusion-weighted MR imaging, in the management of AKI. The use of gadolinium in MR imaging may exacerbate renal impairment and cause nephrogenic systemic fibrosis. Therefore, dynamic contrast-enhanced MR imaging will not be discussed in this paper. PMID:26925411

  1. Oral bisphosphonate use in the elderly is not associated with acute kidney injury.

    PubMed

    Shih, Andrew W Y; Weir, Matthew A; Clemens, Kristin K; Yao, Zhan; Gomes, Tara; Mamdani, Muhammad M; Juurlink, David N; Hird, Amanda; Hodsman, Anthony; Parikh, Chirag R; Wald, Ron; Cadarette, Suzanne M; Garg, Amit X

    2012-10-01

    Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60 ml/min per 1.73 m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.

  2. CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation.

    PubMed

    Ranganathan, Punithavathi; Jayakumar, Calpurnia; Manicassamy, Santhakumar; Ramesh, Ganesan

    2013-11-15

    Organ cross talk exists in many diseases of the human and animal models of human diseases. A recent study demonstrated that inflammatory mediators can cause acute kidney injury and neutrophil infiltration in a mouse model of dextran sodium sulfate (DSS)-colitis. However, the chemokines and their receptors that may mediate distant organ effects in colitis are unknown. We hypothesized that keratinocyte chemoattractant (KC)/IL-8 receptor chemokine (C-X-C motif) ligand 2 (CXCL2) mediates DSS-colitis-induced acute kidney injury. Consistent with our hypothesis, wild-type (WT) mice developed severe colitis with DSS treatment, which was associated with inflammatory cytokine and chemokine expression and neutrophil infiltration in the colon. DSS-colitis in WT was accompanied by acute kidney injury and enhanced expression of inflammatory cytokines in the kidney. However, CXCR2 knockout mice were protected against DSS-colitis as well as acute kidney injury. Moreover, the expression of cytokines and chemokines and neutrophil infiltration was blunted in CXCR2 knockout mice in the colon and kidney. Administration of recombinant KC exacerbated DSS-colitis-induced acute kidney injury. Our results suggest that KC/IL-8 and its receptor CXCR2 are critical and major mediators of organ cross talk in DSS colitis and neutralization of CXCR2 will help to reduce the incidence of acute kidney injury due to ulcerative colitis and Crohn's disease in humans.

  3. Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases

    PubMed Central

    Arcand, Steve; Lin, Han-Bin; Wojnarowicz, Chris; Sawicka, Jolanta; Banerjee, Tamalina; Luo, Yigang; Beck, Gavin R.; Luke, Patrick P.; Sawicki, Grzegorz

    2016-01-01

    Background Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion. Methods Human kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD). Results Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers. Conclusions Based on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury. PMID:27327879

  4. An unusual cause of acute kidney injury due to oxalate nephropathy in systemic scleroderma.

    PubMed

    Mascio, Heather M; Joya, Christie A; Plasse, Richard A; Baker, Thomas P; Flessner, Michael F; Nee, Robert

    2015-08-01

    Oxalate nephropathy is an uncommon cause of acute kidney injury. Far rarer is its association with scleroderma, with only one other published case report in the literature. We report a case of a 75-year-old African-American female with a history of systemic scleroderma manifested by chronic pseudo-obstruction and small intestinal bacterial overgrowth (SIBO) treated with rifaximin, who presented with acute kidney injury with normal blood pressure. A renal biopsy demonstrated extensive acute tubular injury with numerous intratubular birefringent crystals, consistent with oxalate nephropathy. We hypothesize that her recent treatment with rifaximin for SIBO and decreased intestinal transit time in pseudo-obstruction may have significantly increased intestinal oxalate absorption, leading to acute kidney injury. Oxalate nephropathy should be considered in the differential diagnosis of acute kidney injury in scleroderma with normotension, and subsequent evaluation should be focused on bowel function to include alterations in gut flora due to antibiotic administration. PMID:25500295

  5. Potential biomarkers for the early detection of acute kidney injury after percutaneous nephrolithotripsy.

    PubMed

    Daggülli, Mansur; Utangaç, Mehmet M; Dede, Onur; Bodakci, Mehmet N; Hatipoglu, Namık K; Penbegül, Necmettin; Sancaktutar, Ahmet A; Bozkurt, Yaşar; Söylemez, Haluk

    2016-01-01

    This study aims to investigate the role of urinary biomarkers in the determination of the potential risks of renal parenchymal tubular damage in adult patients who underwent percutaneous nephrolithotomy (PNL) with the indication of renal stone. A randomized and prospective controlled study was performed between June and December 2013. We enrolled 29 consecutive patients with renal calculi > 2 cm and who underwent PNL, as well as 47 healthy control subjects. Urine samples, including 2 h before surgery, 2 and 24 h after surgery were collected from the patient group. Freshly voided urine samples were collected from the control group. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-glucosaminidase (NAG), and liver-type fatty acid binding protein (LFABP) levels were measured from these urine samples. The mean KIM-1/Cr value that measured 24 h after the operation was statistically significant, higher than its preoperative (preop) level (p = 0.045). A significant difference was detected between the mean preop and postoperative (postop) 24 h NAG/Cr values (p < 0.001). Also, postop 24 h NGAL/Cr levels were statistically significant, higher than its preop levels (p = 0.013). According to the comparison of preop and postop levels, an increase in LFABP/Cr values secondary to surgical intervention was observed without any statistically significant difference. Besides the LFABP/Cr levels do not change after percutaneous kidney surgery, KIM-1/Cr, NAG/Cr, and NGAL/Cr levels increase postop period, especially at 24 h. Further studies with a larger series and repeated measurements should be performed to clarify if they can be used to demonstrate renal damage after percutaneous surgery or not. PMID:26481764

  6. Postpartum acute kidney injury: a review of 99 cases.

    PubMed

    Eswarappa, Mahesh; Madhyastha, P Rakesh; Puri, Sonika; Varma, Vijay; Bhandari, Aneesh; Chennabassappa, Gurudev

    2016-07-01

    Postpartum acute kidney injury (PPAKI) constitutes an important cause of obstetric AKI. It is associated with high maternal and fetal mortality in developing nations. The aim of this study is to survey the etiology and outcomes of PPAKI in a tertiary care Indian hospital. Ninety-nine patients, without prior comorbidities, treated for PPAKI, between 2005-2014 at M.S. Ramaiah Medical College, were included for analysis in this retrospective, observational study. AKI was analyzed in terms of maximal stage of renal injury attained as per RIFLE criteria. Outcomes included requirement for renal replacement therapy (RRT), maternal and fetal outcomes. PPAKI constituted 60% of all obstetric AKI cases. Median maternal age was 23 years and 52% of patients were primigravidas. Mean serum creatinine was 4.1 mg/dL. Failure (33%) and injury (31%) were the major categories as per RIFLE criteria. Thirty-nine percent of cases required RRT. Sepsis, particularly puerperal sepsis, was the leading causes of PPAKI (75% of cases) and maternal mortality (94% of deaths). Maternal and fetal mortality were 19% and 22% respectively. The incidence of cortical necrosis was 10.3%. Three patients required long-term RRT. In conclusion, consistent with other Indian literature, we report a high incidence of PPAKI. We found incremental mortality on moving from "Risk" to "Failure" category of RIFLE. PPAKI was associated with high maternal and fetal mortality with sepsis being the leading cause. Our study highlights the need for provision of better quality of maternal care and fetal monitoring to decrease mortality associated with PPAKI in developing countries. PMID:27319810

  7. The severity of acute kidney injury predicts progression to chronic kidney disease

    PubMed Central

    Chawla, Lakhmir S; Amdur, Richard L; Amodeo, Susan; Kimmel, Paul L; Palant, Carlos E

    2011-01-01

    Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘c' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD. PMID:21430640

  8. Hydrogen sulphide and the kidney: important roles in renal physiology and pathogenesis and treatment of kidney injury and disease.

    PubMed

    Lobb, I; Sonke, E; Aboalsamh, G; Sener, A

    2015-04-30

    The kidney is an essential mammalian organ that serves to filter toxins and metabolic by-products out of the blood, which are then excreted through urine. Hydrogen sulphide (H2S) is a recently characterized, endogenous gaseous molecule with important physiological roles. Many interesting roles continue to be identified for H2S related specifically to the kidney. The current review discusses how production and action of H2S influences normal physiology of the kidney. We investigate as well the many roles H2S plays in the pathogenesis and treatment of kidney injury and disease, such as chronic kidney disease (CKD), ureteral obstruction (UO), hyperhomocysteinaemia (HHcy), drug-induced nephrotoxicity (DIN) and renal ischaemia reperfusion injury (IRI). We suggest that H2S plays a complex and essential role in the normal function of the kidney and dysregulation of H2S production can directly or indirectly contribute to the pathogenesis of renal disease and injury. Also, H2S could be a promising potential therapeutic treatment to decrease the severity of several renal diseases. Further research will identify increasingly important and complex roles for H2S in renal physiology and how H2S can be effectively utilized to improve clinical outcomes of renal disease.

  9. Dyschloremia Is a Risk Factor for the Development of Acute Kidney Injury in Critically Ill Patients

    PubMed Central

    Shao, Min; Li, Guangxi; Sarvottam, Kumar; Wang, Shengyu; Thongprayoon, Charat; Dong, Yue; Gajic, Ognjen

    2016-01-01

    Introduction Dyschloremia is common in critically ill patients, although its impact has not been well studied. We investigated the epidemiology of dyschloremia and its associations with the incidence of acute kidney injury and other intensive care unit outcomes. Material and Methods This is a single-center, retrospective cohort study at Mayo Clinic Hospital—Rochester. All adult patients admitted to intensive care units from January 1st, 2006, through December 30th, 2012 were included. Patients with known acute kidney injury and chronic kidney disease stage 5 before intensive care unit admission were excluded. We evaluated the association of dyschloremia with ICU outcomes, after adjustments for the effect of age, gender, Charlson comorbidity index and severity of illness score. Results A total of 6,025 patients were enrolled in the final analysis following the implementation of eligibility criteria. From the cohort, 1,970 patients (33%) developed acute kidney injury. Of the total patients enrolled, 4,174 had a baseline serum chloride. In this group, 1,530 (37%) had hypochloremia, and 257 (6%) were hyperchloremic. The incidence of acute kidney injury was higher in hypochloremic and hyperchloremic patients compared to those with a normal serum chloride level (43% vs.30% and 34% vs. 30%, respectively; P < .001). Baseline serum chloride was lower in the acute kidney injury group vs. the non-acute kidney injury group [100 mmol/L (96–104) vs. 102 mmol/L (98–105), P < .0001]. In a multivariable logistic regression model, baseline serum chloride of ≤94 mmol/L found to be independently associated with the risk of acute kidney injury (OR 1.7, 95% CI 1.1–2.6; P = .01). Discussion Dyschloremia is common in critically ill patients, and severe hypochloremia is independently associated with an increased risk of development of acute kidney injury. PMID:27490461

  10. Update in sepsis and acute kidney injury 2014.

    PubMed

    Schortgen, Frédérique; Asfar, Pierre

    2015-06-01

    Sepsis and acute kidney injury (AKI) represent an important burden in intensive care unit clinical practices. The Journal published important contributions in sepsis for novel therapeutic approaches suggesting that combined molecular targets (e.g., dual inhibition of IL-1β and IL-18, and coadministration of endothelial progenitor cells and stromal cell-derived factor-1α analog) could perform better. The clinical effectiveness of 1,25-dihydroxyvitamin D was reported in a double-blind, randomized, placebo-controlled trial. Although its experimental properties appeared favorable in the pro- and antiinflammatory cytokine balance, 1,25-dihydroxyvitamin D failed to improve survival. Strategies for decreasing antimicrobial resistances are of particular importance. Effective (aerosolized antibiotics for ventilator-associated pneumonia) and ineffective (procalcitonin algorithm for antibiotic deescalation) approaches were published. In 2014, several publications raised an important point shared by survivors from sepsis and/or AKI. The increased number of survivors over time brought out long-term sequelae, leading to a poor outcome after hospital discharge. Among them, cardiovascular events and chronic kidney disease may explain the significant increase in the risk of death, which can persist up to 10 years and significantly increases the use of health care. Postdischarge survival represents a new target for future research in sepsis and AKI to find how we can prevent and manage long-term sequelae. A milestone of the year was the Ebola outbreak. The Journal contributed to our better understanding of Ebola virus disease with a paper underlying the crucial role of a large implementation of pragmatic supportive care, including fluid infusion and correction of metabolic abnormalities, to save more lives. PMID:26029837

  11. Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation.

    PubMed

    Li, Cheng-zhen; Jin, Hai-hong; Sun, Hong-xin; Zhang, Zhong-zhe; Zheng, Jia-xin; Li, Shu-hua; Han, Seong-ho

    2016-02-01

    Eriodictyol, a flavonoid present in citrus fruits, has been reported to have antioxidant and anti-inflammatory effects. In this study, the protective effects of eriodictyol on cisplatin (CP)-induced kidney injury were detected. CP-induced kidney injury model was established by administration of CP (20mg/kg). The results showed that treatment of eriodictyol inhibited the production of blood urea nitrogen (BUN), creatinine, MDA, TBARS, reactive oxygen species (ROS), as well as the production of TNF-α, and IL-1β in kidney tissues induced by CP. Eriodictyol also up-regulated the activities of SOD, CAT, and GSH-PX decreased by CP. Furthermore, eriodictyol was found to up-regulate the expression of Nrf2/HO-1 and inhibited CP-induced NF-κB activation in kidney tissues. In conclusion, eriodictyol protected against CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation.

  12. Challenges of treating a 466-kilogram man with acute kidney injury.

    PubMed

    Friedman, Allon N; Decker, Brian; Seele, Louis; Hellman, Richard N

    2008-07-01

    Caring for super obese patients (body mass index > 50 kg/m(2)) presents a number of complex and unique clinical challenges, particularly when acute kidney injury is present. We describe our experience treating the heaviest individual with acute kidney injury requiring renal replacement therapy reported to date. A 24-year-old black man was admitted to our hospital with fever, vomiting, progressive weakness, shortness of breath, and hemoptysis. Admission weight was 1,024 lbs (466 kg), height was 6 ft 4 in (1.9 m), and body mass index was 125 kg/m(2). During hospitalization, the patient experienced oligoanuric acute kidney injury and required initiation of continuous and subsequently intermittent renal replacement therapy. This clinical scenario identifies the many challenges involved in caring for super obese patients with acute kidney injury and may be a harbinger of what awaits the nephrology community in the obesity pandemic era.

  13. Colloid-induced kidney injury: experimental evidence may help to understand mechanisms.

    PubMed

    Schortgen, Frédérique; Brochard, Laurent

    2009-01-01

    Fluid resuscitation is widely used, and many patients are therefore exposed to plasma volume expanders. Among these, colloids, particularly hydroxyethyl starches, have been shown in recent experiments and clinical studies to induce acute kidney injury. The mechanisms of colloid-induced acute kidney injury remain incompletely elucidated. The risks associated with colloid osmotic pressure elevation in vivo and the high incidence of osmotic nephrosis lesions in experimental models and clinical studies indicate that hydroxyethyl starches can no longer be considered safe.

  14. Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis

    PubMed Central

    Ayoob, Rose M.

    2016-01-01

    The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies. PMID:27642522

  15. Hyperglycemia and Acute Kidney Injury During the Perioperative Period.

    PubMed

    Mendez, Carlos E; Der Mesropian, Paul J; Mathew, Roy O; Slawski, Barbara

    2016-01-01

    Hyperglycemia and acute kidney injury (AKI) are frequently observed during the perioperative period. Substantial evidence indicates that hyperglycemia increases the prevalence of AKI as a surgical complication. Patients who develop hyperglycemia and AKI during the perioperative period are at significantly elevated risk for poor outcomes such as major adverse cardiac events and all-cause mortality. Early observational and interventional trials demonstrated that the use of intensive insulin therapy to achieve strict glycemic control resulted in remarkable reductions of AKI in surgical populations. However, more recent interventional trials and meta-analyses have produced contradictory evidence questioning the renal benefits of strict glycemic control. Although the exact mechanisms through which hyperglycemia increases the risk of AKI have not been elucidated, multiple pathophysiologic pathways have been proposed. Hypoglycemia and glycemic variability may also play a significant role in the development of AKI. In this literature review, the complex relationship between hyperglycemia and AKI as well as its impact on clinical outcomes during the perioperative period is explored.

  16. Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis.

    PubMed

    Ayoob, Rose M; Schwaderer, Andrew L

    2016-01-01

    The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies. PMID:27642522

  17. Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis

    PubMed Central

    Ayoob, Rose M.

    2016-01-01

    The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies.

  18. Enabling innovative translational research in acute kidney injury

    PubMed Central

    Zarjou, Abolfazl; Sanders, Paul W; Mehta, Ravindra L; Agarwal, Anupam

    2011-01-01

    Acute kidney injury (AKI) is a common, heterogeneous and detrimental clinical condition that has significant attributable morbidity and mortality. Despite major advances in understanding the epidemiology, pathogenesis and outcomes of AKI, preventive measures remain inadequate and therapeutic approaches (except for renal replacement therapy) have largely proven futile so far. Critical to the process of designing rational therapies is translational research, which involves the transition between the basic research discoveries and everyday clinical applications to prevent, diagnose and treat human diseases. Progress in innovative approaches has been hampered due in part to the reliance on functional markers (serum creatinine and blood urea nitrogen) that are neither sensitive nor specific to diagnose AKI. This limitation has created a great deal of interest and intense investigation to identify a “troponin-like marker” that would facilitate recognition of AKI and allow for timely implementation of the precise therapeutic agent. The other major obstacle in this field is the diverse and complex nature of AKI that involves multiple independent and overlapping pathways, making it difficult to cure AKI with a single approach. In this review, we will summarize the advances, ongoing studies and future perspectives in the field of translational research of AKI. PMID:22376265

  19. Bath salt intoxication causing acute kidney injury requiring hemodialysis.

    PubMed

    Regunath, Hariharan; Ariyamuthu, Venkatesh Kumar; Dalal, Pranavkumar; Misra, Madhukar

    2012-10-01

    Traditional bath salts contain a combination of inorganic salts like Epsom salts, table salt, baking soda, sodium metaphosphate, and borax that have cleansing properties. Since 2010, there have been rising concerns about a new type of substance abuse in the name of "bath salts." They are beta-ketone amphetamine analogs and are derivates of cathinone, a naturally occurring amphetamine analog found in the "khat" plant (Catha edulis). Effects reported with intake included increased energy, empathy, openness, and increased libido. Serious adverse effects reported with intoxication included cardiac, psychiatric, and neurological signs and symptoms. Not much is known about the toxicology and metabolism of these compounds. They inhibit monoamine reuptake (dopamine, nor epinephrine, etc.) and act as central nervous system stimulants with high additive and abuse potential because of their clinical and biochemical similarities to effects from use of cocaine, amphetamine, and 3,4-methylenedioxy-N-methylamphetamine. Deaths associated with use of these compounds have also been reported. We report a case of acute kidney injury associated with the use of "bath salt" pills that improved with hemodialysis. PMID:23036036

  20. Metabonomics of acute kidney injury in children after cardiac surgery.

    PubMed

    Beger, Richard D; Holland, Ricky D; Sun, Jinchun; Schnackenberg, Laura K; Moore, Page C; Dent, Catherine L; Devarajan, Prasad; Portilla, Didier

    2008-06-01

    Acute kidney injury (AKI) is a major complication in children who undergo cardiopulmonary bypass surgery. We performed metabonomic analyses of urine samples obtained from 40 children that underwent cardiac surgery for correction of congenital cardiac defects. Serial urine samples were obtained from each patient prior to surgery and at 4 h and 12 h after surgery. AKI, defined as a 50% or greater rise in baseline level of serum creatinine, was noted in 21 children at 48-72 h after cardiac surgery. The principal component analysis of liquid chromatography/mass spectrometry (LC/MS) negative ionization data of the urine samples obtained 4 h and 12 h after surgery from patients who develop AKI clustered away from patients who did not develop AKI. The LC/MS peak with mass-to-charge ratio (m/z) 261.01 and retention time (tR) 4.92 min was further analyzed by tandem mass spectrometry (MS/MS) and identified as homovanillic acid sulfate (HVA-SO4), a dopamine metabolite. By MS single-reaction monitoring, the sensitivity was 0.90 and specificity was 0.95 for a cut-off value of 24 ng/microl for HVA-SO4 at 12 h after surgery. We concluded that urinary HVA-SO4 represents a novel, sensitive, and predictive early biomarker of AKI after pediatric cardiac surgery.

  1. Clinical Predictors of Acute Kidney Injury Following Snake Bite Envenomation

    PubMed Central

    Dharod, Mrudul V; Patil, Tushar B; Deshpande, Archana S; Gulhane, Ragini V; Patil, Mangesh B; Bansod, Yogendra V

    2013-01-01

    Background: Snake bite envenomation is a major public health concern in developing countries. Acute kidney injury (AKI) is as important cause of mortality in patients with vasculotoxic snake bite. Aims: This study was to evaluate the clinical profile of snake bite patients and to determine the predictors of developing AKI following snake bite. Materials and Methods: Two hundred and eighty-one patients with snake envenomation were included. Eighty-seven patients developed AKI (Group A) and 194 (Group B) did not. History, examination findings and investigations results were recorded and compared between the two groups. Results: In group A, 61 (70.11%) patients were male and in group B, 117 (60.30%) patients were male. Out of 281 patients, 232 had cellulitis, 113 had bleeding tendencies, 87 had oliguria, 76 had neuroparalysis, and 23 had hypotension at presentation. After multivariate analysis, bite to hospital time (P = 0.016), hypotension (P = 0.000), albuminuria (P = 0.000), bleeding time (P = 0.000), prothrombin time (P = 0.000), hemoglobin (P = 0.000) and total bilirubin (P = 0.010) were significant independent predictors of AKI. Conclusions: AKI developed in 30.96% of patients with snake bite, leading to mortality in 39.08% patients. Factors associated with AKI are bite to hospital time, hypotension, albuminuria, prolonged bleeding time, prolonged prothrombin time, low hemoglobin and a high total bilirubin. PMID:24350071

  2. Organophosphate Poisoning and Subsequent Acute Kidney Injury Risk

    PubMed Central

    Lee, Feng-You; Chen, Wei-Kung; Lin, Cheng-Li; Lai, Ching-Yuan; Wu, Yung-Shun; Lin, I-Ching; Kao, Chia-Hung

    2015-01-01

    Abstract Small numbers of the papers have studied the association between organophosphate (OP) poisoning and the subsequent acute kidney injury (AKI). Therefore, we used the National Health Insurance Research Database (NHIRD) to study whether patients with OP poisoning are associated with a higher risk to have subsequent AKI. The retrospective cohort study comprised patients aged ≥20 years with OP poisoning and hospitalized diagnosis during 2000–2011 (N = 8924). Each OP poisoning patient was frequency-matched to 4 control patients based on age, sex, index year, and comorbidities of diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, coronary artery disease, and stroke (N = 35,696). We conducted Cox proportional hazard regression analysis to estimate the effects of OP poisoning on AKI risk. The overall incidence of AKI was higher in the patients with OP poisoning than in the controls (4.85 vs 3.47/1000 person-years). After adjustment for age, sex, comorbidity, and interaction terms, patients with OP poisoning were associated with a 6.17-fold higher risk of AKI compared with the comparison cohort. Patients with highly severe OP poisoning were associated with a substantially increased risk of AKI. The study found OP poisoning is associated with increased risk of subsequent AKI. Future studies are encouraged to evaluate whether long-term effects exist and the best guideline to prevent the continuously impaired renal function. PMID:26632728

  3. Bath salt intoxication causing acute kidney injury requiring hemodialysis.

    PubMed

    Regunath, Hariharan; Ariyamuthu, Venkatesh Kumar; Dalal, Pranavkumar; Misra, Madhukar

    2012-10-01

    Traditional bath salts contain a combination of inorganic salts like Epsom salts, table salt, baking soda, sodium metaphosphate, and borax that have cleansing properties. Since 2010, there have been rising concerns about a new type of substance abuse in the name of "bath salts." They are beta-ketone amphetamine analogs and are derivates of cathinone, a naturally occurring amphetamine analog found in the "khat" plant (Catha edulis). Effects reported with intake included increased energy, empathy, openness, and increased libido. Serious adverse effects reported with intoxication included cardiac, psychiatric, and neurological signs and symptoms. Not much is known about the toxicology and metabolism of these compounds. They inhibit monoamine reuptake (dopamine, nor epinephrine, etc.) and act as central nervous system stimulants with high additive and abuse potential because of their clinical and biochemical similarities to effects from use of cocaine, amphetamine, and 3,4-methylenedioxy-N-methylamphetamine. Deaths associated with use of these compounds have also been reported. We report a case of acute kidney injury associated with the use of "bath salt" pills that improved with hemodialysis.

  4. Plasma FGF23 levels increase rapidly after acute kidney injury

    PubMed Central

    Christov, Marta; Waikar, Sushrut; Pereira, Renata; Havasi, Andrea; Leaf, David E.; Goltzman, David; Pajevic, Paola Divieti; Wolf, Myles; Jüppner, Harald

    2013-01-01

    Emerging evidence suggests that fibroblast growth factor 23 (FGF23) levels are elevated in patients with acute kidney injury (AKI). In order to determine how early this increase occurs we used a murine folic acid nephropathy model and found that plasma FGF23 levels increased significantly from baseline already after 1 hour of AKI, with an 18-fold increase at 24 hours. Similar elevations of FGF23 levels were found when AKI was induced in mice with osteocyte-specific parathyroid hormone receptor ablation or the global deletion of parathyroid hormone or vitamin D receptor, indicating that the increase in FGF23 was independent of parathyroid hormone and vitamin D signaling. Furthermore, FGF23 levels increased to a similar extent in wild-type mice maintained on normal or phosphate-depleted diets prior to induction of AKI, indicating that the marked FGF23 elevation is at least partially independent of dietary phosphate. Bone production of FGF23 was significantly increased in AKI. The half-life of intravenously administered recombinant FGF23 was only modestly increased. Consistent with the mouse data, plasma FGF23 levels rose 15.9-fold by 24 hours following cardiac surgery in patients who developed AKI. The levels were significantly higher than in those without postoperative AKI. Thus, circulating FGF23 levels rise rapidly during AKI in rodents and humans. In mice this increase is independent of established modulators of FGF23 secretion. PMID:23657144

  5. Hospital Mortality in the United States following Acute Kidney Injury

    PubMed Central

    Rezaee, Michael E.; Marshall, Emily J.; Matheny, Michael E.

    2016-01-01

    Acute kidney injury (AKI) is a common reason for hospital admission and complication of many inpatient procedures. The temporal incidence of AKI and the association of AKI admissions with in-hospital mortality are a growing problem in the world today. In this review, we discuss the epidemiology of AKI and its association with in-hospital mortality in the United States. AKI has been growing at a rate of 14% per year since 2001. However, the in-hospital mortality associated with AKI has been on the decline starting with 21.9% in 2001 to 9.1 in 2011, even though the number of AKI-related in-hospital deaths increased almost twofold from 147,943 to 285,768 deaths. We discuss the importance of the 71% reduction in AKI-related mortality among hospitalized patients in the United States and draw on the discussion of whether or not this is a phenomenon of hospital billing (coding) or improvements to the management of AKI. PMID:27376083

  6. Sepsis-induced acute kidney injury in patients with cirrhosis.

    PubMed

    Angeli, Paolo; Tonon, Marta; Pilutti, Chiara; Morando, Filippo; Piano, Salvatore

    2016-01-01

    Acute kidney injury (AKI) is a common and life-threatening complication in patients with cirrhosis. Recently, new criteria for the diagnosis of AKI have been proposed in patients with cirrhosis by the International Club of Ascites. Almost all types of bacterial infections can induce AKI in patients with cirrhosis representing its most common precipitating event. The bacterial infection-induced AKI usually meets the diagnostic criteria of hepatorenal syndrome (HRS). Well in keeping with the "splanchnic arterial vasodilation hypothesis", it has been stated that HRS develops as a consequence of a severe reduction of effective circulating volume related to splanchnic arterial vasodilation and to an inadequate cardiac output. Nevertheless, the role of bacterial infections in precipitating organ failures, including renal failure, is enhanced when their course is characterized by the development of a systemic inflammatory response syndrome (SIRS), thus, when sepsis occurs. Sepsis has been shown to be capable to induce "per se" AKI in animals as well as in patients conditioning also the features of renal damage. This observation suggests that when precipitated by sepsis, the pathogenesis and the clinical course of AKI also in patients with cirrhosis may differentiate to a certain extent from AKI with another or no precipitating factor. The purpose of this review is to describe the features of AKI precipitated by bacterial infections and to highlight whether infection and/or the development of SIRS may influence its clinical course, and, in particular, the response to treatment.

  7. Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet-Induced Obese Mice

    PubMed Central

    Wu, Dongdong; Gao, Biao; Li, Mengling; Yao, Ling; Wang, Shuaiwei; Chen, Mingliang; Li, Hui; Ma, Chunyan

    2016-01-01

    Obesity is prevalent worldwide and is a major risk factor for the development and progression of kidney disease. Hydrogen sulfide (H2S) plays an important role in renal physiological and pathophysiological processes. However, whether H2S is able to mitigate kidney injury induced by obesity in mice remains unclear. In this study, we demonstrated that H2S significantly reduced the accumulation of lipids in the kidneys of high fat diet- (HFD-) induced obese mice. The results of hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining showed that H2S ameliorated the kidney structure, decreased the extent of interstitial injury, and reduced the degree of kidney fibrosis in HFD-induced obese mice. We found that H2S decreased the expression levels of tumor necrosis factor-α, interleukin- (IL-) 6, and monocyte chemoattractant protein-1 but increased the expression level of IL-10. Furthermore, H2S treatment decreased the protein expression of p50, p65, and p-p65 in the kidney of HFD-induced obese mice. In conclusion, H2S is able to mitigate renal injury in HFD-induced obese mice through the reduction of kidney inflammation by downregulating the expression of nuclear factor-kappa B. H2S or its releasing compounds may serve as a potential therapeutic molecule for obesity-induced kidney injury. PMID:27413418

  8. Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet-Induced Obese Mice.

    PubMed

    Wu, Dongdong; Gao, Biao; Li, Mengling; Yao, Ling; Wang, Shuaiwei; Chen, Mingliang; Li, Hui; Ma, Chunyan; Ji, Ailing; Li, Yanzhang

    2016-01-01

    Obesity is prevalent worldwide and is a major risk factor for the development and progression of kidney disease. Hydrogen sulfide (H2S) plays an important role in renal physiological and pathophysiological processes. However, whether H2S is able to mitigate kidney injury induced by obesity in mice remains unclear. In this study, we demonstrated that H2S significantly reduced the accumulation of lipids in the kidneys of high fat diet- (HFD-) induced obese mice. The results of hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining showed that H2S ameliorated the kidney structure, decreased the extent of interstitial injury, and reduced the degree of kidney fibrosis in HFD-induced obese mice. We found that H2S decreased the expression levels of tumor necrosis factor-α, interleukin- (IL-) 6, and monocyte chemoattractant protein-1 but increased the expression level of IL-10. Furthermore, H2S treatment decreased the protein expression of p50, p65, and p-p65 in the kidney of HFD-induced obese mice. In conclusion, H2S is able to mitigate renal injury in HFD-induced obese mice through the reduction of kidney inflammation by downregulating the expression of nuclear factor-kappa B. H2S or its releasing compounds may serve as a potential therapeutic molecule for obesity-induced kidney injury. PMID:27413418

  9. Nanoparticle Detection of Urinary Markers for Point-of-Care Diagnosis of Kidney Injury.

    PubMed

    Chung, Hyun Jung; Pellegrini, Kathryn L; Chung, Jaehoon; Wanigasuriya, Kamani; Jayawardene, Innocent; Lee, Kyungheon; Lee, Hakho; Vaidya, Vishal S; Weissleder, Ralph

    2015-01-01

    The high incidence of acute and chronic kidney injury due to various environmental factors such as heavy metals or chemicals has been a major problem in developing countries. However, the diagnosis of kidney injury in these areas can be more challenging due to the lack of highly sensitive and specific techniques that can be applied in point-of-care settings. To address this, we have developed a technique called 'micro-urine nanoparticle detection (μUNPD)', that allows the detection of trace amounts of molecular markers in urine. Specifically, this technique utilizes an automated on-chip assay followed by detection with a hand-held device for the read-out. Using the μUNPD technology, the kidney injury markers KIM-1 and Cystatin C were detected down to concentrations of 0.1 ng/ml and 20 ng/ml respectively, which meets the cut-off range required to identify patients with acute or chronic kidney injury. Thus, we show that the μUNPD technology enables point of care and non-invasive detection of kidney injury, and has potential for applications in diagnosing kidney injury with high sensitivity in resource-limited settings. PMID:26186708

  10. Nanoparticle Detection of Urinary Markers for Point-of-Care Diagnosis of Kidney Injury

    PubMed Central

    Wanigasuriya, Kamani; Jayawardene, Innocent; Lee, Kyungheon; Lee, Hakho; Vaidya, Vishal S.; Weissleder, Ralph

    2015-01-01

    The high incidence of acute and chronic kidney injury due to various environmental factors such as heavy metals or chemicals has been a major problem in developing countries. However, the diagnosis of kidney injury in these areas can be more challenging due to the lack of highly sensitive and specific techniques that can be applied in point-of-care settings. To address this, we have developed a technique called ‘micro-urine nanoparticle detection (μUNPD)’, that allows the detection of trace amounts of molecular markers in urine. Specifically, this technique utilizes an automated on-chip assay followed by detection with a hand-held device for the read-out. Using the μUNPD technology, the kidney injury markers KIM-1 and Cystatin C were detected down to concentrations of 0.1 ng/ml and 20 ng/ml respectively, which meets the cut-off range required to identify patients with acute or chronic kidney injury. Thus, we show that the μUNPD technology enables point of care and non-invasive detection of kidney injury, and has potential for applications in diagnosing kidney injury with high sensitivity in resource-limited settings. PMID:26186708

  11. Rhabdomyolysis and Acute Kidney Injury Associated with Hypothyroidism and Statin Therapy

    PubMed Central

    Ahn, Pyoung; Min, Hyun-Jun; Park, Sang-Hyun; Lee, Byoung-Mu; Choi, Myung-Jin; Yoon, Jong-Woo

    2013-01-01

    Rhabdomyolysis is a syndrome involving the breakdown of skeletal muscle that causes myoglobin and other intracellular proteins to leak into the circulatory system, resulting in organ injury including acute kidney injury. We report a case of statin-induced rhabdomyolysis and acute kidney injury that developed in a 63-year-old woman with previously undiagnosed hypothyroidism. Untreated hypothyroidism may have caused her hypercholesterolemia requiring statin treatment, and it is postulated that statin-induced muscle injury was aggravated by hypothyroidism resulting in her full-blown rhabdomyolysis. Although this patient was successfully treated with continuous venovenous hemofiltration and L-thyroxin replacement, rhabdomyolysis with acute kidney injury is a potentially life-threatening disorder. Physicians must pay special attention to the possible presence of subclinical hypothyroidism when administering statins in patients with hypercholesterolemia. PMID:24396699

  12. Mitochondria-Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury

    PubMed Central

    Kezic, Aleksandra; Spasojevic, Ivan; Lezaic, Visnja; Bajcetic, Milica

    2016-01-01

    Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury. PMID:27313826

  13. Mitochondria-Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury.

    PubMed

    Kezic, Aleksandra; Spasojevic, Ivan; Lezaic, Visnja; Bajcetic, Milica

    2016-01-01

    Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury. PMID:27313826

  14. Community-acquired acute kidney injury: A challenge and opportunity for primary care in kidney health.

    PubMed

    Mesropian, Paul Der; Othersen, Jennifer; Mason, Darius; Wang, Jeffrey; Asif, Arif; Mathew, Roy O

    2016-09-01

    Community-acquired acute kidney injury (CA-AKI) has been found to be a common event in the population. Current incidence estimates are not available, but evaluations of severe elevations in serum creatinine indicate that incidence can be as high as 989 cases per million population in those older than 80 years. Data on risk factors are limited, but older age and higher comorbid illness burden, especially diabetes and cardiovascular disease, seem to be more common in patients who suffer CA-AKI. In addition to being more common than hospital-acquired AKI, the long-term sequelae of CA-AKI seem to be just as severe, including renal disease progression and mortality. Efforts to better understand the aetiology of CA-AKI and how ultimately to prevent the development of this condition will need to be taken. In the meantime, a concerted effort by general internists and nephrologists will be needed to prevent CA-AKI in the highest risk patients and thus limit the poor outcomes associated with this entity. PMID:26890822

  15. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model.

    PubMed

    Wang, Xuexiang; Johnson, Ashley C; Williams, Jan M; White, Tiffani; Chade, Alejandro R; Zhang, Jie; Liu, Ruisheng; Roman, Richard J; Lee, Jonathan W; Kyle, Patrick B; Solberg-Woods, Leah; Garrett, Michael R

    2015-07-01

    Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney.

  16. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

    PubMed Central

    Wang, Xuexiang; Johnson, Ashley C.; Williams, Jan M.; White, Tiffani; Chade, Alejandro R.; Zhang, Jie; Liu, Ruisheng; Roman, Richard J.; Lee, Jonathan W.; Kyle, Patrick B.; Solberg-Woods, Leah

    2015-01-01

    Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%–75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney. PMID:25349207

  17. Analyses of acute kidney injury biomarkers by ultra-high performance liquid chromatography with mass spectrometry.

    PubMed

    Al Za'abi, Mohammed; Ali, Badreldin H; ALOthman, Zeid A; Ali, Imran

    2016-01-01

    The newly developed acute kidney injury biomarkers are very important for the early and timely detection of kidney diseases. This review contains details of the analyses of several acute kidney injury biomarkers using ultra-high performance liquid chromatography-mass spectrometry in urine and plasma samples. In this review we attempt to discuss some aspects of the types of the biomarkers, patents, sample preparation, and the analyses. Besides, efforts were also made to discuss the possible uses of superficially porous (core-shell) columns in traditional and inexpensive high-performance liquid chromatography instruments. Additionally, the challenges and the future prospects are also highlighted. The present review will be useful for the academicians, scientists, and clinicians for the early detection of acute kidney injury biomarkers.

  18. Assessment of Plasma and NGAL for the Early Prediction of Acute Kidney Injury After Cardiac Surgery in Adults Study

    ClinicalTrials.gov

    2016-04-11

    Acute Kidney Injury (AKI); Chronic Kidney Disease (CKD); End Stage Renal Disease (ESRD); Estimated Glomerular Filtration Rate (eGFR); Neutrophil Gelatinase-associated Lipocalin (NGAL); Serum Creatinine (SCr); Urine Creatinine (UCr); Urine Albumin (UAlb)

  19. Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation.

    PubMed

    Kida, Yujiro; Zullo, Joseph A; Goligorsky, Michael S

    2016-09-23

    Peritubular capillary (PTC) rarefaction along with tissue fibrosis is a hallmark of chronic kidney disease (CKD). However, molecular mechanisms of PTC loss have been poorly understood. Previous studies have demonstrated that functional loss of endothelial sirtuin 1 (SIRT1) impairs angiogenesis during development and tissue damage. Here, we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling, which leads to PTC rarefaction and fibrosis following kidney injury. In mice lacking functional SIRT1 in the endothelium (Sirt1 mutant), kidney injury enhanced apoptosis and senescence of PTC endothelial cells with impaired endothelial proliferation and expanded myofibroblast population and collagen deposition. Compared to wild-type kidneys, Sirt1 mutant kidneys up-regulated expression of Delta-like 4 (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target genes), and Notch intracellular domain-1 (NICD1, active form of Notch1) in microvascular endothelial cells (MVECs) post-injury. Sirt1 mutant primary kidney MVECs reduced motility and vascular assembly and enhanced senescence compared to wild-type kidney MVECs. This difference in the phenotype was negated with Notch inhibition. Concurrent stimulation of DLL4 and transforming growth factor (TGF)-β1 increased trans-differentiation of primary kidney pericytes into myofibroblast more than TGF-β1 treatment alone. Collectively, these results indicate that endothelial SIRT1 counteracts PTC rarefaction by repression of Notch1 signaling and antagonizes fibrosis via suppression of endothelial DLL4 expression.

  20. Cardiac Biomarkers and Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Bucholz, Emily M.; Whitlock, Richard P.; Zappitelli, Michael; Devarajan, Prasad; Eikelboom, John; Garg, Amit X.; Philbrook, Heather Thiessen; Devereaux, Philip J.; Krawczeski, Catherine D.; Kavsak, Peter; Shortt, Colleen

    2015-01-01

    OBJECTIVES: To examine the relationship of cardiac biomarkers with postoperative acute kidney injury (AKI) among pediatric patients undergoing cardiac surgery. METHODS: Data from TRIBE-AKI, a prospective study of children undergoing cardiac surgery, were used to examine the association of cardiac biomarkers (N-type pro–B-type natriuretic peptide, creatine kinase-MB [CK-MB], heart-type fatty acid binding protein [h-FABP], and troponins I and T) with the development of postoperative AKI. Cardiac biomarkers were collected before and 0 to 6 hours after surgery. AKI was defined as a ≥50% or 0.3 mg/dL increase in serum creatinine, within 7 days of surgery. RESULTS: Of the 106 patients included in this study, 55 (52%) developed AKI after cardiac surgery. Patients who developed AKI had higher median levels of pre- and postoperative cardiac biomarkers compared with patients without AKI (all P < .01). Preoperatively, higher levels of CK-MB and h-FABP were associated with increased odds of developing AKI (CK-MB: adjusted odds ratio 4.58, 95% confidence interval [CI] 1.56–13.41; h-FABP: adjusted odds ratio 2.76, 95% CI 1.27–6.03). When combined with clinical models, both preoperative CK-MB and h-FABP provided good discrimination (area under the curve 0.77, 95% CI 0.68–0.87, and 0.78, 95% CI 0.68–0.87, respectively) and improved reclassification indices. Cardiac biomarkers collected postoperatively did not significantly improve the prediction of AKI beyond clinical models. CONCLUSIONS: Preoperative CK-MB and h-FABP are associated with increased risk of postoperative AKI and provide good discrimination of patients who develop AKI. These biomarkers may be useful for risk stratifying patients undergoing cardiac surgery. PMID:25755241

  1. Assessment standards: comparing histopathology, digital image analysis, and stereology for early detection of experimental cisplatin-induced kidney injury in rats.

    PubMed

    Shea, Katherine; Stewart, Sharron; Rouse, Rodney

    2014-08-01

    Histopathology generally represents the reference standard for performance evaluation of nonclinical biomarkers used to inform regulatory decision making. This study uses drug-induced nephrotoxicity in rats to evaluate histopathology methods utilized in biomarker performance assessments. Male Sprague-Dawley rats received a single dose of cisplatin (0.5-5.0 mg/kg, intraperitoneally) to produce mild renal injury. Animals were euthanized 72 hr postdose and perfusion fixed. Kidneys were processed for histology and stereology procedures. Kidney injury molecule-1 (Kim-1) was measured in urine and in kidney tissue. Digital slide images were generated and analyzed by pathologists after collaborating on a training set of glass slides and digital images. Image analysis identified immunohistochemistry (IHC)-defined tubular injury. Stereology methods yielded estimations of proximal tubular cell number and volume. Statistical relationships among data sets were determined using correlation coefficients. Receiver operator characteristic (ROC) analyses determined the effect of method on biomarker assessment. Urinary Kim-1 was strongly correlated with digital image analysis and secondarily to histopathology evaluations. Stereology demonstrated weak or no correlation to pathology and urinary Kim-1. In ROC analyses, semiquantitative evaluations determined higher values for urinary Kim-1 performance than did IHC-based qualitative digital analyses. Semiquantitative evaluation as used in this study was most predictive of urinary Kim-1 values.

  2. Effects of Valproic Acid and Dexamethasone Administration on Early Bio-Markers and Gene Expression Profile in Acute Kidney Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Speir, Ryan W.; Stallings, Jonathan D.; Andrews, Jared M.; Gelnett, Mary S.; Brand, Timothy C.; Salgar, Shashikumar K.

    2015-01-01

    Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (saline) intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL) at 24 h was reduced (P<0.05) in VPA (2.7±1.8) and Dex (2.3±1.2) compared to Vehicle (3.8±0.5) group. At 3 h, urine albumin (mg/mL) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to naïve (uninjured/untreated control) (0.14±0.26) group. At 24 h post-IR urine lipocalin-2 (μg/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (9.61–11.36) compared to naïve group (0.67±0.29); also, kidney injury molecule-1 (KIM-1; ng/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (13.7–18.7) compared to naïve group (1.7±1.9). Histopathology demonstrated reduced (P<0.05) ischemic injury in the renal cortex in VPA (Grade 1.6±1.5) compared to Vehicle (Grade 2.9±1.1). Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI. PMID:25970334

  3. Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium.

    PubMed

    Jacobo-Estrada, Tania; Cardenas-Gonzalez, Mariana; Santoyo-Sánchez, Mitzi; Parada-Cruz, Benjamín; Uria-Galicia, Esther; Arreola-Mendoza, Laura; Barbier, Olivier

    2016-09-01

    Cadmium is a well-characterized nephrotoxic agent that is also capable of accumulating and diffusing across the placenta; however, only a few studies have addressed its effects over fetal kidneys and none of them has used a panel of sensitive and specific biomarkers for the detection of kidney injury. The goal of this study was to determine cadmium renal effects in rat fetuses by the quantification of early kidney injury biomarkers. Pregnant Wistar rats were exposed by inhalation to an isotonic saline solution or to CdCl2 solution (DDel =1.48 mg Cd kg(-1) day(-1) ) during gestational days (GD) 8-20. On GD 21, dams were euthanized and samples obtained. Kidney injury biomarkers were quantified in amniotic fluid samples and fetal kidneys were microscopically evaluated to search for histological alterations. Our results showed that cadmium exposure significantly raised albumin, osteopontin, vascular endothelial growth factor and tissue inhibitor of metalloproteinases-1 levels in amniotic fluid, whereas it decreased creatinine. Clusterin, calbindin and IFN-inducible protein 10 did not show any change. Accordingly, histological findings showed tubular damage and precipitations in the renal pelvis. In conclusion, gestational exposure to cadmium induces structural alterations in fetal renal tissue that can be detected by some kidney injury biomarkers in amniotic fluid samples. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26815315

  4. Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium.

    PubMed

    Jacobo-Estrada, Tania; Cardenas-Gonzalez, Mariana; Santoyo-Sánchez, Mitzi; Parada-Cruz, Benjamín; Uria-Galicia, Esther; Arreola-Mendoza, Laura; Barbier, Olivier

    2016-09-01

    Cadmium is a well-characterized nephrotoxic agent that is also capable of accumulating and diffusing across the placenta; however, only a few studies have addressed its effects over fetal kidneys and none of them has used a panel of sensitive and specific biomarkers for the detection of kidney injury. The goal of this study was to determine cadmium renal effects in rat fetuses by the quantification of early kidney injury biomarkers. Pregnant Wistar rats were exposed by inhalation to an isotonic saline solution or to CdCl2 solution (DDel =1.48 mg Cd kg(-1) day(-1) ) during gestational days (GD) 8-20. On GD 21, dams were euthanized and samples obtained. Kidney injury biomarkers were quantified in amniotic fluid samples and fetal kidneys were microscopically evaluated to search for histological alterations. Our results showed that cadmium exposure significantly raised albumin, osteopontin, vascular endothelial growth factor and tissue inhibitor of metalloproteinases-1 levels in amniotic fluid, whereas it decreased creatinine. Clusterin, calbindin and IFN-inducible protein 10 did not show any change. Accordingly, histological findings showed tubular damage and precipitations in the renal pelvis. In conclusion, gestational exposure to cadmium induces structural alterations in fetal renal tissue that can be detected by some kidney injury biomarkers in amniotic fluid samples. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Changes in Metabolic Profiles during Acute Kidney Injury and Recovery following Ischemia/Reperfusion

    PubMed Central

    Wei, Qingqing; Xiao, Xiao; Fogle, Paul; Dong, Zheng

    2014-01-01

    Changes of metabolism have been implicated in renal ischemia/reperfusion injury (IRI). However, a global analysis of the metabolic changes in renal IRI is lacking and the association of the changes with ischemic kidney injury and subsequent recovery are unclear. In this study, mice were subjected to 25 minutes of bilateral renal IRI followed by 2 hours to 7 days of reperfusion. Kidney injury and subsequent recovery was verified by serum creatinine and blood urea nitrogen measurements. The metabolome of plasma, kidney cortex, and medulla were profiled by the newly developed global metabolomics analysis. Renal IRI induced overall changes of the metabolome in plasma and kidney tissues. The changes started in renal cortex, followed by medulla and plasma. In addition, we identified specific metabolites that may contribute to early renal injury response, perturbed energy metabolism, impaired purine metabolism, impacted osmotic regulation and the induction of inflammation. Some metabolites, such as 3-indoxyl sulfate, were induced at the earliest time point of renal IRI, suggesting the potential of being used as diagnostic biomarkers. There was a notable switch of energy source from glucose to lipids, implicating the importance of appropriate nutrition supply during treatment. In addition, we detected the depressed polyols for osmotic regulation which may contribute to the loss of kidney function. Several pathways involved in inflammation regulation were also induced. Finally, there was a late induction of prostaglandins, suggesting their possible involvement in kidney recovery. In conclusion, this study demonstrates significant changes of metabolome kidney tissues and plasma in renal IRI. The changes in specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery. PMID:25191961

  6. Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword

    PubMed Central

    Zhou, Dong; Tan, Roderick J.; Fu, Haiyan; Liu, Youhua

    2015-01-01

    The Wnt/β-catenin signaling cascade is an evolutionarily conserved, highly complex pathway that is known to be involved in kidney injury and repair after a wide variety of insults. While the kidney displays an impressive ability to repair and recover after injury, these repair mechanisms can be overwhelmed, leading to maladaptive responses and eventual development of chronic kidney disease (CKD). Emerging evidence demonstrates that Wnt/β-catenin signaling possesses dual roles in promoting repair/regeneration or facilitating progression to CKD after acute kidney injury (AKI), depending on the magnitude and duration of its activation. In this review, we summarize the expression, intracellular modification, and secretion of Wnt family proteins and their regulation in a variety of kidney diseases. We also explore our current understanding of the potential mechanisms by which transient Wnt/β-catenin activation positively regulates adaptive responses of the kidney after AKI, and discuss how sustained activation of this signaling triggers maladaptive responses and causes destructive outcomes. A better understanding of these mechanisms may offer important opportunities for designing targeted therapy to promote adaptive kidney repair/recovery and prevent progression to CKD in patients. PMID:26692289

  7. Strategies for prevention of acute kidney injury in cardiac surgery: an integrative review

    PubMed Central

    Santana-Santos, Eduesley; Marcusso, Marila Eduara Fátima; Rodrigues, Amanda Oliveira; de Queiroz, Fernanda Gomes; de Oliveira, Larissa Bertacchini; Rodrigues, Adriano Rogério Baldacin; Palomo, Jurema da Silva Herbas

    2014-01-01

    Acute kidney injury is a common complication after cardiac surgery and is associated with increased morbidity and mortality and increased length of stay in the intensive care unit. Considering the high prevalence of acute kidney injury and its association with worsened prognosis, the development of strategies for renal protection in hospitals is essential to reduce the associated high morbidity and mortality, especially for patients at high risk of developing acute kidney injury, such as patients who undergo cardiac surgery. This integrative review sought to assess the evidence available in the literature regarding the most effective interventions for the prevention of acute kidney injury in patients undergoing cardiac surgery. To select the articles, we used the CINAHL and MedLine databases. The sample of this review consisted of 16 articles. After analyzing the articles included in the review, the results of the studies showed that only hydration with saline has noteworthy results in the prevention of acute kidney injury. The other strategies are controversial and require further research to prove their effectiveness. PMID:25028954

  8. Rhabdomyolysis and acute kidney injury in patients with traumatic spinal cord injury

    PubMed Central

    Galeiras, Rita; Mourelo, Mónica; Pértega, Sonia; Lista, Amanda; Ferreiro, Mª Elena; Salvador, Sebastián; Montoto, Antonio; Rodríguez, Antonio

    2016-01-01

    Background: Patients with acute traumatic spinal cord injuries (SCIs) exhibit factors that, in other populations, have been associated with rhabdomyolysis. Purpose: The aim of the study is to determine the incidence of rhabdomyolysis in patients with acute traumatic SCI admitted to the Intensive Care Unit (ICU), as well as the development of secondary acute kidney injury and associated factors. Study Design and Setting: This was an observational, retrospective study. Patient Sample: All adult patients admitted to the ICU with acute traumatic SCI who presented rhabdomyolysis, diagnosed through creatine phosphokinase (CPK) levels >500 IU/L. Outcome Measures: Incidence of rhabdomyolysis and subsequent renal dysfunction was calculated. Materials and Methods: Data about demographic variables, comorbidity, rhabdomyolysis risk factors, and variables involving SCI, severity scores, and laboratory parameters were obtained from clinical records. Multivariate logistic regression was used to identify renal injury risk factors. Results: In 2006–2014, 200 patients with acute SCI were admitted to ICU. Of these, 103 had rhabdomyolysis (incidence = 51.5%; 95% confidence interval [CI]: 44.3%–58.7%). The most typical American Spinal Injury Association classification was A (70.3%). The injury severity score was 30.3 ± 12.1 and sequential organ failure assessment (SOFA) score was 5.6 ± 3.3 points. During their stay, 57 patients (55.3%; 95% CI: 45.2%–65.4%) presented renal dysfunction (creatinine ≥1.2 mg/dL). In the multivariate analysis, variables associated with renal dysfunction were creatinine at admission (odds ratio [OR] = 9.20; P = 0.006) and hemodynamic SOFA score the day following admission (OR = 1.33; P = 0.024). Creatinine was a better predictor of renal dysfunction than the peak CPK value during the rhabdomyolysis (area under the receiver operating characteristic curve: 0.91 vs. 0.63, respectively). Conclusions: Rhabdomyolysis is a frequent condition in patients

  9. Rhabdomyolysis and acute kidney injury in patients with traumatic spinal cord injury

    PubMed Central

    Galeiras, Rita; Mourelo, Mónica; Pértega, Sonia; Lista, Amanda; Ferreiro, Mª Elena; Salvador, Sebastián; Montoto, Antonio; Rodríguez, Antonio

    2016-01-01

    Background: Patients with acute traumatic spinal cord injuries (SCIs) exhibit factors that, in other populations, have been associated with rhabdomyolysis. Purpose: The aim of the study is to determine the incidence of rhabdomyolysis in patients with acute traumatic SCI admitted to the Intensive Care Unit (ICU), as well as the development of secondary acute kidney injury and associated factors. Study Design and Setting: This was an observational, retrospective study. Patient Sample: All adult patients admitted to the ICU with acute traumatic SCI who presented rhabdomyolysis, diagnosed through creatine phosphokinase (CPK) levels >500 IU/L. Outcome Measures: Incidence of rhabdomyolysis and subsequent renal dysfunction was calculated. Materials and Methods: Data about demographic variables, comorbidity, rhabdomyolysis risk factors, and variables involving SCI, severity scores, and laboratory parameters were obtained from clinical records. Multivariate logistic regression was used to identify renal injury risk factors. Results: In 2006–2014, 200 patients with acute SCI were admitted to ICU. Of these, 103 had rhabdomyolysis (incidence = 51.5%; 95% confidence interval [CI]: 44.3%–58.7%). The most typical American Spinal Injury Association classification was A (70.3%). The injury severity score was 30.3 ± 12.1 and sequential organ failure assessment (SOFA) score was 5.6 ± 3.3 points. During their stay, 57 patients (55.3%; 95% CI: 45.2%–65.4%) presented renal dysfunction (creatinine ≥1.2 mg/dL). In the multivariate analysis, variables associated with renal dysfunction were creatinine at admission (odds ratio [OR] = 9.20; P = 0.006) and hemodynamic SOFA score the day following admission (OR = 1.33; P = 0.024). Creatinine was a better predictor of renal dysfunction than the peak CPK value during the rhabdomyolysis (area under the receiver operating characteristic curve: 0.91 vs. 0.63, respectively). Conclusions: Rhabdomyolysis is a frequent condition in patients

  10. Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

    PubMed

    Schmiedt, C W; Brainard, B M; Hinson, W; Brown, S A; Brown, C A

    2016-01-01

    The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease. PMID:26319781

  11. CD4+CD25+ T Cells in primary malignant hypertension related kidney injury

    PubMed Central

    Huang, Hongdong; Luo, Yang; Liang, Yumei; Long, Xidai; Peng, Youming; Liu, Zhihua; Wen, Xiaojun; Jia, Meng; Tian, Ru; Bai, Chengli; Li, Cui; He, Fuliang; Lin, Qiushi; Wang, Xueyan; Dong, Xiaoqun

    2016-01-01

    CD4+CD25+ T cells are critical for maintenance of immunologic self-tolerance. We measured the number of CD4+CD25+ cells in the patients with primary malignant hypertension related kidney injury, to explore the molecular pathogenesis of this disease. We selected 30 patients with primary malignant hypertension related kidney injury and 30 healthy volunteers. Information on clinical characteristics and laboratory tests was obtained from each subject. The number of CD4+CD25+ cells and glomerular injury were assessed by flow cytometry and histopathology, respectively. Both serum IL-2, IL-4, and IL-6 and endothelial cell markers were analyzed by ELISA. ADAMTS13 antibody was detected by Western blotting. CD4+CD25+ cells were significantly reduced in patients with primary malignant hypertension related kidney injury compared to controls (P < 0.05). The number of CD4+CD25+ cells was negatively related to blood urea nitrogen, serum uric acid, proteinuria, and supernatant IL-4; whereas positively associated with estimated glomerular filtration rate in patients. Gradually decreasing CD4+CD25+ cells were also found as increasing renal injury. Additionally, patients exhibited increasing supernatant IL-4, serum IL-2 and IL-6, endothelial cell markers, and anti-ADAMTS13 antibody compared with controls (all P < 0.05). CD4+CD25+ cells may play a key role in the pathogenesis of primary malignant hypertension related kidney injury. PMID:27278520

  12. A GAP in our knowledge of vascular signaling in acute kidney injury.

    PubMed

    Basile, David P

    2011-08-01

    Injury resulting from ischemia-reperfusion injury is a multifactorial process involving compromised function in both the tubular and the vascular compartments. Multiple vasoactive compounds have been implicated in the profound vasoconstriction that occurs in response to ischemia-reperfusion injury, and many of these factors signal through common G protein-coupled receptors. The report by Siedlecki et al. highlights the important roles of RGS4, a GTPase-accelerating protein (GAP), in the regulation of vascular tone in the setting of acute kidney injury.

  13. Both PD-1 ligands protect the kidney from ischemia reperfusion injury

    PubMed Central

    Jaworska, Katarzyna; Ratajczak, Joanna; Huang, Liping; Whalen, Kristen; Yang, Mana; Stevens, Brian K.; Kinsey, Gilbert R.

    2014-01-01

    Acute kidney injury (AKI) is a common problem in hospitalized patients which enhances morbidity and mortality and promotes the development of chronic and end stage renal disease. Ischemia reperfusion injury (IRI) is one of the major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from IR-induced inflammation and injury. Blockade of programmed cell death 1 (PD-1) on the surface of Tregs, prior to adoptive transfer, negates their ability to protect against ischemic kidney injury. The current study was designed to investigate the role of the known PD-1 ligands, PD-L1 and PD-L2 in kidney IRI. Administration of PD-L1 or PD-L2 blocking antibodies prior to mild or moderate kidney IRI significantly exacerbated the loss of renal function, renal inflammation and acute tubular necrosis (ATN) compared to mice receiving isotype control antibodies. Interestingly, blockade of both PD-1 ligands resulted in worse injury, dysfunction and inflammation than blocking either ligand alone. Genetic deficiency of either PD-1 ligand also exacerbated kidney dysfunction and ATN after sub-threshold ischemia. Bone marrow chimeric studies revealed that PD-L1 expressed on non-bone marrow derived cells is critical for this resistance to IRI. Finally, blockade of either PD-1 ligand negated the protective ability of adoptively-transferred Tregs in IRI. These findings suggest that PD-L1 and PD-L2 are non-redundant aspects of the natural protective response to ischemic injury and may be novel therapeutic targets for AKI. PMID:25404361

  14. Macrophage A2A Adenosine Receptors Are Essential to Protect from Progressive Kidney Injury.

    PubMed

    Truong, Luan D; Trostel, Jessica; McMahan, Rachel; Chen, Jiang-Fan; Garcia, Gabriela E

    2016-10-01

    A2A adenosine receptors (A2ARs) are endogenous inhibitor of inflammation. Macrophages that are key effectors of kidney disease progression express A2ARs. We investigated the role of A2ARs in kidney inflammation in a macrophage-mediated anti-glomerular basement membrane reactive serum-induced immune nephritis in A2AR-deficient mice. Sub-threshold doses of glomerular basement membrane-reactive serum induced more severe and prolonged kidney damage with higher levels of proinflammatory cytokines and greater accumulation of inflammatory cells in A2AR(-/-) mice than wild-type (WT) mice. To investigate the role of macrophage A2AR in progressive kidney injury, glomerulonephritis was induced in CD11b-DTR transgenic mice. Macrophages were selectively depleted in the established phase of the disease and reconstituted with macrophages from WT or A2AR-deficient mice and then treated with an A2AR agonist. In mice receiving WT macrophages and treated with an A2AR agonist, the glomerular cellularity, crescent formation, sclerotic glomeruli, and tubulointerstitial injury were significantly reduced compared with the control group. In contrast, in mice reconstituted with A2AR-deficient macrophages and treated with an A2AR agonist, the kidney injury was more severe with increased deposition of collagen I, III, and IV. These findings suggest that disruption of the protective A2AR amplifies inflammation to accelerate glomerular damage and endogenous macrophage A2ARs are essential to protect from progressive kidney fibrosis.

  15. Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis

    SciTech Connect

    Imamura, Ryoichi; Isaka, Yoshitaka . E-mail: isaka@att.med.osaka-u.ac.jp; Ichimaru, Naotsugu; Takahara, Shiro; Okuyama, Akihiko

    2007-02-16

    Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of {alpha}-smooth muscle actin ({alpha}-SMA), while EPO treatment inhibited tubular apoptosis and {alpha}-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of {alpha}-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.

  16. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury

    PubMed Central

    DiRocco, Derek P.; Bisi, John; Roberts, Patrick; Strum, Jay; Wong, Kwok-Kin; Sharpless, Norman

    2013-01-01

    Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or “pharmacological quiescence,” represents a novel strategy to prevent AKI. PMID:24338822

  17. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury.

    PubMed

    DiRocco, Derek P; Bisi, John; Roberts, Patrick; Strum, Jay; Wong, Kwok-Kin; Sharpless, Norman; Humphreys, Benjamin D

    2014-02-15

    Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or "pharmacological quiescence," represents a novel strategy to prevent AKI.

  18. Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities

    PubMed Central

    Yu, Chen; Qi, Dong; Sun, Ju-Feng; Li, Peng; Fan, Hua-Ying

    2015-01-01

    This study aimed to explore the effect and mechanisms of rhein on sepsis-induced acute kidney injury by injecting lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in vivo, and on LPS-induced HK-2 cells in vitro. For histopathological analysis, rhein effectively attenuated the severity of renal injury. Rhein could significantly decrease concentration of BUN and SCr and level of TNF-α and IL-1β in two different mouse models of experimental sepsis. Moreover, rhein could markedly attenuate circulating leukocyte infiltration and enhance phagocytic activity of macrophages partly impaired at 12 h after CLP. Rhein could enhance cell viability and suppresse the release of MCP-1 and IL-8 in LPS-stimulated HK-2 cells Furthermore, rhein down regulated the expression of phosphorylated NF-κB p65, IκBα and IKKβ stimulated by LPS both in vivo and in vitro. All these results suggest that rhein has protective effects on endotoxin-induced kidney injury. The underlying mechanism of rhein on anti-endotoxin kidney injury may be closely related with its anti-inflammatory and immunomodulatory properties by decreasing NF-κB activation through restraining the expression and phosphorylation of the relevant proteins in NF-κB signal pathway, hindering transcription of NF-κB p65.These evidence suggest that rhein has a potential application to treat endotoxemia-associated acute kidney injury. PMID:26149595

  19. Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities.

    PubMed

    Yu, Chen; Qi, Dong; Sun, Ju-Feng; Li, Peng; Fan, Hua-Ying

    2015-07-07

    This study aimed to explore the effect and mechanisms of rhein on sepsis-induced acute kidney injury by injecting lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in vivo, and on LPS-induced HK-2 cells in vitro. For histopathological analysis, rhein effectively attenuated the severity of renal injury. Rhein could significantly decrease concentration of BUN and SCr and level of TNF-α and IL-1β in two different mouse models of experimental sepsis. Moreover, rhein could markedly attenuate circulating leukocyte infiltration and enhance phagocytic activity of macrophages partly impaired at 12 h after CLP. Rhein could enhance cell viability and suppresse the release of MCP-1 and IL-8 in LPS-stimulated HK-2 cells Furthermore, rhein down regulated the expression of phosphorylated NF-κB p65, IκBα and IKKβ stimulated by LPS both in vivo and in vitro. All these results suggest that rhein has protective effects on endotoxin-induced kidney injury. The underlying mechanism of rhein on anti-endotoxin kidney injury may be closely related with its anti-inflammatory and immunomodulatory properties by decreasing NF-κB activation through restraining the expression and phosphorylation of the relevant proteins in NF-κB signal pathway, hindering transcription of NF-κB p65.These evidence suggest that rhein has a potential application to treat endotoxemia-associated acute kidney injury.

  20. Dexamethasone pretreatment attenuates lung and kidney injury in cholestatic rats induced by hepatic ischemia/reperfusion.

    PubMed

    Zhou, Liangyi; Yao, Xiangqing; Chen, Yanling

    2012-02-01

    Hepatic ischemia followed by reperfusion (IR) results in mild to severe organ injury, in which tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) seem to be involved. Thus, we aim to assess the influence of hepatic ischemia/reperfusion injury on remote organs in addition to cholestasis and consider the possible efficacy of steroid pretreatment in reducing the injury. A common bile duct ligation model was done on 24 male Sprague-Dawley rats. After 7 days, the rats were divided randomly into control group, IR group, and dexamethasone (DEX) group. The IR group showed significant increases in serum alanine aminotransferase, aspartate aminotransferase, and creatinine levels compared with the control and DEX groups. By ELISA techniques, higher levels of TNF-α and IL-1β in lung and kidney tissues were measured in the IR group than in the control and DEX groups, these were verified by immunohistochemistry. The lung histology of the IR group rats showed neutrophil infiltration, interstitial edema, and alveolar wall thickening. Kidney histology of the IR group rats showed vacuolization of the proximal tubular epithelial cells and tubular dilatation with granular eosinophilic casts. Better morphological aspects were observed in the DEX-pretreated animals. Minimal lesions were observed in the control. The results suggest that hepatic ischemia/reperfusion injury in cholestatic rats induced lung and kidney injuries. Pretreatment with dexamethasone reduced the IR-induced injury in addition to cholestasis.

  1. GDF11 improves tubular regeneration after acute kidney injury in elderly mice

    PubMed Central

    Zhang, Ying; Li, Qinggang; Liu, Dong; Huang, Qi; Cai, Guangyan; Cui, Shaoyuan; Sun, Xuefeng; Chen, Xiangmei

    2016-01-01

    The GDF11 expression pattern and its effect on organ regeneration after acute injury in the elderly population are highly controversial topics. In our study, GDF11/8 expression increased after kidney ischemia–reperfusion injury (IRI), and the relatively lower level of GDF11/8 in the kidneys of aged mice was associated with a loss of proliferative capacity and a decline in renal repair, compared to young mice. In vivo, GDF11 supplementation in aged mice increased vimentin and Pax2 expression in the kidneys as well as the percentage of 5-ethynyl-2′-deoxyuridine (EdU)-positive proximal tubular epithelial cells. GDF11 improved the renal repair, recovery of renal function, and survival of elderly mice at 72 h after IRI. Moreover, the addition of recombinant GDF11 to primary renal epithelial cells increased proliferation, migration, and dedifferentiation by upregulating the ERK1/2 pathway in vitro. Our study indicates that GDF11/8 in the kidney decreases with age and that GDF11 can increase tubular cell dedifferentiation and proliferation as well as improve tubular regeneration after acute kidney injury (AKI) in old mice. PMID:27703192

  2. Renal medullary Na-K-ATPase and hypoxic injury in perfused rat kidneys.

    PubMed

    Epstein, F H; Silva, P; Spokes, K; Brezis, M; Rosen, S

    1989-11-01

    We wished to see if chronic alterations in Na-K-ATPase activity in the medullary thick ascending limb would modify the susceptibility of its cells to the hypoxic injury produced by perfusion of the isolated kidney. Rats were fed a diet high (64%) or low (8%) in protein for three weeks. Renal medullary Na-K-ATPase was 75 +/- 12 U/mg protein/hr (mean +/- SE) in the high protein group and 44 +/- 3 in rats given low protein. After 90 minutes of perfusion, the kidneys of rats fed a high protein diet showed almost all mTAL cells near the inner medulla with severe damage (93 +/- 4.8%), whereas the same zone in perfused kidneys of rats on a low protein diet showed only 47 +/- 7.7% injury. In a similar fashion, damage to mTAL cells seen in perfused kidneys was greatly augmented by compensatory renal hypertrophy produced by removal of the contralateral kidney two weeks earlier, and by a diet high in potassium given for two weeks, procedures which also increased the activity of medullary Na-K-ATPase. The results suggest that the level of transport work of medullary cells mediated by Na-K-ATPase is a determinant of the vulnerability of mTAL cells to hypoxic injury.

  3. Effects of sodium citrate on salt sensitivity and kidney injury in chronic renal failure.

    PubMed

    Kim, Sejoong; Yang, Jin Young; Jung, Eun Sook; Lee, Jeonghwan; Heo, Nam Ju; Lee, Jae Wook; Na, Ki Young; Han, Jin Suk

    2014-12-01

    Metabolic acidosis, which is observed in salt-sensitive hypertension, is also associated with kidney injury. Alkali therapy in chronic renal failure (CRF) may ameliorate the progression of kidney disease; however, few studies have examined the effects of alkali therapy on salt sensitivity and kidney injury in CRF. We randomly administered standard diet (SD), sodium chloride with 20% casein diet (NACL), or sodium citrate with 20% casein diet (NACT) to Sprague-Dawley rats after a CRF or a sham operation. Four weeks after 5/6 nephrectomy, serum bicarbonate levels were higher in the NACT-treated group. On the pressure-natriuresis curve, NACT-treated CRF rats were more salt-resistant than NACL-treated CRF rats. Additionally, the NACT-treated CRF group showed less tubulointerstitial damage than the NACL-treated CRF group. The expression and immunoreactivity of NHE3 in the kidney in the NACT-treated CRF group were lower than those in the NACL-treated CRF group. We observed that dietary NACT as alkali therapy in CRF might improve the altered salt-sensitivity and ameliorate the progression of kidney injury compared to the NACL diet, which may be related to reduced renal NHE3 expression.

  4. Acute kidney injury: intravenous fluid to prevent contrast-induced AKI.

    PubMed

    Weisbord, Steven D; Palevsky, Paul M

    2009-05-01

    Trials that compared sodium bicarbonate and sodium chloride for the prevention of contrast-induced acute kidney injury have yielded highly conflicting results. The authors of a recent meta-analysis endeavored to provide a definitive assessment of the relative efficacy of these two intravenous fluids.

  5. 76 FR 42716 - Effects of Ischemia Reperfusion Injury on Outcomes in Kidney Transplantation; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-19

    ... HUMAN SERVICES Food and Drug Administration Effects of Ischemia Reperfusion Injury on Outcomes in Kidney... Food and Drug Administration (FDA) is announcing a public workshop to discuss the effects of ischemia... 7 days in advance. SUPPLEMENTARY INFORMATION: FDA is announcing a public workshop regarding...

  6. Primary cilia and kidney injury: current research status and future perspectives

    PubMed Central

    Wang, Shixuan

    2013-01-01

    Cilia, membrane-enclosed organelles protruding from the apical side of cells, can be divided into two classes: motile and primary cilia. During the past decades, motile cilia have been intensively studied. However, it was not until the 1990s that people began to realize the importance of primary cilia as cellular-specific sensors, particularly in kidney tubular epithelial cells. Furthermore, accumulating evidence indicates that primary cilia may be involved in the regulation of cell proliferation, differentiation, apoptosis, and planar cell polarity. Many signaling pathways, such as Wnt, Notch, Hedgehog, and mammalian target of rapamycin, have been located to the primary cilia. Thus primary cilia have been regarded as a hub that integrates signals from the extracellular environment. More importantly, dysfunction of this organelle may contribute to the pathogenesis of a large spectrum of human genetic diseases, named ciliopathies. The significance of primary cilia in acquired human diseases such as hypertension and diabetes has gradually drawn attention. Interestingly, recent reports disclosed that cilia length varies during kidney injury, and shortening of cilia enhances the sensitivity of epithelial cells to injury cues. This review briefly summarizes the current status of cilia research and explores the potential mechanisms of cilia-length changes during kidney injury as well as provides some thoughts to allure more insightful ideas and promotes the further study of primary cilia in the context of kidney injury. PMID:23904226

  7. Post-Kidney Transplantation Iliac Artery Stenosis due toIatrogenic Injury: Case Report

    SciTech Connect

    Khankan, Azzam Anwar Maeda, Munehiro; Osuga, Keigo; Murakami, Takamichi; Nakamura, Hironobu

    2003-04-15

    We report a case of left external iliac artery lesions as a complication of post-kidney transplantation due to vascular clamp application injury. The lesions were proximal stenosis and distal occlusion just near the graft anastomosis site and they were diagnosed incidentally during the embolization for arteriovenous fistula. Angiography confirmed the diagnosis and it was managed successfully by percutaneous interventional techniques.

  8. Leptospiral outer membrane protein LipL32 induces inflammation and kidney injury in zebrafish larvae

    PubMed Central

    Chang, Ming-Yang; Cheng, Yi-Chuan; Hsu, Shen-Hsing; Ma, Tsu-Lin; Chou, Li-Fang; Hsu, Hsiang-Hao; Tian, Ya-Chung; Chen, Yung-Chang; Sun, Yuh-Ju; Hung, Cheng-Chieh; Pan, Rong-Long; Yang, Chih-Wei

    2016-01-01

    Leptospirosis is an often overlooked cause of acute kidney injury that can lead to multiple organ failure and even death. The principle protein that conserved in many pathogenic leptospires is the outer membrane protein LipL32. However, the role of LipL32 in the pathogenesis of renal injury in leptospirosis is not entirely clear. Here we studied the effects of LipL32 on the developing kidney in zebrafish larvae. Incubation of zebrafish larvae with Leptospira santarosai serovar Shermani induced acute tubular injury predominantly in the proximal pronephric ducts. Furthermore, microinjection of lipl32 mRNA or recombinant LipL32 protein into zebrafish larvae increased macrophage accumulation and disrupted the basolateral location of NA-K-ATPase in pronephric ducts. These changes led to substantial impairment of the pronephric kidney structure. We further demonstrated that morpholino knockdown of tlr2, but not tlr4, reduced the LipL32-induced leukocyte infiltration and kidney injury. These data demonstrate that LipL32 contributes to the renal pathology in leptospirosis and gives some clues to the potential virulence of LipL32. Our results support the use of zebrafish as a model organism for studying the disease mechanism of leptospiral infection. This model might permit the future exploration of the virulence and molecular pathways of different leptospiral outer membrane proteins. PMID:27278903

  9. Leptospiral outer membrane protein LipL32 induces inflammation and kidney injury in zebrafish larvae.

    PubMed

    Chang, Ming-Yang; Cheng, Yi-Chuan; Hsu, Shen-Hsing; Ma, Tsu-Lin; Chou, Li-Fang; Hsu, Hsiang-Hao; Tian, Ya-Chung; Chen, Yung-Chang; Sun, Yuh-Ju; Hung, Cheng-Chieh; Pan, Rong-Long; Yang, Chih-Wei

    2016-01-01

    Leptospirosis is an often overlooked cause of acute kidney injury that can lead to multiple organ failure and even death. The principle protein that conserved in many pathogenic leptospires is the outer membrane protein LipL32. However, the role of LipL32 in the pathogenesis of renal injury in leptospirosis is not entirely clear. Here we studied the effects of LipL32 on the developing kidney in zebrafish larvae. Incubation of zebrafish larvae with Leptospira santarosai serovar Shermani induced acute tubular injury predominantly in the proximal pronephric ducts. Furthermore, microinjection of lipl32 mRNA or recombinant LipL32 protein into zebrafish larvae increased macrophage accumulation and disrupted the basolateral location of NA-K-ATPase in pronephric ducts. These changes led to substantial impairment of the pronephric kidney structure. We further demonstrated that morpholino knockdown of tlr2, but not tlr4, reduced the LipL32-induced leukocyte infiltration and kidney injury. These data demonstrate that LipL32 contributes to the renal pathology in leptospirosis and gives some clues to the potential virulence of LipL32. Our results support the use of zebrafish as a model organism for studying the disease mechanism of leptospiral infection. This model might permit the future exploration of the virulence and molecular pathways of different leptospiral outer membrane proteins. PMID:27278903

  10. Primary cilia and kidney injury: current research status and future perspectives.

    PubMed

    Wang, Shixuan; Dong, Zheng

    2013-10-15

    Cilia, membrane-enclosed organelles protruding from the apical side of cells, can be divided into two classes: motile and primary cilia. During the past decades, motile cilia have been intensively studied. However, it was not until the 1990s that people began to realize the importance of primary cilia as cellular-specific sensors, particularly in kidney tubular epithelial cells. Furthermore, accumulating evidence indicates that primary cilia may be involved in the regulation of cell proliferation, differentiation, apoptosis, and planar cell polarity. Many signaling pathways, such as Wnt, Notch, Hedgehog, and mammalian target of rapamycin, have been located to the primary cilia. Thus primary cilia have been regarded as a hub that integrates signals from the extracellular environment. More importantly, dysfunction of this organelle may contribute to the pathogenesis of a large spectrum of human genetic diseases, named ciliopathies. The significance of primary cilia in acquired human diseases such as hypertension and diabetes has gradually drawn attention. Interestingly, recent reports disclosed that cilia length varies during kidney injury, and shortening of cilia enhances the sensitivity of epithelial cells to injury cues. This review briefly summarizes the current status of cilia research and explores the potential mechanisms of cilia-length changes during kidney injury as well as provides some thoughts to allure more insightful ideas and promotes the further study of primary cilia in the context of kidney injury.

  11. Septic versus non-septic acute kidney injury in critically ill patients: characteristics and clinical outcomes

    PubMed Central

    Cruz, Marília Galvão; Dantas, João Gabriel Athayde de Oliveira; Levi, Talita Machado; Rocha, Mário de Seixas; de Souza, Sérgio Pinto; Boa-Sorte, Ney; de Moura, Carlos Geraldo Guerreiro; Cruz, Constança Margarida Sampaio

    2014-01-01

    Objective This study aimed to describe and compare the characteristics and clinical outcomes of patients with septic and non-septic acute kidney injury. Methods This study evaluated an open cohort of 117 critically ill patients with acute kidney injury who were consecutively admitted to an intensive care unit, excluding patients with a history of advanced-stage chronic kidney disease, kidney transplantation, hospitalization or death in a period shorter than 24 hours. The presence of sepsis and in-hospital death were the exposure and primary variables in this study, respectively. A confounding analysis was performed using logistic regression. Results No significant differences were found between the mean ages of the groups with septic and non-septic acute kidney injury [65.30±21.27 years versus 66.35±12.82 years, respectively; p=0.75]. In the septic and non-septic acute kidney injury groups, a predominance of females (57.4% versus 52.4%, respectively; p=0.49) and Afro-descendants (81.5% versus 76.2%, respectively; p=0.49) was observed. Compared with the non-septic patients, the patients with sepsis had a higher mean Acute Physiology and Chronic Health Evaluation II score [21.73±7.26 versus 15.75±5.98; p<0.001)] and a higher mean water balance (p=0.001). Arterial hypertension (p=0.01) and heart failure (p<0.001) were more common in the non-septic patients. Septic acute kidney injury was associated with a greater number of patients who required dialysis (p=0.001) and a greater number of deaths (p<0.001); however, renal function recovery was more common in this group (p=0.01). Sepsis (OR: 3.88; 95%CI: 1.51-10.00) and an Acute Physiology and Chronic Health Evaluation II score >18.5 (OR: 9.77; 95%CI: 3.73-25.58) were associated with death in the multivariate analysis. Conclusion Sepsis was an independent predictor of death. Significant differences were found between the characteristics and clinical outcomes of patients with septic versus non-septic acute kidney

  12. Tankyrase inhibition aggravates kidney injury in the absence of CD2AP

    PubMed Central

    Kuusela, S; Wang, H; Wasik, A A; Suleiman, H; Lehtonen, S

    2016-01-01

    Inappropriate activation of the Wnt/β-catenin pathway has been indicated in podocyte dysfunction and injury, and shown to contribute to the development and progression of nephropathy. Tankyrases, multifunctional poly(ADP-ribose) polymerase (PARP) superfamily members with features of both signaling and cytoskeletal proteins, antagonize Wnt/β-catenin signaling. We found that tankyrases interact with CD2-associated protein (CD2AP), a protein essential for kidney ultrafiltration as CD2AP-knockout (CD2AP−/−) mice die of kidney failure at the age of 6–7 weeks. We further observed that tankyrase-mediated total poly-(ADP-ribosyl)ation (PARylation), a post-translational modification implicated in kidney injury, was increased in mouse kidneys and cultured podocytes in the absence of CD2AP. The data revealed increased activity of β-catenin, and upregulation of lymphoid enhancer factor 1 (LEF1) (mediator of Wnt/β-catenin pathway) and fibronectin (downstream target of Wnt/β-catenin) in CD2AP−/− podocytes. Total PARylation and active β-catenin were reduced in CD2AP−/− podocytes by tankyrase inhibitor XAV939 treatment. However, instead of ameliorating podocyte injury, XAV939 further upregulated LEF1, failed to downregulate fibronectin and induced plasminogen activator inhibitor-1 (PAI-1) that associates with podocyte injury. In zebrafish, administration of XAV939 to CD2AP-depleted larvae aggravated kidney injury and increased mortality. Collectively, the data reveal sustained activation of the Wnt/β-catenin pathway in CD2AP−/− podocytes, contributing to podocyte injury. However, we observed that inhibition of the PARylation activity of tankyrases in the absence of CD2AP was deleterious to kidney function. This indicates that balance of the PARylation activity of tankyrases, maintained by CD2AP, is essential for normal kidney function. Furthermore, the data reveal that careful contemplation is required when targeting Wnt/β-catenin pathway to treat

  13. Improving the outcome of kidney transplantation by ameliorating renal ischemia reperfusion injury: lost in translation?

    PubMed

    Saat, T C; van den Akker, E K; IJzermans, J N M; Dor, F J M F; de Bruin, R W F

    2016-01-20

    Kidney transplantation is the treatment of choice in patients with end stage renal disease. During kidney transplantation ischemia reperfusion injury (IRI) occurs, which is a risk factor for acute kidney injury, delayed graft function and acute and chronic rejection. Kidneys from living donors show a superior short- and long-term graft survival compared with deceased donors. However, the shortage of donor kidneys has resulted in expansion of the donor pool by using not only living- and brain death donors but also kidneys from donation after circulatory death and from extended criteria donors. These grafts are associated with an increased sensitivity to IRI and decreased graft outcome due to prolonged ischemia and donor comorbidity. Therefore, preventing or ameliorating IRI may improve graft survival. Animal experiments focus on understanding the mechanism behind IRI and try to find methods to minimize IRI either before, during or after ischemia. This review evaluates the different experimental strategies that have been investigated to prevent or ameliorate renal IRI. In addition, we review the current state of translation to the clinical setting. Experimental research has contributed to the development of strategies to prevent or ameliorate IRI, but promising results in animal studies have not yet been successfully translated to clinical use.

  14. Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury.

    PubMed

    Mami, Iadh; Bouvier, Nicolas; El Karoui, Khalil; Gallazzini, Morgan; Rabant, Marion; Laurent-Puig, Pierre; Li, Shuping; Tharaux, Pierre-Louis; Beaune, Philippe; Thervet, Eric; Chevet, Eric; Hu, Guo-Fu; Pallet, Nicolas

    2016-03-01

    Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang(-/-)) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stress-mediated adaptive translational control mechanism. PMID:26195817

  15. Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury.

    PubMed

    Mami, Iadh; Bouvier, Nicolas; El Karoui, Khalil; Gallazzini, Morgan; Rabant, Marion; Laurent-Puig, Pierre; Li, Shuping; Tharaux, Pierre-Louis; Beaune, Philippe; Thervet, Eric; Chevet, Eric; Hu, Guo-Fu; Pallet, Nicolas

    2016-03-01

    Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang(-/-)) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stress-mediated adaptive translational control mechanism.

  16. [New mechanisms and recent insights in the pathogenesis of acute kidney injury (AKI)].

    PubMed

    Cantaluppi, Vincenzo; Quercia, Alessandro Domenico; Dellepiane, Sergio; Figliolini, Federico; Medica, Davide; De Lena, Michela

    2012-01-01

    Acute kidney injury (AKI) is a frequent complication in hospitalized patients often associated with multiple organ failure, increased mortality and progression toward chronic kidney disease. The identification of new cellular and molecular targets involved in AKI may lead to an improvement of diagnostic and therapeutic approaches. In recent years, the pathogenetic mechanisms of AKI have been fully elucidated: tubular epithelial cells and endothelial cells present in the microvasculature have been identified as the main targets of ischemia and of nephrotoxic drugs. Indeed, endothelial cell injury is associated with an extension phase of AKI, whereas tubular cells are subjected to an alteration of cell polarity, mislocalization of tight junction proteins and membrane transporters, and finally to the development of necrosis or apotosis. Apoptosis, or programmed cell death, is also a key component of sepsis-associated AKI in which the mechanisms of tissue damage are associated not only with hypoperfusion but also with a direct detrimental effect of bacterial products and inflammatory mediators on resident kidney cells. Endothelial and tubular epithelial cells also represent the main targets in the immunological mechanisms of AKI in kidney transplantation during cell-mediated and antibody-mediated rejection. Recent studies evidenced new molecules as early biomarkers of AKI. Among these molecules, NGAL and KIM-1 play a possible role in the progression toward chronic kidney disease. Lastly, the new frontier of AKI therapy is represented by the use of bone marrow-derived mesenchymal stem cells able to induce a regenerative program in the damaged kidney.

  17. [Acute Kidney Injury, Type - 3 cardiorenal syndrome, Biomarkers, Renal Replacement Therapy].

    PubMed

    Di Lullo, Luca; Bellasi, Antonio; Barbera, Vincenzo; Cozzolino, Mario; Russo, Domenico; De Pascalis, Antonio; Santoboni, Francesca; Villani, Annalisa; De Rosa, Silvia; Colafelice, Marco; Russo, Luigi; Ronco, Claudio

    2016-01-01

    Cardiovascular disease and major cardiovascular events represent main cause of death in both acute and chronic kidney disease patients. Kidney and heart failure are common and frequently co-exist This organ-organ interaction, also called organ cross-talk, leads to well-known definition of cardiorenal syndrome (CRS). Here we will describe cardiovascular involvement in patients with acute kidney injury (AKI). Also known as Type-3 CRS or acute reno-cardiac CRS, it occurs when AKI contributes and/or precipitates development of acute cardiac injury. AKI may directly or indirectly produces an acute cardiac event and it can be associated with volume overload, metabolic acidosis and electrolytes disorders such as hyperkalemia and hypocalcemia, coronary artery disease, left ventricular dysfunction and fibrosis which has been also described in patients with AKI with the consequence of direct negative effects on cardiac performance. PMID:27374388

  18. Progression of Chronic Kidney Disease After Acute Kidney Injury: Role of Self-Perpetuating Versus Hemodynamic-Induced Fibrosis.

    PubMed

    Picken, Maria; Long, Jianrui; Williamson, Geoffrey A; Polichnowski, Aaron J

    2016-10-01

    The relative contribution of self-perpetuating versus hemodynamic-induced fibrosis to the progression of chronic kidney disease (CKD) after acute kidney injury (AKI) is unclear. In the present study, male Sprague-Dawley rats underwent right uninephrectomy and were instrumented with a blood pressure radiotelemeter. Two weeks later, separate groups of rats were subjected to 40 minutes renal ischemia-reperfusion or sham surgery and followed up for 4 or 16 weeks to determine the extent to which glomerulosclerosis and tubulointerstitial fibrosis as a result of the AKI-CKD transition (ie, at 4 weeks post AKI) change over time during the progression of CKD (ie, at 16 weeks post AKI). On average, tubulointerstitial fibrosis was ≈3-fold lower (P<0.05), whereas glomerulosclerosis was ≈6-fold higher (P<0.05) at 16 versus 4 weeks post AKI. At 16 weeks post AKI, marked tubulointerstitial fibrosis was only observed in rats exhibiting marked glomerulosclerosis, proteinuria, and kidney hypertrophy consistent with a hemodynamic pathogenesis of renal injury. Moreover, quantitative analysis between blood pressure and renal injury revealed a clear and modest blood pressure threshold (average 16-week systolic blood pressure of ≈127 mm Hg) for the development of glomerulosclerosis. In summary, modest levels of blood pressure may be playing a substantial role in the progression of renal disease after AKI in settings of preexisting CKD associated with 50% loss of renal mass. In contrast, these data do not support a major role of self-perpetuating tubulointerstitial fibrosis in the progression CKD after AKI in such settings. PMID:27550923

  19. The long-term prognosis of acute kidney injury: acute renal failure as a cause of chronic kidney disease.

    PubMed

    Basile, Carlo

    2008-01-01

    There is a widespread opinion that acute kidney injury (AKI) is a rather harmless complication and that survival is determined not by renal dysfunction per se, but by the severity of the underlying disease. This opinion is in sharp contrast to evidence from several recent experimental and clinical investigations indicating that AKI is a condition which exerts a fundamental impact on the course of the disease, the evolution of associated complications and on prognosis, independently from the type and severity of the underlying condition. In conclusion, severe AKI in the critically ill patient is associated with high rates of morbidity, mortality and consumption of health care resources.

  20. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage.

    PubMed

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  1. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage

    PubMed Central

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S.; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  2. Design of Clinical Trials in Acute Kidney Injury: Lessons from the Past and Future Directions.

    PubMed

    Weisbord, Steven D; Palevsky, Paul M

    2016-01-01

    Acute kidney injury (AKI) is a common condition with multiple etiologies and variable clinical findings and pathologic manifestations. AKI is associated with serious adverse clinical outcomes, including the development of de novo chronic kidney disease, accelerated progression of pre-existing chronic kidney disease, end-stage kidney disease, and increased mortality. Past research has advanced our understanding of the pathophysiology, epidemiology, and outcomes of AKI significantly, however, little progress has been made in the development of evidence-based interventions for its prevention and treatment. In this review, we discuss key considerations in the design of clinical trials in AKI and highlight significant methodologic limitations that precluded many past studies from determining the effectiveness of preventive and therapeutic strategies for this common and serious condition.

  3. Outcomes After Kidney injury in Surgery (OAKS): protocol for a multicentre, observational cohort study of acute kidney injury following major gastrointestinal and liver surgery

    PubMed Central

    2016-01-01

    Introduction Acute kidney injury (AKI) is associated with increased morbidity and mortality following cardiac surgery. Data focusing on the patterns of AKI following major gastrointestinal surgery could inform quality improvement projects and clinical trials, but there is a lack of reliable evidence. This multicentre study aims to determine the incidence and impact of AKI following major gastrointestinal and liver surgery. Methods and analysis This prospective, collaborative, multicentre cohort study will include consecutive adults undergoing gastrointestinal resection, liver resection or reversal of ileostomy or colostomy. Open and laparoscopic procedures in elective and emergency patients will be included in the study. The primary end point will be the incidence of AKI within 7 days of surgery, identified using an adaptation of the National Algorithm for Detecting Acute Kidney Injury, which is based on the Kidney Disease Improving Global Outcomes (KDIGO) AKI guidelines. Secondary outcomes will include persistent renal dysfunction at discharge and 1 year postoperatively. The 30-day adverse event rate will be measured using the Clavien-Dindo scale. Data on factors that may predispose to the development of AKI will be collected to identify variables associated with AKI. Based on our previous collaborative studies, a minimum of 114 centres are expected to be recruited, contributing over 6500 patients in total. Ethics and dissemination This study will be registered as clinical audit at each participating hospital. The protocol will be disseminated through local and national medical student networks in the UK and Ireland. PMID:26769786

  4. Transgenic expression of proximal tubule peroxisome proliferator-activated receptor-alpha in mice confers protection during acute kidney injury.

    PubMed

    Li, Shenyang; Nagothu, Kiran K; Desai, Varsha; Lee, Taewon; Branham, William; Moland, Carrie; Megyesi, Judit K; Crew, Mark D; Portilla, Didier

    2009-11-01

    Our previous studies suggest that peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a critical role in regulating fatty acid beta-oxidation in kidney tissue and this directly correlated with preservation of kidney morphology and function during acute kidney injury. To further study this, we generated transgenic mice expressing PPARalpha in the proximal tubule under the control of the promoter of KAP2 (kidney androgen-regulated protein 2). Segment-specific upregulation of PPARalpha expression by testosterone treatment of female transgenic mice improved kidney function during cisplatin or ischemia-reperfusion-induced acute kidney injury. Ischemia-reperfusion injury or treatment with cisplatin in wild-type mice caused inhibition of fatty-acid oxidation, reduction of mitochondrial genes of oxidative phosphorylation, mitochondrial DNA, fatty-acid metabolism, and the tricarboxylic acid cycle. Similar injury in testosterone-treated transgenic mice resulted in amelioration of these effects. Similarly, there were increases in the levels of 4-hydroxy-2-hexenal-derived lipid peroxidation products in wild-type mice, which were also reduced in the transgenic mice. Similarly, necrosis of the S3 segment was reduced in the two injury models in transgenic mice compared to wild type. Our results suggest proximal tubule PPARalpha activity serves as a metabolic sensor. Its increased expression without the use of an exogenous PPARalpha ligand in the transgenic mice is sufficient to protect kidney function and morphology, and to prevent abnormalities in lipid metabolism associated with acute kidney injury.

  5. Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents.

    PubMed

    He, Jing; Lu, Yuqiu; Xia, Hong; Liang, Yaojun; Wang, Xiao; Bao, Wenduona; Yun, Shifeng; Ye, Yuting; Zheng, Chunxia; Liu, Zhihong; Shi, Shaolin

    2015-01-01

    Mitochondria in eukaryotic cells are derived from bacteria in evolution. Like bacteria, mitochondria contain DNA with unmethylated CpG motifs and formyl peptides, both of which have recently been shown to be damage associated molecular patterns (DAMPs) and induce immune response and cell injury. Based on the facts that circulating mitochondrial DAMPs (mtDAMPs) are increased in the patients of trauma or burn injury who also have proteinuria, that mtDAMPs can activate immune cells which in turn secrete glomerular permeability factors, that renal intrinsic cells express a variety of DAMP receptors, and that mtDAMPs can directly increase endothelial cell permeability in vitro, we hypothesized that mtDAMPs may be novel circulating factors inducing proteinuria and kidney injury. We tested this hypothesis by directly injecting mtDAMPs into rodents and examining urinary protein and kidney histology. We prepared mtDAMP samples, including mitochondrial DNA (mtDNA) and mitochondrial debris (MTD), from rodent liver. In mice, injection of mtDNA for 20 μg/ml initial concentration in circulation (much higher than the clinical range), did not cause any renal manifestations. However, an increased dose leading to 45 μg/ml initial concentration in circulation resulted in a transient, slight increase in urinary albumin. In rats, MTD injection resulting in 450 μg/ml initial concentration of MTD protein in circulation, which was much higher than the clinical range, caused mild, transient proteinuria and lung lesions. Multiple injections of such large amount of either mtDNA or MTD into rodents on 3 consecutive days also failed in inducing proteinuria and kidney injury. In summary, clinical levels of circulating mtDAMPs do not induce proteinuria and clinically irrelevant high levels of mtDAMPs cause only a transient and slight increase in urinary protein in rodents, suggesting that circulating mtDAMPs may not be responsible for the proteinuria and kidney injury in patients with trauma

  6. The role of the uncertainty of measurement of serum creatinine concentrations in the diagnosis of acute kidney injury.

    PubMed

    Kin Tekce, Buket; Tekce, Hikmet; Aktas, Gulali; Uyeturk, Ugur

    2016-01-01

    Uncertainty of measurement is the numeric expression of the errors associated with all measurements taken in clinical laboratories. Serum creatinine concentration is the most common diagnostic marker for acute kidney injury. The goal of this study was to determine the effect of the uncertainty of measurement of serum creatinine concentrations on the diagnosis of acute kidney injury. We calculated the uncertainty of measurement of serum creatinine according to the Nordtest Guide. Retrospectively, we identified 289 patients who were evaluated for acute kidney injury. Of the total patient pool, 233 were diagnosed with acute kidney injury using the AKIN classification scheme and then were compared using statistical analysis. We determined nine probabilities of the uncertainty of measurement of serum creatinine concentrations. There was a statistically significant difference in the number of patients diagnosed with acute kidney injury when uncertainty of measurement was taken into consideration (first probability compared to the fifth p = 0.023 and first probability compared to the ninth p = 0.012). We found that the uncertainty of measurement for serum creatinine concentrations was an important factor for correctly diagnosing acute kidney injury. In addition, based on the AKIN classification scheme, minimizing the total allowable error levels for serum creatinine concentrations is necessary for the accurate diagnosis of acute kidney injury by clinicians.

  7. Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.

    PubMed

    Tang, Jinhua; Yan, Yanli; Zhao, Ting C; Gong, Rujun; Bayliss, George; Yan, Haidong; Zhuang, Shougang

    2014-08-01

    Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.

  8. [McArdle disease presenting with rhabdomyolisis and acute kidney injury].

    PubMed

    Costa, Rui; Castro, Rui; Costa, Alexandre; Taipa, Ricardo; Vizcaíno, Ramon; Morgado, Teresa

    2013-01-01

    McArdle disease typically presents in childhood or young adults with myalgia, exercise intolerance, cramps and myoglobinuria. Deficiency of myophosphorylase enzyme results in inability to degrade glycogen stores, causing glycogen accumulation in muscle tissue and energy deficit. Evolution with rhabdomiolysis may occur and can be complicated with acute kidney injury but rarely, in about 11% of cases, is the initial disease manifestation. We report a case of McArdle Disease in a 38-year-old male patient. The disease went unrecognized despite previous symptoms (myalgia, exercise intolerance and single myoglobinuria episode) until an episode of rhabdomyolisis complicated with oliguric acute kidney injury requiring hemodialysis. The kidney biopsy showed evidence of acute tubular necrosis. Despite normalization of renal function, muscle lysis markers remained abnormal. Metabolic myopathy was suspected and a muscle biopsy was performed. It showed subsarcolemic glycogen deposition and absence of myophosphorylase activity. This case-report underlines the importance of considering metabolic myopathy in patients with acute kidney injury and severe rhabdomyolisis.

  9. Tubular cross talk in acute kidney injury: a story of sense and sensibility.

    PubMed

    El-Achkar, Tarek M; Dagher, Pierre C

    2015-06-15

    The mammalian kidney is an organ composed of numerous functional units or nephrons. Beyond the filtering glomerulus of each nephron, various tubular segments with distinct populations of epithelial cells sequentially span the kidney from cortex to medulla. The highly organized folding of the tubules results in a spatial distribution that allows intimate contact between various tubular subsegments. This unique arrangement can promote a newly recognized type of horizontal epithelial-to-epithelial cross talk. In this review, we discuss the importance of this tubular cross talk in shaping the response of the kidney to acute injury in a sense and sensibility model. We propose that injury-resistant tubules such as S1 proximal segments and thick ascending limbs (TAL) can act as "sensors" and thus modulate the responsiveness or "sensibility" of the S2-S3 proximal segments to injury. We also discuss new findings that highlight the importance of tubular cross talk in regulating homeostasis and inflammation not only in the kidney, but also systemically.

  10. Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk?

    PubMed

    Chaumont, Martin; Pourcelet, Aline; van Nuffelen, Marc; Racapé, Judith; Leeman, Marc; Hougardy, Jean-Michel

    2016-06-01

    In contrast to angiotensin receptor blockers (ARBs), mainly excreted by the liver, the dosage of angiotensin-converting enzyme (ACE) inhibitors, cleared by the kidney, must be adapted to account for renal clearance in patients with chronic kidney disease (CKD) to avoid acute kidney injury (AKI). Community-acquired AKI and the use of ACE inhibitors or ARBs in the emergency department were retrospectively assessed in 324 patients with baseline stage 3 or higher CKD. After stepwise regression analysis, the use of ACE inhibitors (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1; P=.02) and the presence of dehydration (OR, 30.8; 95% CI, 3.9-239.1) were associated with AKI. A total of 45% of patients using ACE inhibitors experienced overdosing, which causes most of the excess risk of AKI. These results suggest that dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI. Moreover, ACE inhibitors and ARBs should be stopped in cases of dehydration. PMID:27080620

  11. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice.

    PubMed

    Arai, Satoko; Kitada, Kento; Yamazaki, Tomoko; Takai, Ryosuke; Zhang, Xizhong; Tsugawa, Yoji; Sugisawa, Ryoichi; Matsumoto, Ayaka; Mori, Mayumi; Yoshihara, Yasunori; Doi, Kent; Maehara, Natsumi; Kusunoki, Shunsuke; Takahata, Akiko; Noiri, Eisei; Suzuki, Yusuke; Yahagi, Naoki; Nishiyama, Akira; Gunaratnam, Lakshman; Takano, Tomoko; Miyazaki, Toru

    2016-02-01

    Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI. PMID:26726878

  12. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice.

    PubMed

    Arai, Satoko; Kitada, Kento; Yamazaki, Tomoko; Takai, Ryosuke; Zhang, Xizhong; Tsugawa, Yoji; Sugisawa, Ryoichi; Matsumoto, Ayaka; Mori, Mayumi; Yoshihara, Yasunori; Doi, Kent; Maehara, Natsumi; Kusunoki, Shunsuke; Takahata, Akiko; Noiri, Eisei; Suzuki, Yusuke; Yahagi, Naoki; Nishiyama, Akira; Gunaratnam, Lakshman; Takano, Tomoko; Miyazaki, Toru

    2016-02-01

    Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.

  13. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury.

    PubMed

    Zhao, Wen-Yu; Zhang, Lei; Sui, Ming-Xing; Zhu, You-Hua; Zeng, Li

    2016-01-01

    Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD(+) dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18. PMID:27620507

  14. Untethering an unusual cause of kidney injury in a teenager with Down syndrome.

    PubMed

    Yen, Elizabeth; Miele, Niel F; Barone, Joseph G; Tyagi, Rachana; Weiss, Lynne S

    2014-11-01

    Acute kidney injury (AKI) is characterized by the acute nature and the inability of kidneys to maintain fluid homeostasis as well as adequate electrolyte and acid-base balance, resulting in an accumulation of nitrogenous waste and elevation of serum blood urea nitrogen and creatinine values. Acute kidney injury may be a single isolated event, yet oftentimes, it results from an acute chronic kidney disease. It is critical to seek out the etiology of AKI and to promptly manage the underlying chronic kidney disease to prevent comorbidities and mortality that may ensue. We described a case of a 16-year-old adolescent girl with Down syndrome who presented with AKI and electrolyte aberrance.Abdominal and renal ultrasounds demonstrated a significantly dilated bladder as well as frank hydronephrosis and hydroureter bilaterally. Foley catheter was successful in relieving the obstruction and improving her renal function. However, a magnetic resonance imaging was pursued in light of her chronic constipation and back pain, and it revealed a structural defect (tethered cord) that underlies a chronic process that was highly likely contributory to her AKI. She was managed accordingly with a guarded result and required long-term and close monitoring.

  15. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury

    PubMed Central

    Zhao, Wen-Yu; Zhang, Lei; Sui, Ming-Xing; Zhu, You-Hua; Zeng, Li

    2016-01-01

    Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD+ dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18. PMID:27620507

  16. Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice.

    PubMed

    Iwamura, Atsushi; Watanabe, Katsuhito; Akai, Sho; Nishinosono, Tsubasa; Tsuneyama, Koichi; Oda, Shingo; Kume, Toshiyuki; Yokoi, Tsuyoshi

    2016-07-01

    Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by cotreatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers, such as the glutathione/disulfide glutathione ratio and malondialdehyde levels, were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs. PMID:27112166

  17. Development of an Immunoassay for the Kidney Specific Protein myo-Inositol Oxygenase, a Potential Biomarker of Acute Kidney Injury

    PubMed Central

    Gaut, Joseph P.; Crimmins, Dan L.; Ohlendorf, Matt F.; Lockwood, Christina M.; Griest, Terry A.; Brada, Nancy A.; Hoshi, Masato; Sato, Bryan; Hotchkiss, Richard S.; Jain, Sanjay; Ladenson, Jack H.

    2014-01-01

    Background Acute kidney injury (AKI) affects 45% of critically ill patients resulting in increased morbidity and mortality. The diagnostic standard, serum creatinine (SCr), is non-specific and may not increase until days after injury. There is significant need for a renal specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal specific biomarker of AKI. Methods Gene expression data was analyzed from normal mouse tissues to identify kidney specific genes, one of which was Miox. Monoclonal antibodies were generated to recombinant myo-inositol oxygenase (MIOX), and an immunoassay was developed to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. Results Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Plasma MIOX, undetectable at baseline, increased 24 hours following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI (12.4 ± 4.3 ng/mL, n=42) compared with patients without AKI (0.5 ± 0.3 ng/mL, n=17) and was highest in patients with oliguric AKI (20.2 ± 7.5 ng/mL, n=23). Plasma MIOX increased 54.3 ± 3.8 hours before the increase in SCr. Conclusions MIOX is a renal specific, proximal tubule protein that is increased in plasma of animals and critically ill patients with AKI. MIOX preceded the elevation in SCr by approximately two days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker. PMID:24486646

  18. Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1

    PubMed Central

    Bai, Xiao-Zhi; He, Ting; Gao, Jian-Xin; Liu, Yang; Liu, Jia-Qi; Han, Shi-Chao; Li, Yan; Shi, Ji-Hong; Han, Jun-Tao; Tao, Ke; Xie, Song-Tao; Wang, Hong-Tao; Hu, Da-Hai

    2016-01-01

    Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling. PMID:27599451

  19. Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.

    PubMed

    Leventhal, Jeremy S; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G Luca; Salem, Fadi; Ross, Michael J

    2016-01-01

    Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.

  20. Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression

    PubMed Central

    Leventhal, Jeremy S.; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G. Luca; Salem, Fadi; Ross, Michael J.

    2016-01-01

    Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling. PMID:26990086

  1. Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1.

    PubMed

    Bai, Xiao-Zhi; He, Ting; Gao, Jian-Xin; Liu, Yang; Liu, Jia-Qi; Han, Shi-Chao; Li, Yan; Shi, Ji-Hong; Han, Jun-Tao; Tao, Ke; Xie, Song-Tao; Wang, Hong-Tao; Hu, Da-Hai

    2016-01-01

    Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling. PMID:27599451

  2. The growth of acute kidney injury: a rising tide or just closer attention to detail?

    PubMed Central

    Siew, Edward D; Davenport, Andrew

    2015-01-01

    Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors. PMID:25229340

  3. Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay

    PubMed Central

    Ogura, Makoto; Kagami, Shino; Nakao, Masatsugu; Kono, Midori; Kanetsuna, Yukiko; Hosoya, Tatsuo

    2012-01-01

    We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis. PMID:23936627

  4. Cell therapy, advanced materials, and new approaches to acute kidney injury.

    PubMed

    Yevzlin, Alexander S; Humes, H David

    2009-12-01

    Acute renal failure (ARF) is a common clinical syndrome characterized by an abrupt deterioration in kidney function, resulting in abnormalities in volume-regulatory, metabolic-regulatory, excretory, and endocrine functions. Despite decades of improvements in the provision of intensive care, and specifically in the provision of renal replacement therapy, the morbidity and mortality associated with acute kidney injury (AKI) remain extremely high. This article highlights novel cell therapies, advanced materials, and approaches to AKI with the aim of illuminating a potential path for future basic, translational, and clinical research using these novel modalities.

  5. Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay.

    PubMed

    Ogura, Makoto; Kagami, Shino; Nakao, Masatsugu; Kono, Midori; Kanetsuna, Yukiko; Hosoya, Tatsuo

    2012-10-01

    We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis.

  6. Management of Acute Kidney Injury and Acid-Base Balance in the Septic Patient.

    PubMed

    Weyker, Paul D; Pérez, Xosé L; Liu, Kathleen D

    2016-06-01

    Acute kidney injury (AKI) is an abrupt decrease in kidney function that takes place over hours to days. Sepsis is the leading cause of AKI and portends a particularly high morbidity and mortality, although the severity may vary from a transient rise in serum creatinine to end-stage renal disease. With regard to acid-base management in septic AKI, caution should be used with hyperchloremic crystalloid solutions, and dialysis is often used in the setting of severe acidosis. In the future, biomarkers may help clinicians identify AKI earlier and allow for potential interventions before the development of severe AKI. PMID:27229644

  7. A new model to predict acute kidney injury requiring renal replacement therapy after cardiac surgery

    PubMed Central

    Pannu, Neesh; Graham, Michelle; Klarenbach, Scott; Meyer, Steven; Kieser, Teresa; Hemmelgarn, Brenda; Ye, Feng; James, Matthew

    2016-01-01

    Background: Acute kidney injury after cardiac surgery is associated with adverse in-hospital and long-term outcomes. Novel risk factors for acute kidney injury have been identified, but it is unknown whether their incorporation into risk models substantially improves prediction of postoperative acute kidney injury requiring renal replacement therapy. Methods: We developed and validated a risk prediction model for acute kidney injury requiring renal replacement therapy within 14 days after cardiac surgery. We used demographic, and preoperative clinical and laboratory data from 2 independent cohorts of adults who underwent cardiac surgery (excluding transplantation) between Jan. 1, 2004, and Mar. 31, 2009. We developed the risk prediction model using multivariable logistic regression and compared it with existing models based on the C statistic, Hosmer–Lemeshow goodness-of-fit test and Net Reclassification Improvement index. Results: We identified 8 independent predictors of acute kidney injury requiring renal replacement therapy in the derivation model (adjusted odds ratio, 95% confidence interval [CI]): congestive heart failure (3.03, 2.00–4.58), Canadian Cardiovascular Society angina class III or higher (1.66, 1.15–2.40), diabetes mellitus (1.61, 1.12–2.31), baseline estimated glomerular filtration rate (0.96, 0.95–0.97), increasing hemoglobin concentration (0.85, 0.77–0.93), proteinuria (1.65, 1.07–2.54), coronary artery bypass graft (CABG) plus valve surgery (v. CABG only, 1.25, 0.64–2.43), other cardiac procedure (v. CABG only, 3.11, 2.12–4.58) and emergent status for surgery booking (4.63, 2.61–8.21). The 8-variable risk prediction model had excellent performance characteristics in the validation cohort (C statistic 0.83, 95% CI 0.79–0.86). The net reclassification improvement with the prediction model was 13.9% (p < 0.001) compared with the best existing risk prediction model (Cleveland Clinic Score). Interpretation: We have developed

  8. Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

    PubMed

    Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun; Gnana-Prakasam, Jaya P; Veeranan-Karmegam, Rajalakshmi; Huang, Lei; Ravishankar, Buvana; Bradley, Jillian; Kvirkvelia, Nino; McMenamin, Malgorzata; Xiao, Wei; Kleven, Daniel; Mellor, Andrew L; Madaio, Michael P; McGaha, Tracy L

    2015-06-15

    Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.

  9. [Significance of the determination of urinary excretion of kidney injury molecule-1 (KIM-1) in the assessment of the activity and prognosis of chronic glomerulonephritis].

    PubMed

    Brovko, M Yu; Pulin, A A; Kustova, T Yu; Sholomova, V I; Loshkareva, O A; Taranova, M V; Kozlovskaya, L V

    2016-01-01

    Резюме Цель исследования. Оценить экскрецию молекулы повреждения почек 1-го типа (KIM-1) с мочой в группах больных хроническим гломерулонефритом (ХГН), различающихся по степени клинической активности, определить возможность использования концентрации KIM-1 в моче как критерия прогноза течения ХГН. Материалы и методы. Обследовали 47 больных ХГН: в 1-ю группу вошли 10 больных с нефротическим синдромом (НС) и сниженной скоростью клубочковой фильтрации (СКФ), во 2-ю группу — 16 больных с НС и нормальной СКФ, в 3-ю группу — 10 пациентов с частичной ремиссией НС, в 4-ю группу включены 11 пациентов ХГН, с гематурией и умеренной протеинурией при нормальной СКФ. Контроль составили 9 здоровых лиц. В обследованных группах определяли экскрецию с мочой KIM-1 методом непрямого иммуноферментного анализа. Результаты. У больных ХГН экскреция молекулы KIM-1 с мочой выше, чем у здоровых людей (р<0,0001), при этом у пациентов с протеинурическими формами уровень экскреции KIM-1 в среднем статистически значимо выше, чем у больных ХГН c ГУ (р=0,01). Самые высокие уровни получены в 1-й группе, больные 2-й группы занимали промежуточное положение по уровню экскреции KIM-1, а различия между 3-й и 4-й группами оказались статистически незначимыми. Наименьшие уровни отмечены у больных 4-й группы и в контроле, различия между группами статистически незначимы. У больных ХГН установлена корреляция уровня экскреции KIM-1 со всеми показателями тяжести НС. Оценено значение определения KIM-1 как фактора риска персистирования/рефрактерности НС. По результатам построения ROC-кривой уровень KIM-1 больше 2,34 нг/мл с высокой чувствительностью и специфичностью позволил прогнозировать персистенцию НС у больных ХГН. Заключение. Уровень экскреции молекулы KIM-1 с мочой может быть использован для оценки активности ХГН с НС и эффективности лечения. Результаты исследования обосновывают поиск путей фармакологической блокады выработки KIM-1 в почке для оптимизации методов патогенетического воздействия на прогрессирование ХГН.

  10. Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury.

    PubMed

    Skrypnyk, Nataliya I; Voziyan, Paul; Yang, Haichun; de Caestecker, Christian R; Theberge, Marie-Claude; Drouin, Mathieu; Hudson, Billy; Harris, Raymond C; de Caestecker, Mark P

    2016-08-01

    Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI. PMID:27194713

  11. Loxosceles gaucho Venom-Induced Acute Kidney Injury – In Vivo and In Vitro Studies

    PubMed Central

    Lucato, Rui V.; Abdulkader, Regina C. R. M.; Barbaro, Katia C.; Mendes, Glória E.; Castro, Isac; Baptista, Maria A. S. F.; Cury, Patrícia M.; Malheiros, Denise M. C.; Schor, Nestor; Yu, Luis; Burdmann, Emmanuel A.

    2011-01-01

    Background Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury (AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo. Methodology/Principal Findings In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes. Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats. Conclusions/Significance Loxosceles gaucho venom injection caused early AKI, which occurred without blood pressure variation. Changes in glomerular function occurred likely due to renal vasoconstriction and rhabdomyolysis. Direct nephrotoxicity could not be demonstrated in vitro. The development of a consistent model of Loxosceles venom-induced AKI and a better understanding of the mechanisms involved in the renal injury may allow more efficient ways to prevent or attenuate the systemic injury after Loxosceles bite. PMID:21655312

  12. Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in Critically Ill Children (AWARE): A Prospective Study to Improve Diagnostic Precision

    PubMed Central

    Basu, Rajit K; Kaddourah, Ahmad; Terrell, Tara; Mottes, Theresa; Arnold, Patricia; Jacobs, Judd; Andringa, Jennifer; Armor, Melissa; Hayden, Lauren; Goldstein, Stuart L

    2015-01-01

    Background Acute kidney injury (AKI) is associated with poor outcomes in critically ill children. Recent international consensus panels recommend standardized classification systems to improve the precision of AKI diagnosis, but there is a paucity of data to enable this refinement, particularly in pediatric critical care. Methods/Design This is a prospective observational study. We anticipate collecting data from more than 5500 critically ill children admitted to 32 pediatric intensive care units (PICUs) across the world, during the calendar year of 2014. Data will be collected continuously for three months at each center on all children older than 90 days and younger than 25 years admitted to the ICU. Demographic, resuscitative, and daily physiological and lab data will be captured at individual centers using MediData Rave™, a commercial system designed to manage and report clinical research data. Kidney specific measured variables include changes in serum creatinine and urine output, cumulative fluid overload (%), serum creatinine corrected for fluid balance, and KDIGO AKI stage. Urinary AKI biomarkers to be measured include: urinary neutrophil gelatinase lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (l-FABP), and interleukin-18 (IL-18). Biomarker combinations will be created from different pairs and triplets of urinary biomarkers. The primary analysis will compare the discrimination of these panels versus changes in creatinine for prediction of severe AKI by Day 7 of ICU admission. Secondary analysis will investigate the prediction of biomarkers for injury ‘time based phenotypes’: duration (>2 days), severity (KDIGO stage, use of renal replacement therapy), reversibility (time to return of serum creatinine to baseline), association with fluid overload > 10%, and disease association (sepsis, hypovolemia, hypoxemia, or nephrotoxic). Discussion The Assessment of Worldwide Acute Kidney Injury, Renal Angina and

  13. Forced diuresis with the RenalGuard system: impact on contrast induced acute kidney injury.

    PubMed

    Solomon, Richard

    2014-01-01

    Kidney injury following the administration of iodinated contrast media occurs particularly in patients with reduced kidney and cardiac function and when large doses of contrast are used. There is little compelling evidence that vasodilators and anti-oxidants prevent this injury. Most prevention trials have employed intravenous volume loading as a central strategy. However, the success of this approach depends upon maintaining euvolemia while producing a vigorous diuresis. A novel strategy for maintaining euvolemia and inducing a vigorous diuresis has been developed using the RenalGuard system. In this review; the mechanism of protective action is reviewed. The trials of the RenalGuard device are reviewed and future uses of the device are discussed.

  14. A Rare Case of Polyneuropathy and Monoclonalgammopathy with Recurrent Acute Kidney Injury

    PubMed Central

    Kim, Eun Jung; Shin, Dong Ho; Jeon, Hee Jung; Rhee, So Yon; Nam, Eun Sook; Park, Ji Young

    2016-01-01

    POEMS syndrome is a rare paraneoplastic syndrome and there are few reports of polyneuropathy and monoclonal gammopathy associated with kidney dysfunction. Here, we report a case of POEMS syndrome with recurrent acute kidney injury (AKI). A 52-year-old man presented with bilateral aggravating paresthesia and latermotor weakness of the lower extremities accompanied by repeated elevation of serum creatinine. The patient was finally diagnosed with POEMS syndrome on the basis of fulfilling the two mandatory major criteria (polyneuropathy and monoclonal gammopathy), one other major criterion (sclerotic bone lesion), and several minor criteria. A renal biopsy was performed to clarify the cause of AKI and showed membranoproliferative glomerulonephritis-like lesions with mesangiolysis and endothelial cell injury. This case illustrates that renal manifestations, not included in the diagnostic criteria for POEMS, can be apparent before various other systemic symptoms. PMID:27453713

  15. Acute Kidney Injury is More Common in Acute Haemorrhagic Stroke in Mymensingh Medical College Hospital.

    PubMed

    Ray, N C; Chowdhury, M A; Sarkar, S R

    2016-01-01

    Acute kidney injury (AKI) is a common complication after acute stroke and is an independent predictor of both early and long-term mortality after acute stroke. Acute kidney injury is associated with increased mortality in haemorrhagic stroke patients. This cross sectional observational study was conducted in Nephrology, Neuromedicine and Medicine department of Mymensingh Medical College & Hospital, Mymensingh from July 2012 to June 2014. A total of 240 patients with newly detected acute stroke confirmed by CT scan of brain were included in this study. According to this study, 15.42% of acute stroke patients developed AKI. Among the patients with haemorrhagic stroke 21.87% developed AKI while only 13.07% patients with ischaemic stroke developed AKI. So, early diagnosis and management of AKI in patients with acute stroke especially in haemorrhagic stroke is very important to reduce the morbidity and mortality of these patients. PMID:26931240

  16. Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury

    PubMed Central

    2008-01-01

    BACKGROUND The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P = 0.47). There was no significant difference between the two groups in the duration of renalreplacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal

  17. Assessment of cisplatin-induced kidney injury using an integrated rodent platform

    SciTech Connect

    Chen, Yafei; Brott, David; Luo, Wenli; Gangl, Eric; Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Fikes, James; Kinter, Lewis; Valentin, Jean-Pierre; Bialecki, Russell

    2013-05-01

    Current diagnosis of drug-induced kidney injury (DIKI) primarily relies on detection of elevated plasma creatinine (Cr) or blood urea nitrogen (BUN) levels; however, both are indices of overall kidney function and changes are delayed with respect to onset of nephron injury. Our aim was to investigate whether early changes in new urinary DIKI biomarkers predict plasma Cr, BUN, renal hemodynamic and kidney morphological changes associated with kidney injury following a single dose of cisplatin (CDDP) using an integrated platform in rodent. Conscious surgically prepared male Han Wistar rats were given a single intraperitoneal dose of CDDP (15 mg/kg). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), urinalysis, DIKI biomarkers, CDDP pharmacokinetics, blood pressures, heart rate, body temperature and electroencephalogram (EEG) were measured in the same vehicle- or CDDP-treated animals over 72 h. Plasma chemistry (including Cr and BUN) and renal tissues were examined at study termination. Cisplatin caused progressive reductions of GFR, ERPF, heart rate and body temperature from day 1 (0–24 h). DIKI biomarkers including alpha-glutathione S-transferase (α-GST) significantly increased as early as 6 h post-dose, which preceded significant declines of GFR and ERPF (24 h), increased plasma Cr and BUN (72 h), and associated with renal acute tubular necrosis at 72 h post-dose. The present study adds to the current understanding of CDDP action by demonstrating that early increases in urinary excretion of α-GST predict DIKI risk following acute exposure to CDDP in rats, before changes in traditional DIKI markers are evident. - Highlights: ► CDDP causes direct damage to kidneys without affecting EEG or CVS function. ► α-GST and albumin detect DIKI earlier when compared with traditional indices. ► Integrated “cardiovascular-EEG-renal” model to better understand DIKI mechanisms ► Promotes 3R's principles in drug discovery and development.

  18. Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway.

    PubMed

    Wu, Juan; Liu, Xinhui; Fan, Jinjin; Chen, Wenfang; Wang, Juan; Zeng, Youjia; Feng, Xiaorang; Yu, Xueqing; Yang, Xiao

    2014-04-01

    Bardoxolone methyl (BARD) is an antioxidant modulator that acts through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This study aimed to investigate the role of BARD in protecting kidneys from aristolochic acid (AA)-induced acute kidney injury (AKI). Male C57BL/6 mice received intraperitoneal (i.p.) injections of aristolochic acid I (AAI) (5mg/kg/day) for 5 days to produce acute AA nephropathy (AAN) model. BARD (10mg/kg/day, i.p.) was applied for 7 consecutive days, starting 2 days prior to AAI administration. The mice in the AA group showed AKI as evidenced by worsening kidney function evaluated by blood urea nitrogen (BUN) and serum creatinine (SCr) levels, and severe tubulointerstitial injury marked by massive tubule necrosis in kidney tissues. BARD significantly reduced BUN and SCr levels which were elevated by AAI. Additionally, AAI-induced histopathological renal damage was ameliorated by BARD. Furthermore, the expression of Nrf2 was reduced, and its repressor Kelch-like ECH-associated protein 1 (Keap1) was increased significantly, whereas heme oxygenase-1 (HO-1) was upregulated and NAD(P)H quinone oxidoreductase-1 (NQO1) was barely increased in the cytoplasm of tubules in kidneys after treatment with AAI. BARD significantly upregulated renal Nrf2, NQO1 and HO-1 expression and downregulated Keap1 expression compared with those in the AA group. Moreover, it was found that Nrf2 was expressed both in the cytoplasm and nuclear of glomeruli and tubules, whereas NQO1 and HO-1 were localized in the cytoplasm of tubules only. In conclusion, AA-induced acute renal injury was associated with impaired Nrf2 activation and expression of its downstream target genes in renal tissues. BARD prevented renal damage induced by AAI, and this renoprotective effect may be exerted by activating the Nrf2 signaling pathway and increasing expression of the downstream target genes.

  19. Timing is everything? Reconciling the results of recent trials in acute kidney injury.

    PubMed

    Wyatt, Christina M; Coca, Steven G

    2016-10-01

    Observational studies have failed to establish the optimal timing of renal replacement therapy in critically ill adults with acute kidney injury, with some studies suggesting benefit and others suggesting the potential for harm with earlier initiation. Two recent randomized trials have addressed this controversy, also with conflicting results. Careful consideration of differences between the 2 studies is essential when applying the results to clinical practice in the intensive care unit. PMID:27575558

  20. Measuring biomarkers of acute kidney injury during renal replacement therapy: wisdom or folly?

    PubMed

    Ostermann, Marlies; Forni, Lui G

    2014-06-19

    Early data are now appearing relating to the measurement of biomarkers of acute kidney injury during renal replacement therapy. These data go some way in describing the clearance of these molecules during renal support. Understanding the potential clearance, or otherwise, of these proteins may lead to directing our therapies in the future particularly with regard to cessation of renal support. We describe a recent study which has provided data that may aid in addressing this issue.

  1. Sympathomimetic syndrome, choreoathetosis, and acute kidney injury following "bath salts" injection.

    PubMed

    Sutamtewagul, Grerk; Sood, Vineeta; Nugent, Kenneth

    2014-01-01

    "Bath salts" is a well known street drug which can cause several cardiovascular and neuropsychiatric symptoms. However, only one case of acute kidney injury has been reported in the literature. We present a case with sympathomimetic syndrome, choreoathetosis, gustatory and olfactory hallucinations, and acute kidney injury following the use of bath salts. A 37-year-old man with past medical history of hypertension and depression was brought to the emergency center with body shaking. Three days before admission he injected 3 doses of bath salts intravenously and felt eye pain with blurry vision followed by a metallic taste, strange smells, profuse sweating, and body shaking. At presentation he had a sympathomimetic syndrome including high blood pressure, tachycardia, tachypnea, and hyperhydrosis with choreoathetotic movements. Laboratory testing revealed leukocytosis and acute kidney injury with a BUN of 95 mg/ dL and a creatinine of 15.2 mg/dL. Creatine kinase was 4,457 IU/dL. Urine drug screen is negative for amphetamine, cannabinoids, and cocaine; blood alcohol level was zero. During his ICU stay he became disoriented and agitated. Supportive treatment with 7.2 liters of intravenous fluid over 3 days, haloperidol, and lorazepam gradually improved his symptoms and his renal failure. Bath salts contain 3,4-methylenedioxypyrovalerone, a psychoactive norepinephrine and dopamine reuptake inhibitor. Choreoathetosis in this patient could be explained through dopaminergic effect of bath salts or uremic encephalopathy. The mechanism for acute kidney injury from bath salts may involve direct drug effects though norepinephrine and dopamine-induced vasoconstriction (renal ischemia), rhabdomyolysis, hyperthermia, and/or volume contraction. PMID:24356039

  2. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury.

    PubMed

    Lankadeva, Yugeesh R; Kosaka, Junko; Evans, Roger G; Bailey, Simon R; Bellomo, Rinaldo; May, Clive N

    2016-07-01

    Norepinephrine is the principal vasopressor used to restore blood pressure in sepsis, but its effects on intrarenal oxygenation are unknown. To clarify this, we examined renal cortical, medullary, and urinary oxygenation in ovine septic acute kidney injury and the response to resuscitation with norepinephrine. A renal artery flow probe and fiberoptic probes were placed in the cortex and medulla of sheep to measure tissue perfusion and oxygenation. A probe in the bladder catheter measured urinary oxygenation. Sepsis was induced in conscious sheep by infusion of Escherichia coli for 32 hours. At 24 to 30 hours of sepsis, either norepinephrine, to restore mean arterial pressure to preseptic levels or vehicle-saline was infused (8 sheep per group). Septic acute kidney injury was characterized by a reduction in blood pressure of ∼12 mm Hg, renal hyperperfusion, and oliguria. Sepsis reduced medullary perfusion (from an average of 1289 to 628 blood perfusion units), medullary oxygenation (from 32 to 16 mm Hg), and urinary oxygenation (from 36 to 24 mm Hg). Restoring blood pressure with norepinephrine further reduced medullary perfusion to an average of 331 blood perfusion units, medullary oxygenation to 8 mm Hg and urinary oxygenation to 18 mm Hg. Cortical perfusion and oxygenation were preserved. Thus, renal medullary hypoxia caused by intrarenal blood flow redistribution may contribute to the development of septic acute kidney injury, and resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. The parallel changes in medullary and urinary oxygenation suggest that urinary oxygenation may be a useful real-time biomarker for risk of acute kidney injury. PMID:27165831

  3. Nonapoptotic cell death in acute kidney injury and transplantation.

    PubMed

    Linkermann, Andreas

    2016-01-01

    Acute tubular necrosis causes a loss of renal function, which clinically presents as acute kidney failure (AKI). The biochemical signaling pathways that trigger necrosis have been investigated in detail over the past 5 years. It is now clear that necrosis (regulated necrosis, RN) represents a genetically driven process that contributes to the pathophysiology of AKI. RN pathways such as necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-induced regulated necrosis (MPT-RN) may be mechanistically distinct, and the relative contributions to overall organ damage during AKI in living organisms largely remain elusive. In a synchronized manner, some necrotic programs induce the breakdown of tubular segments and multicellular functional units, whereas others are limited to killing single cells in the tubular compartment. Importantly, the means by which a renal cell dies may have implications for the subsequent inflammatory response. In this review, the recent advances in the field of renal cell death in AKI and key enzymes that might serve as novel therapeutic targets will be discussed. As a consequence of the interference with RN, the immunogenicity of dying cells in AKI in renal transplants will be diminished, rendering inhibitors of RN indirect immunosuppressive agents. PMID:26759047

  4. Ergosterol Alleviates Kidney Injury in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Ang, Li; Yuguang, Liu; Liying, Wang; Shuying, Zhang; Liting, Xu; Shumin, Wang

    2015-01-01

    Ergosterol (ERG) has been widely used in the development of novel drugs due to its unique physiological function. However, little is known about the protective effects of ERG on diabetes. Hence, the current study was designed to evaluate the positive role of ergosterol on streptozotocin- (STZ-) induced diabetes in mice. Oral glucose tolerance test (OGTT) was carried out to assess blood glucose level. Biochemical parameters such as uric acid, creatinine, serum insulin, triglycerides (TG), and total cholesterol (TC) were also measured. Pathological condition of kidney was examined by hematoxylin-eosin (H&E) staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, NF-κBp65, p-NF-κBp65, IκBα, and p-IκBα were analyzed by western blot. ERG significantly reduced the concentrations of blood glucose, uric acid, creatinine, TG, and TC. Serum insulin was elevated with ERG treatment. In addition, renal pathologic changes of diabetes mice were also alleviated by ERG. Obtained data revealed that ERG restored the levels of PI3K/Akt/NF-κB signaling-related proteins in comparison with diabetes mice. Above all, it could be assumed that ERG might play a positive role in regulating STZ-induced diabetes through suppressing PI3K/Akt/NF-κB pathway. PMID:26664454

  5. Proteome Analysis of Renoprotection Mediated by a Novel Cyclic Helix B Peptide in Acute Kidney Injury

    PubMed Central

    Yang, Cheng; Liu, Junjun; Li, Long; Hu, Meiyu; Long, Yaqiu; Liu, Xiaohui; Zhu, Tongyu; Huang, Xiao; Zhao, Shouliang; Liu, Shangfeng; Rong, Ruiming

    2015-01-01

    We developed a novel, erythropoietin-derived, non-erythropoiesis, cyclic helix B peptide (CHBP) that displays potent renoprotection against acute kidney injury (AKI). To determine the mechanism of CHBP-mediated protection, we investigated the proteomic profile of mice treated with CHBP in a kidney ischemia-reperfusion (IR) injury model. The isobaric tags for relative and absolute quantitation (iTRAQ)-labeled samples were analyzed using a QSTAR XL LC/MS system. In total, 38 differentially expressed proteins (DEPs) were shared by all experimental groups, while 3 DEPs were detected specifically in the IR + CHBP group. Eight significant pathways were identified, and oxidative phosphorylation was shown to be the most important pathway in CHBP-mediated renoprotection. The significant DEPs in the oxidative phosphorylation pathway elicited by CHBP are NADH-ubiquinone oxidoreductase Fe-S protein 6 (NDUFS6), alpha-aminoadipic semialdehyde synthase (AASS) and ATP-binding cassette sub-family D member 3 (ABCD3). The DEPs mentioned above were verified by RT-qPCR and immunostaining in mouse kidneys. We tested 6 DEPs in human biopsy samples from kidney transplant recipients. The trend of differential expression was consistent with that in the murine model. In conclusion, this study helps to elucidate the pharmacological mechanisms of CHBP before clinical translation. PMID:26655840

  6. [Star fruit as a cause of acute kidney injury].

    PubMed

    Scaranello, Karilla Lany; Alvares, Valeria Regina de Cristo; Carneiro, Daniely Maria Queiroz; Barros, Flávio Henrique Soares; Gentil, Thais Marques Sanches; Thomaz, Myriam José; Pereira, Benedito Jorge; Pereira, Mariana Batista; Leme, Graziella Malzoni; Diz, Mary Carla Esteves; Laranja, Sandra Maria Rodrigues

    2014-01-01

    The star fruit belongs to the family Oxalidacea, species Averrhoa carambola. It is rich in minerals, vitamin A, C, B complex vitamins and oxalic acid. Recent studies show that the toxicity of the fruit differs between the patients and may be explained by single biological responses, age, and the intake quantity of the neurotoxin in each fruit in addition to glomerular filtration rate given by each patient. Additionally, the nephrotoxicity caused by the fruit is dose-dependent and may lead to the deposition of crystals of calcium oxalate intratubular, as well as by direct injury to the renal tubular epithelium, leading to apoptosis of the same. We report the case of a patient who after ingestion of the juice and fresh fruit, developed acute renal failure requiring dialysis, evolving with favourable outcome and recovery of renal function.

  7. Acute Kidney Injury Recognition and Management: A Review of the Literature and Current Evidence.

    PubMed

    Shah, Syed Raza; Tunio, Sameer Altaf; Arshad, Mohammad Hussham; Moazzam, Zorays; Noorani, Komal; Feroze, Anushe Mohsin; Shafquat, Maham; Hussain, Huma Syed; Jeoffrey, Syed Ali Hyder

    2016-01-01

    Acute renal failure is defined as a rapid decrease in the glomerular filtration rate, occurring over a period of hours to days and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. AKI is a catastrophic, life-threatening event in critically ill patients. AKI can be divided into pre-renal injury, intrinsic kidney disease (including vascular insults) and obstructive uropathies. The prognosis of AKI is highly dependent on the underlying cause of the injury. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Treatment of AKI is subjected to risk stratification and ongoing damage control measures, such as patients with sepsis, exposure to nephrotoxic agents, ischemia, bloody diarrhea, or volume loss, could be helped by optimizing the fluid administrations, antibiotics possessing least nephrotoxic potential, blood transfusion where hemoglobin is dangerously low, limiting the use of nephrotoxic agents including radio contrast use, while maximize the nutrition. Acute kidney injury remains a complex disorder with an apparent differentiation in pathology between septic and nonseptic forms of the disease. Although more studies are still required, progress in this area has been steady over the last decade with purposeful international collaboration. PMID:26652074

  8. Mechanisms of Acute Kidney Injury Induced by Experimental Lonomia obliqua Envenomation

    PubMed Central

    Berger, Markus; Santi, Lucélia; Beys-da-Silva, Walter O.; Oliveira, Fabrício Marcus Silva; Caliari, Marcelo Vidigal; Yates, John R.; Ribeiro, Maria Aparecida; Guimarães, Jorge Almeida

    2015-01-01

    Background Lonomia obliqua caterpillar envenomation causes acute kidney injury (AKI), which can be responsible for its deadly actions. This study evaluates the possible mechanisms involved in the pathogenesis of renal dysfunction. Methods To characterize L. obliqua venom effects we subcutaneously injected rats and examined renal functional, morphological and biochemical parameters at several time points. We also performed discovery based proteomic analysis to measure protein expression to identify molecular pathways of renal disease. Results L. obliqua envenomation causes acute tubular necrosis, which is associated with renal inflammation; formation of hematic casts, resulting from intravascular hemolysis; increase in vascular permeability and fibrosis. The dilation of Bowman’s space and glomerular tuft is related to fluid leakage and intra-glomerular fibrin deposition, respectively, since tissue factor procoagulant activity increases in the kidney. Systemic hypotension also contributes to these alterations and to the sudden loss of basic renal functions, including filtration and excretion capacities, urinary concentration and maintenance of fluid homeostasis. In addition, envenomed kidneys increases expression of proteins involved in cell stress, inflammation, tissue injury, heme-induced oxidative stress, coagulation and complement system activation. Finally, the localization of the venom in renal tissue agrees with morphological and functional alterations, suggesting also a direct nephrotoxic activity. Conclusions Mechanisms of L. obliqua-induced AKI are complex involving mainly glomerular and tubular functional impairment and vascular alterations. These results are important to understand the mechanisms of renal injury and may suggest more efficient ways to prevent or attenuate the pathology of Lonomia’s envenomation. PMID:24798088

  9. Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials.

    PubMed

    Westenfelder, Christof; Togel, Florian E

    2011-09-01

    Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts. Infused mesenchymal stem cells, recruited to renal sites of injury, did not significantly differentiate into target cells but rather disappeared from kidneys and other organs within 72 h. Furthermore, at 3 months, compared with vehicle-treated controls, renal function was well preserved and interstitial fibrosis was absent. These preclinical data served as the scientific basis for a recently completed Phase I Clinical Trial (http://www.clinicaltrials.gov; # NCT00733876), in which patients at high risk for cardiac surgery-associated AKI were treated with allogeneic mesenchymal stem cells. Until now, MSC therapy in the study subjects has been safe, and none of the patients has developed postoperative AKI or subsequent loss of renal function, suggesting that this novel form of therapy may have promise in this group of high-risk patients, which will be further investigated in a Phase II Trial.

  10. The neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats

    PubMed Central

    Li, Guofu; Jia, Jia; Ji, Kaiqiang; Gong, Xiaoying; Wang, Rui; Zhang, Xiaoli; Wang, Haiyuan; Zang, Bin

    2016-01-01

    Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury. PMID:27430552

  11. Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

    PubMed Central

    Agarwal, Banwari; Davenport, Andrew

    2014-01-01

    Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease (MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period. PMID:25349641

  12. Acute Kidney Injury Recognition and Management: A Review of the Literature and Current Evidence

    PubMed Central

    Shah, Syed Raza; Tunio, Sameer Altaf; Arshad, Mohammad Hussham; Moazzam, Zorays; Noorani, Komal; Feroze, Anushe Mohsin; Shafquat, Maham; Hussain, Huma Syed; Jeoffrey, Syed Ali Hyder

    2016-01-01

    Acute renal failure is defined as a rapid decrease in the glomerular filtration rate, occurring over a period of hours to days and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. AKI is a catastrophic, life-threatening event in critically ill patients. AKI can be divided into pre-renal injury, intrinsic kidney disease (including vascular insults) and obstructive uropathies. The prognosis of AKI is highly dependent on the underlying cause of the injury. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Treatment of AKI is subjected to risk stratification and ongoing damage control measures, such as patients with sepsis, exposure to nephrotoxic agents, ischemia, bloody diarrhea, or volume loss, could be helped by optimizing the fluid administrations, antibiotics possessing least nephrotoxic potential, blood transfusion where hemoglobin is dangerously low, limiting the use of nephrotoxic agents including radio contrast use, while maximize the nutrition. Acute kidney injury remains a complex disorder with an apparent differentiation in pathology between septic and nonseptic forms of the disease. Although more studies are still required, progress in this area has been steady over the last decade with purposeful international collaboration. PMID:26652074

  13. Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

    SciTech Connect

    Chen, Jiao; Shetty, Sreerama; Zhang, Ping; Gao, Rong; Hu, Yuxin; Wang, Shuxia; Li, Zhenyu; Fu, Jian

    2014-06-01

    The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

  14. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury.

    PubMed

    de Bragança, Ana C; Volpini, Rildo A; Mehrotra, Purvi; Andrade, Lúcia; Basile, David P

    2016-07-01

    Reductions in renal microvasculature density and increased lymphocyte activity may play critical roles in the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) induced by ischemia/reperfusion injury (IRI). Vitamin D deficiency is associated with tubulointerstitial damage and fibrosis progression following IRI-AKI We evaluated the effect of vitamin D deficiency in sustained IRI-AKI, hypothesizing that such deficiency contributes to the early reduction in renal capillary density or alters the lymphocyte response to IRI Wistar rats were fed vitamin D-free or standard diets for 35 days. On day 28, rats were randomized into four groups: control, vitamin D deficient (VDD), bilateral IRI, and VDD+IRI Indices of renal injury and recovery were evaluated for up to 7 days following the surgical procedures. VDD rats showed reduced capillary density (by cablin staining), even in the absence of renal I/R. In comparison with VDD and IRI rats, VDD+IRI rats manifested a significant exacerbation of capillary rarefaction as well as higher urinary volume, kidney weight/body weight ratio, tissue injury scores, fibroblast-specific protein-1, and alpha-smooth muscle actin. VDD+IRI rats also had higher numbers of infiltrating activated CD4(+) and CD8(+) cells staining for interferon gamma and interleukin-17, with a significant elevation in the Th17/T-regulatory cell ratio. These data suggest that vitamin D deficiency impairs renal repair responses to I/R injury, exacerbates changes in renal capillary density, as well as promoting fibrosis and inflammation, which may contribute to the transition from AKI to CKD.

  15. Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies).

    PubMed

    Ichai, Carole; Vinsonneau, Christophe; Souweine, Bertrand; Armando, Fabien; Canet, Emmanuel; Clec'h, Christophe; Constantin, Jean-Michel; Darmon, Michaël; Duranteau, Jacques; Gaillot, Théophille; Garnier, Arnaud; Jacob, Laurent; Joannes-Boyau, Olivier; Juillard, Laurent; Journois, Didier; Lautrette, Alexandre; Muller, Laurent; Legrand, Matthieu; Lerolle, Nicolas; Rimmelé, Thomas; Rondeau, Eric; Tamion, Fabienne; Walrave, Yannick; Velly, Lionel

    2016-12-01

    Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall. PMID:27230984

  16. Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies).

    PubMed

    Ichai, Carole; Vinsonneau, Christophe; Souweine, Bertrand; Armando, Fabien; Canet, Emmanuel; Clec'h, Christophe; Constantin, Jean-Michel; Darmon, Michaël; Duranteau, Jacques; Gaillot, Théophille; Garnier, Arnaud; Jacob, Laurent; Joannes-Boyau, Olivier; Juillard, Laurent; Journois, Didier; Lautrette, Alexandre; Muller, Laurent; Legrand, Matthieu; Lerolle, Nicolas; Rimmelé, Thomas; Rondeau, Eric; Tamion, Fabienne; Walrave, Yannick; Velly, Lionel

    2016-12-01

    Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall.

  17. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: part 2: renal replacement therapy.

    PubMed

    Jörres, Achim; John, Stefan; Lewington, Andrew; ter Wee, Pieter M; Vanholder, Raymond; Van Biesen, Wim; Tattersall, James

    2013-12-01

    This paper provides an endorsement of the KDIGO guideline on acute kidney injury; more specifically, on the part that concerns renal replacement therapy. New evidence that has emerged since the publication of the KDIGO guideline was taken into account, and the guideline is commented on from a European perspective. Advice is given on when to start and stop renal replacement therapy in acute kidney injury; which modalities should be preferentially be applied, and in which conditions; how to gain access to circulation; how to measure adequacy; and which dose can be recommended.

  18. CXCR₄antagonism as a therapeutic approach to prevent acute kidney injury.

    PubMed

    Zuk, A; Gershenovich, M; Ivanova, Y; MacFarland, R T; Fricker, S P; Ledbetter, S

    2014-10-01

    We examined whether antagonism of the CXCR₄receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR₄is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR₄antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR₄inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR₄antagonism with plerixafor may be a potential option to prevent AKI. PMID:25080523

  19. Hemojuvelin Modulates Iron Stress During Acute Kidney Injury: Improved by Furin Inhibitor

    PubMed Central

    Young, Guang-Huar; Huang, Tao-Min; Wu, Che-Hsiung; Lai, Chun-Fu; Hou, Chun-Cheng; Peng, Kang-Yung; Liang, Chan-Jung; Lin, Shuei-Liong; Chang, Shih-Chung; Tsai, Pi-Ru; Wu, Kwan-Dun

    2014-01-01

    Abstract Aims: Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI. Results: By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor (FI) decreases furin-mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The FI could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1, prevent the accumulation of iron in the kidney, and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite. Innovation: This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI. Conclusion: Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the FI. Antioxid. Redox Signal. 20, 1181–1194. PMID:23901875

  20. Farnesoid X Receptor Protects against Kidney Injury in Uninephrectomized Obese Mice.

    PubMed

    Gai, Zhibo; Gui, Ting; Hiller, Christian; Kullak-Ublick, Gerd A

    2016-01-29

    Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (Grp78), and C/EBP-homologous protein, markers of endoplasmic reticulum stress, was more prominent in the proximal tubules of 15 obese patients compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid, renal injury, renal lipid accumulation, apoptosis, and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following obeticholic acid treatment. Culturing renal proximal tubular cells with free fatty acid and FXR agonists showed that FXR activation protected cells from free fatty acid-induced oxidative stress and endoplasmic reticulum stress, as denoted by a reduction in the level of reactive oxygen species staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide/glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury.

  1. Bardoxolone methyl modulates efflux transporter and detoxifying enzyme expression in cisplatin-induced kidney cell injury.

    PubMed

    Atilano-Roque, Amandla; Aleksunes, Lauren M; Joy, Melanie S

    2016-09-30

    Cisplatin is prescribed for the treatment of solid tumors and elicits toxicity to kidney tubules, which limits its clinical use. Nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2) is a critical transcription factor that has been shown to protect against kidney injury through activation of antioxidant mechanisms. We aimed to evaluate the ability of short-term treatment with the Nrf2 activator bardoxolone methyl (CDDO-Me) to protect against cisplatin-induced kidney cell toxicity. Cell viability was assessed in human kidney proximal tubule epithelial cells (hPTCs) exposed to low, intermediate, and high cisplatin concentrations in the presence and absence of CDDO-Me, administered either prior to or after cisplatin. Treatment with cisplatin alone resulted in reductions in hPTC viability, while CDDO-Me administered prior to or after cisplatin exposure yielded significantly higher cell viability (17%-71%). Gene regulation (mRNA expression) studies revealed the ability of CDDO-Me to modify protective pathways including Nrf2 induced detoxifying genes [GCLC (increased 1.9-fold), NQO1 (increased 9.3-fold)], and an efflux transporter [SLC47A1 (increased 4.5-fold)] at 12h. Protein assessments were in agreement with gene expression. Immunofluorescence revealed localization of GCLC and NQO1 to the nucleus and cytosol, respectively, with CDDO-Me administered prior to or after cisplatin exposure. The findings of enhanced cell viability and increased expression of detoxifying enzymes (GCLC and NQO1) and the multidrug and toxin extrusion protein 1 (MATE1) efflux transporter (SLC47A1) in hPTCs exposed to CDDO-Me, suggest that intermittent treatment with CDDO-Me prior to or after cisplatin exposure may be a promising approach to mitigate acute kidney injury.

  2. Bardoxolone methyl modulates efflux transporter and detoxifying enzyme expression in cisplatin-induced kidney cell injury.

    PubMed

    Atilano-Roque, Amandla; Aleksunes, Lauren M; Joy, Melanie S

    2016-09-30

    Cisplatin is prescribed for the treatment of solid tumors and elicits toxicity to kidney tubules, which limits its clinical use. Nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2) is a critical transcription factor that has been shown to protect against kidney injury through activation of antioxidant mechanisms. We aimed to evaluate the ability of short-term treatment with the Nrf2 activator bardoxolone methyl (CDDO-Me) to protect against cisplatin-induced kidney cell toxicity. Cell viability was assessed in human kidney proximal tubule epithelial cells (hPTCs) exposed to low, intermediate, and high cisplatin concentrations in the presence and absence of CDDO-Me, administered either prior to or after cisplatin. Treatment with cisplatin alone resulted in reductions in hPTC viability, while CDDO-Me administered prior to or after cisplatin exposure yielded significantly higher cell viability (17%-71%). Gene regulation (mRNA expression) studies revealed the ability of CDDO-Me to modify protective pathways including Nrf2 induced detoxifying genes [GCLC (increased 1.9-fold), NQO1 (increased 9.3-fold)], and an efflux transporter [SLC47A1 (increased 4.5-fold)] at 12h. Protein assessments were in agreement with gene expression. Immunofluorescence revealed localization of GCLC and NQO1 to the nucleus and cytosol, respectively, with CDDO-Me administered prior to or after cisplatin exposure. The findings of enhanced cell viability and increased expression of detoxifying enzymes (GCLC and NQO1) and the multidrug and toxin extrusion protein 1 (MATE1) efflux transporter (SLC47A1) in hPTCs exposed to CDDO-Me, suggest that intermittent treatment with CDDO-Me prior to or after cisplatin exposure may be a promising approach to mitigate acute kidney injury. PMID:27480280

  3. Biochemical and histological study of rat liver and kidney injury induced by Cisplatin.

    PubMed

    Palipoch, Sarawoot; Punsawad, Chuchard

    2013-09-01

    Cisplatin is a chemotherapeutic agent widely used in treatment of several cancers. It is documented as a major cause of clinical nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the involvement of oxidative stress in the pathogenesis of cisplatin-induced liver and kidney injury. Wistar rats were divided into four groups. Group 1 (control) was intraperitoneally (IP) injected with a single dose of 0.85% normal saline. Groups 2, 3 and 4 were IP injected with single doses of cisplatin at 10, 25 and 50 mg/kg body weight (BW), respectively. At 24, 48, 72, 96 and 120 h after injection, BW, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and activity of superoxide dismutase (SOD) and histology of the liver and kidney were evaluated. Cisplatin caused a reduction in BW of rats in groups 2, 3 and 4 at all post injection intervals. The levels of serum ALT, AST, BUN and creatinine and MDA of the kidney and liver were markedly increased especially at 48 and 72 h, whereas the activity of SOD was decreased after cisplatin injection. Liver sections revealed moderate to severe congestion with dilation of the hepatic artery, portal vein and bile duct and disorganization of hepatic cords at 50 mg/kg of cisplatin. Kidney sections illustrated mild to moderate tubular necrosis at 25 and 50 mg/kg of cisplatin. Therefore, oxidative stress was implicated in the pathogenesis of liver and kidney injury causing biochemical and histological alterations.

  4. Urine Injury Biomarkers and Risk of Adverse Outcomes in Recipients of Prevalent Kidney Transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial.

    PubMed

    Bansal, Nisha; Carpenter, Myra A; Weiner, Daniel E; Levey, Andrew S; Pfeffer, Marc; Kusek, John W; Cai, Jianwen; Hunsicker, Lawrence G; Park, Meyeon; Bennett, Michael; Liu, Kathleen D; Hsu, Chi-Yuan

    2016-07-01

    Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% CI, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes. PMID:26538631

  5. Gene Expression Analysis Reveals the Cell Cycle and Kinetochore Genes Participating in Ischemia Reperfusion Injury and Early Development in Kidney

    PubMed Central

    Barrera-Chimal, Jonatan; Bobadilla, Norma A.; Park, Peter J.; Vaidya, Vishal S.

    2011-01-01

    Background The molecular mechanisms that mediate the ischemia-reperfusion (I/R) injury in kidney are not completely understood. It is also largely unknown whether such mechanisms overlap with those governing the early development of kidney. Methodology/Principal Findings We performed gene expression analysis to investigate the transcriptome changes during regeneration after I/R injury in the rat (0 hr, 6 hr, 24 hr, and 120 hr after reperfusion) and early development of mouse kidney (embryonic day 16 p.c. and postnatal 1 and 7 day). Pathway analysis revealed a wide spectrum of molecular functions that may participate in the regeneration and developmental processes of kidney as well as the functional association between them. While the genes associated with cell cycle, immunity, inflammation, and apoptosis were globally activated during the regeneration after I/R injury, the genes encoding various transporters and metabolic enzymes were down-regulated. We also observed that these injury-associated molecular functions largely overlap with those of early kidney development. In particular, the up-regulation of kinases and kinesins with roles in cell division was common during regeneration and early developmental kidney as validated by real-time PCR and immunohistochemistry. Conclusions In addition to the candidate genes whose up-regulation constitutes an overlapping expression signature between kidney regeneration and development, this study lays a foundation for studying the functional relationship between two biological processes. PMID:21980527

  6. Toll‑like receptor 4 contributes to acute kidney injury after cardiopulmonary resuscitation in mice.

    PubMed

    Zhang, Qingsong; Li, Gang; Xu, Li; Li, Qian; Wang, Qianyan; Zhang, Yue; Zhang, Qing; Sun, Peng

    2016-10-01

    Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild‑type (C3H/HeN) and TLR4‑mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule‑1 (ICAM‑1), myeloperoxidase (MPO) and growth‑regulated oncogene‑β (GRO‑β) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM‑1, GRO‑β and MPO in a CA‑duration dependent manner. However, there was decreased expression of ICAM‑1, GRO‑β and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM‑1 and GRO‑β may be important in mediating inflammatory responses to renal injury after CPR. PMID:27510583

  7. Toll‑like receptor 4 contributes to acute kidney injury after cardiopulmonary resuscitation in mice.

    PubMed

    Zhang, Qingsong; Li, Gang; Xu, Li; Li, Qian; Wang, Qianyan; Zhang, Yue; Zhang, Qing; Sun, Peng

    2016-10-01

    Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild‑type (C3H/HeN) and TLR4‑mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule‑1 (ICAM‑1), myeloperoxidase (MPO) and growth‑regulated oncogene‑β (GRO‑β) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM‑1, GRO‑β and MPO in a CA‑duration dependent manner. However, there was decreased expression of ICAM‑1, GRO‑β and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM‑1 and GRO‑β may be important in mediating inflammatory responses to renal injury after CPR.

  8. Contrast-induced acute kidney injury: short- and long-term implications.

    PubMed

    Weisbord, Steven D; Palevsky, Paul M

    2011-05-01

    The intravascular administration of iodine-based contrast media remains a common cause of acute kidney injury and a leading cause of iatrogenic renal disease. Past research has elucidated the principal risk factors for contrast-induced acute kidney injury (CIAKI) and helped to establish the efficacy of various interventions for the prevention of this condition. The importance of preventing CIAKI has been underscored by a growing number of studies showing strong associations of CIAKI with serious adverse short- and long-term outcomes. However, it remains unclear whether these associations are causal. This is important because considerable health care resources are used to prevent CIAKI. If CIAKI is a marker, but not a mediator, of serious adverse downstream outcomes, more judicious and selective use of preventive care may be appropriate. Moreover, with an increasing number of studies reporting the underuse of coronary angiography in patients with acute coronary syndrome and underlying chronic kidney disease, presumably in part because of a fear of CIAKI, a clear understanding of whether this condition directly results in adverse downstream outcomes is essential. Careful inspection of past studies that investigated the association of CIAKI with adverse short- and long-term events sheds light on their strengths and weaknesses and provides insight into how future research may be better able to characterize the short- and long-term implications of this iatrogenic condition.

  9. Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.

    PubMed

    Palevsky, Paul M; Molitoris, Bruce A; Okusa, Mark D; Levin, Adeera; Waikar, Sushrut S; Wald, Ron; Chertow, Glenn M; Murray, Patrick T; Parikh, Chirag R; Shaw, Andrew D; Go, Alan S; Faubel, Sarah G; Kellum, John A; Chinchilli, Vernon M; Liu, Kathleen D; Cheung, Alfred K; Weisbord, Steven D; Chawla, Lakhmir S; Kaufman, James S; Devarajan, Prasad; Toto, Robert M; Hsu, Chi-yuan; Greene, Tom; Mehta, Ravindra L; Stokes, John B; Thompson, Aliza M; Thompson, B Taylor; Westenfelder, Christof S; Tumlin, James A; Warnock, David G; Shah, Sudhir V; Xie, Yining; Duggan, Emily G; Kimmel, Paul L; Star, Robert A

    2012-05-01

    Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.

  10. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

    PubMed Central

    Mori, Kiyoshi; Lee, H. Thomas; Rapoport, Dana; Drexler, Ian R.; Foster, Kirk; Yang, Jun; Schmidt-Ott, Kai M.; Chen, Xia; Li, Jau Yi; Weiss, Stacey; Mishra, Jaya; Cheema, Faisal H.; Markowitz, Glenn; Suganami, Takayoshi; Sawai, Kazutomo; Mukoyama, Masashi; Kunis, Cheryl; D’Agati, Vivette; Devarajan, Prasad; Barasch, Jonathan

    2005-01-01

    Neutrophil gelatinase–associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 μg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment. PMID:15711640

  11. Rapamycin protects against gentamicin-induced acute kidney injury via autophagy in mini-pig models.

    PubMed

    Cui, Jing; Bai, Xue-Yuan; Sun, Xuefeng; Cai, Guangyan; Hong, Quan; Ding, Rui; Chen, Xiangmei

    2015-01-01

    Gentamicin may cause acute kidney injury. The pathogenesis of gentamicin nephrotoxicity is unclear. Autophagy is a highly conserved physiological process involved in removing damaged or aged biological macromolecules and organelles from the cytoplasm. The role of autophagy in the pathogenesis of gentamicin nephrotoxicity is unclear. The miniature pigs are more similar to humans than are those of rodents, and thus they are more suitable as human disease models. Here we established the first gentamicin nephrotoxicity model in miniature pigs, investigated the role of autophagy in gentamicin-induced acute kidney injury, and determined the prevention potential of rapamycin against gentamicin-induced oxidative stress and renal dysfunction. At 0, 1, 3, 5, 7 and 10 days after gentamicin administration, changes in autophagy, oxidative damage, apoptosis and inflammation were assessed in the model group. Compared to the 0-day group, gentamicin administration caused marked nephrotoxicity in the 10-day group. In the kidneys of the 10-day group, the level of autophagy decreased, and oxidative damage and apoptosis were aggravated. After rapamycin intervention, autophagy activity was activated, renal damage in proximal tubules was markedly alleviated, and interstitium infiltration of inflammatory cells was decreased. These results suggest that rapamycin may ameliorate gentamicin-induced nephrotoxicity by enhancing autophagy. PMID:26052900

  12. NADPH Oxidase as a Therapeutic Target for Oxalate Induced Injury in Kidneys

    PubMed Central

    Peck, Ammon B.; Khan, Saeed R.

    2013-01-01

    A major role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes is to catalyze the production of superoxides and other reactive oxygen species (ROS). These ROS, in turn, play a key role as messengers in cell signal transduction and cell cycling, but when they are produced in excess they can lead to oxidative stress (OS). Oxidative stress in the kidneys is now considered a major cause of renal injury and inflammation, giving rise to a variety of pathological disorders. In this review, we discuss the putative role of oxalate in producing oxidative stress via the production of reactive oxygen species by isoforms of NADPH oxidases expressed in different cellular locations of the kidneys. Most renal cells produce ROS, and recent data indicate a direct correlation between upregulated gene expressions of NADPH oxidase, ROS, and inflammation. Renal tissue expression of multiple NADPH oxidase isoforms most likely will impact the future use of different antioxidants and NADPH oxidase inhibitors to minimize OS and renal tissue injury in hyperoxaluria-induced kidney stone disease. PMID:23840917

  13. Etiology and outcomes of anuria in acute kidney injury: a single center study

    PubMed Central

    Choi, Hye Min; Kim, Sun Chul; Kim, Myung-Gyu; Jo, Sang-Kyung; Cho, Won Yong; Kim, Hyoung Kyu

    2014-01-01

    Background It was previously known that anuric acute kidney injury (AKI) is uncommon and its occurrence suggests complete ureteral obstruction, shock, or a major vascular event. As the epidemiology of AKI has significantly changed over the past decade, it is possible that the incidence, etiology, or clinical characteristics of anuric AKI have also changed. Methods A prospective cohort study was conducted that included all patients undergoing renal replacement therapy (RRT) for AKI during a 2-year period in a tertiary hospital. Patients were classified as having anuric, oliguric, or nonoliguric AKI based on their volume of urine when RRT started using the modified Acute Kidney Injury Network criteria. Results Of the 203 patients included in the study, 21.2% met the criteria for anuric AKI. Septic and postoperative AKI were the main causes of anuric AKI, with 60.5% of incidences occurring in hospital. Anuric AKI was associated with a younger age, a lower prevalence of pre-morbid chronic kidney disease and diabetes, more frequent continuous RRT requirement, and multi-organ dysfunction. In addition, patients with anuric AKI had a higher rate of in-hospital mortality and long-term dependence on RRT than patients with nonanuric AKI. Conclusion Anuric AKI is common, with sepsis as the main etiological insult, and is associated with adverse outcomes among patients with AKI who require RRT. PMID:26484014

  14. New Biomarkers of Acute Kidney Injury and the Cardio-renal Syndrome

    PubMed Central

    2011-01-01

    Changes in renal function are one of the most common manifestations of severe illness. There is a clinical need to intervene early with proven treatments in patients with potentially deleterious changes in renal function. Unfortunately progress has been hindered by poor definitions of renal dysfunction and a lack of early biomarkers of renal injury. In recent years, the definitional problem has been addressed with the establishment of a new well-defined diagnostic entity, acute kidney injury (AKI), which encompasses the wide spectrum of kidney dysfunction, together with clearer definition and sub-classification of the cardio-renal syndromes. From the laboratory have emerged new biomarkers which allow early detection of AKI, including neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C. This review describes the new concepts of AKI and the cardio-renal syndromes as well as novel biomarkers which allow early detection of AKI. Panels of AKI biomarker tests are likely to revolutionise the diagnosis and management of critically ill patients in the coming years. Earlier diagnosis and intervention should significantly reduce the morbidity and mortality associated with acute kidney damage. PMID:21474979

  15. Rapamycin protects against gentamicin-induced acute kidney injury via autophagy in mini-pig models

    PubMed Central

    Cui, Jing; Bai, Xue-Yuan; Sun, Xuefeng; Cai, Guangyan; Hong, Quan; Ding, Rui; Chen, Xiangmei

    2015-01-01

    Gentamicin may cause acute kidney injury. The pathogenesis of gentamicin nephrotoxicity is unclear. Autophagy is a highly conserved physiological process involved in removing damaged or aged biological macromolecules and organelles from the cytoplasm. The role of autophagy in the pathogenesis of gentamicin nephrotoxicity is unclear. The miniature pigs are more similar to humans than are those of rodents, and thus they are more suitable as human disease models. Here we established the first gentamicin nephrotoxicity model in miniature pigs, investigated the role of autophagy in gentamicin-induced acute kidney injury, and determined the prevention potential of rapamycin against gentamicin-induced oxidative stress and renal dysfunction. At 0, 1, 3, 5, 7 and 10 days after gentamicin administration, changes in autophagy, oxidative damage, apoptosis and inflammation were assessed in the model group. Compared to the 0-day group, gentamicin administration caused marked nephrotoxicity in the 10-day group. In the kidneys of the 10-day group, the level of autophagy decreased, and oxidative damage and apoptosis were aggravated. After rapamycin intervention, autophagy activity was activated, renal damage in proximal tubules was markedly alleviated, and interstitium infiltration of inflammatory cells was decreased. These results suggest that rapamycin may ameliorate gentamicin-induced nephrotoxicity by enhancing autophagy. PMID:26052900

  16. Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

    PubMed Central

    Braga, Tárcio Teodoro; Felizardo, Raphael José Ferreira; Andrade-Oliveira, Vinícius; Hiyane, Meire Ioshie; da Silva, João Santana; Câmara, Niels Olsen Saraiva

    2014-01-01

    Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN. PMID:25132730

  17. Major comorbid disease processes associated with increased incidence of acute kidney injury

    PubMed Central

    Farooqi, Salwa; Dickhout, Jeffrey G

    2016-01-01

    Acute kidney injury (AKI) is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS). This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including: Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI. PMID:26981437

  18. EFFECTS OF MATERNAL EXPOSURE TO CADMIUM OXIDE NANOPARTICLES DURING PREGNANCY ON MATERNAL AND OFFSPRING KIDNEY INJURY MARKERS USING A MURINE MODEL

    PubMed Central

    Blum, Jason L.; Edwards, Joshua R.; Prozialeck, Walter C.; Xiong, Judy Q.; Zelikoff, Judith T.

    2015-01-01

    Nanoparticles (NP) are pervasive in many areas of modern life, with little known about their potential toxicities. One commercially important NP is cadmium oxide (CdO), which is used to synthesize other Cd-containing NP, such as quantum dots. Cadmium (Cd) is a well-known nephrotoxicant, but the nephrotoxic potential of CdO NP remains unknown, particularly when exposure occurs during pregnancy. Therefore, pregnant CD-1 mice were used to examine the effects of inhaled CdO NP (230 μg CdO NP/m3) on maternal and neonatal renal function by examining urinary creatinine and urinary biomarkers of kidney injury, including kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhalation of CdO NP by dams produced a fivefold increase in urinary Kim-1 with no marked effect on urinary creatinine levels. Kim-1 mRNA expression peaked by gestational day (GD) 10.5, and NGAL expression increased from GD 10.5 to 17.5. In addition, histological analyses revealed proximal tubular pathology at GD 10.5. Neonatal Kim-1 mRNA expression rose between postnatal days (PND) 7 and 14, with mammary glands/milk being the apparent source of Cd for offspring. These studies demonstrate that, similar to what is seen with other Cd forms, Cd associated with inhaled CdO NP results in renal injury to both directly exposed dam and offspring. As commercial uses for nanotechnology continue to expand throughout the world, risks for unintentional exposure in the workplace increase. Given the large number of women in the industrial workforce, care needs to be taken to protect these already vulnerable populations. PMID:26090557

  19. Effects of Maternal Exposure to Cadmium Oxide Nanoparticles During Pregnancy on Maternal and Offspring Kidney Injury Markers Using a Murine Model.

    PubMed

    Blum, Jason L; Edwards, Joshua R; Prozialeck, Walter C; Xiong, Judy Q; Zelikoff, Judith T

    2015-01-01

    Nanoparticles (NP) are pervasive in many areas of modern life, with little known about their potential toxicities. One commercially important NP is cadmium oxide (CdO), which is used to synthesize other Cd-containing NP, such as quantum dots. Cadmium (Cd) is a well-known nephrotoxicant, but the nephrotoxic potential of CdO NP remains unknown, particularly when exposure occurs during pregnancy. Therefore, pregnant CD-1 mice were used to examine the effects of inhaled CdO NP (230 μg CdO NP/m(3)) on maternal and neonatal renal function by examining urinary creatinine and urinary biomarkers of kidney injury, including kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhalation of CdO NP by dams produced a fivefold increase in urinary Kim-1 with no marked effect on urinary creatinine levels. Kim-1 mRNA expression peaked by gestational day (GD) 10.5, and NGAL expression increased from GD 10.5 to 17.5. In addition, histological analyses revealed proximal tubular pathology at GD 10.5. Neonatal Kim-1 mRNA expression rose between postnatal days (PND) 7 and 14, with mammary glands/milk being the apparent source of Cd for offspring. These studies demonstrate that, similar to what is seen with other Cd forms, Cd associated with inhaled CdO NP results in renal injury to both directly exposed dam and offspring. As commercial uses for nanotechnology continue to expand throughout the world, risks for unintentional exposure in the workplace increase. Given the large number of women in the industrial workforce, care needs to be taken to protect these already vulnerable populations. PMID:26090557

  20. Ulinastatin Protects against Acute Kidney Injury in Infant Piglets Model Undergoing Surgery on Hypothermic Low-Flow Cardiopulmonary Bypass

    PubMed Central

    Wang, Xiaocou; Xue, Qinghua; Yan, Fuxia; Liu, Jinping; Li, Shoujun; Hu, Shengshou

    2015-01-01

    Objective Infants are more vulnerable to kidney injuries induced by inflammatory response syndrome and ischemia-reperfusion injury following cardiopulmonary bypass especially with prolonged hypothermic low-flow (HLF). This study aims to evaluate the protective role of ulinastatin, an anti-inflammatory agent, against acute kidney injuries in infant piglets model undergoing surgery on HLF cardiopulmonary bypass. Methods Eighteen general-type infant piglets were randomly separated into the ulinastatin group (Group U, n = 6), the control group (Group C, n = 6), and the sham operation group (Group S, n = 6), and anaesthetized. The groups U and C received following experimental procedure: median thoracotomy, routine CPB and HLF, and finally weaned from CPB. The group S only underwent sham median thoracotomy. Ulinastatin at a dose of 5,000 units/kg body weight and a certain volume of saline were administrated to animals of the groups U and C at the beginning of CPB and at aortic declamping, respectively. Venous blood samples were collected at 3 different time points: after anesthesia induction in all experimental groups, 5 minutes, and 120 minutes after CPB in the Groups U and C. Markers for inflammation and acute kidney injury were tested in the collected plasma. N-acetyl-β-D-glucosaminidase (NAG) from urine, markers of oxidative stress injury and TUNEL-positive cells in kidney tissues were also detected. Results The expressions of plasma inflammatory markers and acute kidney injury markers increased both in Group U and Group C at 5 min and 120 min after CPB. Also, numbers of TUNEL-positive cells and oxidative stress markers in kidney rose in both groups. At the time point of 120-min after CPB, compared with the Group C, some plasma inflammatory and acute kidney injury markers as well as TUNEL-positive cells and oxidative stress markers in kidney were significantly reduced in the Group U. Histologic analyses showed that HLF promoted acute tubular necrosis and dilatation

  1. Taurine protected kidney from oxidative injury through mitochondrial-linked pathway in a rat model of nephrolithiasis.

    PubMed

    Li, Cheng Yang; Deng, Yao Liang; Sun, Bing Hua

    2009-08-01

    Hyperoxaluria and crystal deposition induce oxidative stress (OS) and renal epithelial cells injury, both mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are considered as the main sources of reactive oxygen species (ROS). Taurine is known to have antioxidant activity and shows renoprotective effect. We investigate the effect of taurine treatment on renal protection, and the putative source of ROS, in a rat model of calcium oxalate nephrolithiasis. Rats were administered with 2.5% (V/V) ethylene glycol + 2.5% (W/V) ammonium chloride (4 ml/day), with restriction on intake of drinking water (20 ml/day) for 4 weeks. Simultaneous treatment with taurine (2% W/W, mixed with the chow) was performed. At the end of the study, indexes of OS and renal injury were assessed. Renal tubular ultrastructure changes were analyzed under transmission electron microscopy. Crystal deposition in kidney was scored under light microscopy. Angiotensin II in kidney homogenates was determined by radioimmunoassay. Expression of NADPH oxidase subunits p47phox and Nox-4 mRNAs in kidney was evaluated by real time-polymerase chain reaction. The data showed that oxidative injury of the kidney occurred in nephrolithiasis-induced rats. Hyperplasia of mitochondria developed in renal tubular epithelium. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mitochondria decreased and the mitochondrial membrane showed oxidative injury. Taurine treatment alleviated the oxidative injury of the kidney, improved SOD and GSH-Px activities, as well as the mitochondrial membrane injury, with lesser crystal depositions in the kidney. We could not detect statistical changes in the renal angiotensin II level, and the renal p47phox and Nox-4 mRNAs expression in those rats. The results suggest that mitochondria but not NADPH oxidase may account for the OS and taurine protected kidney from oxidative injury through mitochondrial-linked pathway in this rat

  2. Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model

    PubMed Central

    Park, Jong Hee; Lee, Jung Hwa; Lee, Hi Bahl; Miyata, Toshio; Ha, Hunjoo

    2016-01-01

    Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, but no effective therapeutic strategy is available. Because plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a key factor in extracellular matrix (ECM) accumulation in diabetic nephropathy, this study examined the renoprotective effects of TM5275 and TM5441, two novel orally active PAI-1 inhibitors that do not trigger bleeding episodes, in streptozotocin (STZ)-induced diabetic mice. TM5275 (50 mg/kg) and TM5441 (10 mg/kg) were administered orally for 16 weeks to STZ-induced diabetic and age-matched control mice. Relative to the control mice, the diabetic mice showed significantly increased (p < 0.05) plasma glucose and creatinine levels, urinary albumin excretion, kidney-to-bodyweight ratios, glomerular volume, and fractional mesangial area. Markers of fibrosis and inflammation along with PAI-1 were also upregulated in the kidney of diabetic mice, and treatment with TM5275 and TM5441 effectively inhibited albuminuria, mesangial expansion, ECM accumulation, and macrophage infiltration in diabetic kidneys. Furthermore, in mouse proximal tubular epithelial (mProx24) cells, both TM5275 and TM5441 effectively inhibited PAI-1-induced mRNA expression of fibrosis and inflammation markers and also reversed PAI-1-induced inhibition of plasmin activity, which confirmed the efficacy of the TM compounds as PAI-1 inhibitors. These data suggest that TM compounds could be used to prevent diabetic kidney injury. PMID:27258009

  3. From the nephrologist's point of view: diversity of causes and clinical features of acute kidney injury

    PubMed Central

    Bienholz, Anja; Wilde, Benjamin; Kribben, Andreas

    2015-01-01

    Acute kidney injury (AKI) is a clinical syndrome with multiple entities. Although AKI implies renal damage, functional impairment or both, diagnosis is solely based on the functional parameters of serum creatinine and urine output. The latest definition was provided by the Kidney Disease Improving Global Outcomes (KDIGO) working group in 2012. Independent of the underlying disease, and even in the case of full recovery, AKI is associated with an increased morbidity and mortality. Awareness of the patient's individual risk profile and the diversity of causes and clinical features of AKI is pivotal for optimization of prophylaxes, diagnosis and therapy of each form of AKI. A differentiated and individualized approach is required to improve patient mortality, morbidity, long-term kidney function and eventually the quality of life. In this review, we provide an overview of the different clinical settings in which specific forms of AKI may occur and point out possible diagnostic as well as therapeutic approaches. Secifically AKI is discussed in the context of non-kidney organ failure, organ transplantation, sepsis, malignancy and autoimmune disease. PMID:26251707

  4. An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis.

    PubMed

    Choudhry, Wajid M; Nori, Uday S; Nadasdy, Tibor; Satoskar, Anjali A

    2016-05-01

    Diagnostic kidney biopsies sometimes yield clinically unsuspected diagnoses. We present a case of a 69-year-old woman with established ANCA-associated vasculitis (AAV) of 4 years duration who was in clinical remission following cytotoxic therapy and was on maintenance immunosuppression. She presented to the hospital with acute kidney injury (AKI), symptoms suggestive of a systemic vasculitis, and in addition had hypercalcemia, metabolic alkalosis. A relapse in the AAV was suspected but a diagnostic kidney biopsy showed acute tubular necrosis, patchy interstitial inflammation, and calcium phosphate deposits. It was found that the patient recently started consuming large doses of over-the-counter calcium-containing antacids and vitamin Dcontaining multivitamin supplements. Cessation of these drugs led to improvement of renal function to baseline. This case highlights several teaching points: (1) the kidney biopsy can prove to be critically important even in cases where there appears to be a more obvious clinical diagnosis, (2) AK due to calcium-alkali syndrome has characteristic histopathological changes, and (3) that the triad of hypercalcemia, metabolic alkalosis, and AKI is exclusively associated with the ingestion of excessive quantities of calcium-containing antacids. The physician should keep this in mind, and pro-actively seek pertinent medication history from the patient. A brief review of calcium-alkali syndrome is given.

  5. An unexpected cause of acute kidney injury in a patient with ANCA associated vasculitis.

    PubMed

    Choudhry, Wajid M; Nori, Uday S; Nadasdy, Tibor; Satoskar, Anjali A

    2016-05-01

    Diagnostic kidney biopsies sometimes yield clinically unsuspected diagnoses. We present a case of a 69-year-old woman with established ANCA-associated vasculitis (AAV) of 4 years duration who was in clinical remission following cytotoxic therapy and was on maintenance immunosuppression. She presented to the hospital with acute kidney injury (AKI), symptoms suggestive of a systemic vasculitis, and in addition had hypercalcemia, metabolic alkalosis. A relapse in the AAV was suspected but a diagnostic kidney biopsy showed acute tubular necrosis, patchy interstitial inflammation, and calcium phosphate deposits. It was found that the patient recently started consuming large doses of over-the-counter calcium-containing antacids and vitamin Dcontaining multivitamin supplements. Cessation of these drugs led to improvement of renal function to baseline. This case highlights several teaching points: (1) the kidney biopsy can prove to be critically important even in cases where there appears to be a more obvious clinical diagnosis, (2) AK due to calcium-alkali syndrome has characteristic histopathological changes, and (3) that the triad of hypercalcemia, metabolic alkalosis, and AKI is exclusively associated with the ingestion of excessive quantities of calcium-containing antacids. The physician should keep this in mind, and pro-actively seek pertinent medication history from the patient. A brief review of calcium-alkali syndrome is given. PMID:26932179

  6. Lysosomal protease cathepsin D; a new driver of apoptosis during acute kidney injury

    PubMed Central

    Cocchiaro, Pasquale; Fox, Christopher; Tregidgo, Nicholas W.; Howarth, Rachel; Wood, Katrina M.; Situmorang, Gerhard R.; Pavone, Luigi M.; Sheerin, Neil S.; Moles, Anna

    2016-01-01

    Acute kidney injury (AKI) is an abrupt reduction in kidney function caused by different pathological processes. It is associated with a significant morbidity and mortality in the acute phase and an increased risk of developing End Stage Renal Disease. Despite the progress in the management of the disease, mortality rates in the last five decades remain unchanged at around 50%. Therefore there is an urgent need to find new therapeutic strategies to treat AKI. Lysosomal proteases, particularly Cathepsin D (CtsD), play multiple roles in apoptosis however, their role in AKI is still unknown. Here we describe a novel role for CtsD in AKI. CtsD expression was upregulated in damaged tubular cells in nephrotoxic and ischemia reperfusion (IRI) induced AKI. CtsD inhibition using Pepstatin A led to an improvement in kidney function, a reduction in apoptosis and a decrease in tubular cell damage in kidneys with nephrotoxic or IRI induced AKI. Pepstatin A treatment slowed interstitial fibrosis progression following IRI induced AKI. Renal transplant biopsies with acute tubular necrosis demonstrated high levels of CtsD in damaged tubular cells. These results support a role for CtsD in apoptosis during AKI opening new avenues for the treatment of AKI by targeting lysosomal proteases. PMID:27271556

  7. Statins for the prevention of contrast-induced acute kidney injury.

    PubMed

    Ball, Timothy; McCullough, Peter A

    2014-01-01

    Acute kidney injury (AKI) is a common medical problem, especially in patients undergoing cardiovascular procedures. The risk of kidney damage has multiple determinants and is often related to or exacerbated by intravenous or intra-arterial iodinated contrast. Contrast-induced AKI (CI-AKI) has been associated with an increased risk of subsequent myocardial infarction, stroke, the development of heart failure, rehospitalization, progression of chronic kidney disease, end-stage renal disease, and death. Statins have been studied extensively in the setting of chronic kidney disease and they have been shown to reduce albuminuria, but they have had no effect on the progressive reduction of glomerular filtration or the need for renal replacement therapy. Several meta-analyses have shown a protective effect of short-term statin administration on CI-AKI and led to two large randomized controlled trials evaluating the role of rosuvastatin in the prevention of CI-AKI in high-risk patients with acute coronary syndrome and diabetes mellitus. Both trials showed a benefit of rosuvastatin prior to contrast administration in a statin-naive patient population. In aggregate, these studies support the short-term use of statins specifically for the prevention of CI-AKI in patients undergoing coronary angiography with or without percutaneous coronary intervention. PMID:25343843

  8. NLRP3 inflammasome mediates contrast media-induced acute kidney injury by regulating cell apoptosis

    PubMed Central

    Shen, Jianxiao; Wang, Ling; Jiang, Na; Mou, Shan; Zhang, Minfang; Gu, Leyi; Shao, Xinghua; Wang, Qin; Qi, Chaojun; Li, Shu; Wang, Wanpeng; Che, Xiajing; Ni, Zhaohui

    2016-01-01

    Iodinated contrast media serves as a direct causative factor of acute kidney injury (AKI) and is involved in the progression of cellular dysfunction and apoptosis. Emerging evidence indicates that NLRP3 inflammasome triggers inflammation, apoptosis and tissue injury during AKI. Nevertheless, the underlying renoprotection mechanism of NLRP3 inflammasome against contrast-induced AKI (CI-AKI) was still uncertain. This study investigated the role of NLRP3 inflammasome in CI-AKI both in vitro and in vivo. In HK-2 cells and unilateral nephrectomy model, NLRP3 and NLRP3 inflammasome member ASC were significantly augmented with the treatment of contrast media. Moreover, genetic disruption of NLRP3 notably reversed contrast-induced expression of apoptosis related proteins and secretion of proinflammatory factors, similarly to the effects of ASC deletion. Consistent with above results, absence of NLRP3 in mice undergoing unilateral nephrectomy also protected against contrast media-induced renal cells phenotypic alteration and cell apoptosis via modulating expression level of apoptotic proteins. Collectively, we demonstrated that NLRP3 inflammasome mediated CI-AKI through modulating the apoptotic pathway, which provided a potential therapeutic target for the treatment of contrast media induced acute kidney injury. PMID:27721494

  9. Cell-cycle arrest and acute kidney injury: the light and the dark sides

    PubMed Central

    Kellum, John A.; Chawla, Lakhmir S.

    2016-01-01

    Acute kidney injury (AKI) is a common consequence of systemic illness or injury and it complicates several forms of major surgery. Two major difficulties have hampered progress in AKI research and clinical management. AKI is difficult to detect early and its pathogenesis is still poorly understood. We recently reported results from multi-center studies where two urinary markers of cell-cycle arrest, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were validated for development of AKI well ahead of clinical manifestations—azotemia and oliguria. Cell-cycle arrest is known to be involved in the pathogenesis of AKI and this ‘dark side’ may also involve progression to chronic kidney disease. However, cell-cycle arrest has a ‘light side’ as well, since this mechanism can protect cells from the disastrous consequences of entering cell division with damaged DNA or insufficient bioenergetic resources during injury or stress. Whether we can use the light side to help prevent AKI remains to be seen, but there is already evidence that cell-cycle arrest biomarkers are indicators of both sides of this complex physiology. PMID:26044835

  10. HDL Cholesterol Level Is Associated with Contrast Induced Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing PCI

    PubMed Central

    Park, Hoon Suk; Kim, Chan Joon; Hwang, Byung-Hee; Kim, Tae-Hoon; Koh, Yoon Seok; Park, Hun-Jun; Her, Sung-Ho; Jang, Sung Won; Park, Chul-Soo; Lee, Jong Min; Kim, Hee-Yeol; Jeon, Doo Soo; Kim, Pum-Joon; Yoo, Ki-Dong; Chang, Kiyuk; Jin, Dong Chan; Seung, Ki-Bae

    2016-01-01

    Chronic kidney disease (CKD) is a significant risk factor for contrast induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI). This study included 1592 CKD patients extracted from a prospective multicenter, all comer-based registry of patients undergoing PCI. In multivariate logistic analysis for CI-AKI development, a significant linear trend was observed between the quartiles of HDL-C (quartile 1 vs. 2: odds ratio [OR], 0.716; 95% confidence interval [CI], 0.421–1.219; quartile 1 vs. 3: OR, 0.534; 95% CI, 0.301–0.947; quartile 1 vs. 4: OR, 0.173; 95% CI, 0.079–0.377; P for trend < 0.001). HDL-C quartiles were also negatively correlated with the incidence of CI-AKI; 19.0%, 12.1%, 8.7%, and 3.7% for quartile 1(Q1) (<34 mg/dL), Q2 (34–40 mg/dL), Q3 (40–48 mg/dL), and Q4 (>48 mg/dL) respectively (P < 0.001 overall and for the trend). Multivariate Cox regression analysis for the long term mortality, the highest HDL-C quartile was associated with decreased mortality compared with the lowest HDL-C quartile (hazard ratio [HR] 0.516, 95% CI, 0.320–0.832, P = 0.007). Our study suggests more intensive strategies should be considered for preventing CI-AKI in CKD patients with low serum HDL-C level who is planned for PCI. PMID:27775043

  11. Hypercalcemia, Anemia, and Acute Kidney Injury: A Rare Presentation of Sarcoidosis

    PubMed Central

    Sharma, Neeraj; Tariq, Hassan; Uday, Kalpana; Skaradinskiy, Yevgeniy; Niazi, Masooma; Chilimuri, Sridhar

    2015-01-01

    We discuss a case of a 61-year-old woman who presented with substernal chest pain. She was found to have elevated calcium levels, anemia, and acute kidney injury. The hypercalcemia persisted despite therapy with fluids and bisphosphonates. She was found to have nonparathyroid hormone (PTH) mediated hypercalcemia. The chest X-ray did not reveal any pathology. Our Initial impression was likely underlying hematologic malignancy such as lymphoma or multiple myeloma. A bone marrow biopsy was performed that revealed nonnecrotizing granulomatous inflammation. Further workup revealed elevated vitamin 1,25 dihydroxy level, beta-two microglobulin level, and ACE levels. Noncontrast computed tomography (CT) scan of chest showed bilateral apical bronchiectasis, but did not show any lymphadenopathy or evidence of malignancy. Subsequently, a fiber optic bronchoscopy with transbronchial biopsy showed nonnecrotizing granulomatous inflammation consistent with sarcoidosis. After initiating glucocorticoid therapy, the patient's hypercalcemia improved and her kidney function returned to baseline. PMID:26199627

  12. Foetal serum but not urinary β2-microglobulin correlates with histological injury to the kidney.

    PubMed

    Luton, D; Delezoide, A L; Leguy, M C; Gobeaux, C; Vuillard, E; Grangé, G; Guibourdenche, J

    2013-10-01

    In a context of foetal obstructive uropathies, biochemical markers can be helpful to assess the renal function, but most studies to date have focused on their correlation with ultrasound findings and neonatal outcome. Our aim was to evaluate foetal β2-microglobulin as an index of histological injury to the kidney. β2-microglobulin was measured in serum and/or urine from 27 foetuses with bilateral obstructive uropathy, and compared to the findings of kidney examination following the termination of pregnancy. In serum, increased β2-microglobulin levels correlated to a decreased number of glomeruli, a reduction in the blastema and the presence of primitive ducts reflecting renal hypoplasia and dysplasia. However, elevated β2-microglobulin levels in the urine correlated only to a decreased number of glomeruli.

  13. An initial evaluation of post-cardiopulmonary bypass acute kidney injury in swine☆

    PubMed Central

    Murphy, Gavin J.; Lin, Hua; Coward, Richard J.; Toth, Tibor; Holmes, Robin; Hall, David; Angelini, Gianni D.

    2016-01-01

    Objective Acute kidney injury (AKI) post-cardiac surgery is associated with mortality rates approaching 20%. The development of effective treatments is hindered by the poor homology between rodent models, the mainstay of research into AKI, and that which occurs in humans. This pilot study aims to characterise post-cardiopulmonary bypass (CPB) AKI in an animal model with potentially greater homology to cardiac surgery patients. Methods and results Adult pigs, weighing 50–75 kg, underwent 2.5 h of CPB. Pigs undergoing saphenous vein grafting procedures served as controls. Pre-CPB measures of porcine renal function were within normal ranges for adult humans. The effect of CPB on renal function; a 25% reduction in 51Cr-EDTA clearance ( p = 0.068), and a 33% reduction in creatinine clearance (p = 0.043), was similar to those reported in clinical studies. CPB resulted in tubular epithelial injury (median NAG/creatinine ratio 2.6 u mmol−1 (interquartile range (IQR): 0.81–5.43) post-CPB vs 0.48 u mmol−1 (IQR: 0.37–0.97) pre-CPB, p = 0.043) as well as glomerular and/or proximal tubular injury (median albumin/creatinine ratio 6.8 mg mmol−1 (IQR: 5.45–13.06) post-CPB vs 1.10 mg mmol−1 (IQR: 0.05–2.00) pre-CPB, p = 0.080). Tubular injury scores were significantly higher in kidneys post-CPB (median score 2.0 (IQR: 1.0–2.0) relative to vein graft controls (median score 1.0 (IQR 1.0–1.0), p = 0.019). AKI was associated with endothelial injury and activation, as demonstrated by reduced DBA (dolichos biflorus agglutinin) lectin and increased endothelin-1 and vascular cell adhesion molecule (VCAM) staining. Conclusions The porcine model of post-CPB AKI shows significant homology to AKI in cardiac surgical patients. It links functional, urinary and histological measures of kidney injury and may offer novel insights into the mechanisms underlying post-CPB AKI. PMID:19692256

  14. Urine Levels of Defensin α1 Reflect Kidney Injury in Leptospirosis Patients

    PubMed Central

    Chagan-Yasutan, Haorile; Chen, Yue; Lacuesta, Talitha Lea; Leano, Prisca Susan A.; Iwasaki, Hiroko; Hanan, Firmanto; Taurustiati, Delsi; Ohmoto, Yasukazu; Ashino, Yugo; Saitoh, Hiroki; Kiyomoto, Hideyasu; Suzuki, Yasuhiko; Telan, Freda O. Elizabeth; Hattori, Toshio

    2016-01-01

    Leptospirosis is a zoonotic disease whose severe forms are often accompanied by kidney dysfunction. In the present study, urinary markers were studied for potential prediction of disease severity. Urine samples from 135 patients with or without leptospirosis at San Lazaro Hospital, the Philippines, were analyzed. Urine levels of defensin α1 (uDA1) were compared with those of neutrophil gelatinase-associated lipocalin (uNGAL) and N-acetyl-β-d-glucosidase (uNAG). Serum creatinine (Cr) was used as a marker of kidney injury. The levels of uDA1/Cr, uNGAL/Cr, and uNAG/Cr were positive in 46%, 90%, and 80% of leptospirosis patients, and 69%, 70%, and 70% of non-leptospirosis patients, respectively. In leptospirosis patients, the correlation of uDA1/Cr, uNGAL/Cr and uNAG/Cr levels with serum Cr were r = 0.3 (p < 0.01), r = 0.29 (p < 0.01), and r = 0.02 (p = 0.81), respectively. uDA1/Cr levels were correlated with uNGAL/Cr levels (r = 0.49, p < 0.01) and uNAG/Cr levels (r = 0.47, p < 0.0001) in leptospirosis patients. These findings suggest that uDA1, uNGAL, and uNAG were elevated in leptospirosis patients and reflected various types of kidney damage. uDA1 and uNGAL can be used to track kidney injury in leptospirosis patients because of their correlation with the serum Cr level. PMID:27689992

  15. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

    PubMed

    Vliegenthart, A D B; Shaffer, J M; Clarke, J I; Peeters, L E J; Caporali, A; Bateman, D N; Wood, D M; Dargan, P I; Craig, D G; Moore, J K; Thompson, A I; Henderson, N C; Webb, D J; Sharkey, J; Antoine, D J; Park, B K; Bailey, M A; Lader, E; Simpson, K J; Dear, J W

    2015-01-01

    Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury. PMID:26489516

  16. Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

    PubMed

    Vliegenthart, A D B; Shaffer, J M; Clarke, J I; Peeters, L E J; Caporali, A; Bateman, D N; Wood, D M; Dargan, P I; Craig, D G; Moore, J K; Thompson, A I; Henderson, N C; Webb, D J; Sharkey, J; Antoine, D J; Park, B K; Bailey, M A; Lader, E; Simpson, K J; Dear, J W

    2015-10-22

    Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

  17. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery.

    PubMed

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-03-01

    Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a protective

  18. Hsp72 Is a Novel Biomarker to Predict Acute Kidney Injury in Critically Ill Patients

    PubMed Central

    Morales-Buenrostro, Luis E.; Salas-Nolasco, Omar I.; Barrera-Chimal, Jonatan; Casas-Aparicio, Gustavo; Irizar-Santana, Sergio; Pérez-Villalva, Rosalba; Bobadilla, Norma A.

    2014-01-01

    Background and Objectives Acute kidney injury (AKI) complicates the course of disease in critically ill patients. Efforts to change its clinical course have failed because of the fail in the early detection. This study was designed to assess whether heat shock protein (Hsp72) is an early and sensitive biomarker of acute kidney injury (AKI) compared with kidney injury molecule (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) biomarkers. Methods A total of 56 critically ill patients fulfilled the inclusion criteria. From these patients, 17 developed AKI and 20 were selected as controls. In AKI patients, Kim-1, IL-18, NGAL, and Hsp72 were measured from 3 days before and until 2 days after the AKI diagnosis and in no-AKI patients at 1, 5 and 10 days after admission. Biomarker sensitivity and specificity were determined. To validate the results obtained with ROC curves for Hsp72, a new set of critically ill patients was included, 10 with AKI and 12 with no-AKI patients. Results Urinary Hsp72 levels rose since 3 days before the AKI diagnosis in critically ill patients; this early increase was not seen with any other tested biomarkers. Kim-1, IL-18, NGAL, and Hsp72 significantly increased from 2 days before AKI and remained elevated during the AKI diagnosis. The best sensitivity/specificity was observed in Kim-1 and Hsp72: 83/95% and 100/90%, respectively, whereas 1 day before the AKI diagnosis, the values were 100/100% and 100/90%, respectively. The sensibility, specificity and accuracy in the validation test for Hsp72 were 100%, 83.3% and 90.9%, respectively. Conclusions The biomarker Hsp72 is enough sensitive and specific to predict AKI in critically ill patients up to 3 days before the diagnosis. PMID:25313566

  19. Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease.

    PubMed

    Luo, Renna; Zhang, Weiru; Zhao, Cheng; Zhang, Yujin; Wu, Hongyu; Jin, Jianping; Zhang, Wenzheng; Grenz, Almut; Eltzschig, Holger K; Tao, Lijian; Kellems, Rodney E; Xia, Yang

    2015-07-01

    Hypertensive chronic kidney disease is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. However, early events initiating the progression to hypertensive chronic kidney disease are poorly understood. We hypothesized that elevated endothelial hypoxia-inducible factor-1α (HIF-1α) is a common early insult triggering initial glomerular injury leading to hypertensive chronic kidney disease. To test our hypothesis, we used an angiotensin II infusion model of hypertensive chronic kidney disease to determine the specific cell type and mechanisms responsible for elevation of HIF-1α and its role in the progression of hypertensive chronic kidney disease. Genetic studies coupled with reverse transcription polymerase chain reaction profiling revealed that elevated endothelial HIF-1α is essential to initiate glomerular injury and progression to renal fibrosis by the transcriptional activation of genes encoding multiple vasoactive proteins. Mechanistically, we found that endothelial HIF-1α gene expression was induced by angiotensin II in a nuclear factor-κB-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1α and Nf-κb genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1α gene expression in endothelial cells is detrimental to induce kidney injury, hypertension, and disease progression. Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive chronic kidney disease.

  20. Resveratrol attenuates acute kidney injury by inhibiting death receptor‑mediated apoptotic pathways in a cisplatin‑induced rat model.

    PubMed

    Hao, Qiufa; Xiao, Xiaoyan; Zhen, Junhui; Feng, Jinbo; Song, Chun; Jiang, Bei; Hu, Zhao

    2016-10-01

    Acute kidney injury is a clinical syndrome characterized by a loss of renal function and acute tubular necrosis. Resveratrol exerts a wide range of pharmacological effects based on its anti‑inflammatory, antioxidant and cytoprotective properties. The present study aimed to evaluate whether resveratrol attenuates acute kidney injury in a cisplatin‑induced rat model and to investigate the potential mechanisms involved. Rats were randomly divided into four treatment groups: control, cisplatin, resveratrol, and cisplatin plus resveratrol. Rats exposed to cisplatin displayed acute kidney injury, identified by analysis of renal function and histopathological observation. Resveratrol significantly ameliorated the increased serum creatinine, blood urea nitrogen, renal index and histopathological damage induced by cisplatin. Furthermore, compared with untreated control animals, cisplatin lead to significantly increased expression of Fas ligand, tumor necrosis factor‑α (TNF‑α), caspase‑8 and Bcl‑2 associated protein X apoptosis regulator (Bax), and decreased expression of anti‑apoptosis regulators, BH3 interacting domain death agonist (BID) and B cell lymphoma 2 apoptosis regulator (Bcl‑2). Administration of resveratrol significantly reversed the cisplatin‑induced alteration in these apoptosis‑associated proteins. In conclusion, these findings suggest that resveratrol attenuates cisplatin‑induced acute kidney injury through inactivation of the death receptor‑mediated apoptotic pathway, and may provide a new therapeutic strategy to ameliorate the process of acute kidney injury. PMID:27600998

  1. Resveratrol attenuates acute kidney injury by inhibiting death receptor-mediated apoptotic pathways in a cisplatin-induced rat model

    PubMed Central

    Hao, Qiufa; Xiao, Xiaoyan; Zhen, Junhui; Feng, Jinbo; Song, Chun; Jiang, Bei; Hu, Zhao

    2016-01-01

    Acute kidney injury is a clinical syndrome characterized by a loss of renal function and acute tubular necrosis. Resveratrol exerts a wide range of pharmacological effects based on its anti-inflammatory, antioxidant and cytoprotective properties. The present study aimed to evaluate whether resveratrol attenuates acute kidney injury in a cisplatin-induced rat model and to investigate the potential mechanisms involved. Rats were randomly divided into four treatment groups: Control, cisplatin, resveratrol, and cisplatin plus resveratrol. Rats exposed to cisplatin displayed acute kidney injury, identified by analysis of renal function and histopathological observation. Resveratrol significantly ameliorated the increased serum creatinine, blood urea nitrogen, renal index and histopathological damage induced by cisplatin. Furthermore, compared with untreated control animals, cisplatin lead to significantly increased expression of Fas ligand, tumor necrosis factor-α (TNF-α), caspase-8 and Bcl-2 associated protein X apoptosis regulator (Bax), and decreased expression of anti-apoptosis regulators, BH3 interacting domain death agonist (BID) and B cell lymphoma 2 apoptosis regulator (Bcl-2). Administration of resveratrol significantly reversed the cisplatin-induced alteration in these apoptosis-associated proteins. In conclusion, these findings suggest that resveratrol attenuates cisplatin-induced acute kidney injury through inactivation of the death receptor-mediated apoptotic pathway, and may provide a new therapeutic strategy to ameliorate the process of acute kidney injury. PMID:27600998

  2. Acute kidney injury on admission to the intensive care unit: where to go from here?

    PubMed

    Ostermann, Marlies

    2008-01-01

    Acute kidney injury (AKI) is a common problem, especially in critically ill patients. In Critical Care, Kolhe and colleagues report that 6.3% of 276,731 patients in 170 intensive care units (ICUs) in the UK had evidence of severe AKI within the first 24 hours of admission to ICU. ICU and hospital mortality as well as length of stay in hospital were significantly increased. In light of this serious burden on individuals and the health system in general, the following commentary discusses the current state of knowledge of AKI in ICU and calls for more attention to preventive strategies.

  3. Radiographic Contrast-Media-Induced Acute Kidney Injury: Pathophysiology and Prophylactic Strategies

    PubMed Central

    2013-01-01

    Contrast-induced acute kidney injury (CI-AKI) is one of the most widely discussed and debated topics in cardiovascular medicine. With increasing number of contrast-media- (CM-) enhanced imaging studies being performed and growing octogenarian population with significant comorbidities, incidence of CI-AKI remains high. In this review, pathophysiology of CI-AKI, its relationship with different types of CM, role of serum and urinary biomarkers for diagnosing CI-AKI, and various prophylactic strategies used for nephroprotection against CI-AKI are discussed in detail. PMID:24967281

  4. Acute kidney injury and disseminated intravascular coagulation due to mercuric chloride poisoning

    PubMed Central

    Dhanapriya, J.; Gopalakrishnan, N.; Arun, V.; Dineshkumar, T.; Sakthirajan, R.; Balasubramaniyan, T.; Haris, M.

    2016-01-01

    Mercury is a toxic heavy metal and occurs in organic and inorganic forms. Inorganic mercury includes elemental mercury and mercury salts. Mercury salts are usually white powder or crystals, and widely used in indigenous medicines and folk remedies in Asia. Inorganic mercury poisoning causes acute kidney injury (AKI) and gastrointestinal manifestations and can be life-threatening. We describe a case with unknown substance poisoning who developed AKI and disseminated intravascular coagulation (DIC). Renal biopsy showed acute tubular necrosis. Later, the consumed substance was proven to be mercuric chloride. His renal failure improved over time, and his creatinine normalized after 2 months. PMID:27194836

  5. Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment.

    PubMed

    Lattanzio, Michael R; Kopyt, Nelson P

    2009-01-01

    Acute kidney injury (AKI) is increasingly recognized in all fields of medical practice. Unfortunately, this syndrome has been plagued by inconsistent definitions, simplistic pathophysiologic schemas, and insensitive diagnostic tools. Recent advances in defining AKI, understanding its pathophysiology, and improving the diagnostic accuracy of the testing tools available eventually will impact disease management and clinical outcomes. Prompt recognition and treatment of AKI remain the cornerstone of clinical management for this high-mortality, high-cost syndrome. The authors provide the most recent updates in the definition, diagnosis, pathophysiology, and treatment options for patients with AKI, providing a stepwise approach to clinical evaluation for use in all fields of medical practice.

  6. AKI and Genetics: Evolving Concepts in the Genetics of Acute Kidney Injury: Implications for Pediatric AKI.

    PubMed

    Lee-Son, Kathy; Jetton, Jennifer G

    2016-03-01

    In spite of recent advances in the field of acute kidney injury (AKI) research, morbidity and mortality remain high for AKI sufferers. The study of genetic influences in AKI pathways is an evolving field with potential for improving outcomes through the identification of risk and protective factors at the individual level that may in turn allow for the development of rational therapeutic interventions. Studies of single nucleotide polymorphisms, individual susceptibility to nephrotoxic medications, and epigenetic factors comprise a growing body of research in this area. While promising, this field is still only emerging, with a small number of studies in humans and very little data in pediatric patients. PMID:27617143

  7. Acute kidney injury: risk factors and management challenges in developing countries.

    PubMed

    Ponce, Daniela; Balbi, Andre

    2016-01-01

    Acute kidney injury (AKI) is a major global health problem in both developed and developing nations, negatively affecting patient morbidity and responsible for an estimated 1.4 million deaths per year. Although the International Society of Nephrology set a goal of eliminating preventable deaths from AKI by 2025, implementation of this program in developing countries presents major challenges not only because of the lack of resources but also because of the scarce data addressing the epidemiology and causes of AKI in developing countries, the limited health care resources to diagnose and treat AKI, and the poor awareness of the impact of AKI on patient outcomes. PMID:27578995

  8. Successful recovery from an acute kidney injury due to amniotic fluid embolism.

    PubMed

    Ihara, Katsuhito; Naito, Shotaro; Okado, Tomokazu; Rai, Tatemitu; Mori, Yutaro; Toda, Takayuki; Uchida, Shinichi; Sasaki, Sei; Matsui, Noriaki

    2015-01-01

    A 33-year-old Japanese woman at 40 weeks gestation visited the maternity hospital after imminent labor had begun. After the delivery, persistent bleeding developed resulting in hemorrhagic shock. Although the hemorrhage was eventually controlled, hepatic and renal dysfunction occurred, leading to acute kidney injury (AKI). The patient's clinical presentation was suggestive of amniotic fluid embolism (AFE). We subsequently initiated continuous renal replacement therapy (RRT) for AKI. The patient's condition improved, she discontinued RRT, and her renal function recovered. We herein report a patient who successfully recovered from AKI caused by AFE. PMID:25742893

  9. Acute kidney injury: risk factors and management challenges in developing countries

    PubMed Central

    Ponce, Daniela; Balbi, Andre

    2016-01-01

    Acute kidney injury (AKI) is a major global health problem in both developed and developing nations, negatively affecting patient morbidity and responsible for an estimated 1.4 million deaths per year. Although the International Society of Nephrology set a goal of eliminating preventable deaths from AKI by 2025, implementation of this program in developing countries presents major challenges not only because of the lack of resources but also because of the scarce data addressing the epidemiology and causes of AKI in developing countries, the limited health care resources to diagnose and treat AKI, and the poor awareness of the impact of AKI on patient outcomes. PMID:27578995

  10. Renal blood flow and acute kidney injury in septic shock: an arduous conflict that smolders intrarenally?

    PubMed

    Honore, Patrick M; Jacobs, Rita; De Waele, Elisabeth; Diltoer, Marc; Spapen, Herbert D

    2016-07-01

    Sepsis-induced acute kidney injury (SAKI) is traditionally viewed as a process driven by a reduced blood flow and prone to benefit from vasopressive support. In ovine hyperdynamic septic shock, Lankadeva et al. report a significant and flow-independent intrarenal perfusion and oxygenation "mismatch" jeopardizing the renal medulla that was aggravated by norepinephrine. Medullary and urinary oxygenation changed in parallel, suggesting that urinary oxygenation may act as a biomarker to predict SAKI. PMID:27312443

  11. Methemoglobinemia due to quinine causing severe acute kidney injury in a child

    PubMed Central

    Kudale, S.; Sethi, S. K.; Dhaliwal, M.; Kher, V.

    2014-01-01

    Congenital methemoglobinemia is a rare condition resulting from a deficiency of nicotinamide adenine dinucleotide-cytochrome b5 reductase. Acquired methemoglobinemia may result due to certain drugs, chemicals and food items. Information on epidemiological determinants from India is sparse. This report describes methemoglobinemia in a 4-year-old child after parenteral administration of quinine causing acute kidney injury. This case emphasizes the need of awareness of potential adverse events of antimalarial drugs. Prompt management of methemoglobinemia is essential to avoid potential life-threatening complications. PMID:25484537

  12. Pathfinder cells provide a novel therapeutic intervention for acute kidney injury.

    PubMed

    McGlynn, Liane M; Eller, Kathrin; MacDonald, Alasdair I; Macintyre, Alan; Russell, David; Koppelstaetter, Christian; Davies, R W; Shiels, Paul G

    2013-02-01

    Pathfinder cells (PCs) are a novel class of adult-derived cells that facilitate functional repair of host tissue. We used rat PCs to demonstrate that they enable the functional mitigation of ischemia reperfusion (I/R) injury in a mouse model of renal damage. Female C57BL/6 mice were subjected to 30 min of renal ischemia and treated with intravenous (i.v.) injection of saline (control) or male rat pancreas-derived PCs in blinded experimentation. Kidney function was assessed 14 days after treatment by measuring serum creatinine (SC) levels. Kidney tissue was assessed by immunohistochemistry (IHC) for markers of cellular damage, proliferation, and senescence (TUNEL, Ki67, p16(ink4a), p21). Fluorescence in situ hybridization (FISH) was performed to determine the presence of any rat (i.e., pathfinder) cells in the mouse tissue. PC-treated animals demonstrated superior renal function at day 14 post-I/R, in comparison to saline-treated controls, as measured by SC levels (0.13 mg/dL vs. 0.23 mg/dL, p<0.001). PC-treated kidney tissue expressed significantly lower levels of p16(ink4a) in comparison to the control group (p=0.009). FISH analysis demonstrated that the overwhelming majority of repaired kidney tissue was mouse in origin. Rat PCs were only detected at a frequency of 0.02%. These data confirm that PCs have the ability to mitigate functional damage to kidney tissue following I/R injury. Kidneys of PC-treated animals showed evidence of improved function and reduced expression of damage markers. The PCs appear to act in a paracrine fashion, stimulating the host tissue to recover functionally, rather than by differentiating into renal cells. This study demonstrates that pancreatic-derived PCs from the adult rat can enable functional repair of renal damage in mice. It validates the use of PCs to regenerate damaged tissues and also offers a novel therapeutic intervention for repair of solid organ damage in situ.

  13. Ischemic Acute Kidney Injury Perturbs Homeostasis of Serine Enantiomers in the Body Fluid in Mice: Early Detection of Renal Dysfunction Using the Ratio of Serine Enantiomers

    PubMed Central

    Sasabe, Jumpei; Suzuki, Masataka; Miyoshi, Yurika; Tojo, Yosuke; Okamura, Chieko; Ito, Sonomi; Konno, Ryuichi; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

    2014-01-01

    The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D−/L-serine from 2.82±0.18 to 1.10±0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D−/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D−/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury. PMID:24489731

  14. First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort

    PubMed Central

    Coca, Steven G.; Nadkarni, Girish N.; Garg, Amit X.; Koyner, Jay; Thiessen-Philbrook, Heather; McArthur, Eric; Shlipak, Michael G.; Parikh, Chirag R.

    2016-01-01

    Background We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation. Methods We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0–6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1–2, 3–6, ≥7 days). Results Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1–2 days, 118 (28.9%) had duration 3–6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13–1.32; KIM-1: 1.36, 1.21–1.52; albumin 1.20, 1.09–1.32; L-FABP 1.11, 1.04–1.19; NGAL 1.06, 1.00–1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years. Conclusions There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI. PMID:27537050

  15. Role of TRPV1 Channels in Ischemia/Reperfusion-Induced Acute Kidney Injury

    PubMed Central

    Chen, Lan; Markó, Lajos; Kaßmann, Mario; Zhu, Ye; Wu, Kaiyin; Gollasch, Maik

    2014-01-01

    Objectives Transient receptor potential vanilloid 1 (TRPV1) -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist), capsazepine (TRPV1 antagonist) and using Trpv1−/− mice. Methods and Results Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight) or capsazepine (50 mg/kg body weight). Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL) abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE) or epoxyeicosatrienoic acids (EETs) are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. Conclusions Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli. PMID:25330307

  16. Clinical analysis of cause, treatment and prognosis in acute kidney injury patients.

    PubMed

    Yang, Fan; Zhang, Li; Wu, Hao; Zou, Hongbin; Du, Yujun

    2014-01-01

    Acute kidney injury (AKI) is characterized by an abrupt decline in renal function, resulting in an inability to secrete waste products and maintain electrolyte and water balance, and is associated with high risks of morbidity and mortality. This study retrospectively analyzed clinical data, treatment, and prognosis of 271 hospitalized patients (172 males and 99 females) diagnosed with AKI from December, 2008 to December, 2011. In addition, this study explored the association between the cause of AKI and prognosis, severity and treatment of AKI. The severity of AKI was classified according to the Acute Kidney Injury Network (AKIN) criteria. Renal recovery was defined as a decrease in a serum creatinine level to the normal value. Prerenal, renal, and postrenal causes accounted for 36.5% (99 patients), 46.5% (126 patients) and 17.0% (46 patients), respectively, of the incidence of AKI. Conservative, surgical, and renal replacement treatments were given to 180 (66.4%), 30 (11.1%) and 61 patients (22.5%), respectively. The overall recovery rate was 21.0%, and the mortality rate was 19.6%. Levels of Cl(-), Na(+) and carbon dioxide combining power decreased with increasing severity of AKI. Cause and treatment were significantly associated with AKI prognosis. Likewise, the severity of AKI was significantly associated with cause, treatment and prognosis. Multivariate logistic regression analysis found that respiratory injury and multiple organ dysfunction syndrome (MODS) were associated with AKI patient death. Cause, treatment and AKIN stage are associated with the prognosis of AKI. Respiratory injury and MODS are prognostic factors for death of AKI patients.

  17. Clinical analysis of cause, treatment and prognosis in acute kidney injury patients.

    PubMed

    Yang, Fan; Zhang, Li; Wu, Hao; Zou, Hongbin; Du, Yujun

    2014-01-01

    Acute kidney injury (AKI) is characterized by an abrupt decline in renal function, resulting in an inability to secrete waste products and maintain electrolyte and water balance, and is associated with high risks of morbidity and mortality. This study retrospectively analyzed clinical data, treatment, and prognosis of 271 hospitalized patients (172 males and 99 females) diagnosed with AKI from December, 2008 to December, 2011. In addition, this study explored the association between the cause of AKI and prognosis, severity and treatment of AKI. The severity of AKI was classified according to the Acute Kidney Injury Network (AKIN) criteria. Renal recovery was defined as a decrease in a serum creatinine level to the normal value. Prerenal, renal, and postrenal causes accounted for 36.5% (99 patients), 46.5% (126 patients) and 17.0% (46 patients), respectively, of the incidence of AKI. Conservative, surgical, and renal replacement treatments were given to 180 (66.4%), 30 (11.1%) and 61 patients (22.5%), respectively. The overall recovery rate was 21.0%, and the mortality rate was 19.6%. Levels of Cl(-), Na(+) and carbon dioxide combining power decreased with increasing severity of AKI. Cause and treatment were significantly associated with AKI prognosis. Likewise, the severity of AKI was significantly associated with cause, treatment and prognosis. Multivariate logistic regression analysis found that respiratory injury and multiple organ dysfunction syndrome (MODS) were associated with AKI patient death. Cause, treatment and AKIN stage are associated with the prognosis of AKI. Respiratory injury and MODS are prognostic factors for death of AKI patients. PMID:24586237

  18. Topiramate as a rare cause of reversible Fanconi syndrome and acute kidney injury: a case report and literature review.

    PubMed

    Meseeha, Marcelle G; Attia, Maximos N; Kolade, Victor O

    2016-01-01

    Topiramate (TPM) is a sulfa-derivative monosaccharide that has been used for multiple indications in the last several years. We describe a 53-year-old woman with known chronic kidney disease stage 2 and baseline creatinine of 1 mg/dL who developed acute kidney injury and proximal renal tubular dysfunction while on TPM for depression. The Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between TPM and acute kidney injury as well as proximal tubular dysfunction; these renal conditions resolved on withdrawal of TPM. To our knowledge, this is the first report of such a scenario. Patients receiving TPM therapy should be closely monitored for evidence of kidney dysfunction and electrolyte abnormalities. PMID:26908388

  19. Topiramate as a rare cause of reversible Fanconi syndrome and acute kidney injury: a case report and literature review

    PubMed Central

    Meseeha, Marcelle G.; Attia, Maximos N.; Kolade, Victor O.

    2016-01-01

    Topiramate (TPM) is a sulfa-derivative monosaccharide that has been used for multiple indications in the last several years. We describe a 53-year-old woman with known chronic kidney disease stage 2 and baseline creatinine of 1 mg/dL who developed acute kidney injury and proximal renal tubular dysfunction while on TPM for depression. The Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between TPM and acute kidney injury as well as proximal tubular dysfunction; these renal conditions resolved on withdrawal of TPM. To our knowledge, this is the first report of such a scenario. Patients receiving TPM therapy should be closely monitored for evidence of kidney dysfunction and electrolyte abnormalities. PMID:26908388

  20. Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy.

    PubMed

    Liu, Feng; Zong, Ming; Wen, Xiaofei; Li, Xuezhu; Wang, Jun; Wang, Yi; Jiang, Wei; Li, Xiaojun; Guo, Zhongliang; Qi, Hualin

    2016-01-01

    Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment. PMID:27633396

  1. Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy

    PubMed Central

    Liu, Feng; Zong, Ming; Wen, Xiaofei; Li, Xuezhu; Wang, Jun; Wang, Yi; Jiang, Wei; Li, Xiaojun; Guo, Zhongliang; Qi, Hualin

    2016-01-01

    Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment. PMID:27633396

  2. Glomerular endothelial cell injury and cross talk in diabetic kidney disease

    PubMed Central

    Fu, Jia; Lee, Kyung; Chuang, Peter Y.; Liu, Zhihong

    2014-01-01

    Diabetic kidney disease (DKD) remains a leading cause of new-onset end-stage renal disease (ESRD), and yet, at present, the treatment is still very limited. A better understanding of the pathogenesis of DKD is therefore necessary to develop more effective therapies. Increasing evidence suggests that glomerular endothelial cell (GEC) injury plays a major role in the development and progression of DKD. Alteration of the glomerular endothelial cell surface layer, including its major component, glycocalyx, is a leading cause of microalbuminuria observed in early DKD. Many studies suggest a presence of cross talk between glomerular cells, such as between GEC and mesangial cells or GEC and podocytes. PDGFB/PDGFRβ is a major mediator for GEC and mesangial cell cross talk, while vascular endothelial growth factor (VEGF), angiopoietins, and endothelin-1 are the major mediators for GEC and podocyte communication. In DKD, GEC injury may lead to podocyte damage, while podocyte loss further exacerbates GEC injury, forming a vicious cycle. Therefore, GEC injury may predispose to albuminuria in diabetes either directly or indirectly by communication with neighboring podocytes and mesangial cells via secreted mediators. Identification of novel mediators of glomerular cell cross talk, such as microRNAs, will lead to a better understanding of the pathogenesis of DKD. Targeting these mediators may be a novel approach to develop more effective therapy for DKD. PMID:25411387

  3. The role of the polyol pathway in acute kidney injury caused by hindlimb ischaemia in mice.

    PubMed

    Yagihashi, Soroku; Mizukami, Hiroki; Ogasawara, Saori; Yamagishi, Shin-Ichiro; Nukada, Hitoshi; Kato, Noriaki; Hibi, Chihiro; Chung, Sookja; Chung, Stephen

    2010-04-01

    The polyol pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the polyol pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the polyol pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-alpha as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the polyol pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition. PMID:20112370

  4. Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury.

    PubMed

    Aihara, Miki; Fujiki, Hiroyuki; Mizuguchi, Hiroshi; Hattori, Katsuji; Ohmoto, Koji; Ishikawa, Makoto; Nagano, Keisuke; Yamamura, Yoshitaka

    2014-05-01

    Tolvaptan, a selective vasopressin V2 receptor antagonist, slows the increase in total kidney volume and the decline in kidney function in patients with the results of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Outcome (TEMPO) 3:4 trial. However, it was unclear which dose of tolvaptan was optimal or whether tolvaptan was able to delay progression to end-stage renal disease (ESRD). Here we examined the relationship with aquaresis and the inhibitory effect on cyst development in short-term treatment and mortality as an index of ESRD in long-term treatment with tolvaptan using DBA/2FG-pcy mice, an animal model of nephronophthisis. With short-term treatment from 5 to 15 weeks of age, tolvaptan (0.01-0.3% via diet) dose-dependently enhanced aquaresis, prevented increases in kidney weight and cyst volume, and was associated with significant reductions in kidney cAMP levels and extracellular signal-regulated kinase activity. Maximal effects of tolvaptan on aquaresis and the prevention of development of polycystic kidney disease (PKD) were obtained at 0.1%. Interestingly, tolvaptan also dose-dependently reduced urinary neutrophil gelatinase-associated lipocalin levels in correlation with the kidney volume. With long-term treatment from 5 to 29 weeks of age, tolvaptan significantly attenuated the increase in kidney volume by up to 50% and reduced urinary albumin excretion. Furthermore, tolvaptan significantly reduced the mortality rate to 20%, compared with 60% in the control group. These data indicate that tolvaptan may delay the onset of ESRD in PKD by suppressing the increases in kidney volume and renal injury, providing a promising treatment for PKD. PMID:24570071

  5. Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury.

    PubMed

    Aihara, Miki; Fujiki, Hiroyuki; Mizuguchi, Hiroshi; Hattori, Katsuji; Ohmoto, Koji; Ishikawa, Makoto; Nagano, Keisuke; Yamamura, Yoshitaka

    2014-05-01

    Tolvaptan, a selective vasopressin V2 receptor antagonist, slows the increase in total kidney volume and the decline in kidney function in patients with the results of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Outcome (TEMPO) 3:4 trial. However, it was unclear which dose of tolvaptan was optimal or whether tolvaptan was able to delay progression to end-stage renal disease (ESRD). Here we examined the relationship with aquaresis and the inhibitory effect on cyst development in short-term treatment and mortality as an index of ESRD in long-term treatment with tolvaptan using DBA/2FG-pcy mice, an animal model of nephronophthisis. With short-term treatment from 5 to 15 weeks of age, tolvaptan (0.01-0.3% via diet) dose-dependently enhanced aquaresis, prevented increases in kidney weight and cyst volume, and was associated with significant reductions in kidney cAMP levels and extracellular signal-regulated kinase activity. Maximal effects of tolvaptan on aquaresis and the prevention of development of polycystic kidney disease (PKD) were obtained at 0.1%. Interestingly, tolvaptan also dose-dependently reduced urinary neutrophil gelatinase-associated lipocalin levels in correlation with the kidney volume. With long-term treatment from 5 to 29 weeks of age, tolvaptan significantly attenuated the increase in kidney volume by up to 50% and reduced urinary albumin excretion. Furthermore, tolvaptan significantly reduced the mortality rate to 20%, compared with 60% in the control group. These data indicate that tolvaptan may delay the onset of ESRD in PKD by suppressing the increases in kidney volume and renal injury, providing a promising treatment for PKD.

  6. Neutrophil Gelatinase-Associated Lipocalin as an Early Sign of Diabetic Kidney Injury in Children

    PubMed Central

    Yürük Yıldırım, Zeynep; Nayır, Ahmet; Yılmaz, Alev; Gedikbaşı, Asuman; Bundak, Rüveyde

    2015-01-01

    Objective: There is some evidence indicating that histopathological changes in type 1 diabetes mellitus (T1DM) emerge before onset of microalbuminuria. The aim of our study was to determine whether urine neutrophil gelatinase-associated lipocalin (NGAL) levels can be considered as an early sign of diabetic kidney injury. Methods: Urine NGAL (uNGAL) levels and urinary NGAL/creatinine ratio (uNGAL/Cr) were assessed in 76 patients with T1DM and compared with the findings of 35 healthy individuals. The relationship of uNGAL levels with diabetes duration, body mass index (BMI), serum lipids, HbA1c, and microalbuminuria was also evaluated. Results: Mean uNGAL (100.16±108.28 ng/mL) and uNGAL/Cr (118.93-117.97 ng/mg) levels in both microalbuminuric and non-microalbuminuric diabetic patients were found to be higher than those in the control group (uNGAL: 21.46±18.59 ng/mL and uNGAL/Cr: 32.1±51.48 ng/mg) (p=0.0001). Conclusion: Urine NGAL level increases in the very early phase of T1DM before microalbuminuria develops. The patients with T1DM should be considered to have diabetic kidney injury from the time of diagnosis on and preventive interventions need to be initiated at an early stage to preclude the progression to end-stage renal disease. PMID:26777038

  7. Contrast-Induced Acute Kidney Injury: Short and Long-term Implications

    PubMed Central

    Weisbord, Steven D.; Palevsky, Paul M.

    2011-01-01

    The intravascular administration of iodine-based contrast media remains a common cause of acute kidney injury and a leading cause of iatrogenic renal disease. Past research has elucidated the principal risk factors for contrast-induced acute kidney injury (CIAKI) and helped to establish the efficacy of various interventions for the prevention of this condition. The importance of preventing CIAKI has been underscored by a growing number of studies demonstrating strong associations of CIAKI with serious, adverse short and long-term outcomes. However, it remains unclear whether these associations are causal. This is important as considerable healthcare resources are used to prevent CIAKI. If CIAKI is a marker, but not a mediator, of serious, adverse downstream outcomes, more judicious and selective utilization of preventive care may be appropriate. Moreover, with an increasing number of studies reporting the under-utilization of coronary angiography in patients with acute coronary syndrome and underlying CKD, presumably due in part out of a fear of CIAKI, a clear understanding of whether this condition directly results in adverse downstream outcomes is essential. Careful inspection of past studies that investigated the association of CIAKI with adverse short and long-term events sheds light on their strengths and weaknesses and provides insight into how future research may be better able to characterize the short and long-term implications of this iatrogenic condition. PMID:21784279

  8. The wnt/β-catenin signaling pathway participates in rhein ameliorating kidney injury in DN mice.

    PubMed

    Duan, Suyan; Wu, Yingyi; Zhao, Chuanyan; Chen, Mingyu; Yuan, Yanggang; Xing, Changying; Zhang, Bo

    2016-01-01

    The present study aimed to investigate the relationship between wnt/β-catenin signaling pathway and kidney impairment in diabetic nephropathy (DN) mice as well as the renoprotective effect of rhein (RH). Mice were randomly divided into four groups (n = 6): db/db mice treated with RH (DN + RH), db/db mice (DN), db/m mice treated with RH (NC + RH) and db/m mice (NC). RH-treated groups were administered orally at a daily dose 120 mg/kg. Mice were sacrificed after 12 weeks of treatments. In our study, increased albuminuria, together with weight gain and hyperglycemia was observed in the beginning of the study and continued to increase throughout the length of the study (12 weeks). Histopathologic changes were observed in the DN group. Expectedly, mice receiving the treatment with RH were protected from this injury. Meanwhile, the expression of nephrin, a podocyte-specific marker, was significantly reduced while wnt1, p-GSK-3β/tGSK-3β, p-β-catenin/tβ-catenin were higher in the DN group mice when analyzed by immunofluorescence and Western blotting. RH reversed these above changes. wnt/β-catenin signaling pathway participates in RH ameliorating kidney injury in DN mice. The manipulation of RH might act as a promising therapeutic intervention for DN.

  9. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury

    PubMed Central

    Sallustio, Fabio; Serino, Grazia; Schena, Francesco Paolo

    2015-01-01

    Abstract Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133+/CD24+ cells, with a view to a future application of these cells for the treatment of acute renal injury. PMID:26309808

  10. Controversies on the Origin of Proliferating Epithelial Cells after Kidney Injury

    PubMed Central

    Kusaba, Tetsuro; Humphreys, Benjamin D.

    2014-01-01

    The kidney possesses the capacity to repair after an acute insult, even one that causes complete organ failure. This regenerative response is characterized by robust proliferation of epithelial cells, principally those located in the proximal tubule. Because defining the origin of these reparative cells has important consequences for stem cell and regenerative approaches to treat kidney injury, this area has been the subject of intense investigation and debate. While progress has been made in narrowing the possible origin of these cells to an intratubular source, there has been no consensus between the possibility of a preexisting intratubular stem or progenitor cell versus the possibility that fully differentiated epithelial cells re-enter the cell cycle after injury and generate new proximal tubule cells through self-duplication. This review will summarize the evidence on both sides of this active controversy and provide support for the notion that no preexisting proximal tubule stem cell population exists, but rather all differentiated proximal tubule epithelia have the capacity to proliferate during repair by a mechanism of dedifferentiation and self-duplication. PMID:24322596

  11. Optical spectroscopy approach for the predictive assessment of kidney functional recovery following ischemic injury

    NASA Astrophysics Data System (ADS)

    Raman, Rajesh N.; Pivetti, Christopher D.; Rubenchik, Alexander M.; Matthews, Dennis L.; Troppmann, Christoph; Demos, Stavros G.

    2010-02-01

    Tissue that has undergone significant yet unknown amount of ischemic injury is frequently encountered in organ transplantation and trauma clinics. With no reliable real-time method of assessing the degree of injury incurred in tissue, surgeons generally rely on visual observation which is subjective. In this work, we investigate the use of optical spectroscopy methods as a potentially more reliable approach. Previous work by various groups was strongly suggestive that tissue autofluorescence from NADH obtained under UV excitation is sensitive to metabolic response changes. To test and expand upon this concept, we monitored autofluorescence and light scattering intensities of injured vs. uninjured rat kidneys via multimodal imaging under 355 nm, 325 nm, and 266 nm excitation as well as scattering under 500 nm illumination. 355 nm excitation was used to probe mainly NADH, a metabolite, while 266 nm excitation was used to probe mainly tryptophan to correct for non-metabolic signal artifacts. The ratio of autofluorescence intensities derived under these two excitation wavelengths was calculated and its temporal profile was fit to a relaxation model. Time constants were extracted, and longer time constants were associated with kidney dysfunction. Analysis of both the autofluorescence and light scattering images suggests that changes in microstructure tissue morphology, blood absorption spectral characteristics, and pH contribute to the behavior of the observed signal which may be used to obtain tissue functional information and offer predictive capability.

  12. The definition of acute kidney injury and its use in practice.

    PubMed

    Thomas, Mark E; Blaine, Caroline; Dawnay, Anne; Devonald, Mark A J; Ftouh, Saoussen; Laing, Chris; Latchem, Susan; Lewington, Andrew; Milford, David V; Ostermann, Marlies

    2015-01-01

    Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

  13. Sesamin Ameliorates High-Fat Diet–Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress

    PubMed Central

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-01-01

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia. PMID:27171111

  14. Pyruvate Kinase M2: A Novel Biomarker for the Early Detection of Acute Kidney Injury

    PubMed Central

    Cheon, Ji Hyun; Kim, Sun Young; Son, Ji Yeon; Kang, Ye Rim; An, Ji Hye; Kwon, Ji Hoon; Song, Ho Sub; Moon, Aree; Lee, Byung Mu; Kim, Hyung Sik

    2016-01-01

    The identification of biomarkers for the early detection of acute kidney injury (AKI) is clinically important. Acute kidney injury (AKI) in critically ill patients is closely associated with increased morbidity and mortality. Conventional biomarkers, such as serum creatinine (SCr) and blood urea nitrogen (BUN), are frequently used to diagnose AKI. However, these biomarkers increase only after significant structural damage has occurred. Recent efforts have focused on identification and validation of new noninvasive biomarkers for the early detection of AKI, prior to extensive structural damage. Furthermore, AKI biomarkers can provide valuable insight into the molecular mechanisms of this complex and heterogeneous disease. Our previous study suggested that pyruvate kinase M2 (PKM2), which is excreted in the urine, is a sensitive biomarker for nephrotoxicity. To appropriately and optimally utilize PKM2 as a biomarker for AKI requires its complete characterization. This review highlights the major studies that have addressed the diagnostic and prognostic predictive power of biomarkers for AKI and assesses the potential usage of PKM2 as an early biomarker for AKI. We summarize the current state of knowledge regarding the role of biomarkers and the molecular and cellular mechanisms of AKI. This review will elucidate the biological basis of specific biomarkers that will contribute to improving the early detection and diagnosis of AKI. PMID:26977258

  15. Sesamin Ameliorates High-Fat Diet-Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress.

    PubMed

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-01-01

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia. PMID:27171111

  16. Optical Spectroscopy Approach for the Predictive Assessment of Kidney Functional Recovery Following Ischemic Injury

    SciTech Connect

    Raman, R N; Pivetti, C D; Rubenchik, A M; Matthews, D L; Troppmann, C; Demos, S G

    2010-02-11

    Tissue that has undergone significant yet unknown amount of ischemic injury is frequently encountered in organ transplantation and trauma clinics. With no reliable real-time method of assessing the degree of injury incurred in tissue, surgeons generally rely on visual observation which is subjective. In this work, we investigate the use of optical spectroscopy methods as a potentially more reliable approach. Previous work by various groups was strongly suggestive that tissue autofluorescence from NADH obtained under UV excitation is sensitive to metabolic response changes. To test and expand upon this concept, we monitored autofluorescence and light scattering intensities of injured vs. uninjured rat kidneys via multimodal imaging under 355 nm, 325 nm, and 266 nm excitation as well as scattering under 500 nm illumination. 355 nm excitation was used to probe mainly NADH, a metabolite, while 266 nm excitation was used to probe mainly tryptophan to correct for non-metabolic signal artifacts. The ratio of autofluorescence intensities derived under these two excitation wavelengths was calculated and its temporal profile was fit to a relaxation model. Time constants were extracted, and longer time constants were associated with kidney dysfunction. Analysis of both the autofluorescence and light scattering images suggests that changes in microstructure tissue morphology, blood absorption spectral characteristics, and pH contribute to the behavior of the observed signal which may be used to obtain tissue functional information and offer predictive capability.

  17. A Case of Primary Hypoparathyroidism Presenting with Acute Kidney Injury Secondary to Rhabdomyolysis

    PubMed Central

    Aydin, Zeki; Gursu, Meltem; Uzun, Sami; Karadag, Serhat; Cebeci, Egemen; Ozturk, Savas; Kazancioglu, Rumeyza

    2016-01-01

    Hypoparathyroidism is the most common cause of symmetric calcification of the basal ganglia. Herein, a case of primary hypoparathyroidism with severe tetany, rhabdomyolysis, and acute kidney injury is presented. A 26-year-old male was admitted to the emergency clinic with leg pain and cramps, nausea, vomiting, and decreased amount of urine. He had been treated for epilepsy for the last 10 years. He was admitted to the emergency department for leg pain, cramping in the hands and legs, and agitation multiple times within the last six months. He was prescribed antidepressant and antipsychotic medications. He had a blood pressure of 150/90 mmHg, diffuse abdominal tenderness, and abdominal muscle rigidity on physical examination. Pathological laboratory findings were as follows: creatinine, 7.5 mg/dL, calcium, 3.7 mg/dL, alanine transaminase, 4349 U/L, aspartate transaminase, 5237 U/L, creatine phosphokinase, 262.000 U/L, and parathyroid hormone, 0 pg/mL. There were bilateral symmetrical calcifications in basal ganglia and the cerebellum on computerized tomography. He was diagnosed as primary hypoparathyroidism and acute kidney injury secondary to severe rhabdomyolysis. Brain calcifications, although rare, should be considered in dealing with patients with neurological symptoms, symmetrical cranial calcifications, and calcium metabolism abnormalities. PMID:27034860

  18. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.

    PubMed

    Palevsky, Paul M; Liu, Kathleen D; Brophy, Patrick D; Chawla, Lakhmir S; Parikh, Chirag R; Thakar, Charuhas V; Tolwani, Ashita J; Waikar, Sushrut S; Weisbord, Steven D

    2013-05-01

    In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their widespread application to clinical care in the United States. The panel generally concurred with the remainder of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of nephrotoxins for the prevention and treatment of AKI.

  19. The balance of powers: Redox regulation of fibrogenic pathways in kidney injury

    PubMed Central

    Okamura, Daryl M.; Pennathur, Subramaniam

    2015-01-01

    Oxidative stress plays a central role in the pathogenesis of diverse chronic inflammatory disorders including diabetic complications, cardiovascular disease, aging, and chronic kidney disease (CKD). Patients with moderate to advanced CKD have markedly increased levels of oxidative stress and inflammation that likely contribute to the unacceptable high rates of morbidity and mortality in this patient population. Oxidative stress is defined as an imbalance of the generation of reactive oxygen species (ROS) in excess of the capacity of cells/tissues to detoxify or scavenge them. Such a state of oxidative stress may alter the structure/function of cellular macromolecules and tissues that eventually leads to organ dysfunction. The harmful effects of ROS have been largely attributed to its indiscriminate, stochastic effects on the oxidation of protein, lipids, or DNA but in many instances the oxidants target particular amino acid residues or lipid moieties. Oxidant mechanisms are intimately involved in cell signaling and are linked to several key redox-sensitive signaling pathways in fibrogenesis. Dysregulation of antioxidant mechanisms and overproduction of ROS not only promotes a fibrotic milieu but leads to mitochondrial dysfunction and further exacerbates kidney injury. Our studies support the hypothesis that unique reactive intermediates generated in localized microenvironments of vulnerable tissues such as the kidney activate fibrogenic pathways and promote end-organ damage. The ability to quantify these changes and assess response to therapies will be pivotal in understanding disease mechanisms and monitoring efficacy of therapy. PMID:26448394

  20. Classical and remote post-conditioning effects on ischemia/reperfusion-induced acute oxidant kidney injury.

    PubMed

    Kadkhodaee, Mehri; Najafi, Atefeh; Seifi, Behjat

    2014-11-01

    The present study aimed to analyze and compare the effects of classical and remote ischemic postconditioning (POC) on rat renal ischemia/reperfusion (IR)-induced acute kidney injury. After right nephrectomy, male rats were randomly assigned into four groups (n = 8). In the IR group, 45 min of left renal artery occlusion was induced followed by 24 h of reperfusion. In the classical POC group, after induction of 45 min ischemia, 4 cycles of 10 s of intermittent ischemia and reperfusion were applied to the kidney before complete restoring of renal blood. In the remote POC group, 4 cycles of 5 min ischemia and reperfusion of left femoral artery were applied after 45 min renal ischemia and right at the time of renal reperfusion. There was a reduction in renal function (increase in blood urea and creatinine) in the IR group. Application of both forms of POC prevented the IR-induced reduction in renal function and histology. There were also significant improvements in kidney oxidative stress status in both POC groups demonstrated by a reduction in malondialdehyde (MDA) formation and preservation of antioxidant levels comparing to the IR group. We concluded that both methods of POC have protective effects on renal function and histology possibly by a reduction in IR-induced oxidative stress.

  1. Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia.

    PubMed

    Gupta, Kamlesh K; Donahue, Deborah L; Sandoval-Cooper, Mayra J; Castellino, Francis J; Ploplis, Victoria A

    2015-01-01

    Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/-) or expressing a PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT) mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC) in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity.

  2. Quantification and localization of M2 macrophages in human kidneys with acute tubular injury

    PubMed Central

    Palmer, Matthew B; Vichot, Alfred A; Cantley, Lloyd G; Moeckel, Gilbert W

    2014-01-01

    This study addresses for the first time the question whether there is significant macrophage population in human kidney sections from patients with acute tubular injury (ATI). We examined therefore the interstitial macrophage population in human kidney tissue with biopsy-proven diagnosis of ATI, minimal change disease (MCD), and MCD with ATI. Kidney biopsies from patients with the above diagnoses were stained with antibodies directed against CD68 (general macrophage marker), CD163 (M2 marker), and HLA-DR (M1 marker) and their respective electron microscopy samples were evaluated for the presence of interstitial macrophages. Our study shows that patients with ATI have significantly increased numbers of interstitial CD68+ macrophages, with an increase in both HLA-DR+ M1 macrophages and CD163+ M2 macrophages as compared to patients with MCD alone. Approximately 75% of macrophages were M2 (CD163+) whereas only 25% were M1 (HLA-DR+). M2 macrophages, which are believed to be critical for wound healing, were found to localize close to the tubular basement membrane of injured proximal tubule cells. Ultra structural examination showed close adherence of macrophages to the basement membrane of injured tubular epithelial cells. We conclude that macrophages accumulate around injured tubules following ATI and exhibit predominantly an M2 phenotype. We further speculate that macrophage-mediated repair may involve physical contact between the M2 macrophage and the injured tubular epithelial cell. PMID:25404860

  3. Acute kidney injury induced by antimicrobial agents in the elderly: awareness and mitigation strategies.

    PubMed

    Mizokami, Fumihiro; Mizuno, Tomohiro

    2015-01-01

    The use of antimicrobial agents has increased in recent years as treatments have diversified and resistant bacteria have appeared. With increased use of antimicrobial agents, elderly patients are prone to adverse drug reactions (ADRs) as a result of factors such as drug-drug interactions, polypharmacy, long-term use, and over- or under-dosage. In particular, elderly patients using antimicrobials are at increased risk to develop drug-induced acute kidney injury (AKI), which is the most common severe ADR in such patients. AKI is a serious problem that is associated with mortality amongst hospitalized patients. Antimicrobial-induced AKI can be classified into three different types: acute tubular necrosis (ATN), acute interstitial nephritis (AIN), and renal tubule lumen obstruction. AKI can generally be prevented by proper maintenance of fluid balance. To design dosage regimens that ensure efficient drug excretion via the kidney, it is necessary to accurately estimate renal function; however, the kidney undergoes age-dependent structural and functional alterations over time. Therefore, proper management of antimicrobial agents by an antimicrobial stewardship team may lead to decreased incidence of AKI. This article reviews antimicrobial-induced AKI and discusses potential strategies for increasing awareness of AKI and mitigating its clinical effects.

  4. Chronic Kidney Disease Induced Intestinal Mucosal Barrier Damage Associated with Intestinal Oxidative Stress Injury

    PubMed Central

    Yu, Chao; Wang, Qiang; Zhou, Chunyu; Kang, Xin; Zhao, Shuang; Liu, Shuai; Fu, Huijun; Yu, Zhen; Peng, Ai

    2016-01-01

    Background. To investigate whether intestinal mucosal barrier was damaged or not in chronic kidney disease progression and the status of oxidative stress. Methods. Rats were randomized into two groups: a control group and a uremia group. The uremia rat model was induced by 5/6 kidney resection. In postoperative weeks (POW) 4, 6, 8, and 10, eight rats were randomly selected from each group to prepare samples for assessing systemic inflammation, intestinal mucosal barrier changes, and the status of intestinal oxidative stress. Results. The uremia group presented an increase trend over time in the serum tumor necrosis factor-alpha, interleukin-6 (IL-6) and IL-10, serum D-lactate and diamine oxidase, and intestinal permeability, and these biomarkers were significantly higher than those in control group in POW 8 and/or 10. Chiu's scores in uremia group were also increased over time, especially in POW 8 and 10. Furthermore, the intestinal malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were significantly higher in uremia group when compared with those in control group in POW 8 and/or 10. Conclusions. The advanced chronic kidney disease could induce intestinal mucosal barrier damage and further lead to systemic inflammation. The underlying mechanism may be associated with the intestinal oxidative stress injury. PMID:27493661

  5. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.

    PubMed

    Chevalier, Robert L

    2016-07-01

    There is an alarming global increase in the incidence of end-stage kidney disease, for which early biomarkers and effective treatment options are lacking. Largely based on the histology of the end-stage kidney and on the model of unilateral ureteral obstruction, current investigation is focused on the pathogenesis of renal interstitial fibrosis as a central mechanism in the progression of chronic kidney disease (CKD). It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to CKD, and, conversely, CKD is a risk factor for AKI. Based on recent and historic studies, this review shifts attention from the glomerulus and interstitium to the proximal tubule as the primary sensor and effector in the progression of CKD as well as AKI. Packed with mitochondria and dependent on oxidative phosphorylation, the proximal tubule is particularly vulnerable to injury (obstructive, ischemic, hypoxic, oxidative, metabolic), resulting in cell death and ultimately in the formation of atubular glomeruli. Animal models of human glomerular and tubular disorders have provided evidence for a broad repertoire of morphological and functional responses of the proximal tubule, revealing processes of degeneration and repair that may lead to new therapeutic strategies. Most promising are studies that encompass the entire life cycle from fetus to senescence, recognizing epigenetic factors. The application of techniques in molecular characterization of tubule segments and the development of human kidney organoids may provide new insights into the mammalian kidney subjected to stress or injury, leading to biomarkers of early CKD and new therapies.

  6. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.

    PubMed

    Chevalier, Robert L

    2016-07-01

    There is an alarming global increase in the incidence of end-stage kidney disease, for which early biomarkers and effective treatment options are lacking. Largely based on the histology of the end-stage kidney and on the model of unilateral ureteral obstruction, current investigation is focused on the pathogenesis of renal interstitial fibrosis as a central mechanism in the progression of chronic kidney disease (CKD). It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to CKD, and, conversely, CKD is a risk factor for AKI. Based on recent and historic studies, this review shifts attention from the glomerulus and interstitium to the proximal tubule as the primary sensor and effector in the progression of CKD as well as AKI. Packed with mitochondria and dependent on oxidative phosphorylation, the proximal tubule is particularly vulnerable to injury (obstructive, ischemic, hypoxic, oxidative, metabolic), resulting in cell death and ultimately in the formation of atubular glomeruli. Animal models of human glomerular and tubular disorders have provided evidence for a broad repertoire of morphological and functional responses of the proximal tubule, revealing processes of degeneration and repair that may lead to new therapeutic strategies. Most promising are studies that encompass the entire life cycle from fetus to senescence, recognizing epigenetic factors. The application of techniques in molecular characterization of tubule segments and the development of human kidney organoids may provide new insights into the mammalian kidney subjected to stress or injury, leading to biomarkers of early CKD and new therapies. PMID:27194714

  7. Age of red blood cells and outcome in acute kidney injury

    PubMed Central

    2013-01-01

    Introduction Transfusion of red blood cells (RBCs) and, in particular, older RBCs has been associated with increased short-term mortality in critically ill patients. We evaluated the association between age of transfused RBCs and acute kidney injury (AKI), hospital, and 90-day mortality in critically ill patients. Methods We conducted a prospective, observational, predefined sub-study within the FINNish Acute Kidney Injury (FINNAKI) study. This study included all elective ICU admissions with expected ICU stay of more than 24 hours and all emergency admissions from September to November 2011. To study the age of RBCs, we classified transfused patients into quartiles according to the age of oldest transfused RBC unit in the ICU. AKI was defined according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Results Out of 1798 patients, 652 received at least one RBC unit. The median [interquartile range] age of the oldest RBC unit transfused was 12 [11-13] days in the freshest quartile and 21 [17-27] days in the quartiles 2 to 4. On logistic regression, RBC age was not associated with the development of KDIGO stage 3 AKI. Patients in the quartile of freshest RBCs had lower crude hospital and 90-day mortality rates compared to those in the quartiles of older blood. After adjustments, older RBC age was associated with significantly increased risk for hospital mortality. Age, Simplified Acute Physiology Score II (SAPS II)-score without age points, maximum Sequental Organ Failure Assessment (SOFA) score and the total number of transfused RBC units were independently associated with 90-day mortality. Conclusions The age of transfused RBC units was independently associated with hospital mortality but not with 90-day mortality or KDIGO stage 3 AKI. The number of transfused RBC units was an independent risk factor for 90-day mortality. PMID:24093554

  8. Diagnostic accuracy of urinary neutrophil gelatinase-associated lipocalin in patients with septic acute kidney injury

    PubMed Central

    Patel, Munna Lal; Sachan, Rekha; Shyam, Radhey; Kumar, Satish; Kamal, Ritul; Misra, Arvind

    2016-01-01

    Background Sepsis is the most common cause of acute kidney injury (AKI). Very few studies have investigated the predictive properties of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a marker of AKI in septic patients. The aim of this study is to examine uNGAL in septic patients with and without AKI and to evaluate its predictive value. Methods We prospectively studied 155 patients with sepsis over a period of 1 year. Urine was analyzed for neutrophil gelatinase-associated lipocalin at 12, 24, and 48 hours after admission. Patients with <24-hour stay and those with chronic kidney disease were excluded. AKI was classified according to the Acute Kidney Injury Network guidelines. Results The differences in mean change of uNGAL at 12, 24, and 48 hours were 80.00±7.00 ng/mL and 128.13±22.46 ng/mL, respectively in septic AKI, and 02.07±0.80 ng/mL and 26.13±15.12 ng/mL, respectively in septic non-AKI. At baseline or 12 hours, the cutoff value of 34.32 ng/mL had a sensitivity and specificity of 86.36 and 80.60, respectively and an area under curve of 0.81 (95% CI: 0.73–0.89) for predicting AKI. At the cutoff value 199.99 ng/mL sensitivity and specificity of 90.0 and 64.66, respectively and an area under curve of 0.82 (95% CI, 0.75–0.88) for predicting AKI. Conclusion The baseline or 12-hour uNGAL is highly sensitive but a less specific predictor of AKI in septic patients. PMID:27471404

  9. Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Zhang, Zhi-Hui; Wang, Hua; Zhao, Hui; Yu, De-Xin; Xu, De-Xiang

    2015-01-01

    Vitamin D receptor (VDR) is highly expressed in human and mouse kidneys. Nevertheless, its functions remain obscure. This study investigated the effects of vitamin D3 (VitD3) pretreatment on renal inflammation during lipopolysaccharide (LPS)-induced acute kidney injury. Mice were intraperitoneally injected with LPS. In VitD3 + LPS group, mice were pretreated with VitD3 (25 μg/kg) at 48, 24 and 1 h before LPS injection. As expected, an obvious reduction of renal function and pathological damage was observed in LPS-treated mice. VitD3 pretreatment significantly alleviated LPS-induced reduction of renal function and pathological damage. Moreover, VitD3 pretreatment attenuated LPS-induced renal inflammatory cytokines, chemokines and adhesion molecules. In addition, pretreatment with 1,25(OH)2D3, the active form of VitD3, alleviated LPS-induced up-regulation of inflammatory cytokines and chemokines in human HK-2 cells, a renal tubular epithelial cell line, in a VDR-dependent manner. Further analysis showed that VitD3, which activated renal VDR, specifically repressed LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit in the renal tubules. LPS, which activated renal NF-κB, reciprocally suppressed renal VDR and its target gene. Moreover, VitD3 reinforced the physical interaction between renal VDR and NF-κB p65 subunit. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity during LPS-induced acute kidney injury. PMID:26691774

  10. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury.

    PubMed

    Basile, David P; Friedrich, Jessica L; Spahic, Jasmina; Knipe, Nicole; Mang, Henry; Leonard, Ellen C; Changizi-Ashtiyani, Saeed; Bacallao, Robert L; Molitoris, Bruce A; Sutton, Timothy A

    2011-03-01

    Acute kidney injury induces the loss of renal microvessels, but the fate of endothelial cells and the mechanism of potential vascular endothelial growth factor (VEGF)-mediated protection is unknown. Cumulative cell proliferation was analyzed in the kidney of Sprague-Dawley rats following ischemia-reperfusion (I/R) injury by repetitive administration of BrdU (twice daily) and colocalization in endothelial cells with CD31 or cablin. Proliferating endothelial cells were undetectable for up to 2 days following I/R and accounted for only ∼1% of BrdU-positive cells after 7 days. VEGF-121 preserved vascular loss following I/R but did not affect proliferation of endothelial, perivascular cells or tubular cells. Endothelial mesenchymal transition states were identified by localizing endothelial markers (CD31, cablin, or infused tomato lectin) with the fibroblast marker S100A4. Such structures were prominent within 6 h and sustained for at least 7 days following I/R. A Tie-2-cre transgenic crossed with a yellow fluorescent protein (YFP) reporter mouse was used to trace the fate of endothelial cells and demonstrated interstititial expansion of YFP-positive cells colocalizing with S100A4 and smooth muscle actin following I/R. The interstitial expansion of YFP cells was attenuated by VEGF-121. Multiphoton imaging of transgenic mice revealed the alteration of YFP-positive vascular cells associated with blood vessels characterized by limited perfusion in vivo. Taken together, these data indicate that vascular dropout post-AKI results from endothelial phenotypic transition combined with an impaired regenerative capacity, which may contribute to progressive chronic kidney disease. PMID:21123492

  11. Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function

    PubMed Central

    Siew, Edward D.; Ware, Lorraine B.; Bian, Aihua; Shintani, Ayumi; Eden, Svetlana; Wickersham, Nancy; Cripps, Ben; Ikizler, T. Alp

    2013-01-01

    The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type Fatty Acid Binding Protein (L-FABP), and Cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min/1.73 m2. One-hundred thirty AKI cases were identified following biomarker measurement and were compared to 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58(95%CI: 0.52-0.64), 0.59(0.52-0.65), and 0.50(0.48-0.57) for urine NGAL, L-FABP, and Cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59(56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis [NGAL hazard ratio 1.35(95%CI: 0.93-1.96), L-FABP 1.15(0.82-1.61)] though both independently predicted the need for acute dialysis [NGAL 3.44(1.73-6.83), L-FABP 2.36(1.30-4.25)]. Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions. PMID:23698227

  12. Spectrum of glomerular diseases causing acute kidney injury; 25 years experience from a single center

    PubMed Central

    Naqvi, Rubina; Mubarak, Muhammed; Ahmed, Ejaz; Akhtar, Fazal; Bhatti, Sajid; Naqvi, Anwar; Rizvi, Adib

    2015-01-01

    Introduction: Acute kidney injury (AKI) is common in nephro-urological practice. Its incidence, prevalence and etiology vary widely, mainly due to variations in the definitions of AKI. Objectives: We aim to report the spectrum of glomerular diseases presenting as AKI at a kidney referral center in Pakistan. Patients and Methods: An observational cohort of patients identified as having AKI which was defined according to RIFLE criteria, with normal size, non-obstructed kidneys on ultrasonography, along with active urine sediment, edema and new onset hypertension. Results: From 1990 to 2014, 236 cases of AKI secondary to acute glomerulonephritis (AGN) registered at this institution. Mean age of patients was 27.94± 12.79 years and M:F ratio was 0.77:1. Thirty percent patients revealed crescents on renal biopsy. AGN without crescents was seen in 33.05% of cases. Postinfectious GN was found in 14.4%, lupus nephritis in 8.5% and mesangiocapillary GN in 3.4% cases. Renal replacement therapy (RRT) required in 75.84% patients. Pulse steroids were given in 45.33% cases followed by oral steroids. Pulse cyclophoshphamide was given in 23.7% cases and plasmapheresis was used in 3.38% cases. Complete recovery was seen in 44%, while 11.44% died during acute phase of illness. About 19.49 % developed chronic kidney disease (CKD) and 25.84% were lost to long- term follow-up. Conclusion: Although glomerular diseases contribute only 4.19 % of total AKI at this center, morbidity associated with illness and its treatment is more marked than other AKI groups. Another notable factor is late referral of these patients to specialized centers resulting in undesirable outcome. PMID:26693497

  13. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury

    PubMed Central

    Leonard, Ellen C.; Friedrich, Jessica L.; Basile, David P.

    2008-01-01

    Acute kidney injury induced by renal ischemia-reperfusion (I/R) compromises microvascular density and predisposes to chronic kidney disease (CKD) and sodium-dependent hypertension. VEGF-121 was administered to rats fed a standard (0.4%) sodium diet at various times following recovery from I/R injury for up to 35 days. VEGF-121 had no effect on the initial loss of renal function, as indicated by serum creatinine levels measured 24 h after injury. Serum creatinine levels declined thereafter, indicative of renal repair. Rats were then switched to an elevated (4.0%) sodium diet for an additional 28 days to induce CKD. The 4.0% sodium diet enhanced renal hypertrophy, interstitial volume, albuminuria, and cardiac hypertrophy relative to postischemic animals maintained on the 0.4% sodium diet. Administration of VEGF-121 from day 0 to 14, day 0 to 35, or day 3 to 35 after I/R suppressed the effects of sodium diet on CKD development, while delayed administration of VEGF-121 from day 21 to 35 had no effect. Endothelial nitric oxide synthase protein levels were upregulated in postischemic animals, and this effect was significantly increased by the 4.0% sodium diet but was not influenced by prior treatment with VEGF. Conversely, microvascular density was preserved in postischemic animals treated with VEGF-121 relative to vehicle-treated postischemic animals. These data suggest that early, but not delayed, treatment with VEGF-121 can preserve vascular structure after ischemia and influence chronic renal function in response to elevated sodium intake. PMID:18799550

  14. Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor, Fidarestat

    PubMed Central

    Takahashi, Kazunori; Mizukami, Hiroki; Kamata, Kosuke; Inaba, Wataru; Kato, Noriaki; Hibi, Chihiro; Yagihashi, Soroku

    2012-01-01

    Background Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Methods Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Results Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. Conclusion AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality. PMID:22253906

  15. ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury

    SciTech Connect

    Arfian, Nur; Emoto, Noriaki; Vignon-Zellweger, Nicolas; Nakayama, Kazuhiko; Yagi, Keiko; Hirata, Ken-ichi

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Ischemia/reperfusion injury (IRI) induced increased endothelin-1 (ET-1) expression. Black-Right-Pointing-Pointer IRI was accompanied by tubular injury and remodeling of renal arteries. Black-Right-Pointing-Pointer IRI increased oxidative stress and inflammation. Black-Right-Pointing-Pointer Genetic suppression of ET-1 in endothelial cells attenuates IRI in the kidney. Black-Right-Pointing-Pointer The mechanisms include the inhibition of oxidative stress and inflammation. -- Abstract: Background: The prognosis of patients after acute kidney injury (AKI) is poor and treatment is limited. AKI is mainly caused by renal ischemia/reperfusion injury (IRI). During the extension phase of IRI, endothelial damage may participate in ischemia and inflammation. Endothelin-1 (ET-1) which is mostly secreted by endothelial cells is an important actor of IRI, particularly through its strong vasoconstrictive properties. We aimed to analyze the specific role of ET-1 from the endothelial cells in AKI. Methods: We used mice lacking ET-1 in the vascular endothelial cells (VEETKO). We induced IRI in VEETKO mice and wild type controls by clamping both kidneys for 30 min. Sham operated mice were used as controls. Mice were sacrificed one day after IRI in order to investigate the extension phase of IRI. Kidney function was assessed based on serum creatinine concentration. Levels of expression of ET-1, its receptor ET{sub A}, protein kinase C, eNOS, E-Cadherin and inflammation markers were evaluated by real time PCR or western blot. Tubular injury was scored on periodic acid Schiff stained kidney preparations. Lumen and wall area of small intrarenal arteries were measured on kidney slices stained for alpha smooth muscle cell actin. Oxidative stress, macrophage infiltration and cell proliferation was evaluated on slices stained for 8-hydroxy-2 Prime -deoxyguanosine, F4/80 and PCNA, respectively. Results: IRI induced kidney failure and increased ET-1 and

  16. Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury.

    PubMed

    Umbro, Ilaria; Gentile, Giuseppe; Tinti, Francesca; Muiesan, Paolo; Mitterhofer, Anna Paola

    2016-02-01

    Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infective insult. This process often leads to widespread tissue injury and multiple organ dysfunction. In particular, the development of acute kidney injury (AKI) is one of the most frequent complications, which increases the complexity and cost of care, and is an independent risk factor for mortality. Previous suggestions highlighting systemic hypotension, renal vasoconstriction and ischaemia-reperfusion injury as the primary pathophysiological mechanisms involved in sepsis-induced AKI have been challenged. Recently it has been shown that sepsis-induced AKI occurs in the setting of microvascular dysfunction with release of microparticles, inflammation and energetic adaptation of highly metabolic organs to cellular stress. The intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an incomplete understanding of its pathophysiology and a delay in diagnosis. The aim of this review is to focus on advances in understanding the sepsis pathophysiology, with particular attention to the fundamental mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers involved.

  17. Global miRNA expression is temporally correlated with acute kidney injury in mice

    PubMed Central

    Chen, Xiao

    2016-01-01

    MicroRNAs (miRNAs) are negative regulators of gene expression and protein abundance. Current evidence shows an association of miRNAs with acute kidney injury (AKI) leading to substantially increased morbidity and mortality. Here, we investigated whether miRNAs are inductive regulators responsible for the pathological development of AKI. Microarray analysis was used to detect temporal changes in global miRNA expression within 48 h after AKI in mice. Results indicated that global miRNA expression gradually increased over 24 h from ischemia reperfusion injury after 24 h, and then decreased from 24 h to 48 h. A similar trend was observed for the index of tubulointerstitial injury and the level of serum creatinine, and there was a significant correlation between the level of total miRNA expression and the level of serum creatinine (p < 0.05). This expression-phenotype correlation was validated by quantitative reverse transcription PCR on individual miRNAs, including miR-18a, -134, -182, -210 and -214. Increased global miRNA expression may lead to widespread translational repression and reduced cellular activity. Furthermore, significant inflammatory cytokine release and peritubular capillary loss were observed, suggesting that the initiation of systematic destruction programs was due to AKI. Our findings provide new understanding of the dominant role of miRNAs in promoting the pathological development of AKI. PMID:26966664

  18. Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury.

    PubMed

    Umbro, Ilaria; Gentile, Giuseppe; Tinti, Francesca; Muiesan, Paolo; Mitterhofer, Anna Paola

    2016-02-01

    Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infective insult. This process often leads to widespread tissue injury and multiple organ dysfunction. In particular, the development of acute kidney injury (AKI) is one of the most frequent complications, which increases the complexity and cost of care, and is an independent risk factor for mortality. Previous suggestions highlighting systemic hypotension, renal vasoconstriction and ischaemia-reperfusion injury as the primary pathophysiological mechanisms involved in sepsis-induced AKI have been challenged. Recently it has been shown that sepsis-induced AKI occurs in the setting of microvascular dysfunction with release of microparticles, inflammation and energetic adaptation of highly metabolic organs to cellular stress. The intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an incomplete understanding of its pathophysiology and a delay in diagnosis. The aim of this review is to focus on advances in understanding the sepsis pathophysiology, with particular attention to the fundamental mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers involved. PMID:26702738

  19. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A.; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-01-01

    Abstract Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a

  20. Evaluation of kidney repair capacity using 99mTc-DMSA in ischemia/reperfusion injury models.

    PubMed

    Kwak, Wonjung; Jang, Hee-Seong; Belay, Takele; Kim, Jinu; Ha, Yeong Su; Lee, Sang Woo; Ahn, Byeong-Cheol; Lee, Jaetae; Park, Kwon Moo; Yoo, Jeongsoo

    2011-03-01

    Quantitative (99m)Tc-DMSA renal uptake was studied in different renal ischemia/reperfusion (I/R) mice models for the assessment of renal repair capacity. Mice models of nephrectomy, uni- and bi-lateral I/R together with sham-operated mice were established. At 1h, 1d, 4d, 1, 2 and 3 wk after I/R, (99m)Tc-DMSA (27.7 ± 1.3 MBq) was injected via tail vein and after 3h post-injection, the mice were scanned for 30 min with pinhole equipped gamma camera. Higher uptake of (99m)Tc-DMSA was measured in normal kidneys of uni-lateral I/R model and nephrectomized kidney I/R model at 3 wk post-surgery. Comparing the restoration capacities of the affected kidneys of nephrectomy, uni- and bi-lateral I/R models, higher repair capacity was observed in the nephrectomized model followed by bi-lateral then uni-lateral models. The normal kidney may retard the restoration of damaged kidney in uni-lateral I/R model. Moreover, 3 wk after Uni-I/R, the size of injured kidney was significantly smaller than non-ischemic contralateral and sham operated kidneys, while nephrectomy I/R kidneys were significantly enlarged compared to all others at 3 wk post-surgery. Very strong correlation between (99m)Tc-DMSA uptake and weight of dissected kidneys in I/R models was observed. Consistent with (99m)Tc-DMSA uptake results, all histological results indicate that kidney recovery after injury is correlated with the amount of intact tubules and kidney sizes. In summary, our study showed good potentials of (99m)Tc-DMSA scan as a promising non-invasive method for evaluation of kidney restoration after I/R injuries. Interestingly, mice with Bi-I/R injury showed faster repair capacity than those with uni-I/R.

  1. Potential of IL-33 for Preventing the Kidney Injury via Regulating the Lipid Metabolism in Gout Patients.

    PubMed

    Duan, Lihua; Huang, Yan; Su, Qun; Lin, Qingyan; Liu, Wen; Luo, Jiao; Yu, Bing; He, Yan; Qian, Hongyan; Liu, Yuan; Chen, Jie; Shi, Guixiu

    2016-01-01

    Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout. PMID:27579324

  2. Potential of IL-33 for Preventing the Kidney Injury via Regulating the Lipid Metabolism in Gout Patients

    PubMed Central

    Huang, Yan; Su, Qun; Lin, Qingyan; Liu, Wen; Yu, Bing; Liu, Yuan

    2016-01-01

    Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout. PMID:27579324

  3. High Risk of Herpes Zoster among Patients with Advance Acute Kidney Injury--A Population-Based Study.

    PubMed

    Yang, Wei-Shun; Hu, Fu-Chang; Chen, Meng-Kan; Ko, Wen-Je; Chen, Likwang; Wu, Kwan-Dun; Wu, Vin-Cent

    2015-09-03

    The risk for herpes zoster (HZ) in acute kidney injury (AKI) survivors was never explored. We identified 2,387 adults in the Taiwan National Health Insurance Research Database who recovered from dialysis-requiring AKI and matched them with non-recovery and non-AKI patients by propensity score. During a mean follow-up of 2.7 years, the incidences of HZ were 6.9, 8.2 and 4.8 episodes per 1,000 person-years in AKI-non-recovery, AKI-recovery and non-AKI group, respectively. The recovery group was more likely to develop herpes zoster than those without acute kidney injury [incidence-rate ratios 1.71, 95% confidence interval 1.16-2.52; p = 0.007]. Patients without acute kidney injury were less likely to develop herpes zoster than those AKI, recovered from dialysis or not (hazard ratio HR 0.66, 95% CI 0.46-0.95). Dialysis-requiring acute kidney injury poses a long-term risk of herpes zoster after hospital discharge. Even patients who have recovered from dialysis still carry a significantly higher risk of developing herpes zoster.

  4. Expression, Circulation, and Excretion Profile of MicroRNA-21, -155, and -18a Following Acute Kidney Injury

    PubMed Central

    Vaidya, Vishal S.

    2012-01-01

    MicroRNAs (miRNAs) are endogenous noncoding RNA molecules that are involved in post-transcriptional gene silencing. Using global miRNA expression profiling, we found miR-21, -155, and 18a to be highly upregulated in rat kidneys following tubular injury induced by ischemia/reperfusion (I/R) or gentamicin administration. Mir-21 and -155 also showed decreased expression patterns in blood and urinary supernatants in both models of kidney injury. Furthermore, urinary levels of miR-21 increased 1.2-fold in patients with clinical diagnosis of acute kidney injury (AKI) (n = 22) as compared with healthy volunteers (n = 25) (p < 0.05), and miR-155 decreased 1.5-fold in patients with AKI (p < 0.01). We identified 29 messenger RNA core targets of these 3 miRNAs using the context likelihood of relatedness algorithm and found these predicted gene targets to be highly enriched for genes associated with apoptosis or cell proliferation. Taken together, these results suggest that miRNA-21 and -155 could potentially serve as translational biomarkers for detection of AKI and may play a critical role in the pathogenesis of kidney injury and tissue repair process. PMID:22705808

  5. HIV-induced kidney cell injury: role of ROS-induced downregulated vitamin D receptor

    PubMed Central

    Salhan, Divya; Husain, Mohammad; Subrati, Ashaan; Goyal, Rohan; Singh, Tejinder; Rai, Partab; Malhotra, Ashwani

    2012-01-01

    Reactive oxygen species (ROS) have been demonstrated to contribute to HIV-induced tubular cell injury. We hypothesized that HIV-induced ROS generation may be causing tubular cell injury through downregulation of vitamin D receptor (VDR) and associated downstream effects. In the present study, HIV not only downregulated tubular cell VDR expression but also inflicted DNA injury. On the other hand, EB-1089, a VDR agonist (VD), inhibited both downregulation of VDR and tubular cell DNA injury in the HIV milieu. H2O2 (an O− donor) directly downregulated tubular cell VDR, whereas catalase, a free radical scavenger, inhibited HIV-induced downregulation of tubular cell VDR expression. HIV also stimulated the tubular cell renin-angiotensin system (RAS) through downregulation of VDR. Because losartan (an ANG II blolcker) partially inhibited HIV-induced tubular cell ROS generation while ANG II directly stimulated tubular cell ROS generation, it appears that HIV-induced ROS production was partly contributed by the RAS activation. VD not only inhibited HIV-induced RAS activation but also attenuated tubular cell ROS generation. Tubular cells displayed double jeopardy in the HIV milieu induction of double-strand breaks and attenuated DNA repair; additionally, in the HIV milieu, tubular cells exhibited enhanced expression of phospho-p53 and associated downstream signaling. A VDR agonist and an ANG II blocker not only preserved expression of tubular cell DNA repair proteins but also inhibited induction of double-strand breaks. In in vivo studies, renal cortical sections of Tg26 mice displayed attenuated expression of VDR both in podocytes and tubular cells. In addition, renal cortical sections of Tg26 mice displayed enhanced oxidative stress-induced kidney cell DNA damage. These findings indicated that HIV-induced tubular cell downregulation of VDR contributed to the RAS activation and associated tubular cell DNA damage. However, both VD and RAS blockade provided protection

  6. Electronic Medical Record-Based Predictive Model for Acute Kidney Injury in an Acute Care Hospital.

    PubMed

    Laszczyńska, Olga; Severo, Milton; Azevedo, Ana

    2016-01-01

    Patients with acute kidney injury (AKI) are at risk for increased morbidity and mortality. Lack of specific treatment has meant that efforts have focused on early diagnosis and timely treatment. Advanced algorithms for clinical assistance including AKI prediction models have potential to provide accurate risk estimates. In this project, we aim to provide a clinical decision supporting system (CDSS) based on a self-learning predictive model for AKI in patients of an acute care hospital. Data of all in-patient episodes in adults admitted will be analysed using "data mining" techniques to build a prediction model. The subsequent machine-learning process including two algorithms for data stream and concept drift will refine the predictive ability of the model. Simulation studies on the model will be used to quantify the expected impact of several scenarios of change in factors that influence AKI incidence. The proposed dynamic CDSS will apply to future in-hospital AKI surveillance in clinical practice. PMID:27577501

  7. Moving beyond supportive care--current status of specific therapies in pediatric acute kidney injury.

    PubMed

    Symons, Jordan M

    2014-02-01

    Acute kidney injury (AKI) remains a significant challenge, leading to increased morbidity, mortality, and medical costs. Therapy for AKI to this point has largely been supportive; specific interventions to treat established AKI have had minimal effect. Review of the pathogenesis of AKI reveals complex, interacting mechanisms, including changes in microcirculation, the immune system, and inflammation, and cell death from both necrosis and apoptosis. Past definitions of AKI have been imprecise; newer methods for AKI identification and classification, including novel biomarkers and improved criteria for defining AKI, may permit earlier intervention with greater potential for success. With improved understanding of pathophysiology and the opportunity for intervention before AKI is fully established, clinicians may be able to move beyond supportive care and improve outcomes.

  8. Acute kidney injury after contrast-enhanced examination among elderly1

    PubMed Central

    Aoki, Beatriz Bonadio; Fram, Dayana; Taminato, Mônica; Batista, Ruth Ester Sayad; Belasco, Angélica; Barbosa, Dulce Aparecida

    2014-01-01

    OBJECTIVES: to assess renal function in elderly patients undergoing contrast-enhanced computed tomography and identify the preventive measures of acute kidney injury in the period before and after the examination. METHOD: longitudinal cohort study conducted at the Federal University of São Paulo Hospital, from March 2011 to March 2013. All hospitalized elderly, of both sexes, aged 60 years and above, who performed the examination, were included (n=93). We collected sociodemographic data, data related to the examination and to the care provided, and creatinine values prior and post exam. RESULTS: an alteration in renal function was observed in 51 patients (54%) with a statistically significant increase of creatinine values (p<0.04), and two patients (4.0%) required hemodialysis. CONCLUSION: There is an urgent need for protocols prior to and post contrast-enhanced examination in the elderly, and other studies to verify the prognosis of this population. PMID:25296148

  9. Acute kidney injury associated with androgenic steroids and nutritional supplements in bodybuilders†

    PubMed Central

    Almukhtar, Safa E.; Abbas, Alaa A.; Muhealdeen, Dana N.; Hughson, Michael D.

    2015-01-01

    Four bodybuilders who injected anabolic steroids and ingested commercial protein (78–104 g/day) and creatine (15 g/day) products presented with serum creatinine levels between 229.84 and 335.92 µmol/L (2.6–3.8 mg/dL). Renal biopsies revealed acute tubular necrosis. Four weeks after discontinuing injections and supplements, serum creatinine was in the normal range and estimated glomerular filtration rate > 1.00 mL/s (60 mL/min), including two patients with biopsies showing >30% interstitial fibrosis and tubular atrophy. The findings highlight a risk for acute and potentially chronic kidney injury among young men abusing anabolic steroids and using excessive amounts of nutritional supplements. PMID:26251708

  10. Acute kidney injury in patients with paraquat intoxication; a case report and review of the literature.

    PubMed

    Safaei Asl, Afshin; Dadashzadeh, Peyman

    2016-01-01

    Paraquat and diquat are classified as bipyridyl compounds not only leads to acute organ damage, but also to a variety of complications. Patients with severe paraquat-induced poisoning may succumb to multiple organ failure involving the circulatory and respiratory systems. Deliberate self-poisoning with paraquat continues to be a major public health concern in many developing countries. At present there is no specific antidote to paraquat poisoning, hence the need to more focus on prevention and in cases of poisoning aggressive decontamination to prevent further absorption. This article presented a 12-year-old male with acute kidney injury following the ingestion of paraquat in suicidal attempt and serves to explore the complications associated with paraquat poisoning and current recommended treatment. PMID:27689124

  11. Acute kidney injury in patients with paraquat intoxication; a case report and review of the literature

    PubMed Central

    Safaei Asl, Afshin; Dadashzadeh, Peyman

    2016-01-01

    Paraquat and diquat are classified as bipyridyl compounds not only leads to acute organ damage, but also to a variety of complications. Patients with severe paraquat-induced poisoning may succumb to multiple organ failure involving the circulatory and respiratory systems. Deliberate self-poisoning with paraquat continues to be a major public health concern in many developing countries. At present there is no specific antidote to paraquat poisoning, hence the need to more focus on prevention and in cases of poisoning aggressive decontamination to prevent further absorption. This article presented a 12-year-old male with acute kidney injury following the ingestion of paraquat in suicidal attempt and serves to explore the complications associated with paraquat poisoning and current recommended treatment PMID:27689124

  12. Heart block and acute kidney injury due to hyperparathyroidism-induced hypercalcemic crisis.

    PubMed

    Brown, Taylor C; Healy, James M; McDonald, Mary J; Hansson, Joni H; Quinn, Courtney E

    2014-12-01

    We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life-saving bridge to definitive parathyroidectomy in cases of HIHC.

  13. Acute kidney injury in patients with paraquat intoxication; a case report and review of the literature

    PubMed Central

    Safaei Asl, Afshin; Dadashzadeh, Peyman

    2016-01-01

    Paraquat and diquat are classified as bipyridyl compounds not only leads to acute organ damage, but also to a variety of complications. Patients with severe paraquat-induced poisoning may succumb to multiple organ failure involving the circulatory and respiratory systems. Deliberate self-poisoning with paraquat continues to be a major public health concern in many developing countries. At present there is no specific antidote to paraquat poisoning, hence the need to more focus on prevention and in cases of poisoning aggressive decontamination to prevent further absorption. This article presented a 12-year-old male with acute kidney injury following the ingestion of paraquat in suicidal attempt and serves to explore the complications associated with paraquat poisoning and current recommended treatment

  14. We Use Permcaths Instead of Peritoneal Catheters for Acute Kidney Injury and Urgent-Start Dialysis.

    PubMed

    Dean, Daniel; Cruz, Dinna N

    2016-07-01

    The rising tide of severe acute kidney injury requiring dialysis (AKI-D) and unplanned dialysis initiation for advanced CKD patients remains a major problem for the nephrology community worldwide. Hemodialysis (HD) through a central venous catheter remains the most common practice for both. Peritoneal dialysis (PD) remains greatly underutilized despite mounting evidence of equipoise with HD for a significant proportion of patients. PD is technically simpler, requires less infrastructure, and costs less. However, the structure of our healthcare system, hospital logistics, and the current state of nephrology training all contribute to the reflexive consult for a central venous catheter. As clinicians, we must ask ourselves if we are doing our patients and our healthcare system a disservice by not offering PD in AKI and urgent-start situations. PMID:27154837

  15. Acute kidney injury associated with androgenic steroids and nutritional supplements in bodybuilders(†).

    PubMed

    Almukhtar, Safa E; Abbas, Alaa A; Muhealdeen, Dana N; Hughson, Michael D

    2015-08-01

    Four bodybuilders who injected anabolic steroids and ingested commercial protein (78-104 g/day) and creatine (15 g/day) products presented with serum creatinine levels between 229.84 and 335.92 µmol/L (2.6-3.8 mg/dL). Renal biopsies revealed acute tubular necrosis. Four weeks after discontinuing injections and supplements, serum creatinine was in the normal range and estimated glomerular filtration rate > 1.00 mL/s (60 mL/min), including two patients with biopsies showing >30% interstitial fibrosis and tubular atrophy. The findings highlight a risk for acute and potentially chronic kidney injury among young men abusing anabolic steroids and using excessive amounts of nutritional supplements. PMID:26251708

  16. A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury.

    PubMed

    Hirsch, Sara; El-Achkar, Tarek; Robbins, Lynn; Basta, Jeannine; Heitmeier, Monique; Nishinakamura, Ryuichi; Rauchman, Michael

    2015-11-15

    It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS (Sall1TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury. PMID:26311113

  17. National Veterans Health Administration inpatient risk stratification models for hospital-acquired acute kidney injury

    PubMed Central

    Cronin, Robert M; VanHouten, Jacob P; Siew, Edward D; Eden, Svetlana K; Fihn, Stephan D; Nielson, Christopher D; Peterson, Josh F; Baker, Clifton R; Ikizler, T Alp; Speroff, Theodore

    2015-01-01

    Objective Hospital-acquired acute kidney injury (HA-AKI) is a potentially preventable cause of morbidity and mortality. Identifying high-risk patients prior to the onset of kidney injury is a key step towards AKI prevention. Materials and Methods A national retrospective cohort of 1,620,898 patient hospitalizations from 116 Veterans Affairs hospitals was assembled from electronic health record (EHR) data collected from 2003 to 2012. HA-AKI was defined at stage 1+, stage 2+, and dialysis. EHR-based predictors were identified through logistic regression, least absolute shrinkage and selection operator (lasso) regression, and random forests, and pair-wise comparisons between each were made. Calibration and discrimination metrics were calculated using 50 bootstrap iterations. In the final models, we report odds ratios, 95% confidence intervals, and importance rankings for predictor variables to evaluate their significance. Results The area under the receiver operating characteristic curve (AUC) for the different model outcomes ranged from 0.746 to 0.758 in stage 1+, 0.714 to 0.720 in stage 2+, and 0.823 to 0.825 in dialysis. Logistic regression had the best AUC in stage 1+ and dialysis. Random forests had the best AUC in stage 2+ but the least favorable calibration plots. Multiple risk factors were significant in our models, including some nonsteroidal anti-inflammatory drugs, blood pressure medications, antibiotics, and intravenous fluids given during the first 48 h of admission. Conclusions This study demonstrated that, although all the models tested had good discrimination, performance characteristics varied between methods, and the random forests models did not calibrate as well as the lasso or logistic regression models. In addition, novel modifiable risk factors were explored and found to be significant. PMID:26104740

  18. Urinary Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury after Major Surgery

    PubMed Central

    Gocze, Ivan; Koch, Matthias; Renner, Philipp; Zeman, Florian; Graf, Bernhard M.; Dahlke, Marc H.; Nerlich, Michael; Schlitt, Hans J.; Kellum, John A.; Bein, Thomas

    2015-01-01

    Objective To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients. Introduction Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function. Methods In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test. Results 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l2/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001). Conclusions Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI. PMID:25798585

  19. The significance of tubular and glomerular proteinuria in critically ill patients with severe acute kidney injury

    PubMed Central

    Lim, Christopher Thiam Seong; Tan, Han Khim; Lau, Yeow Kok

    2014-01-01

    Objective: Critically ill patients with acute kidney injury (AKI) frequently need acute renal replacement therapy (aRRT). We evaluated an inexpensive, rapid quantitative and qualitative analysis of proteinuria on the course of AKI patients requiring aRRT in intensive care. Method: This was a prospective, observational study of critically ill patients with severe established AKI or Acute on Chronic Kidney Injury (AoCKI) requiring aRRT. Urine samples were analyzed using Sodium-Dodecyl-Sulphate-Polyacryamide Gel Electrophoresis (SDS-PAGE). Results: A total of 30 critically ill patients were studied. Those who died have higher APACHE II (29 ± 6 vs. 20 ± 5, p<0.001), multi-organ failure (0.7 ± 0.5 vs. 0.2 ± 0.4, p < 0.02) and Tubular/Glomerular ratio (114 ± 60 vs. 75± 37, p < 0.05).The renal non-recoverers have higher baseline creatinine (415 ± 328 vs. 125± 19 umol/l, p < 0.01), urinary Dipstick value (1.8±0.8 vs. 0.5±0, p <0.05) and Glomerular score (3.0 ± 1.8 vs. 0.6 ± 0.2, p < 0.02).Heavy tubular proteinuria also predicts a longer duration of interim dialysis support and mortality whereas glomerular proteinuria correlates with development of chronicity and End Stage Renal Disease (ESRD). Conclusions: The dominant presence of tubular proteinuria is associated with poor survival in patients who have high APACHE II score and multi-organ failure. It also correlates with a longer duration of dialysis support in survivals. Renal Non-recoverers had heavy dominant presence of glomerular proteinuria. SDS-PAGE proteinuria analysis offers a reliable and inexpensive method to prognosticate proteinuria in this group of critically ill patients. PMID:25674105

  20. Preventive effect of pentoxifylline on contrast-induced acute kidney injury in hypercholesterolemic rats

    PubMed Central

    YANG, SHI-KUN; DUAN, SHAO-BIN; PAN, PENG; XU, XIANG-QING; LIU, NA; XU, JUN

    2015-01-01

    Oxidative stress is an important mechanism of contrast-induced acute kidney injury (CIAKI). The optimal strategy to prevent CIAKI remains unclear. The aim of the present study was to assess the effect of pentoxifylline, a nonspecific phosphodiesterase inhibitor, on the prevention of CIAKI. A total of 32 healthy male Sprague-Dawley rats were randomly divided into normal dietary group (NN; n=8) and a high cholesterol-supplemented dietary group (HN; 4% cholesterol and 1% cholic acid; n=24). At the end of eight weeks, the rats in the high cholesterol diet group were randomly divided into three subgroups (n=8 in each group). CIAKI was induced in two of the subgroups via intravenous injection of the radiocontrast media iohexol (10 ml/kg). Pentoxifylline (50 mg/kg) was administered to one of the iohexol-treated groups via intraperitoneal injection 12 h prior to and following contrast media (CM) injection. Kidney function parameters and oxidative stress markers were then measured. The renal pathological changes were evaluated using hematoxylin and eosin staining and scored semi-quantitatively. In iohexol-injected rats, serum creatinine (Scr), renal pathological scores, renal malondialdehyde (MDA) content, renal NADPH oxidase activity, fractional excretion of sodium (FENa%) and fractional excretion of potassium (FEK%) were significantly increased (P<0.01). The Scr, histologic scores, renal MDA content, NADPH oxidase activity, FENa% and FEK% in the rats treated with pentoxifylline prior to iohexol were observed to be reduced compared with those in rats treated with iohexol alone (P<0.01). This suggests that pentoxifylline significantly attenuates renal injuries, including tubular necrosis and proteinaceous casts induced by CM. It may be concluded that pentoxifylline protected the renal tissue from the nephrotoxicity induced by low-osmolar CM via an antioxidant effect. PMID:25574202

  1. Split liver transplant recipients do not have an increased frequency of acute kidney injury.

    PubMed

    Leithead, Joanna A; Armstrong, Matthew J; Corbett, Christopher; Andrew, Mark; Kothari, Chirag; Gunson, Bridget K; Mirza, Darius; Muiesan, Paolo; Ferguson, James W

    2014-11-01

    Small series have suggested that split liver transplantation (SLT) has an increased frequency of peri-operative acute kidney injury (AKI). However, the optimal donor selection in this setting could have a favourable impact on renal outcomes. This was a retrospective single-centre study of 76 adults who underwent SLT (right extended lobe) and 301 adults who underwent elective full-size donation after brain death liver transplantation (FSLT). SLT recipients were less likely than unmatched FSLT recipients to develop AKI (≥stage 1 KDIGO criteria) (40.3% vs. 56.1%, P = 0.016) and had a reduced frequency of renal replacement therapy (11.8% vs. 21.9%, P = 0.049). In 72 pairs of SLT patients and propensity risk score-matched FSLT controls the incidence of AKI was not significantly different (40.3% vs. 47.2%, P = 0.473). However, SLT patients were less likely to require renal replacement therapy (11.1% vs. 23.6%, P = 0.078; adjusted OR 0.32; 95% CI 0.11-0.87, P = 0.026). There was no association between SLT and the development of chronic kidney disease (eGFR<60 ml/min/1.73 m(2) , log rank P = 0.534). In conclusion, SLT is not associated with an increased frequency of AKI. These observations support the postulation that the optimal donor status of SLT may result in less graft injury with renal sparing effects. PMID:24964222

  2. Incidence and Risk Factors for Acute Kidney Injury Following Mannitol Infusion in Patients With Acute Stroke

    PubMed Central

    Lin, Shin-Yi; Tang, Sung-Chun; Tsai, Li-Kai; Yeh, Shin-Joe; Shen, Li-Jiuan; Wu, Fe-Lin Lin; Jeng, Jiann-Shing

    2015-01-01

    Abstract Mannitol, an osmotic diuretic, is commonly used to treat patients with acute brain edema, but its use also increases the risk of developing acute kidney injury (AKI). In this study, we investigated the incidence and risk factors of mannitol-related AKI in acute stroke patients. A total of 432 patients (ischemic stroke 62.3%) >20 years of age who were admitted to the neurocritical care center in a tertiary hospital and received mannitol treatment were enrolled in this study. Clinical parameters including the scores of National Institutes of Health Stroke Scale (NIHSS) at admission, vascular risk factors, laboratory data, and concurrent nephrotoxic medications were registered. Acute kidney injury was defined as an absolute elevation in the serum creatinine (Scr) level of ≥0.3 mg/dL from the baseline or a ≥50% increase in Scr. The incidence of mannitol-related AKI was 6.5% (95% confidence interval, 4.5%–9.3%) in acute stroke patients, 6.3% in patients with ischemic stroke, and 6.7% in patients with intracerebral hemorrhage. Multivariate analysis revealed that diabetes, lower estimated glomerular filtration rate at baseline, higher initial NIHSS score, and concurrent use of diuretics increased the risk of mannitol-related AKI. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.839 (95% confidence interval, 0.770–0.909). In conclusion, mannitol-related AKI is not uncommon in the treatment of acute stroke patients, especially in those with vulnerable risk factors. PMID:26632702

  3. Utility of citrate dialysate in management of acute kidney injury in children.

    PubMed

    Hanevold, Coral; Lu, Sharon; Yonekawa, Karyn

    2010-10-01

    Dialysis concentrate acidified with citrate as opposed to acetate has been reported to prevent clotting in hemodialysis circuits, and improve dialysis efficiency in adults. There is no information on its use in children. The purpose of the study was to evaluate the utility of citrate dialysate for renal replacement therapy in a pediatric population with acute kidney injury. We performed a retrospective review of our experience using Citrasate(®) concentrate from December 2007 to August 2009. All treatments were provided using the Fresenius 2008 dialysis machine. Citrasate(®) was utilized in 7 children aged 60.3±51.0 months (mean±SD), range 13 months to 12 years. The number of treatments varied from 4 to 31 (mean 12±8 treatments) for a total of 89 treatments. Rare sporadic mild hypocalcemia was noted but could not be definitively linked with the use of Citrasate(®). Four children also required low-dose heparin (3.6-15 U/kg/h) due to clotting. Activated clotting times (when checked) were not affected by this low-dose heparin therapy. Some degree of clotting occurred in 21 of 89 (23.5%) treatments. Early termination of treatment due to thrombosis was required in 7 of 89 (7.8%) treatments. In summary, use of Citrasate(®) dialysis concentrate was well tolerated in critically ill children with acute kidney injury. Citrasate(®) reduced but did not completely eliminate the need for heparin in our population. Further study in a more diverse population would be helpful. PMID:21040414

  4. Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model

    PubMed Central

    Keller, Anna K.; Hansen, Rie Schultz; Nørregaard, Rikke; Krag, Søren Palmelund; Møldrup, Ulla; Pedersen, Michael; Jespersen, Bente; Birn, Henrik

    2016-01-01

    Introduction Ischemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up. Methods Unilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI. Results Unilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function. Conclusions As expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I. PMID:27760220

  5. Factors Associated with the Use of Preventive Care for Contrast-Induced Acute Kidney Injury

    PubMed Central

    Mor, Maria K.; Kim, Sunghee; Hartwig, Kathryn C.; Sonel, Ali F.; Palevsky, Paul M.; Fine, Michael J.

    2009-01-01

    BACKGROUND The factors that affect the implementation of preventive care for contrast-induced acute kidney injury (CIAKI) are unknown. OBJECTIVE To assess patient and provider factors associated with the use of preventive care for CIAKI. DESIGN Prospective cohort study. PARTICIPANTS Patients with kidney disease undergoing procedures with intravascular iodinated radiocontrast. MEASUREMENTS We recorded the use of preventive care defined as the administration of: (1) pre- and post-procedure isotonic intravenous (IV) fluid, (2) N-acetylcysteine, and (3) iso-osmolal radiocontrast. We surveyed patients’ providers to assess their knowledge, experience, and training on CIAKI and used multiple logistic regression to assess the independent associations of patient and provider factors with the use of these preventive interventions. RESULTS We enrolled 660 patients and 87 providers. Patient factors associated with use of IV fluid and N-acetylcysteine were higher baseline serum creatinine (OR 1.5 and 5.0, p < 0.05) and inpatient status (OR 3.0 and 6.3, p < 0.05), while higher baseline serum creatinine was associated with the use of iso-osmolal contrast (OR = 13.4, p < 0.01). The primary provider characteristics associated with the use of IV fluid and N-acetylcysteine were a greater degree of prior training on CIAKI (OR 1.9 and 2.8, p < 0.05) and higher number of prior patients with CIAKI (OR 2.7 and 2.6, p < 0.05). CONCLUSIONS Patient baseline kidney function and provider training and experience with CIAKI are independently associated with the use of preventive care. Efforts to increase and intensify the training providers receive on CIAKI may help decrease the incidence of this costly iatrogenic condition. PMID:19156472

  6. Vorinostat protects against calcium oxalate-induced kidney injury in mice.

    PubMed

    Wang, Li; Chen, Wei; Peng, Zhongjiang; Liu, Changcheng; Zhang, Caihong; Guo, Zhiyong

    2015-09-01

    The present study aimed to examine the effect of the histone deacetylase inhibitor, vorinostat (SAHA), on renal function in a calcium oxalate crystal mouse model, and to investigate the mechanism underlying the renoprotective effect of SAHA. Calcium oxalate crystal formation was induced in 8 week‑old male C57BL/6 mice by administering 100 mg/kg glyoxylate for 7 days. A total of 24 male C57BL/6 mice were randomly divided into a control group and the following experimental groups: 50 mg/kg normal saline + 100 mg/kg glyoxylate; 50 mg/kg dimethyl sulfoxide (DMSO) + 100 mg/kg glyoxylate; and 50 mg/kg SAHA + 100 mg/kg glyoxylate. The mice in each of the experimental groups were injected with the saline, DMSO or SAHA into their abdominal cavities 6 h prior to the glyoxylate injection. The mice were sacrificed after 7 days, following which blood and urine samples were collected. The kidneys were harvested to analyze the levels of calcium concentrations and the levels of malondialdehyde (MDA), superoxide dismutase and glutathione reductase. Immunohistochemical staining and semi‑quantitative analyses were performed to detect the expression levels of osteopontin (OPN) and CD44. Renal tubular cell apoptosis was detected using a TUNEL assay. The concentrations of calcium and malondialdehyde were significantly decreased in the SAHA group, and calcium oxalate crystals in the kidney tissue and the expression levels of OPN and CD44 in the SAHA group were lower, compared with the other experimental groups. SAHA significantly reduced the urinary excretion of KIM‑1 and renal tubular cell apoptosis. In conclusion, SAHA reduced calcium oxalate crystal deposition and protected against kidney injury.

  7. Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients.

    PubMed

    Peters, Esther; Heemskerk, Suzanne; Masereeuw, Rosalinde; Pickkers, Peter

    2014-06-01

    Acute kidney injury (AKI) is a common disease in the intensive care unit and accounts for high morbidity and mortality. Sepsis, the predominant cause of AKI in this setting, involves a complex pathogenesis in which renal inflammation and hypoxia are believed to play an important role. A new therapy should be aimed at targeting both these processes, and the enzyme alkaline phosphatase, with its dual mode of action, might be a promising candidate. First, alkaline phosphatase is able to reduce inflammation through dephosphorylation and thereby detoxification of endotoxin (lipopolysaccharide), which is an important mediator of sepsis. Second, adenosine triphosphate, released during cellular stress caused by inflammation and hypoxia, has detrimental effects but can be converted by alkaline phosphatase into adenosine with anti-inflammatory and tissue-protective effects. These postulated beneficial effects of alkaline phosphatase have been confirmed in animal experiments and two phase 2a clinical trials showing that kidney function improved in critically ill patients with sepsis-associated AKI. Because renal inflammation and hypoxia also are observed commonly in AKI induced by other causes, it would be of interest to investigate the therapeutic effect of alkaline phosphatase in these nephropathies as well.

  8. Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy.

    PubMed

    Morrell, Eric D; Kellum, John A; Pastor-Soler, Núria M; Hallows, Kenneth R

    2014-01-01

    The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis. PMID:25575158

  9. Acute kidney injury following cardiac surgery: current understanding and future directions.

    PubMed

    O'Neal, Jason B; Shaw, Andrew D; Billings, Frederic T

    2016-07-04

    Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

  10. Acute kidney injury and hyperbilirubinemia in a young male after ingestion of Tribulus terrestris.

    PubMed

    Ryan, Margaret; Lazar, Ira; Nadasdy, Gyongyi M; Nadasdy, Tibor; Satoskar, Anjali A

    2015-03-01

    Acute tubular necrosis (ATN), especially from toxic injury is frequently accompanied by tubular casts and crystals. Myeloma casts, myoglobin, red blood cell and granular casts are well described. However, bile casts in tubules are rarely seen. We describe a case of Tribulus terrestris toxicity in a young healthy male, presenting with severe hyperbilirubinemia followed by acute renal failure and bile containing casts in the tubules. Tribulus terrestris is an herb often used by athletes as a nutritional supplement for performance enhancement. Although it is thought to be relatively safe, serious side effects have been reported before. Our aim is to increase awareness of the potential toxicities of performance enhancing herbal medications. These are often sold over-the-counter and therefore casually used, especially by young healthy individuals. Beneficial effects are controversial. Under-reporting by patients and infrequent documentation by health-care providers can delay diagnosis. We elaborately describe the kidney biopsy findings in Tribulus terrestris toxicity, and also provide a concise overview of the spectrum of tubular casts and their staining patterns, found in various kidney diseases.

  11. Naringenin Ameliorated Kidney Injury through Let-7a/TGFBR1 Signaling in Diabetic Nephropathy

    PubMed Central

    Yan, Ning; Peng, Rui; Li, Hongmei; Liu, Handeng; Peng, Huimin; Sun, Yan; Wu, Tianhui; Chen, Lei; Duan, Qingrui; Sun, Yixuan; Zhou, Qin; Wei, Lijiang

    2016-01-01

    Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). However, the exact mechanism is not clearly understood. In this study, our results showed that 24 h urinary protein, kidney index, and glomerular area were decreased, while creatinine clearance ratio was increased in DN rats when the rats were treated with NAR 50 mg/d for 6 weeks. Mesangial cell (MMCs) proliferation was inhibited in the NAR group by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and the cell cycle analysis showed that cells stayed in G2 phase in NAR group. And NAR treatment attenuated the deposition of ECM in DN rats and MMCs. Moreover, our data showed that let-7a was downexpressed in both DN rats and MMCs under high glucose condition. Surprisingly, NAR affected the expressions of Col4 and FN through upregulating let-7a in MMCs. In addition, we found that let-7a negatively regulated the expression of transforming growth factor-β1 receptor 1 (TGFBR1), and TGFBR1 was required for the let-7a-mediated downregulation of TGF-β1/smad signaling. Interestingly, NAR inhibited TGF-β1/smads signaling activation by upregulating let-7a. Therefore, our findings indicated that NAR ameliorated kidney injury by regulating let-7a/TGFBR1 signaling. PMID:27446963

  12. Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer

    PubMed Central

    Lewington, Andrew JP; Cerdá, Jorge; Mehta, Ravindra L

    2013-01-01

    Worldwide, acute kidney injury (AKI) is associated with poor patient outcomes. Over the last few years, collaborative efforts, enabled by a common definition of AKI, have provided a description of the epidemiology, natural history and outcomes of this disease and improved our understanding of the pathophysiology. There is increased recognition that AKI is encountered in multiple settings and in all age groups, and that its course and outcomes are influenced by the severity and duration of the event. The effect of AKI on an individual patient and the resulting societal burden that ensues from the long term effects of the disease, including development of chronic kidney disease (CKD) and end stage renal disease (ESRD), is attracting increasing scrutiny. There is evidence of marked variation in the management of AKI which is, to a large extent, due to a lack of awareness and an absence of standards for prevention, early recognition and intervention. These emerging data point to an urgent need for a global effort to highlight that AKI is preventable, its course modifiable, and its treatment can improve outcomes. In this article, we provide a framework of reference and propose specific strategies to raise awareness of AKI globally, with the goal to ultimately improve outcomes from this devastating disease. PMID:23636171

  13. Acute kidney injury following cardiac surgery: current understanding and future directions.

    PubMed

    O'Neal, Jason B; Shaw, Andrew D; Billings, Frederic T

    2016-01-01

    Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI. PMID:27373799

  14. Assessment of Cell-Cycle Arrest Biomarkers to Predict Early and Delayed Acute Kidney Injury

    PubMed Central

    Bell, Max; Larsson, Anders; Venge, Per; Bellomo, Rinaldo; Mårtensson, Johan

    2015-01-01

    Purpose. To assess urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 ([TIMP-2]·[IGFBP7]), urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary cystatin-C as acute kidney injury predictors (AKI) exploring the association of nonrenal factors with elevated biomarker levels. Methods. We studied 94 patients with urine collected within 48 hours of ICU admission and no AKI at sampling. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Predictive performance was assessed by the area under the receiver operating characteristics (ROC) curve. Associations between biomarkers and clinical factors were assessed by multivariate linear regression. Results. Overall, 19 patients (20%) developed AKI within 48 hours. [TIMP-2]·[IGFBP7], NGAL, or cystatin-C admission levels did not differ between patients without AKI and patients developing AKI. [TIMP-2]·[IGFBP7], NGAL, and cystatin-C were poor AKI predictors (ROC areas 0.34–0.51). Diabetes was independently associated with higher [TIMP-2]·[IGFBP7] levels (P = 0.02) but AKI was not (P = 0.24). Sepsis was independently associated with higher NGAL (P < 0.001) and cystatin-C (P = 0.003) levels. Conclusions. Urinary [TIMP-2]·[IGFBP7], NGAL, and cystatin-C should be used cautiously as AKI predictors in general ICU patients since urine levels of these biomarkers are affected by factors other than AKI and their performance can be poor. PMID:25866432

  15. Serum metabolomic profiles from patients with acute kidney injury: a pilot study.

    PubMed

    Sun, Jinchun; Shannon, Melissa; Ando, Yosuke; Schnackenberg, Laura K; Khan, Nasim A; Portilla, Didier; Beger, Richard D

    2012-04-15

    Low sensitivity of current clinical markers (serum creatinine and blood urea nitrogen (BUN)) in early stages of the development of acute kidney injury (AKI) limits their utility. Rapid LC/MS-based metabolic profiling of serum demonstrated in a pilot study that metabolomics could provide novel indicators of AKI. Metabolic profiles of serum samples from seventeen hospitalized patients with newly diagnosed AKI were compared with the profiles of serum from age-matched subjects with normal kidney function. Increases in acylcarnitines and amino acids (methionine, homocysteine, pyroglutamate, asymmetric dimethylarginine (ADMA), and phenylalanine) and a reduction in serum levels of arginine and several lysophosphatidyl cholines were observed in patients with AKI compared to healthy subjects. Increases in homocysteine, ADMA and pyroglutamate have been recognized as biomarkers of cardiovascular and renal disease, and acylcarnitines represent biomarkers of defective fatty acid oxidation. The results of this pilot study demonstrate the utility of metabolomics in the discovery of novel serum biomarkers that can facilitate the diagnosis and determine prognosis of AKI in hospitalized patients.

  16. Serum Metabolomic Profiles from Patients with Acute Kidney Injury: A Pilot Study

    PubMed Central

    Sun, Jinchun; Shannon, Melissa; Ando, Yosuke; Schnackenberg, Laura K.; Khan, Nasim A.; Portilla, Didier; Beger, Richard D

    2012-01-01

    Low sensitivity of current clinical markers (serum creatinine, blood urea nitrogen (BUN)) in early stages of the development of acute kidney injury (AKI) limits their utility. Rapid LC/MS-based metabolic profiling of serum demonstrated in a pilot study that metabolomics could provide novel indicators of AKI. Metabolic profiles of serum samples from seventeen hospitalized patients with newly diagnosed AKI were compared with the profiles of serum from age-matched subjects with normal kidney function. Increases in acylcarnitines and amino acids (methionine, homocysteine, pyroglutamate, asymmetric dimethylarginine (ADMA), and phenylalanine) and a reduction in serum levels of arginine and several lysophosphatidyl cholines were observed in patients with AKI compared to healthy subjects. Increases in homocysteine, ADMA and pyroglutamate have been recognized as biomarkers of cardiovascular and renal disease, and acylcarnitines represent biomarkers of defective fatty acid oxidation. The results of this pilot study demonstrate the utility of metabolomics in the discovery of novel serum biomarkers that can facilitate the diagnosis and determine prognosis of AKI in hospitalized patients. PMID:22429878

  17. Multidimensional Approach to Adequacy of Renal Replacement Therapy in Acute Kidney Injury.

    PubMed

    Villa, Gianluca; Ricci, Zaccaria; Romagnoli, Stefano; Ronco, Claudio

    2016-01-01

    Acute kidney injury (AKI) is frequently observed among hospitalized and critical care patients. In the absence of any effective therapies aiming to actively restore kidney function, AKI is usually managed through acute renal replacement therapy (ARRT). 'Optimization' of ARRT may reduce the mortality of patients with AKI. Although several studies have tried to identify the most adequate approach to ARRT in terms of dose, treatment modality and all other important dimensions, the literature has provided controversial results. Nowadays, adequate ARRT still appears difficult to dose, prescribe, deliver and monitor among different critical care patients. The identification of the major elements involved for a multidimensional approach to adequacy of ARRT in patients with AKI should consider the patient, the applied technology and the environment. All these aspects should be carefully evaluated and adequately applied in clinical practice through a patient-oriented approach. Adequacy of ARRT imposes the concomitant consideration of more complex issues, such as the timing, modality and technique of ARRT delivery; anticoagulation and substitution fluid choice; membrane selection; monitor accuracy; the role of fluid overload; and other patient comorbidities. The capacity of clinicians to consider all these aspects through a multidimensional approach, adapting the different dimensions of ARRT to actual patients' needs, might be the fundamental missing element in the pathway toward significant outcome improvements among critically ill patients with AKI. This narrative review provides a systematic approach to the major dimensions of ARRT and their multidimensional rationalization for adequate treatment prescription, monitoring and evaluation. PMID:26881756

  18. Development of Inpatient Risk Stratification Models of Acute Kidney Injury for Use in Electronic Health Records

    PubMed Central

    Matheny, Michael E.; Miller, Randolph A.; Ikizler, T. Alp; Waitman, Lemuel R.; Denny, Joshua C.; Schildcrout, Jonathan S.; Dittus, Robert S.; Peterson, Josh F.

    2016-01-01

    Objective Patients with hospital-acquired acute kidney injury (AKI) are at risk for increased mortality and further medical complications. Evaluating these patients with a prediction tool easily implemented within an electronic health record (EHR) would identify high risk patients prior to the development of AKI, and could prevent iatrogenically induced episodes of AKI and improve clinical management. Methods We used structured clinical data acquired from an EHR to identify patients with normal kidney function for admissions from August 1st, 1999 to July 31st, 2003. Using administrative, computerized provider order entry, and laboratory test data, we developed a 3-level risk stratification model to predict each of two severity levels of in-hospital AKI as defined by RIFLE criteria. The severity levels were defined as 150% or 200% of baseline serum creatinine. Model discrimination and calibration was evaluated using 10-fold cross-validation. Results Cross-validation of the models resulted in area under the receiver operating characteristic (AUC) curves of 0.75 (150% elevation) and 0.78 (200% elevation). Both models were adequately calibrated as measured by the Hosmer-Lemeshow goodness-of-fit test chi-squared values of 9.7 (p = 0.29) and 12.7 (p = 0.12), respectively. Conclusions We generated risk prediction models for hospital-acquired AKI using only commonly available electronic data. The models identify patients at high risk for AKI who might benefit from early intervention or increased monitoring. PMID:20354229

  19. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury.

    PubMed

    Kapitsinou, Pinelopi P; Jaffe, Jonathan; Michael, Mark; Swan, Christina E; Duffy, Kevin J; Erickson-Miller, Connie L; Haase, Volker H

    2012-05-01

    Acute kidney injury (AKI) due to ischemia is an important contributor to the progression of chronic kidney disease (CKD). Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia-inducible factors (HIF), which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. While activation of HIF protects from ischemic cell death, HIF has been shown to promote fibrosis in experimental models of CKD. The impact of HIF activation on AKI-induced fibrosis has not been defined. Here, we investigated the role of pharmacologic HIF activation in AKI-associated fibrosis and inflammation. We found that pharmacologic inhibition of HIF prolyl hydroxylation before AKI ameliorated fibrosis and prevented anemia, while inhibition of HIF prolyl hydroxylation in the early recovery phase of AKI did not affect short- or long-term clinical outcome. Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials. PMID:22262480

  20. Preconditioning with Physiological Levels of Ethanol Protect Kidney against Ischemia/Reperfusion Injury by Modulating Oxidative Stress

    PubMed Central

    Zeng, Li; Liu, Fang; Ding, Guoshan; Kang, Yindong; Mao, Jingyan; Cai, Ming; Zhu, Youhua; Wang, Quan-xing

    2011-01-01

    Background Oxidative stress due to excessive production of reactive oxygen species (ROS) and subsequent lipid peroxidation plays a critical role in renal ischemia/reperfusion (IR) injury. The purpose of current study is to demonstrate the effect of antecedent ethanol exposure on IR-induced renal injury by modulation of oxidative stress. Materials and Methods Bilateral renal warm IR was induced in male C57BL/6 mice after ethanol or saline administration. Blood ethanol concentration, kidney function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity and Aldehyde dehydrogenase (ALDH) enzymatic activity were assessed to evaluate the impact of antecedent ethanol exposure on IR-induced renal injury. Results After bilateral kidney ischemia, mice preconditioned with physiological levels of ethanol displayed significantly preserved renal function along with less histological tubular damage as manifested by the reduced inflammatory infiltration and cytokine production. Mechanistic studies revealed that precondition of mice with physiological levels of ethanol 3 h before IR induction enhanced antioxidant capacity characterized by significantly higher superoxidase dismutase (SOD) activities. Our studies further demonstrated that ethanol pretreatment specifically increased ALDH2 activity, which then suppressed lipid peroxidation by promoting the detoxification of Malondialdehyde (MDA) and 4-hydroxynonenal (HNE). Conclusions Our results provide first line of evidence indicating that antecedent ethanol exposure can provide protection for kidneys against IR-induced injury by enhancing antioxidant capacity and preventing lipid peroxidation. Therefore, ethanol precondition and ectopic ALDH2 activation could be potential therapeutic approaches to prevent renal IR injury relevant to various clinical conditions. PMID:22022451