Osthole Preconditioning Protects Rats Against Renal Ischemia-Reperfusion Injury.

PubMed

Xie, D-Q; Sun, G-Y; Zhang, X-G; Gan, H

2015-01-01

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms of renal I/R injury involve inflammation, oxidative stress, and apoptosis. Osthole, a natural coumarin derivative, has potential anti-inflammatory effects. This study investigated the effect of osthole on renal I/R injury and its potential mechanism. We induced renal I/R injury by clamping the left renal artery for 45 min followed by reperfusion, along with a contralateral nephrectomy. We randomly assigned 30 rats to 3 groups (n = 10): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intra-peritoneally with osthole (40 mg/kg) or vehicle (40 mg/kg) 45 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6) in renal tissue and serum were examined by means of RT-PCR and ELISA, respectively. The expression of p-p85, p85, p-Akt, Akt, p-p65, and p65 were measured by means of Western blotting. Osthole pre-treatment significantly attenuated renal dysfunction, renal histological changes, NF-κB activation, and the expression of TNF-α, IL-8, and IL-6 induced by I/R injury, but the activation of PI3K/Akt signaling was further increased. Osthole pre-treatment protects rats against renal I/R injury by suppressing NF-κB activation, which is involved in PI3K/Akt signaling activation. Thus, osthole may be a novel practical strategy to prevent renal I/R injury. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Endoglin regulates renal ischaemia-reperfusion injury.

PubMed

Docherty, Neil G; López-Novoa, José M; Arevalo, Miguel; Düwel, Annette; Rodriguez-Peña, Ana; Pérez-Barriocanal, Fernando; Bernabeu, Carmelo; Eleno, Nélida

2006-08-01

Renal ischaemia-reperfusion (I-R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-beta1 (TGF-beta1), is expressed on activated endothelium during macrophage maturation and implicated in the control of fibrosis, angiogenesis and inflammation. Endoglin expression was monitored over 14 days after renal I-R in rats. As endoglin-null mice are not viable, the role of endoglin in I-R was studied by comparing renal I-R injury in haploinsufficient mice (Eng(+/-)) and their wild-type littermates (Eng(+/+)). Renal function, morphology and molecular markers of acute renal injury and inflammation were compared. Endoglin mRNA up-regulation in the post-ischaemic kidneys of rats occurred at 12 h after I-R; endoglin protein levels were elevated throughout the study period. Expression was initially localized to the vascular endothelium, then extended to fibrotic and inflamed areas of the interstitium. Two days after I-R, plasma creatinine elevation and acute tubular necrosis were less marked in Eng(+/-) than in Eng(+/+) mice. Significant up-regulation of endoglin protein was found only in the post-ischaemic kidneys of Eng(+/+) mice and coincided with an increased mRNA expression of the TGF-beta1 and collagen IV (alpha1) chain genes. Significant increases in vascular cell adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase (iNOS) expression, nitrosative stress, myeloperoxidase activity and CD68 staining for macrophages were evident in post-ischaemic kidneys of Eng(+/+), but not Eng(+/-) mice, suggesting that impaired endothelial activation and macrophage maturation may account for the reduced injury in post-ischaemic kidneys of Eng(+/-) mice. Endoglin is up-regulated in the post-ischaemic kidney and endoglin-haploinsufficient mice are protected from renal I-R injury. Endoglin may play a primary role in promoting inflammatory responses following renal I-R.

Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury.

PubMed

Mulder, Gemma M; Nijboer, Willemijn N; Seelen, Marc A; Sandovici, Maria; Bos, Eelke M; Melenhorst, Wynand B W H; Trzpis, Monika; Kloosterhuis, Niels J; Visser, Lydia; Henning, Rob H; Leuvenink, Henri G D; Ploeg, Rutger J; Sunnarborg, Susan W; van Goor, Harry

2010-06-01

The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats, cells, and human donor biopsies. Treatment with PKI-166 reduces macrophage accumulation and interstitial alpha-SMA in the early phase of IRI in rats. In vitro, PKI-166 causes a marked reduction in HB-EGF-induced cellular proliferation. Urinary HB-EGF is increased after transplantation compared with control urines from healthy subjects. HB-EGF KO mice subjected to IRI revealed significantly less morphological damage after IRI, compared with WT mice. We conclude that IRI results in early induction of HB-EGF mRNA and protein in vivo and in vitro. Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF.

Characteristics and Management of Blunt Renal Injury in Children

PubMed Central

Ishida, Yuichi; Tyroch, Alan H.; Emami, Nader; McLean, Susan F.

2017-01-01

Background: Renal trauma in the pediatric population is predominately due to blunt mechanism of injury. Our purpose was to determine the associated injuries, features, incidence, management, and outcomes of kidney injuries resulting from blunt trauma in the pediatric population in a single level I trauma center. Methods: This was a retrospective chart and trauma registry review of all pediatric blunt renal injuries at a regional level I trauma center that provides care to injured adults and children. The inclusion dates were January 2001–June 2014. Results: Of 5790 pediatric blunt trauma admissions, 68 children sustained renal trauma (incidence: 1.2%). Only two had nephrectomies (2.9%). Five renal angiograms were performed, only one required angioembolization. Macroscopic hematuria rate was significantly higher in the high-grade injury group (47% vs. 16%; P = 0.031). Over half of the patients had other intra-abdominal injuries. The liver and spleen were the most frequently injured abdominal organs. Conclusion: Blunt renal trauma is uncommon in children and is typically of low American Association for the Surgery of Trauma injury grade. It is commonly associated with other intra-abdominal injuries, especially the liver and the spleen. The nephrectomy rate in pediatric trauma is lower compared to adult trauma. Most pediatric blunt renal injury can be managed conservatively by adult trauma surgeons. PMID:28855777

High-grade renal injuries are often isolated in sports-related trauma.

PubMed

Patel, Darshan P; Redshaw, Jeffrey D; Breyer, Benjamin N; Smith, Thomas G; Erickson, Bradley A; Majercik, Sarah D; Gaither, Thomas W; Craig, James R; Gardner, Scott; Presson, Angela P; Zhang, Chong; Hotaling, James M; Brant, William O; Myers, Jeremy B

2015-07-01

Most high-grade renal injuries (American Association for Surgery of Trauma (AAST) grades III-V) result from motor vehicle collisions associated with numerous concomitant injuries. Sports-related blunt renal injury tends to have a different mechanism, a solitary blow to the flank. We hypothesized that high-grade renal injury is often isolated in sports-related renal trauma. We identified patients with AAST grades III-V blunt renal injuries from four level 1 trauma centres across the United States between 1/2005 and 1/2014. Patients were divided into "Sport" or "Non-sport" related groups. Outcomes included rates of hypotension (systolic blood pressure <90mm Hg), tachycardia (>110bpm), concomitant abdominal injury, and procedural/surgical intervention between sports and non-sports related injury. 320 patients met study criteria. 18% (59) were sports-related injuries with the most common mechanisms being skiing, snowboarding and contact sports (25%, 25%, and 24%, respectively). Median age was 24 years for sports and 30 years for non-sports related renal injuries (p=0.049). Males were more commonly involved in sports related injuries (85% vs. 72%, p=0.011). Median injury severity score was lower for sports related injuries (10 vs. 27, p<0.001). There was no difference in renal abbreviated injury scale scores. Sports related trauma was more likely to be isolated without other significant injury (69% vs. 39% (p<0.001)). Haemodynamic instability was present in 40% and 51% of sports and non-sports renal injuries (p=0.30). Sports injuries had lower transfusion (7% vs. 47%, p<0.001) and lower mortality rates (0% vs. 6%, p=0.004). There was no difference in renal-specific procedural interventions between the two groups (17% sports vs. 18% non-sports, p=0.95). High-grade sports-related blunt renal trauma is more likely to occur in isolation without other abdominal or thoracic injuries and clinicians must have a high suspicion of renal injury with significant blows to the flank

High-grade renal injuries are often isolated in sports-related trauma

PubMed Central

Patel, Darshan P.; Redshaw, Jeffrey D.; Breyer, Benjamin N.; Smith, Thomas G.; Erickson, Bradley A.; Majercik, Sarah D.; Gaither, Thomas W.; Craig, James R.; Gardner, Scott; Presson, Angela P.; Zhang, Chong; Hotaling, James M.; Brant, William O.; Myers, Jeremy B.

2016-01-01

Introduction Most high-grade renal injuries (American Association for Surgery of Trauma (AAST) grades III–V) result from motor vehicle collisions associated with numerous concomitant injuries. Sports-related blunt renal injury tends to have a different mechanism, a solitary blow to the flank. We hypothesized that high-grade renal injury is often isolated in sports-related renal trauma. Material and methods We identified patients with AAST grades III–V blunt renal injuries from four level 1 trauma centres across the United States between 1/2005 and 1/2014. Patients were divided into “Sport” or “Non-sport” related groups. Outcomes included rates of hypotension (systolic blood pressure <90 mm Hg), tachycardia (>110 bpm), concomitant abdominal injury, and procedural/surgical intervention between sports and non-sports related injury. Results 320 patients met study criteria. 18% (59) were sports-related injuries with the most common mechanisms being skiing, snowboarding and contact sports (25%, 25%, and 24%, respectively). Median age was 24 years for sports and 30 years for non-sports related renal injuries (p = 0.049). Males were more commonly involved in sports related injuries (85% vs. 72%, p = 0.011). Median injury severity score was lower for sports related injuries (10 vs. 27, p < 0.001). There was no difference in renal abbreviated injury scale scores. Sports related trauma was more likely to be isolated without other significant injury (69% vs. 39% (p < 0.001)). Haemodynamic instability was present in 40% and 51% of sports and non-sports renal injuries (p = 0.30). Sports injuries had lower transfusion (7% vs. 47%, p < 0.001) and lower mortality rates (0% vs. 6%, p = 0.004). There was no difference in renal-specific procedural interventions between the two groups (17% sports vs. 18% non-sports, p = 0.95). Conclusions High-grade sports-related blunt renal trauma is more likely to occur in isolation without other abdominal or thoracic injuries and

Osthole ameliorates renal ischemia-reperfusion injury by inhibiting inflammatory response.

PubMed

Zheng, Yi; Lu, Min; Ma, Lulin; Zhang, Shudong; Qiu, Min; Ma, Xin

2013-01-01

Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model. Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed. Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys. Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury. Copyright © 2013 S. Karger AG, Basel.

Renal artery and vein injury following blunt trauma.

PubMed Central

Sturm, J T; Perry, J F; Cass, A S

1975-01-01

Blunt injuries of the renal vascular pedicle occur infrequently. The experience with fourteen cases of blunt renal vascular trauma is presented. Most patients were injured in motor vehicle accidents. The diagnosis was made immediately after admission in 6 patients, delayed in 5, and at autopsy in 3. Most patients presented with gross or microscopic hematuria. The diagnosis of renal vascular injury was suggested by IVP in most instances. Surgical management was used in the 6 patients in whom the immediate diagnosis of renal pedicle injury was made; primary vascular repair was carried out in 4 patients and nephrectomy in two. Conservative management was used in 4 of the 5 patients with delayed diagnosis, and nephrectomy was required in the fifth. Three patients received no treatment as two were dead on arrival and one die during laparotomy. Seven patients died (50%). One of the 7 survivors has a functioning kidney following repair of a renal vein laceration. Three patients with devascularized kidneys have been followed long term and have not developed hypertension. An IVP should be mandatory following severe blunt trauma, especially when hematuria is present. Renal arteriography is indicated with distortion of calyces, extravasation or nonfunction seen on IVP and allows a definitive diagnosis of renal vessel injury to be made. PMID:1190872

Protection against renal ischemia-reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ.

PubMed

Dare, Anna J; Bolton, Eleanor A; Pettigrew, Gavin J; Bradley, J Andrew; Saeb-Parsy, Kourosh; Murphy, Michael P

2015-08-01

Ischemia-reperfusion (IR) injury to the kidney occurs in a range of clinically important scenarios including hypotension, sepsis and in surgical procedures such as cardiac bypass surgery and kidney transplantation, leading to acute kidney injury (AKI). Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury and may initiate a damaging inflammatory response. Here we assessed whether the mitochondria targeted antioxidant MitoQ could decrease oxidative damage during IR injury and thereby protect kidney function. To do this we exposed kidneys in mice to in vivo ischemia by bilaterally occluding the renal vessels followed by reperfusion for up to 24h. This caused renal dysfunction, measured by decreased creatinine clearance, and increased markers of oxidative damage. Administering MitoQ to the mice intravenously 15 min prior to ischemia protected the kidney from damage and dysfunction. These data indicate that mitochondrial oxidative damage contributes to kidney IR injury and that mitochondria targeted antioxidants such as MitoQ are potential therapies for renal dysfunction due to IR injury. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Protection against renal ischemia–reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ

PubMed Central

Dare, Anna J.; Bolton, Eleanor A.; Pettigrew, Gavin J.; Bradley, J. Andrew; Saeb-Parsy, Kourosh; Murphy, Michael P.

2015-01-01

Ischemia–reperfusion (IR) injury to the kidney occurs in a range of clinically important scenarios including hypotension, sepsis and in surgical procedures such as cardiac bypass surgery and kidney transplantation, leading to acute kidney injury (AKI). Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury and may initiate a damaging inflammatory response. Here we assessed whether the mitochondria targeted antioxidant MitoQ could decrease oxidative damage during IR injury and thereby protect kidney function. To do this we exposed kidneys in mice to in vivo ischemia by bilaterally occluding the renal vessels followed by reperfusion for up to 24 h. This caused renal dysfunction, measured by decreased creatinine clearance, and increased markers of oxidative damage. Administering MitoQ to the mice intravenously 15 min prior to ischemia protected the kidney from damage and dysfunction. These data indicate that mitochondrial oxidative damage contributes to kidney IR injury and that mitochondria targeted antioxidants such as MitoQ are potential therapies for renal dysfunction due to IR injury. PMID:25965144

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

Detection of occupational lead nephropathy using early renal markers.

PubMed

Kumar, B D; Krishnaswamy, K

1995-01-01

Automotive use of leaded gasoline continues to be an important source of occupational exposure to lead in India and other countries. The present study assessed the renal function and markers of early renal damage of 22 mechanics at three automobile garages. Urinary N-acetyl-3-D-glucosaminidase activity and beta-2-microglobulin levels were significantly increased in auto garage mechanics with blood leads of 30-69 micrograms/dL. A significant correlation was observed between blood lead levels and urinary N-acetyl-3-D-glucosaminidase activity but not with urine beta-2-microglobulin levels. A marginal impairment in creatinine clearance was not statistically significant. Urinary N-acetyl-3-D-glucosaminidase activity offers a sensitive monitor of blood lead and renal tubular injury.

The use of cell cycle arrest biomarkers in the early detection of acute kidney injury. Is this the new renal troponin?

PubMed

Ortega, Luis M; Heung, Michael

2018-04-05

Acute kidney injury (AKI) has a high prevalence in critical care patients. Early detection might prevent patients from developing chronic kidney disease and requirement for renal replacement therapy. If we compare AKI with acute coronary syndrome, in which an increase in cardiac troponin may trigger early diagnosis and therapeutic intervention, we could extrapolate a similar technique in patients with early AKI without changes in urinary frequency or serum creatinine. The objective is to identify biomarker-positive, creatinine-negative patients that would allow therapeutic interventions to be initiated before finding changes in serum creatinine, preventing kidney damage. Tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 are cell cycle arrest biomarkers that have demonstrated, in recent clinical trials, to have good sensitivity and specificity for early detection of AKI. Other recent studies have shown that the joint use of these biomarkers with serum creatinine and urine production could improve the prognosis of AKI in critical patients. The application of these biomarkers in clinical practice would enable the early identification of patients at risk of AKI, establishing interventions that would improve the survival of renal function. Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

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. Copyright © 2015 by the American Society of Nephrology.

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. © The Author(s) 2015.

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis.

PubMed

Lin, Miao; Li, Long; Li, Liping; Pokhrel, Gaurab; Qi, Guisheng; Rong, Ruiming; Zhu, Tongyu

2014-01-13

Renal ischemia-reperfusion injury (IRI) increases the rates of acute kidney failure, delayed graft function, and early mortality after kidney transplantation. The pathophysiology involved includes oxidative stress, mitochondrial dysfunction, and immune-mediated injury. The anti-oxidation, anti-apoptosis, and anti-inflammation properties of baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, have been verified. This study therefore assessed the effects of baicalin against renal IRI in rats. Baicalin was intraperitoneally injected 30 min before renal ischemia. Serum and kidneys were harvested 24 h after reperfusion. Renal function and histological changes were assessed. Markers of oxidative stress, the Toll-like receptor (TLR)2 and TLR4 signaling pathway, mitochondrial stress, and cell apoptosis were also evaluated. Baicalin treatment decreased oxidative stress and histological injury, and improved kidney function, as well as inhibiting proinflammatory responses and tubular apoptosis. Baicalin pretreatment also reduced the expression of TLR2, TLR4, MyD88, p-NF-κB, and p-IκB proteins, as well as decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. Baicalin may attenuate renal ischemia-reperfusion injury by inhibiting proinflammatory responses and mitochondria-mediated apoptosis. These effects are associated with the TLR2/4 signaling pathway and mitochondrial stress.

The protective effect of baicalin against renal ischemia-reperfusion injury through inhibition of inflammation and apoptosis

PubMed Central

2014-01-01

Background Renal ischemia-reperfusion injury (IRI) increases the rates of acute kidney failure, delayed graft function, and early mortality after kidney transplantation. The pathophysiology involved includes oxidative stress, mitochondrial dysfunction, and immune-mediated injury. The anti-oxidation, anti-apoptosis, and anti-inflammation properties of baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, have been verified. This study therefore assessed the effects of baicalin against renal IRI in rats. Methods Baicalin was intraperitoneally injected 30 min before renal ischemia. Serum and kidneys were harvested 24 h after reperfusion. Renal function and histological changes were assessed. Markers of oxidative stress, the Toll-like receptor (TLR)2 and TLR4 signaling pathway, mitochondrial stress, and cell apoptosis were also evaluated. Results Baicalin treatment decreased oxidative stress and histological injury, and improved kidney function, as well as inhibiting proinflammatory responses and tubular apoptosis. Baicalin pretreatment also reduced the expression of TLR2, TLR4, MyD88, p-NF-κB, and p-IκB proteins, as well as decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. Conclusions Baicalin may attenuate renal ischemia-reperfusion injury by inhibiting proinflammatory responses and mitochondria-mediated apoptosis. These effects are associated with the TLR2/4 signaling pathway and mitochondrial stress. PMID:24417870

Examination of the impact of airbags on renal injury using a national database.

PubMed

Smith, Thomas G; Wessells, Hunter B; Mack, Chris D; Kaufman, Robert; Bulger, Eileen M; Voelzke, Bryan B

2010-09-01

Little is known about preventative measures to lessen solid organ injury in motor vehicle collisions (MVCs). To evaluate the efficacy of airbags in reducing renal injuries in MVC, we analyzed renal injury rates in vehicles with and without airbags using the Crash Injury Research and Engineering Network (CIREN) database. The CIREN database was queried for MVC and renal injury from 1996 to September 2008. CIREN is weighted toward late model vehicles and selects more severely injured patients. Search fields were primary direction of force (PDOF), presence of airbags, and location of airbags (steering wheel, instrument panel, seat back, door panel, and roof-side curtain). Abdominal Abbreviated Injury Score was converted to AAST renal injury grade. Renal injury rates were compared between vehicles with and without frontal and side airbags. We reviewed 2,864 records and identified 139 renal injuries (28.9% AAST grade III to V). In MVCs with renal injuries, frontal impact was 54.7% of total (n = 76) and side impact was 45.3% of total (n = 63). Most occupants in frontal impact MVCs had exposure to a steering wheel airbag (74.9%); 16.6% had an instrument panel (passenger) airbags. In side impact MVCs, 32.2% of occupants had a side airbag. Compared with the non-airbags cohort, frontal airbags and side airbags were associated with a 45.3% and 52.8% reduction in renal injury, respectively. Passengers in automobiles with frontal and side airbags have a reduced rate of renal injury compared with those without airbags. Our data support further study of the role of airbags in reducing renal injury after MVC. Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Depletion of Gut Microbiota Protects against Renal Ischemia-Reperfusion Injury

PubMed Central

Rampanelli, Elena; Stroo, Ingrid; Butter, Loes M.; Teske, Gwendoline J.; Claessen, Nike; Stokman, Geurt; Florquin, Sandrine; Leemans, Jaklien C.; Dessing, Mark C.

2017-01-01

An accumulating body of evidence shows that gut microbiota fulfill an important role in health and disease by modulating local and systemic immunity. The importance of the microbiome in the development of kidney disease, however, is largely unknown. To study this concept, we depleted gut microbiota with broad-spectrum antibiotics and performed renal ischemia-reperfusion (I/R) injury in mice. Depletion of the microbiota significantly attenuated renal damage, dysfunction, and remote organ injury and maintained tubular integrity after renal I/R injury. Gut flora–depleted mice expressed lower levels of F4/80 and chemokine receptors CX3CR1 and CCR2 in the F4/80+ renal resident macrophage population and bone marrow (BM) monocytes than did control mice. Additionally, compared with control BM monocytes, BM monocytes from gut flora–depleted mice had decreased migratory capacity toward CX3CL1 and CCL2 ligands. To study whether these effects were driven by depletion of the microbiota, we performed fecal transplants in antibiotic-treated mice and found that transplant of fecal material from an untreated mouse abolished the protective effect of microbiota depletion upon renal I/R injury. In conclusion, we show that depletion of gut microbiota profoundly protects against renal I/R injury by reducing maturation status of F4/80+ renal resident macrophages and BM monocytes. Therefore, dampening the inflammatory response by targeting microbiota-derived mediators might be a promising therapy against I/R injury. PMID:27927779

Endovascular management of arterial injuries after blunt or iatrogenic renal trauma

PubMed Central

Chevallier, Olivier; Gehin, Sophie; Midulla, Marco; Berthod, Pierre-Emmanuel; Galland, Christophe; Briche, Pascale; Duperron, Céline; Majbri, Nabil; Mousson, Christiane; Falvo, Nicolas

2017-01-01

The kidney is the third most common abdominal organ to be injured in trauma, following the spleen and liver, respectively. The most commonly used classification scheme is the American Association for the Surgery of Trauma (AAST) classification of blunt renal injuries, which grades renal injury according to the size of laceration and its proximity to the renal hilum. Arteriovenous fistula and pseudoaneurysm are the most common iatrogenic biopsy-related or surgery-related vascular injuries in native kidneys. The approach to renal artery injuries has changed over time from more aggressive intervention to more conservative observational or endovascular management, including selective transcatheter arterial embolization (TAE) and the placement of stents/stent grafts. In this article, we describe the role and technical aspects of endovascular interventions in the management of arterial injuries after blunt or iatrogenic renal trauma. PMID:28932700

Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury

PubMed Central

Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

2015-01-01

Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID:26108065

Oxidant Mechanisms in Renal Injury and Disease

PubMed Central

Ratliff, Brian B.; Abdulmahdi, Wasan; Pawar, Rahul

2016-01-01

Abstract Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119–146. PMID:26906267

Quantified kidney echogenicity in mice with renal ischemia reperfusion injury: evaluation as a noninvasive biomarker of acute kidney injury.

PubMed

Murata, Shinya; Sugiyama, Noriyuki; Maemura, Kentaro; Otsuki, Yoshinori

2017-09-01

The purpose is to evaluate quantified kidney echogenicity as a biomarker for the early diagnosis of acute kidney injury (AKI) and predicting progression to chronic kidney disease (CKD) in a mouse model of ischemia-reperfusion injury (IRI). Two separate protocols of murine models of IRI were used: (1) 10, 30, and 40 min of bilateral ischemia duration and (2) 45 and 60 min of unilateral ischemia duration. Renal echogenicity was measured with ultrasound and compared with serum creatinine or urine neutrophil gelatinase-associated lipocalin (NGAL) at various timepoints after IRI. In mice subjected to 10, 30, and 40 min of bilateral ischemia, renal echogenicity increased about 2 h after IRI for all ischemia times, earlier than serum creatinine or urine NGAL. In those subjected to 45 and 60 min of unilateral ischemia, 60 min of unilateral ischemia, which represents atrophic changes 28 days after IRI, resulted in a sustained high level of echogenicity and was significantly different 24 h after IRI, while 45 min of unilateral ischemia resulted in trivial levels of histological damage 28 days after IRI. Renal echogenicity might have the potential to be a biomarker for the early diagnosis of AKI and the prognosis of CKD.

Severe post-renal acute kidney injury, post-obstructive diuresis and renal recovery.

PubMed

Hamdi, Aïcha; Hajage, David; Van Glabeke, Emmanuel; Belenfant, Xavier; Vincent, François; Gonzalez, Frédéric; Ciroldi, Magali; Obadia, Edouard; Chelha, Riad; Pallot, Jean-Louis; Das, Vincent

2012-12-01

Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The pathophysiology of post-renal acute kidney injury (PR-AKI), i.e. caused by urinary tract obstruction, has been extensively studied in animal models but clinical studies on this subject are outdated, and/or have focused on the mechanisms of 'post-obstructive diuresis' (POD), a potentially life-threatening polyuria that can develop after the release of obstruction. In severe PR-AKI, the risk of occurrence of POD is high. POD occurrence predicts renal recovery without the persistence of severe chronic kidney failure. In the present study, the occurrence of POD and the persistence of chronic renal sequelae could be predicted early from clinical variables at admission before the release of obstruction. • To identify predictors of post-obstructive diuresis (POD) occurrence or severe chronic renal failure (CRF) persistence after the release of urinary tract obstruction in the setting of post-renal acute kidney injury (PR-AKI). • Bi-centre retrospective observational study of all patients with PR-AKI treated in two intensive care units (ICUs) from 1998 to 2010. • Clinical, biological and imaging characteristics on admission and after the release of obstruction were analysed with univariate and, if possible, multivariate analysis to search for predictors of (i) occurrence of POD (diuresis >4 L/day) after the release of obstruction; (ii) persistence of severe CRF (estimated glomerular filtration rate <30 mL/min/1.73 m(2), including end-stage CRF) at 3 months. • On admission, median (range) serum creatinine was 866 (247-3119) µmol/L. • POD occurred in 34 (63%) of the 54 analysable patients. On admission, higher serum creatinine (Odds ratio [OR] 1.002 per 1 µmol/L, 95% confidence interval [CI] 1.000-1.004, P = 0.004), higher serum bicarbonate (OR 1.36 per 1 mmol/L, 95% CI 1.13-1.65, P < 0.001), and urinary retention (OR 6.96, 95% CI 1.34-36.23, P

Endoplasmic Reticulum Chaperon Tauroursodeoxycholic Acid Attenuates Aldosterone-Infused Renal Injury

PubMed Central

Guo, Honglei; Li, Hongmei; Ling, Lilu

2016-01-01

Aldosterone (Aldo) is critically involved in the development of renal injury via the production of reactive oxygen species and inflammation. Endoplasmic reticulum (ER) stress is also evoked in Aldo-induced renal injury. In the present study, we investigated the role of ER stress in inflammation-mediated renal injury in Aldo-infused mice. C57BL/6J mice were randomized to receive treatment for 4 weeks as follows: vehicle infusion, Aldo infusion, vehicle infusion plus tauroursodeoxycholic acid (TUDCA), and Aldo infusion plus TUDCA. The effect of TUDCA on the Aldo-infused inflammatory response and renal injury was investigated using periodic acid-Schiff staining, real-time PCR, Western blot, and ELISA. We demonstrate that Aldo leads to impaired renal function and inhibition of ER stress via TUDCA attenuates renal fibrosis. This was indicated by decreased collagen I, collagen IV, fibronectin, and TGF-β expression, as well as the downregulation of the expression of Nlrp3 inflammasome markers, Nlrp3, ASC, IL-1β, and IL-18. This paper presents an important role for ER stress on the renal inflammatory response to Aldo. Additionally, the inhibition of ER stress by TUDCA negatively regulates the levels of these inflammatory molecules in the context of Aldo. PMID:27721575

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion.

PubMed

Xue, Yuquan; Xu, Zhibin; Chen, Haiwen; Gan, Weimin; Chong, Tie

2017-07-01

To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion. The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy. Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4. Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat.

PubMed

Sayhan, Mustafa Burak; Kanter, Mehmet; Oguz, Serhat; Erboga, Mustafa

2012-12-01

Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. This study was designed to investigate the effect of Urtica dioica L. (UD), in I/R induced renal injury. A total of 32 male Sprague-Dawley rats were divided into four groups: control, UD alone, I/R and I/R + UD; each group contain 8 animals. A rat model of renal I/R injury was induced by 45-min occlusion of the bilateral renal pedicles and 24-h reperfusion. In the UD group, 3 days before I/R, UD (2 ml/kg/day intraperitoneal) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and kidney tissues samples were obtained for histopathological investigation in all groups. To date, no more histopathological changes on intestinal I/R injury in rats by UD treatment have been reported. Renal I/R caused severe histopathological injury including tubular damage, atrophy dilatation, loss of brush border and hydropic epithelial cell degenerations, renal corpuscle atrophy, glomerular shrinkage, markedly focal mononuclear cell infiltrations in the kidney. UD treatment significantly attenuated the severity of intestinal I/R injury and significantly lowered tubulointerstitial damage score than the I/R group. The number of PCNA and TUNEL positive cells in the control and UD alone groups was negligible. When kidney sections were PCNA and TUNEL stained, there was a clear increase in the number of positive cells in the I/R group rats in the renal cortical tissues. However, there is a significant reduction in the activity of PCNA and TUNEL in kidney tissue of renal injury induced by renal I/R with UD therapy. Our results suggest that administration of UD attenuates renal I/R injury. These results suggest that UD treatment has a protective effect against renal damage induced by renal I/R. This protective effect is possibly due to its ability to inhibit I/R induced renal damage, apoptosis and cell proliferation.

Renal autotransplantation--a possibility in the treatment of complex renal vascular diseases and ureteric injuries.

PubMed

Hau, Hans Michael; Bartels, Michael; Tautenhahn, Hans-Michael; Morgul, Mehmet Haluk; Fellmer, Peter; Ho-Thi, Phuc; Benckert, Christoph; Uhlmann, Dirk; Moche, Michael; Thelen, Armin; Schmelzle, Moritz; Jonas, Sven

2012-12-31

We report our contemporary experiences with renal autotransplantation in patients with complicated renal vascular diseases and/or complex ureteral injuries. Since its first performance, renal autotransplantation has been steadily improved and become a safe and effective procedure. Between 1998 and 2006, 6 renal autotransplantations in 6 patients were performed at the University Medical Center of Leipzig. After nephrectomy and renal perfusion ex vivo, the kidney was implanted standardized in the fossa iliaca. The vessels were anastomized to the iliac vessels, the ureter was reimplanted in an extravesical tunneled ureteroneocystostomy technique according to Lich-Gregoir. Demographic, clinical, and laboratory data of the patients were collected and analyzed for pre-, intra-, and postoperative period. Indications for renal autotransplantation were complex renovascular diseases in 2 patients (1 with fibromuscular dysplasia and 1 with Takayasu's arteritis) and in 4 patients with complex ureteral injuries. The median duration of follow-up was 9.7 years (range: 5.6-13.3). The laboratory values of our 6 patients showed improvements of creatinine, urea and blood pressure levels in comparison to the preoperative status at the end of follow-up period. The present study reports excellent results of renal autotransplantation in patients with renovascular disease or complex ureteric injuries. After a median follow-up of 9.7 years all 6 patients present with stable renal function as well as normal blood pressure values. Postoperative complications were observed with a rate comparable to other studies.

Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats.

PubMed

Liu, Wen-Jun; Tang, Hong-Tai; Jia, Yi-Tao; Ma, Bing; Fu, Jin-Feng; Wang, Yu; Lv, Kai-Yang; Xia, Zhao-Fan

2010-09-01

Ischemia-reperfusion (I/R) injury of the kidney is a complex pathophysiological process and a major cause of acute renal failure. It has been shown that I/R injury is related to inflammatory responses and activation of apoptotic pathways. Inhibition of certain elements of inflammatory responses and apoptotic pathway seemed to ameliorate renal I/R injury. As an effective element of Panax notoginseng, NR1 has antioxidant, anti-inflammatory, antiapoptotic, and immune-stimulatory activities. Therefore, we speculate that NR1 can attenuate renal I/R injury. Ischemia-reperfusion injury was induced by renal pedicle ligation followed by reperfusion along with a contralateral nephrectomy. Male Sprague-Dawley rats were randomized to four groups: sham group, I/R control group, NR1-1 group (rats treated with NR1, 20 mg.kg.d) and NR1-2 group (rats treated with NR1, 40 mg.kg.d). All animals were killed 72 h after I/R induction. Blood and renal tissues were collected. Renal dysfunction was observed by the level of serum creatinine and histological evaluation. Apoptosis and inflammatory response in the tissue of kidney were detected mainly with molecular biological methods. NR1 attenuated I/R-induced renal dysfunction as indicated by the level of serum creatinine and histological evaluation. It prevented the I/R-induced increases in the levels of proinflammatory cytokine TNF-alpha, myeloperoxidase activity, phosphorylation of p38, and activation of nuclear factor kappaB with cell apoptosis in the kidney and enhanced expression of antiapoptosis cytokine bcl-2. Treatment with NR1 improves renal function after I/R associated with a significant reduction in cell apoptosis and inflammatory responses, which may be related to p38 and nuclear factor kappaB inhibition.

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney.

PubMed

Kelsen, Silvia; He, Xiaochen; Chade, Alejandro R

2012-08-15

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney

PubMed Central

Kelsen, Silvia; He, Xiaochen

2012-01-01

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution

Burn injury mortality in patients with preexisting and new onset renal disease.

PubMed

Knowlin, Laquanda T; Purcell, Laura; Cairns, Bruce A; Charles, Anthony G

2018-06-01

We sought to examine the impact of preexisting and new onset renal disease on burn injury mortality. Retrospective analysis of patients admitted to a regional burn center from 2002-2012 was performed. Variables analyzed included demographics, burn mechanism, inhalation injury status, and % TBSA. Poisson regression was performed to estimate risk of in-hospital burn mortality. There were a total of 7640 patients over the study period. The adjusted 60-day risk of in-hospital mortality in patients with preexisting renal disease (PRD was 3 times higher compared to patients with no preexisting renal disease (IRR = 3.22, 95% CI = 1.26-8.25). The adjusted 60-day risk of mortality is 2 times higher for patients with new onset renal disease compared to those without (IRR = 2.11, 95% CI = 1.55-2.87). Preexisting and new onset renal disease results in a significantly higher risk of mortality following burn injury compared to patients without renal disease. Prevention of new onset renal injury and careful management of patients with preexisting renal disease to prevent exacerbation should be pursued. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats.

PubMed

Mori, Takefumi; Cowley, Allen W

2004-04-01

Renal perfusion pressure was servo-controlled chronically in rats to quantify the relative contribution of elevated arterial pressure versus angiotensin II (Ang II) on the induction of renal injury in Ang II-induced hypertension. Sprague-Dawley rats fed a 4% salt diet were administered Ang II for 14 days (25 ng/kg per minute IV; saline only for sham rats), and the renal perfusion pressure to the left kidney was continuously servo-controlled to maintain a normal pressure in that kidney throughout the period of hypertension. An aortic occluder was implanted around the aorta between the two renal arteries and carotid and femoral arterial pressure were measured continuously throughout the experiment to determine uncontrolled and controlled renal perfusion pressure, respectively. Renal perfusion pressure of uncontrolled, controlled, and sham kidneys over the period of Ang II or saline infusion averaged 152.6+/-7.0, 117.4+/-3.5, and 110.7+/-2.2 mm Hg, respectively. The high-pressure uncontrolled kidneys exhibited tubular necrosis and interstitial fibrosis, especially prominent in the outer medullary region. Regional glomerular sclerosis and interlobular artery injury were also pronounced. Controlled kidneys were significantly protected from interlobular artery injury, juxtamedullary glomeruli injury, tubular necrosis, and interstitial fibrosis as determined by comparing the level of injury. Glomerular injury was not prevented in the outer cortex. Transforming growth factor (TGF)-beta and active NF-kappaB proteins determined by immunohistochemistry were colocalized in the uncontrolled kidney in regions of interstitial fibrosis. We conclude that the preferential juxtamedullary injury found in Ang II hypertension is largely induced by pressure and is probably mediated through the TGF-beta and NF-kappaB pathway.

The effect of a concomitant renal injury on the outcome of colonic trauma.

PubMed

Oosthuizen, G V; Weale, R; Kong, V Y; Bruce, J L; Urry, R J; Laing, G L; Clarke, D L

2017-12-06

The management of colon injuries has steadily evolved over the course of the last half century. So too has the management of renal trauma. It is not clear from the literature as to whether concomitant colon and renal injuries carry increased risk of morbidity and mortality, and whether this combination of injuries necessitates a specifically tailored management approach. A retrospective review was carried out for the period January 2012 to December 2016. All patients over the age of 18 years who were subjected to laparotomy for penetrating trauma (gunshot wounds or stab wounds) and who sustained an intra-operatively proven colonic injury were included in this study. Operative management and outcomes were investigated. A direct comparison was made between patients with a combined colonic and renal injury and those with only a colonic injury. Over the five-year period a total of 268 patients sustained a colonic injury. The 239 patients with a colonic injury (Group A) were compared to the 29 patients with a combined colonic and renal injury (Group B). Regarding the management of the colonic injuries, there were no differences in the rates of primary repair, anastomosis, exteriorization, or damage control surgery between groups A and B. As for the management of the renal injury, 14 were not explored at laparotomy; in 12 a nephrectomy was performed and in 3 the renal injury was repaired. The nephrectomy cohort were more likely to have undergone damage control surgery, to be admitted to ICU, to receive a colostomy, and had higher mortality. While there was no difference in the need for damage control surgery or mortality between groups, Group B had a significantly greater need for ICU admission. Morbidity was similar between the two groups - in particular, there was no difference in the rates of either gastro-intestinal complications or acute kidney injury between the two groups. In patients with combined colon and renal injuries, it seems reasonable to treat each organ

Serum Iron Protects from Renal Postischemic Injury.

PubMed

Vaugier, Céline; Amano, Mariane T; Chemouny, Jonathan M; Dussiot, Michael; Berrou, Claire; Matignon, Marie; Ben Mkaddem, Sanae; Wang, Pamella H M; Fricot, Aurélie; Maciel, Thiago T; Grapton, Damien; Mathieu, Jacques R R; Beaumont, Carole; Peraldi, Marie-Noëlle; Peyssonnaux, Carole; Mesnard, Laurent; Daugas, Eric; Vrtovsnik, François; Monteiro, Renato C; Hermine, Olivier; Ginzburg, Yelena Z; Benhamou, Marc; Camara, Niels O S; Flamant, Martin; Moura, Ivan C

2017-12-01

Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients ( n =169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF- κ B and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants. Copyright © 2017 by the American Society of Nephrology.

Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions.

PubMed

Lobb, I; Jiang, J; Lian, D; Liu, W; Haig, A; Saha, M N; Torregrossa, R; Wood, M E; Whiteman, M; Sener, A

2017-02-01

Ischemia-reperfusion injury is unavoidably caused by loss and subsequent restoration of blood flow during organ procurement, and prolonged ischemia-reperfusion injury IRI results in increased rates of delayed graft function and early graft loss. The endogenously produced gasotransmitter, hydrogen sulfide (H 2 S), is a novel molecule that mitigates hypoxic tissue injury. The current study investigates the protective mitochondrial effects of H 2 S during in vivo cold storage and subsequent renal transplantation (RTx) and in vitro cold hypoxic renal injury. Donor allografts from Brown Norway rats treated with University of Wisconsin (UW) solution + H 2 S (150 μM NaSH) during prolonged (24-h) cold (4°C) storage exhibited significantly (p < 0.05) decreased acute necrotic/apoptotic injury and significantly (p < 0.05) improved function and recipient Lewis rat survival compared to UW solution alone. Treatment of rat kidney epithelial cells (NRK-52E) with the mitochondrial-targeted H 2 S donor, AP39, during in vitro cold hypoxic injury improved the protective capacity of H 2 S >1000-fold compared to similar levels of the nonspecific H 2 S donor, GYY4137 and also improved syngraft function and survival following prolonged cold storage compared to UW solution. H 2 S treatment mitigates cold IRI-associated renal injury via mitochondrial actions and could represent a novel therapeutic strategy to minimize the detrimental clinical outcomes of prolonged cold IRI during RTx. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development.

PubMed

Fan, Ying; Xiao, Wenzhen; Lee, Kyung; Salem, Fadi; Wen, Jiejun; He, Li; Zhang, Jing; Fei, Yang; Cheng, Dongsheng; Bao, Hongda; Liu, Yumei; Lin, Fujun; Jiang, Gengru; Guo, Zhiyong; Wang, Niansong; He, John Cijiang

2017-07-01

Several animal studies have shown an important role for endoplasmic reticulum (ER) stress in AKI, whereas human studies are lacking. We recently reported that Reticulon-1A (RTN1A) is a key mediator of ER stress and kidney cell injury. Here, we investigated whether modulation of RTN1A expression during AKI contributes to the progression to CKD. In a retrospective study of 51 patients with AKI, increased expression of RTN1A and other ER stress markers were associated with the severity of kidney injury and with progression to CKD. In an inducible tubular cell-specific RTN1A-knockdown mouse model subjected to folic acid nephropathy (FAN) or aristolochic acid nephropathy, reduction of RTN1A expression during the initial stage of AKI attenuated ER stress and kidney cell injury in early stages and renal fibrosis development in later stages. Treatment of wild-type mice with tauroursodeoxycholic acid, an inhibitor of ER stress, after the induction of kidney injury with FA facilitated renoprotection similar to that observed in RTN1A-knockdown mice. Conversely, in transgenic mice with inducible tubular cell-specific overexpression of RTN1A subjected to FAN, induction of RTN1A overexpression aggravated ER stress and renal injury at the early stage and renal fibrosis at the late stage of FAN. Together, our human and mouse data suggest that the RTN1A-mediated ER stress response may be an important determinant in the severity of AKI and maladaptive repair that may promote progression to CKD. Copyright © 2017 by the American Society of Nephrology.

Amelioration of renal ischaemia–reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells

PubMed Central

Rogers, NM; Stephenson, MD; Kitching, AR; Horowitz, JD; Coates, PTH

2012-01-01

BACKGROUND AND PURPOSE Renal ischaemia–reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. EXPERIMENTAL APPROACH We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. KEY RESULTS Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. CONCLUSIONS AND IMPLICATIONS Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury. PMID:21745189

Alteration of renal excretion pathways in gentamicin-induced renal injury in rats.

PubMed

Ma, Yan-Rong; Luo, Xuan; Wu, Yan-Fang; Zhang, Tiffany; Zhang, Fan; Zhang, Guo-Qiang; Wu, Xin-An

2018-07-01

The kidney plays a major part in the elimination of many drugs and their metabolites, and drug-induced kidney injury commonly alters either glomerular filtration or tubular transport, or both. However, the renal excretion pathway of drugs has not been fully elucidated at different stages of renal injury. This study aimed to evaluate the alteration of renal excretion pathways in gentamicin (GEN)-induced renal injury in rats. Results showed that serum cystatin C, creatinine and urea nitrogen levels were greatly increased by the exposure of GEN (100 mg kg -1 ), and creatinine concentration was increased by 39.7% by GEN (50 mg kg -1 ). GEN dose-dependently upregulated the protein expression of rOCT1, downregulated rOCT2 and rOAT1, but not affected rOAT2. Efflux transporters, rMRP2, rMRP4 and rBCRP expressions were significantly increased by GEN(100), and the rMATE1 level was markedly increased by GEN(50) but decreased by GEN(100). GEN(50) did not alter the urinary excretion of inulin, but increased metformin and furosemide excretion. However, GEN(100) resulted in a significant decrease of the urinary excretion of inulin, metformin and p-aminohippurate. In addition, urinary metformin excretions in vivo were significantly decreased by GEN(100), but slightly increased by GEN(50). These results suggested that GEN(50) resulted in the induction of rOCTs-rMATE1 and rOAT3-rMRPs pathway, but not changed the glomerular filtration rate, and GEN(100)-induced acute kidney injury caused the downregulated function of glomerular filtration -rOCTs-rMATE1 and -rOAT1-rMRPs pathway. Copyright © 2018 John Wiley & Sons, Ltd.

Prophylactic role of phycocyanin: a study of oxalate mediated renal cell injury.

PubMed

Farooq, Shukkur Muhammed; Asokan, Devarajan; Kalaiselvi, Periandavan; Sakthivel, Ramasamy; Varalakshmi, Palaninathan

2004-08-10

Oxalate induced renal calculi formation and the associated renal injury is thought to be caused by free radical mediated mechanisms. An in vivo model was used to investigate the effect of phycocyanin (from Spirulina platensis), a known antioxidant, against calcium oxalate urolithiasis. Male Wistar rats were divided into four groups. Hyperoxaluria was induced in two of these groups by intraperitoneal infusion of sodium oxalate (70 mg/kg) and a pretreatment of phycocyanin (100 mg/kg) as a single oral dosage was given, 1h prior to sodium oxalate infusion. An untreated control and drug control (phycocyanin alone) were also included in the study. We observed that phycocyanin significantly controlled the early biochemical changes in calcium oxalate stone formation. The antiurolithic nature of the drug was evaluated by the assessment of urinary risk factors and light microscopic observation of urinary crystals. Renal tubular damage as divulged by urinary marker enzymes (alkaline phosphatase, acid phosphatase and gamma-glutamyl transferase) and histopathological observations such as decreased tubulointerstitial, tubular dilatation and mononuclear inflammatory cells, indicated that renal damage was minimised in drug-pretreated group. Oxalate levels (P < 0.001) and lipid peroxidation (P < 0.001) in kidney tissue were significantly controlled by drug pretreatment, suggesting the ability of phycocyanin to quench the free radicals, thereby preventing the lipid peroxidation mediated tissue damage and oxalate entry. This accounts for the prevention of CaOx stones. Thus, the present analysis revealed the antioxidant and antiurolithic potential of phycocyanin thereby projecting it as a promising therapeutic agent against renal cell injury associated kidney stone formation.

Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells.

PubMed

Rogers, N M; Stephenson, M D; Kitching, A R; Horowitz, J D; Coates, P T H

2012-05-01

Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Arterial Embolization for the Treatment of Renal Masses and Traumatic Renal Injuries.

PubMed

Ramaswamy, Raja S; Darcy, Michael D

2016-09-01

Renal artery embolization (RAE) for a variety of indications has been performed for several decades. RAE techniques have been refined over time for clinical efficacy and a more favorable safety profile. Owing to improved catheters, embolic agents for precise delivery, and clinical experience, RAE is increasingly used as an adjunct to, or as the preferred alternative to surgical interventions. The indications for RAE are expanding for many urologic and medical conditions. In this article, we focus on the role and technical aspects of RAE in the treatment of renal masses and traumatic renal injuries. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-invasive detection of the early phase of kidney injury by photoacoustic/computed tomography imaging.

PubMed

Pan, Wanma; Peng, Wen; Ning, Fengling; Zhang, Yu; Zhang, Yunfei; Wang, Yinhang; Xie, Weiyi; Zhang, Jing; Xin, Hong; Li, Cong; Zhang, Xuemei

2018-06-29

The early diagnosis of kidney diseases, which can remarkably impair the quality of life and are costly, has encountered great difficulties. Therefore, the development of methods for early diagnosis has great clinical significance. In this study, we used an emerging technique of photoacoustic (PA) imaging, which has relatively high spatial resolution and good imaging depth. Two kinds of PA gold nanoparticle (GNP)-based bioprobes were developed based on their superior photo detectability, size controllability and biocompatibility. The kidney injury mouse model was developed by unilateral ureteral obstruction for 96 h and the release of obstruction model). Giving 3.5 and 5.5 nm bioprobes by tail vein injection, we found that the 5.5 nm probe could be detected in the bladder in the model group, but not in the control group. These results were confirmed by computed tomography imaging. Furthermore, the model group did not show changes in the blood biochemical indices (BUN and Scr) and histologic examination. The 5.5 nm GNPs were found to be the critical point for early diagnosis of kidney injury. This new method was faster and more sensitive and accurate for the detection of renal injury, compared with conventional methods, and can be used for the development of a PA GNP-based bioprobe for diagnosing renal injury.

Non-invasive detection of the early phase of kidney injury by photoacoustic/computed tomography imaging

NASA Astrophysics Data System (ADS)

Pan, Wanma; Peng, Wen; Ning, Fengling; Zhang, Yu; Zhang, Yunfei; Wang, Yinhang; Xie, Weiyi; Zhang, Jing; Xin, Hong; Li, Cong; Zhang, Xuemei

2018-06-01

The early diagnosis of kidney diseases, which can remarkably impair the quality of life and are costly, has encountered great difficulties. Therefore, the development of methods for early diagnosis has great clinical significance. In this study, we used an emerging technique of photoacoustic (PA) imaging, which has relatively high spatial resolution and good imaging depth. Two kinds of PA gold nanoparticle (GNP)-based bioprobes were developed based on their superior photo detectability, size controllability and biocompatibility. The kidney injury mouse model was developed by unilateral ureteral obstruction for 96 h and the release of obstruction model). Giving 3.5 and 5.5 nm bioprobes by tail vein injection, we found that the 5.5 nm probe could be detected in the bladder in the model group, but not in the control group. These results were confirmed by computed tomography imaging. Furthermore, the model group did not show changes in the blood biochemical indices (BUN and Scr) and histologic examination. The 5.5 nm GNPs were found to be the critical point for early diagnosis of kidney injury. This new method was faster and more sensitive and accurate for the detection of renal injury, compared with conventional methods, and can be used for the development of a PA GNP-based bioprobe for diagnosing renal injury.

Effect of sulfasalazine on renal ischemia/reperfusion injury in rats.

PubMed

Cámara-Lemarroy, Carlos Rodrigo; Guzmán-de la Garza, Francisco Javier; Alarcón-Galván, Gabriela; Cordero-Pérez, Paula; Fernández-Garza, Nancy Esthela

2009-01-01

Renal ischemia/reperfusion (I/R) occurs during shock and transplant procedures, greatly affecting outcome. A definitive treatment has not been found. One of the pathophysiological bases of renal I/R injury is the activation of the transcription factor nuclear factor-kappaB (NF-KappaB). We studied the effects of sulfasalazine (SFZ), a NF-kappaB inhibitor, over renal injury in a bilateral renal I/R model in rats. Ten male Wistar rats were subjected to bilateral renal I/R for 45 min followed by 24 h of reperfusion. Half of these received 100 mg/kg SFZ orally before the induction of I/R, while the others received only saline. Five rats served as sham-operated controls. At the end of the reperfusion period, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), P-selectin, tumor necrosis factor-alpha (TNF-alpha), intracellular adhesion molecule-1 (ICAM-1), and endothelin-1 (ET-1) concentrations were determined in serum, and renal samples were taken for histological evaluation. After renal I/R, AST, LDH, BUN, TNF-alpha, ICAM-1, and ET-1 serum levels were significantly increased, and tubules were severely damaged on histological analysis, compared to sham controls. SFZ treatment reduced the AST, LDH, BUN, TNF-alpha, and ET-1 elevations, as well as the tubular damage, induced by renal I/R. Serum ICAM-1 and P-selectin were unchanged. These results show that SFZ has a protective effect over renal IR injury. The modulation of adhesion molecules probably does not play a part in these effects, but TNF-alpha and ET-1 modulation could be partly responsible for the effects we observed.

Microdialysis assessment of shock wave lithotripsy-induced renal injury.

PubMed

Brown, S A; Munver, R; Delvecchio, F C; Kuo, R L; Zhong, P; Preminger, G M

2000-09-01

Shock wave lithotripsy (SWL) is the primary treatment modality for managing the majority of symptomatic renal calculi. However, the fundamental mechanisms for stone fragmentation and the resultant morphologic changes that occur are not fully understood. Furthermore, a thorough understanding of the complex biologic pathways involved in SWL-induced renal injury does not exist at present. To elucidate the biologic processes involved in tissue injury after SWL, an animal model was designed to mimic the pathogenesis of high-energy SWL in humans. Juvenile female swine were anesthetized, and a midline laparotomy incision was performed to expose the right kidney. Using an introducer apparatus, a microdialysis probe was placed into the renal parenchyma of the right kidney lower pole and a tunnel was generated to exit the distal ends of the inlet and outlet tubing outside the body. After a 72-hour postoperative recovery period, SWL was performed to the lower pole renal region of the kidney, as a microdialysis pump continuously infused dialysate through the inlet tubing. Microdialysis fluids were collected during SWL, and lipid peroxidation, as measured by conjugated diene concentrations, was monitored. All microdialysis probes remained patent for a total of 2000 shock waves. A significant elevation in conjugated diene levels was observed in the SWL versus untreated kidneys after 1000 shock waves were administered (P <0.02). This animal model is unique in that it represents the first system for the real-time collection of renal interstitial fluids during SWL. Analysis of this fluid may provide insight into the physiologic mechanisms responsible for shock wave-induced renal injury.

Evidence of uncoupling between renal dysfunction and injury in cardiorenal syndrome: insights from the BIONICS study.

PubMed

Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S; Januzzi, James L

2014-01-01

The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153).

Evidence of Uncoupling between Renal Dysfunction and Injury in Cardiorenal Syndrome: Insights from the BIONICS Study

PubMed Central

Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K.; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S.; Januzzi, James L.; (GREAT), from the Global Research on Acute Conditions Team

2014-01-01

Objective The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). Methods In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. Results 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. Conclusions In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153). PMID:25386851

Trajectory of Estimated Glomerular Filtration Rate Predicts Renal Injury in Children with Multicystic Dysplastic Kidney.

PubMed

Matsumura, Kazuya; Sugii, Kyoko; Awazu, Midori

2018-06-07

Children with a solitary functioning kidney have a risk of renal injury caused by hyperfiltration. Timely intervention with renin-angiotensin inhibitors may be beneficial. We examined whether trajectory of estimated glomerular filtration rate (eGFR) would predict renal injury, defined as microalbuminuria/proteinuria, hypertension, and/or a decline in eGFR. Seventeen patients (male 7, female 10) with multicystic dysplastic kidney (MCDK; median age 13 years, range 6-19 years) followed in our clinic were examined retrospectively. An eGFR decline was defined as a fall to < 90 mL/min/1.73 m2 or a decline of > 5 mL/min/1.73 m2/year for those with baseline eGFR of ≥90 or < 90 mL/min/1.73 m2 respectively. Nine patients had renal injury at the time of investigation. Compared with 8 patients without renal injury, those with renal injury tended to be older (14.7 ± 4.2 vs. 11.4 ± 4.6 years) and the birth weight was smaller (2,538 ± 281 vs. 2,966 ± 361 g, p < 0.05). The frequency of contralateral congenital anomaly of kidney and urinary tract (cyst, hydronephrosis, or vesicoureteral reflux) were not different. The trajectory of eGFR in those without renal injury was either an increase (n = 3) or unidentifiable (n = 5), whereas that in the renal injury group was exclusively an increase followed by decline (p < 0.05). The average age of the onset of eGFR decline was 9.4 ± 4.2 years and that of the start of renal injury (albuminuria/proteinuria 5, eGFR decline 4, hypertension 1) was 12.5 ± 4.2 years. All the children with MCDK who developed renal injury had eGFR trajectory of increase followed by decline. Renal injury followed the peak eGFR by 3 years on average. This observation is in agreement with the hyperfiltration theory and underscores the importance of following eGFR trajectory closely. © 2018 S. Karger AG, Basel.

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

PubMed

Eun Lee, Jee; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Ghee, Jung Yeon; Kang, Young Sun; Min, Hye Sook; Kim, Hyun Wook; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong

2016-05-01

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm

PubMed Central

Pang, Paul; Jin, Xiaohua; Proctor, Brandon M.; Farley, Michelle; Roy, Nilay; Chin, Matthew S.; von Andrian, Ulrich H.; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J.; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J.; Bonventre, Joseph V.; Siedlecki, Andrew M.

2014-01-01

Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

Bedside biomarkers in pediatric cardio renal injuries in emergency

PubMed Central

Singhal, Noopur; Saha, Abhijeet

2014-01-01

Point of care testing (POCT) using biomarkers in the emergency department reduces turnaround time for clinical decision making. An ideal biomarker should be accurate, reliable and easy to measure with a standard assay, non-invasive, sensitive and specific with defined cutoff values. Conventional biomarkers for renal injuries include rise in serum creatinine and fluid overload. Recently, neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18) and liver fatty acid binding protein (L-FABP) have been studied extensively for their role in acute kidney injury associated with various clinical entities. Biochemical markers of ischaemic cardiac damage commonly used are plasma creatine kinase and cardiac troponins (cTn). Clinically valuable cardiac markers for myocardial injury in research at present comprise BNP/NT-proBNP and to a lesser extent, CRP, which are independent predictors of adverse events including death and heart failure. Current status of point of care biomarkers for diagnosis and prognostication of renal and cardiac injuries in pediatric emergency care is appraised in this review. PMID:25337487

Lacking Ketohexokinase-A Exacerbates Renal Injury in Streptozotocin-induced Diabetic Mice.

PubMed

Doke, Tomohito; Ishimoto, Takuji; Hayasaki, Takahiro; Ikeda, Satsuki; Hasebe, Masako; Hirayama, Akiyoshi; Soga, Tomoyoshi; Kato, Noritoshi; Kosugi, Tomoki; Tsuboi, Naotake; Lanaspa, Miguel A; Johnson, Richard J; Kadomatsu, Kenji; Maruyama, Shoichi

2018-03-28

Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6 J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediates levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD + level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD. Copyright © 2018. Published by Elsevier Inc.

RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice

PubMed Central

Khaibullina, Alfia; Adjei, Elena A.; Afangbedji, Nowah; Ivanov, Andrey; Kumari, Namita; Almeida, Luis E.F.; Quezado, Zenaide M.N.; Nekhai, Sergei; Jerebtsova, Marina

2018-01-01

Sickle cell disease patients are at increased risk of developing a chronic kidney disease. Endothelial dysfunction and inflammation associated with hemolysis lead to vasculopathy and contribute to the development of renal disease. Here we used a Townes sickle cell disease mouse model to examine renal endothelial injury. Renal disease in Townes mice was associated with glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury. We also detected substantial renal macrophage infiltration, and accumulation of macrophage stimulating protein 1 in glomerular capillary. Treatment of human cultured macrophages with hemin or red blood cell lysates significantly increased expression of macrophage membrane-associated protease that might cleave and activate circulating macrophage stimulating protein 1 precursor. Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase. In cultured human renal glomerular endothelial cells, macrophage stimulating protein 1 induced RON downstream signaling, resulting in increased phosphorylation of ERK and AKT kinases, expression of Von Willebrand factor, increased cell motility, and re-organization of F-actin. Specificity of macrophage stimulating protein 1 function was confirmed by treatment with RON kinase inhibitor BMS-777607 that significantly reduced downstream signaling. Moreover, treatment of sickle cell mice with BMS-777607 significantly reduced glomerular hypertrophy, capillary dilation and congestion, and endothelial injury. Taken together, our findings demonstrated that RON kinase is involved in the induction of renal endothelial injury in sickle cell mice. Inhibition of RON kinase activation may provide a novel approach for prevention of the development of renal disease in sickle cell disease. PMID:29519868

Iron restriction inhibits renal injury in aldosterone/salt-induced hypertensive mice.

PubMed

Sawada, Hisashi; Naito, Yoshiro; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Masuyama, Tohru

2015-05-01

Excess iron is associated with the pathogenesis of several renal diseases. Aldosterone is reported to have deleterious effects on the kidney, but there have been no reports of the role of iron in aldosterone/salt-induced renal injury. Therefore, we investigated the effects of dietary iron restriction on the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice. Ten-week-old male C57BL/6J mice were uninephrectomized and infused with aldosterone for four weeks. These were divided into two groups: one fed a high-salt diet (Aldo) and the other fed a high-salt with iron-restricted diet (Aldo-IR). Vehicle-infused mice without a uninephrectomy were also divided into two groups: one fed a normal diet (control) and the other fed an iron-restricted diet (IR) for 4 weeks. As compared with control and IR mice, Aldo mice showed an increase in both systolic blood pressure and urinary albumin/creatinine ratio, but these increases were reduced in the Aldo-IR group. In addition, renal histology revealed that Aldo mice exhibited glomerulosclerosis and tubulointerstitial fibrosis, whereas these changes were attenuated in Aldo-IR mice. Expression of intracellular iron transport protein transferrin receptor 1 was increased in the renal tubules of Aldo mice compared with control mice. Dietary iron restriction attenuated the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice.

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

PubMed

Mackenzie, H S; Azuma, H; Troy, J L; Rennke, H G; Tilney, N L; Brenner, B M

1996-03-01

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Early Implementation of Continuous Renal Replacement Therapy Optimizes Casualty Evacuation for Combat-Related Acute Kidney Injury

DTIC Science & Technology

2013-08-01

were Acute Kidney Injury Network (AKIN) 3 and all developed critical hyperkalemia (mean [SD], peak K+ 6.4 [0.4]). The peak plasma creatinine ranged...related acid-base disorders, severe hyperkalemia , and metabolic disorders became apparent. Based on the mounting pressure and internal performance im...with severe hyperkalemia was the most common indication for renal replacement. Validation for critical care evacuation to the Role IV facility mandated a

Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRT-AKI): study protocol for a randomized controlled trial.

PubMed

Smith, Orla M; Wald, Ron; Adhikari, Neill K J; Pope, Karen; Weir, Matthew A; Bagshaw, Sean M

2013-10-05

Acute kidney injury is a common and devastating complication of critical illness, for which renal replacement therapy is frequently needed to manage severe cases. While a recent systematic review suggested that "earlier" initiation of renal replacement therapy improves survival, completed trials are limited due to small size, single-centre status, and use of variable definitions to define "early" renal replacement therapy initiation. This is an open-label pilot randomized controlled trial. One hundred critically ill patients with severe acute kidney injury will be randomly allocated 1:1 to receive "accelerated" initiation of renal replacement therapy or "standard" initiation at 12 centers across Canada. In the accelerated arm, participants will have a venous catheter placed and renal replacement therapy will be initiated within 12 hours of fulfilling eligibility. In the standard initiation arm, participants will be monitored over 7 days to identify indications for renal replacement therapy. For participants in the standard arm with persistent acute kidney injury, defined as a serum creatinine not declining >50% from the value at the time of eligibility, the initiation of RRT will be discouraged unless one or more of the following criteria are fulfilled: serum potassium ≥6.0 mmol/L; serum bicarbonate ≤10 mmol/L; severe respiratory failure (PaO₂/FiO₂<200) or persisting acute kidney injury for ≥72 hours after fulfilling eligibility. The inclusion criteria are designed to identify a population of critically ill adults with severe acute kidney injury who are likely to need renal replacement therapy during their hospitalization, but not immediately. The primary outcome is protocol adherence (>90%). Secondary outcomes include measures of feasibility (proportion of eligible patients enrolled in the trial, proportion of enrolled patients followed to 90 days for assessment of vital status and the need for renal replacement therapy) and safety (occurrence of adverse

Kidney injury after sodium phosphate solution beyond the acute renal failure.

PubMed

Fernández-Juárez, Gema; Parejo, Leticia; Villacorta, Javier; Tato, Ana; Cazar, Ramiro; Guerrero, Carmen; Marin, Isabel Martinez; Ocaña, Javier; Mendez-Abreu, Angel; López, Katia; Gruss, Enrique; Gallego, Eduardo

2016-01-01

Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24ml/min/1.73m(2). The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats.

PubMed

Zafrani, Lara; Ergin, Bulent; Kapucu, Aysegul; Ince, Can

2016-12-20

The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in renal microvascular oxygenation and sepsis-induced endothelial dysfunction via the restoration of eNOS expression within the kidney.

Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps.

PubMed

Jansen, Marcel P B; Emal, Diba; Teske, Gwendoline J D; Dessing, Mark C; Florquin, Sandrine; Roelofs, Joris J T H

2017-02-01

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs.

PubMed

Baek, Jin Hyen; Zhang, Xiaoyuan; Williams, Matthew C; Hicks, Wayne; Buehler, Paul W; D'Agnillo, Felice

2015-07-03

Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia. Published by Elsevier Ireland Ltd.

Perioperative Acute Kidney Injury: Prevention, Early Recognition, and Supportive Measures.

PubMed

Romagnoli, Stefano; Ricci, Zaccaria; Ronco, Claudio

2018-06-26

Acute kidney injury (AKI) is a frequent complication of both cardiac and major non-cardiac surgery. AKI is independently associated with morbidity, mortality, and long-term adverse events including chronic kidney disease in postsurgical patients. Since specific treatment options for kidney failure are very limited, early identification, diagnosis, and renal support strategies are key steps to improve patients' outcome. According to current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, AKI diagnosis is based on 2 functional markers, serum creatinine increase and urine output decrease, that are not renal-specific and have important limitations. However, preoperative risk stratification for postoperative AKI and/or early diagnosis after surgery could be the best way to apply preventive or timely supportive therapeutic measures. Clinical prediction scores, renal functional reserve assessment, and new biomarkers of kidney stress (suppression of tumorigenicity-2, insulin-like growth factor binding protein-7, tissue inhibitor metalloproteinase-2) may help the clinicians to identify patients at risk of AKI and that could benefit from the application of nephroprotective bundles suggested by the KDIGO guidelines. In severe AKI patients with oligoanuria and fluid accumulation, renal replacement therapy is the only supportive measure even if mode and timing remain open to investigation. Key messages: Perioperative AKI is an important and underdiagnosed complication. Identifying patients at high risk of AKI and diagnosing AKI early are major goals. Preventive interventions are mainly based on the KDIGO guidelines and bundles. Furthermore, a personalized multidisciplinary approach should always be considered to minimize the progression of disease and the complications related to kidney damage. © 2018 S. Karger AG, Basel.

Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

PubMed Central

Barroso, Lívia Corrêa; Silveira, Kátia Daniela; Lima, Cristiano Xavier; Borges, Valdinéria; Bader, Michael; Rachid, Milene; Santos, Robson Augusto Souza; Souza, Danielle Gloria; Simões e Silva, Ana Cristina; Teixeira, Mauro Martins

2012-01-01

Renal ischemia and reperfusion (I/R) is the major cause of acute kidney injury in hospitalized patients. Mechanisms underlying reperfusion-associated injury include recruitment and activation of leukocytes and release of inflammatory mediators. In this study, we investigated the renal effects of acute administration of AVE0991, an agonist of Mas, the angiotensin-(1–7) receptor, the angiotensin-(1–7) receptor, in a murine model of renal I/R. Male C57BL/6 wild-type or Mas−/− mice were subjected to 30 min of bilateral ischemia and 24 h of reperfusion. Administration of AVE0991 promoted renoprotective effects, as seen by improvement of function, decreased tissue injury, prevention of local and remote leucocyte infiltration, and release of the chemokine, CXCL1. I/R injury was similar in WT and Mas−/− mice, suggesting that endogenous activation of this receptor does not control renal damage under baseline conditions. In conclusion, pharmacological interventions using Mas receptor agonists may represent a therapeutic opportunity for the treatment of renal I/R injury. PMID:22319645

Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery.

PubMed

Stafford-Smith, Mark; Podgoreanu, Mihai; Swaminathan, Madhav; Phillips-Bute, Barbara; Mathew, Joseph P; Hauser, Elizabeth H; Winn, Michelle P; Milano, Carmelo; Nielsen, Dahlia M; Smith, Mike; Morris, Richard; Newman, Mark F; Schwinn, Debra A

2005-03-01

Post-cardiac surgery renal dysfunction is a common, serious, multifactorial disorder, with interpatient variability predicted poorly by preoperative clinical, procedural, and biological markers. Therefore, we tested the hypothesis that selected gene variants are associated with acute renal injury, reflected by a serum creatinine level increase after cardiac surgery. One thousand six hundred seventy-one patients undergoing aortocoronary surgery were studied. Clinical covariates were recorded. DNA was isolated from preoperative blood; mass spectrometry was used for genotype analysis. A model was developed relating clinical and genetic factors to postoperative acute renal injury. A race effect was found; therefore, Caucasians and African Americans were analyzed separately. Overall, clinical factors alone account poorly for postoperative renal injury, although more so in African Americans than Caucasians. When 12 candidate polymorphisms were assessed, 2 alleles (interleukin 6 -572C and angiotensinogen 842C) showed a strong association with renal injury in Caucasians (P < 0.0001; >50% decrease in renal filtration when they present together). Using less stringent criteria for significance (0.01 > P > 0.001), 4 additional polymorphisms are identified (apolipoproteinE 448C [4], angiotensin receptor1 1166C, and endothelial nitric oxide synthase [eNOS] 894T in Caucasians; eNOS 894T and angiotensin-converting enzyme deletion and insertion in African Americans). Adding genetic to clinical factors resulted in the best model, with overall ability to explain renal injury increasing approximately 4-fold in Caucasians and doubling in African Americans (P < 0.0005). In this study, we identify genetic polymorphisms that collectively provide 2- to 4-fold improvement over preoperative clinical factors alone in explaining post-cardiac surgery renal dysfunction. From a mechanistic perspective, most identified genetic variants are associated with increased renal inflammatory and

Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.

PubMed

Masola, Valentina; Zaza, Gianluigi; Bellin, Gloria; Dall'Olmo, Luigi; Granata, Simona; Vischini, Gisella; Secchi, Maria Francesca; Lupo, Antonio; Gambaro, Giovanni; Onisto, Maurizio

2018-02-01

Heparanase (HPSE) is part of the biologic network triggered by ischemia/reperfusion (I/R) injury, a complication of renal transplantation and acute kidney injury. During this period, the kidney or graft undergoes a process of macrophages recruitment and activation. HPSE may therefore control these biologic effects. We measured the ability of HPSE and its inhibitor, SST0001, to regulate macrophage polarization and the crosstalk between macrophages and HK-2 renal tubular cells during in vitro hypoxia/reoxygenation (H/R). Furthermore, we evaluated in vivo renal inflammation, macrophage polarization, and histologic changes in mice subjected to monolateral I/R and treated with SST0001 for 2 or 7 d. The in vitro experiments showed that HPSE sustained M1 macrophage polarization and modulated apoptosis, the release of damage associated molecular patterns in post-H/R tubular cells, the synthesis of proinflammatory cytokines, and the up-regulation of TLRs on both epithelial cells and macrophages. HPSE also regulated M1 polarization induced by H/R-injured tubular cells and the partial epithelial-mesenchymal transition of these epithelial cells by M1 macrophages. All these effects were prevented by inhibiting HPSE. Furthermore, the inhibition of HPSE in vivo reduced inflammation and M1 polarization in mice undergoing I/R injury, partially restored renal function and normal histology, and reduced apoptosis. These results show for the first time that HPSE regulates macrophage polarization as well as renal damage and repair after I/R. HPSE inhibitors could therefore provide a new pharmacologic approach to minimize acute kidney injury and to prevent the chronic profibrotic damages induced by I/R.-Masola, V., Zaza, G., Bellin, G., Dall'Olmo, L., Granata, S., Vischini, G., Secchi, M. F., Lupo, A., Gambaro, G., Onisto, M. Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.

Protective role of apigenin in cisplatin-induced renal injury.

PubMed

He, Xuexiu; Li, Chunmei; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Shi, Mingyu; Yang, Zhengtao; Fu, Yunhe

2016-10-15

This study aimed to investigate the effects and molecular mechanisms of the effects of apigenin on cisplatin (CP)-induced kidney injury in mice. Apigenin was intraperitoneally administered for 3 consecutive days before CP treatment. We found that apigenin pretreatment significantly attenuated the damage to the kidneys and decreased the levels of serum creatinine, blood urea nitrogen (BUN), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD), which were increased by CP. Apigenin significantly decreased the levels of TNF-α, IL-1β and TGFβ in the kidneys. Additionally, apigenin inhibited the activations of CYP2E1, phospho-NF-κB p65 and phospho-P38 MAPK in CP-induced renal injury. These results suggest that the renoprotective effects of apigenin may be related to the suppressions of oxidative stress and inflammation in CP-induced renal injury in mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Incidence and Patient Outcomes in Renal Replacement Therapy After Orthotopic Liver Transplant.

PubMed

Ayhan, Asude; Ersoy, Zeynep; Ulas, Aydin; Zeyneloglu, Pinar; Pirat, Arash; Haberal, Mehmet

2017-02-01

Our objective was to evaluate the incidence of renal replacement therapy after orthotopic liver transplant and to evaluate and analyze patient outcomes. We performed a retrospective analysis of 177 consecutive patients at a tertiary care unit who underwent orthotopic liver transplant between January 2010 and June 2016. Patients who were admitted to the intensive care unit after orthotopic liver transplant and who required renal replacement therapy were included. A total of 177 (79 adult, 98 pediatric) orthotopic liver transplants were performed during the study period. Of these, 35 patients (19%) required renal replacement therapy during the early posttransplantation period. After excluding 5 patients with previous chronic renal failure, 30 patients (17%; 20 adult [25% ], 10 pediatric [10% ]) with acute kidney injury required renal replacement therapy. The mean patient age was 31.1 ± 20.0 years, with a mean Model for End-stage Liver Disease score of 16.7 ± 12.3. Of the patients with acute kidney injury who underwent renal replacement therapy, in-hospital mortality was 23.3% (7 of 30 patients), and 40% remained on dialysis. No significant difference was seen in mortality between early versus delayed initiation of renal replacement therapy in patients with stage 3 acute kidney injury (P = .17). Of liver transplant recipients who present with acute kidney injury, 19% require renal replacement therapy, and in-hospital mortality is 20% in the early postoperative period.

Sevoflurane pretreatment enhance HIF-2α expression in mice after renal ischemia/reperfusion injury

PubMed Central

Zheng, Beijie; Zhan, Qionghui; Chen, Jue; Xu, Huan; He, Zhenzhou

2015-01-01

Ischemia/reperfusion (I/R) injury often occurs, which is one of the major causes of acute kidney injury, thus increasing in-hospital mortality. HIF-2α has a protective role against ischemia of the kidney. Renal ischemia/reperfusion under sevoflurane anesthesia resulted in drastic improvements in renal function. We hypothesized that underlying mechanism responsible for renal protection from sevoflurane pretreatment involves the upregulation of HIF-2α. Sevoflurane pretreatment were performed on WT and HIF-2α knockout mice before renal ischemia/reperfusion. Levels of blood urea nitrogen (BUN) and serum creatinine (Cr) were determined with a standard clinical automatic analyzer. The left kidneys were taken for morphological examination. Expression of HIF-2α in kidney tissue was examined by western blotting. In WT mice, group I/R injury had significantly higher BUN and Cr levels than group control, whereas group I/R + Sev had significantly lower BUN and Cr levels than group I/R injury. Renal HIF-2α expression levels were significantly higher in WT mice of group I/R + Sev than group control and group I/R. In HIF-2α-/- mice, group I/R + Sev showed much higher BUN and Cr levels and severer histological damage than group I/R and group control. Renal HIF-2α expression levels were significantly higher in WT mice of group I/R + Sev than group control and group I/R. Our findings suggested that HIF-2α might contribute to the beneficial effect of sevoflurane in renal ischemia/reperfusion injury. PMID:26722509

Diagnostic value of quantitative contrast-enhanced ultrasound (CEUS) for early detection of renal hyperperfusion in diabetic kidney disease.

PubMed

Wang, Ling; Wu, Jian; Cheng, Jia-Fen; Liu, Xin-Ying; Ma, Fang; Guo, Le-Hang; Xu, Jun-Mei; Wu, Tianfu; Mohan, Chandra; Peng, Ai; Xu, Hui-Xiong; Song, Ya-Xiang

2015-12-01

To investigate the diagnostic value of quantitative contrast-enhanced ultrasound (CEUS) for early detection of renal hyperperfusion in diabetic kidney disease (DKD). 55 DKD patients with estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and 26 normal controls (NCs) were enrolled. Clinical data was well documented. Blood samples were drawn for evaluation of renal function including blood urea nitrogen (BUN), serum creatinine (SCr) and serum uric acid (SUA), and urine samples were assayed for total protein quantification, and various microprotein markers. According to eGFR level, DKD patients were divided into early-stage DKD (eGFR ≥90 ml/min/1.73 m(2), n = 18) and middle-stage DKD (eGFR 30-90 ml/min/1.73 m(2), n = 37). Based on urinary microalbumin/creatinine ratio (MALB/UCR), early-stage DKD patients were further classified into two groups: MALB/UCR <10 g/mol (n = 11) and MALB/UCR ≥10 g/mol (n = 7). Then, CEUS was performed to observe the real-time renal perfusion, and low acoustic power contrast-specific imaging was used for quantitative analysis. The renal perfusion images of CEUS were well developed successively. The corresponding perfusion curves based on echo-power signals in time series were constructed. Quantitative analysis showed that area under the descending curve (AUC2) was significantly increased in early-stage DKD compared to middle-stage DKD (p < 0.05), but AUC showed no significant difference. Further comparison between different MALB/UCR levels of early-stage DKD showed that patients with MALB/UCR ≥10 g/mol had significantly increased levels of AUC, AUC2 and proteinuria than patients with low MALB/UCR (p < 0.05). Also, high MALB/UCR DKD patients had increased proteinuria but similar eGFR compared to low MALB/UCR patients. Renal microvascular hyperperfusion may be responsible for overt proteinuria until decline of renal filtration in DKD. AUC2 could be an early and sensitive marker for early renal injury and renal microvascular

Protective effect of agmatine on ischemia/reperfusion-induced renal injury in rats.

PubMed

Sugiura, Takahiro; Tsutsui, Hidenobu; Takaoka, Masanori; Kobuchi, Shuhei; Hayashi, Kentaro; Fujii, Toshihide; Matsumura, Yasuo

2008-03-01

Enhanced renal sympathetic nerve activity (RSNA) during ischemic period and the renal venous norepinephrine (NE) overflow after reperfusion play important roles in the development of ischemic/reperfusion (I/R)-induced acute renal failure (ARF) in rats. This study evaluated whether agmatine, which is known to reduce sympathetic nerve activity and NE overflow by electrical stimulation, would prevent the I/R-induced renal dysfunction. Ischemic ARF was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Intravenous (IV) injection of agmatine (100 and 300 micromol/kg) to ischemic ARF rats dose-dependently suppressed the enhanced RSNA and attenuated the I/R-induced renal dysfunction and histological damage. Intracerebroventricular (ICV) injection of agmatine (600 nmol/kg) to ischemic ARF rats suppressed the enhanced RSNA during the ischemic period and attenuated the I/R-induced renal injury. Furthermore, both IV and ICV injection of agmatine significantly suppressed the renal venous NE overflow after the reperfusion. These results indicate that agmatine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppression of the enhanced RSNA during ischemic period and NE overflow from renal sympathetic nerve endings.

NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats.

PubMed

Zhang, Ya-Li; Qiao, Shu-Kai; Wang, Rong-Ying; Guo, Xiao-Nan

2018-06-01

Ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI), and currently lacks effective therapies. This study is to investigate the level of Neutrophil gelatinase-associated lipocalin (NGAL) and autophagy status during renal I/R injury, so as to determine whether the exogenous NGAL protein could exert a protective effect for I/R injury and explore the potential mechanisms. Forty male Wistar rats were randomly divided into the following four groups: Sham, I/R, pre-treated with NGAL before I/R (I/R + pre-N), treated with NGAL after I/R (I/R + post-N). All rats were subjected to clamping the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. Serum creatinine (SCr) and blood urea nitrogen (BUN) were used for renal function, tubular cell apoptosis and autophagy were measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, histological examination and electron microscope, respectively. The tubular cell proliferation was assessed by the protein expression of proliferating cell nuclear antigen (PCNA). Western blotting was used to quantitate the levels of LC3, Beclin-1, Bcl-2 and Bax in kidney tissues. Exogenous NGAL protein intervention significantly improved renal function, reduced tubular cell apoptosis, increased tubular cell proliferation and promoted autophagy activation after renal I/R injury. Further, the efficacy in pre-N was significantly better than post-N. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Our study demonstrated that exogenous NGAL protein play a protective role during I/R injury, which may offer a novel may for prevention and treatment of renal I/R injury. Copyright © 2018. Published by Elsevier B.V.

ROLE OF THE RENAL MICROCIRCULATION IN PROGRESSION OF CHRONIC KIDNEY INJURY IN OBESITY

PubMed Central

Chade, Alejandro R.; Hall, John E.

2016-01-01

Background Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular, and renal disease. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity. Summary and Key message Microvascular disease plays a pivotal role in progressive kidney injury from different etiologies such as hypertension, diabetes, and atherosclerosis, which are all important consequences of chronic obesity. The microvascular networks are anatomical units that are closely adapted to specific functions of nutrition and removal of waste in every organ. Damage of the small vessels in several tissues and organs has been reported in obesity and may increase cardio-renal risk. However, the mechanisms by which obesity and its attendant cardiovascular and metabolic consequences interact to cause renal microvascular injury and chronic kidney disease are still unclear, although substantial progress has been made in recent years. This review addresses potential mechanisms and consequences of obesity-induced renal microvascular injury as well as current treatments that may provide protection of the renal microcirculation and slow progressive kidney injury in obesity. PMID:27771702

Histological, molecular and biochemical detection of renal injury after Echis pyramidum snake envenomation in rats

PubMed Central

Al-Johany, Awadh M.; Al-Sadoon, Mohamed K.; Abdel Moneim, Ahmed E.; Bauomy, Amira A.; Diab, Marwa S.M.

2014-01-01

Nephrotoxicity is a common sign of snake envenomation. The present work aimed to clarify the effect of intraperitoneal injection of 1/8 LD50 and 1/4 LD50 doses of Echis pyramidum snake venom on the renal tissue of rats after 2, 4 and 6 h from envenomation. Histopathological examination showed intense dose and time dependent abnormalities, including swelling glomerulus and tubular necrosis and damage as well as signs of intertubular medullary hemorrhage at early stages of envenomation. However, at late stages of envenomation by any of the doses under investigation, no intact renal corpuscles were recorded and complete lysis in renal corpuscles with ruptured Bowman’s capsules was observed. Immunohistochemistry by immunohistochemical staining was used to test the protein expression of Bax in renal tissue of rats. The result showed that the expression of Bax in renal tissue sections of envenomated rats was increased according to dose and time-dependant manner. The isolation of DNA from the renal cells of envenomed rats pointed out to the occurrence of DNA fragmentation, which is another indicator for renal tissue injury especially after 6 h of 1/4 LD50 of E. pyramidum envenomation. Oxidative stress biomarkers malondialdehyde and nitrite/nitrate levels, antioxidant parameters; glutathione, total antioxidant capacity and catalase were assayed in renal tissue homogenates. The venom induced significant increase in the levels of malondialdehyde and nitrite/nitrate while the levels of glutathione, total antioxidant capacity and catalase were significantly decreased, especially after 6 h of envenomation. The results revealed that the E. pyramidum induced dose and time-dependant significant disturbances in the physiological parameters in the kidney. We conclude that the use of the immunohistochemical techniques, the detection of DNA integrity and oxidative stress marker estimations are more specific tools that can clarify cellular injury and could point out to the defense

Histological, molecular and biochemical detection of renal injury after Echis pyramidum snake envenomation in rats.

PubMed

Al-Johany, Awadh M; Al-Sadoon, Mohamed K; Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa S M

2015-05-01

Nephrotoxicity is a common sign of snake envenomation. The present work aimed to clarify the effect of intraperitoneal injection of 1/8 LD50 and 1/4 LD50 doses of Echis pyramidum snake venom on the renal tissue of rats after 2, 4 and 6 h from envenomation. Histopathological examination showed intense dose and time dependent abnormalities, including swelling glomerulus and tubular necrosis and damage as well as signs of intertubular medullary hemorrhage at early stages of envenomation. However, at late stages of envenomation by any of the doses under investigation, no intact renal corpuscles were recorded and complete lysis in renal corpuscles with ruptured Bowman's capsules was observed. Immunohistochemistry by immunohistochemical staining was used to test the protein expression of Bax in renal tissue of rats. The result showed that the expression of Bax in renal tissue sections of envenomated rats was increased according to dose and time-dependant manner. The isolation of DNA from the renal cells of envenomed rats pointed out to the occurrence of DNA fragmentation, which is another indicator for renal tissue injury especially after 6 h of 1/4 LD50 of E. pyramidum envenomation. Oxidative stress biomarkers malondialdehyde and nitrite/nitrate levels, antioxidant parameters; glutathione, total antioxidant capacity and catalase were assayed in renal tissue homogenates. The venom induced significant increase in the levels of malondialdehyde and nitrite/nitrate while the levels of glutathione, total antioxidant capacity and catalase were significantly decreased, especially after 6 h of envenomation. The results revealed that the E. pyramidum induced dose and time-dependant significant disturbances in the physiological parameters in the kidney. We conclude that the use of the immunohistochemical techniques, the detection of DNA integrity and oxidative stress marker estimations are more specific tools that can clarify cellular injury and could point out to the defense

Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement.

PubMed

Gholampour, Hanieh; Moezi, Leila; Shafaroodi, Hamed

2017-10-15

Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-α and IL-1β were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1β and TNF-α were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury - probably through the involvement of nitric oxide. Copyright © 2017 Elsevier B.V. All rights reserved.

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

PubMed

Nishida, T; Hayashi, T; Inamoto, T; Kato, R; Ibuki, N; Takahara, K; Takai, T; Yoshikawa, Y; Uchimoto, T; Saito, K; Tanda, N; Kouno, J; Minami, K; Uehara, H; Hirano, H; Nomi, H; Okada, Y; Azuma, H

Hydrogen (H 2 ) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H 2 gas and CO gas (dual gas) in comparison with hydrogen gas (H 2 : 2%) alone on I-R renal injury (composition of dual gas; N 2 : 77.8%; O 2 : 20.9%; H 2 : 1.30%; CO: 250 parts per million). Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H 2 gas alone inhalation (H 2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H 2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Diannexin Protects against Renal Ischemia Reperfusion Injury and Targets Phosphatidylserines in Ischemic Tissue

PubMed Central

Wever, Kimberley E.; Wagener, Frank A. D. T. G.; Frielink, Cathelijne; Boerman, Otto C.; Scheffer, Gert J.; Allison, Anthony; Masereeuw, Rosalinde; Rongen, Gerard A.

2011-01-01

Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo. PMID:21918686

Mechanism of intracellular signal transduction during injury of renal tubular cells induced by postasphyxial serum in neonates with asphyxia.

PubMed

Zhao, Jin; Dong, Wen-Bin; Li, Peng-yun; Deng, Chun-liang

2009-01-01

Renal injury is a severe and extremely common complication that occurs early in neonates with asphyxia. Reperfusion injury has been suggested as the cause of kidney damage during resuscitation of neonatal asphyxia. Previous studies have demonstrated that postasphyxial serum from neonates with asphyxia may result in apoptosis of renal tubular cells. However, the mechanisms that mediate renal tubular cell apoptosis induced by postasphyxial serum remain poorly understood. In this report we investigate the intracellular signal transduction mechanisms that operate during injury of renal tubular cells induced by postasphyxial serum in neonates. Cultured human renal proximal tubular cells HK-2 cell were exposed to 10% fetal calf serum (normal control), 20% postasphyxial serum or 20% postasphyxial serum with pyrrolidine dithiocarbamate (PDTC). The expression of both BAD and BAX in the cytoplasm was detected by immunohistochemistry. The mitochondria membrane potential (Deltapsim) was examined by confocal microscopy, and the release of the apoptogenic mitochondrial proteins cytochrome C and AIF was assessed by Western blot analysis. Loss of mitochondria membrane potential was detected in HK-2 cells treated with 20% postasphyxial serum as compared to cells in normal serum or PTDC-pretreated cells in 20% postasphyxial serum. A significant increase of Bad and Bax protein expression was also detected, along with the release of cytochrome C and AIF from mitochondria to cytosol in the postasphyxial serum treated cells, but not in the normal or PTDC-pretreated control cells. Our findings suggest that postasphyxial serum may induce renal tubular cell apoptosis through the mitochondrial pathway, and its intracellular signal transduction mechanism includes the activation of nuclear factor-kappaB. Copyright 2009 S. Karger AG, Basel.

Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peters, Esther, E-mail: esther.peters@radboudumc.n

Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n = 18) were subjected to renal ischemia (30 min) and reperfusion (I/R), or sham-operated. In a second model, rats (n = 18) received a 30 minmore » infusion of lipopolysaccharide (LPS; 2.5 mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000 U/kg) was administered intravenously (15 min before reperfusion, or 90 min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial. - Highlights: • Human recombinant alkaline phosphatase (recAP) is a potential new therapy for sepsis-associated acute kidney injury (AKI). • RecAP can modulate renal oxygenation and hemodynamics immediately following I/R-induced AKI. • RecAP did not modulate endotoxemia-induced changes in systemic hemodynamics and renal oxygenation. • RecAP did exert a clear renal

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

PubMed

Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

Tisp40 deficiency attenuates renal ischemia reperfusion injury induced apoptosis of tubular epithelial cells.

PubMed

Qin, Cong; Xiao, Chengcheng; Su, Yang; Zheng, Haizhou; Xu, Tao; Lu, Jingxiao; Luo, Pengcheng; Zhang, Jie

2017-10-01

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury (AKI) and no effective treatments have been established. Tisp40 is a transcription factor of the CREB/ATF family and involves in cell apoptosis, proliferation and differentiation, but its role in renal IR remains unknown. Here, we investigated the role of Tisp40 in renal IR injury. In vivo, Tisp40 knockout (KO) and wild-type (WT) mice were subjected to thirty minutes of bilateral renal ischemia and 48h reperfusion, the blood and kidneys were harvested for analysis. In vitro, Tisp40 overexpression and vector cells were subjected to hypoxia/reoxygenation (HR), the apoptosis rate and the expressions of related proteins were measured. Following IR, the expressions of Tisp40 protein, serum creatinine (sCr), blood urea nitrogen (BUN) and apoptosis of tubular cells were significantly increased in WT mice. However, Tisp40 deficiency significantly attenuated the increase of sCr, BUN and apoptosis of tubular cells. Following HR, apoptosis of tubular cells was increased in Tisp40 overexpression cells compared with vector cells. Mechanistically, Tisp40 promoted the expressions of C/EBP homologous protein (CHOP), Bax and Cleaved caspase3 and suppressed the expression of Bcl-2 in renal IR injury. In conclusion, Tisp40 aggravates tubular cells apoptosis in renal IR injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Renal injury in neonates: use of "omics" for developing precision medicine in neonatology.

PubMed

Joshi, Mandar S; Montgomery, Kelsey A; Giannone, Peter J; Bauer, John A; Hanna, Mina H

2017-01-01

Preterm birth is associated with increased risks of morbidity and mortality along with increased healthcare costs. Advances in medicine have enhanced survival for preterm infants but the overall incidence of major morbidities has changed very little. Abnormal renal development is an important consequence of premature birth. Acute kidney injury (AKI) in the neonatal period is multifactorial and may increase lifetime risk of chronic kidney disease.Traditional biomarkers in newborns suffer from considerable confounders, limiting their use for early identification of AKI. There is a need to develop novel biomarkers that can identify, in real time, the evolution of renal dysfunction in an early diagnostic, monitoring and prognostic fashion. Use of "omics", particularly metabolomics, may provide valuable information regarding functional pathways underlying AKI and prediction of clinical outcomes.The emerging knowledge generated by the application of "omics" (genomics, proteomics, metabolomics) in neonatology provides new insights that can help to identify markers of early diagnosis, disease progression, and identify new therapeutic targets. Additionally, omics will have major implications in the field of personalized healthcare in the future. Here, we will review the current knowledge of different omics technologies in neonatal-perinatal medicine including biomarker discovery, defining as yet unrecognized biologic therapeutic targets, and linking of omics to relevant standard indices and long-term outcomes.

Successful renal transplantation from a brain-dead deceased donor with head injury, disseminated intravascular coagulation and deranged renal functions.

PubMed

Ghuge, P P; Kute, V B; Vanikar, A V; Gumber, M R; Gera, D N; Patel, H V; Shah, P R; Modi, P R; Shah, V R; Trivedi, H L

2013-11-01

Deceased donors (DDs) with the brain death due to head injury are the major source of organs for transplantation. The incidence of post-head injury disseminated intravascular coagulation (DIC) ranges from 24% to 50%. Many centers do not accept organs from donors with DIC due to increased risk of primary graft non-function and/or high chances of morbidity/mortality. We performed two successful renal transplants from a DD with head injury with DIC and deranged renal function. One of the recipients developed transient thrombocytopenia, but there was no evidence of DIC or delayed graft functions in either of the recipients. Over a follow-up of 1 month, both are doing well with stable graft function and hematological profile. Thus, a carefully selected DD with severe DIC even with deranged renal function is not a contraindication for organ donation if other risk factors for primary non-function are excluded. This approach will also help in overcoming organ shortage.

Detection and Evaluation of Renal Injury in Burst Wave Lithotripsy Using Ultrasound and Magnetic Resonance Imaging.

PubMed

May, Philip C; Kreider, Wayne; Maxwell, Adam D; Wang, Yak-Nam; Cunitz, Bryan W; Blomgren, Philip M; Johnson, Cynthia D; Park, Joshua S H; Bailey, Michael R; Lee, Donghoon; Harper, Jonathan D; Sorensen, Mathew D

2017-08-01

Burst wave lithotripsy (BWL) is a transcutaneous technique with potential to safely and effectively fragment renal stones. Preclinical investigations of BWL require the assessment of potential renal injury. This study evaluates the capabilities of real-time ultrasound and MRI to detect and evaluate BWL injury that was induced in porcine kidneys. Ten kidneys from five female farm pigs were treated with either a 170 or 335 kHz BWL transducer using variable treatment parameters and monitored in real-time with ultrasound. Eight kidneys were perfusion fixed and scanned with a 3-Tesla MRI scanner (T1-weighted, T2-weighted, and susceptibility-weighted imaging), followed by processing via an established histomorphometric technique for injury quantification. In addition, two kidneys were separately evaluated for histologic characterization of injury quality. Observed B-mode hyperechoes on ultrasound consistent with cavitation predicted the presence of BWL-induced renal injury with a sensitivity and specificity of 100% in comparison to the histomorphometric technique. Similarly, MRI detected renal injury with a sensitivity of 90% and specificity of 100% and was able to identify the scale of lesion volumes. The injuries purposefully generated with BWL were histologically similar to those formed by shock wave lithotripsy. BWL-induced renal injury can be detected with a high degree of sensitivity and specificity by real-time ultrasound and post-treatment ex vivo MRI. No injury occurred in this study without cavitation detected on ultrasound. Such capabilities for injury detection and lesion volume quantification on MRI can be used for preclinical testing of BWL.

Surrogate markers of subtle renal injury in patients with visceral leishmaniasis.

PubMed

Elnojomi, N A A; Musa, A M; Younis, B M; Elfaki, M E E; El-Hassan, A M; Khalil, E A G

2010-09-01

Sudanese visceral leishmaniasis (VL) is a disease of children that is characterized by fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, and renal injury. Microalbuminuria (MA) and urinary retinol binding protein (urRBP) are useful markers for glomerular and tubular dysfunctions, respectively. We report the prevalence of subtle renal injury in 88 parasitologically confirmed VL patients in a cross-sectional and hospital-based study. Blood and urine were collected before treatment for hematological, biochemical profiles in addition to MA and urRBP measurement using competitive solid phase, sandwich enzyme-linked immune sorbent assay (ELISA), and immunoturbidometry. All the patients had normal serum urea and creatinine levels and no detectable urRBP. However, 40% of the patients had MA detected by ELISA, and 42% were reactive with turbidometry. The sensitivity, specificity, positive and negative predictive values for MA turbidometric technique were calculated as 100%; 96%; 95% and 100%, respectively. In conclusion; subtle renal injury in VL is mainly glomerular. Turbidometry for MA measurement is a simple, inexpensive, sensitive, and specific technique with high predictive values.

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

PubMed Central

Fakhruddin, Selim; Alanazi, Wael

2017-01-01

Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure. PMID:28164134

The Impact of Seat belts and Airbags on High Grade Renal Injuries and Nephrectomy Rates in Motor Vehicle Collisions

PubMed Central

Bjurlin, Marc A; Fantus, Richard J.; Mellett, Michele M.; Fantus, Richard J.; Villines, Dana

2015-01-01

Purpose Motor vehicle collisions (MVCs) are the most common cause of blunt genitourinary trauma. We compared renal injuries with no protective device to those with seat belts and/or airbags utilizing the National Trauma Data Bank (NTDB). Our primary endpoint was a reduction in high-grade renal injuries (grades III-V) with a secondary endpoint of reduction in nephrectomy rate. Materials and Methods The NTDB research datasets, admission year 2010, 2011, and 2012, were queried for MVC occupants with renal injury. Subjects were stratified by protective device and airbag deployment. Abbreviated Injury Score was converted to American Association for the Surgery of Trauma renal injury grade and nephrectomy rates were evaluated. Intergroup comparisons were analyzed for renal injury grades, nephrectomy, length of stay, and mortality with chi-square or one-way ANOVA. Protective device relative risk reduction was determined. Results A review of 466,028 MVCs revealed 3,846 renal injuries. Injured occupants without a protective device had a higher rate of high grade renal injury (45.1%) compared to those with seat belts (39.9%, p=0.008), airbags (42.3%, p=0.317), and seat belts with airbags (34.7%, p<0.001). Seat belts (20.0%, p<0.001), airbags (10.5% p<0.001), and seat belts with airbags (13.3%, p<0.001) reduced the rate of nephrectomy compared to no protective device (56.2%). The combination of seatbelts and airbags also reduced total hospital length of stay (p<0.001) and ICU days (p=0.005). Relative risk reduction of high-grade renal injuries (23.1%) and nephrectomy (39.9%) were highest for combined protective devices. Conclusions Occupants of MVCs with protective devices have reduced rates of high-grade renal injury and nephrectomy. Reduction appears most pronounced with the combination of seat belts and airbags. PMID:24846798

Maternal diet during gestation and lactation modifies the severity of salt-induced hypertension and renal injury in Dahl salt-sensitive rats.

PubMed

Geurts, Aron M; Mattson, David L; Liu, Pengyuan; Cabacungan, Erwin; Skelton, Meredith M; Kurth, Theresa M; Yang, Chun; Endres, Bradley T; Klotz, Jason; Liang, Mingyu; Cowley, Allen W

2015-02-01

Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116±9 versus 154±25 mm Hg; urinary albumin excretion, 23±12 versus 170±80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational-lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats. © 2014 American Heart Association, Inc.

Low molecular weight fucoidan protects renal tubular cells from injury induced by albumin overload.

PubMed

Jia, Yingli; Sun, Yi; Weng, Lin; Li, Yingjie; Zhang, Quanbin; Zhou, Hong; Yang, Baoxue

2016-08-22

Albuminuria is a causative and aggravating factor for progressive renal damage in chronic kidney disease (CKD). The aim of this study was to determine if low molecular weight fucoidan (LMWF) could protect renal function and tubular cells from albumin overload caused injury. Treatment with 10 mg/g bovine serum albumin caused renal dysfunction, morphological changes, and overexpression of inflammation and fibrosis associated proteins in 129S2/Sv mice. LMWF (100 mg/kg) protected against kidney injury and renal dysfunction with decreased blood creatinine by 34% and urea nitrogen by 25%, increased creatinine clearance by 48%, and decreased significantly urinary albumin concentration. In vitro proximal tubule epithelial cell (NRK-52E) model showed that LMWF dose-dependently inhibited overexpression of proinflammatory and profibrotic factors, oxidative stress and apoptosis caused by albumin overload. These experimental results indicate that LMWF protects against albumin overload caused renal injury by inhibiting inflammation, fibrosis, oxidative stress and apoptosis, which suggests that LMWF could be a promising candidate drug for preventing CKD.

Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury

PubMed Central

Pollen, Sean; Greco, Elisabetta; Courtneidge, Holly; Hall, Andrew M.; Duchen, Michael R.; Tam, Frederick W. K.; Unwin, Robert J.; Singer, Mervyn

2018-01-01

Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism. PMID:29293148

Acute Pretreatment with Chloroquine Attenuates Renal I/R Injury in Rats

PubMed Central

Todorovic, Zoran; Medic, Branislava; Basta-Jovanovic, Gordana; Radojevic Skodric, Sanja; Stojanovic, Radan; Rovcanin, Branislav; Prostran, Milica

2014-01-01

Background Acute kidney injury (AKI) still remains an unresolved problem in pharmacotherapy and renal inflammation is a major factor in its development. Chloroquine, a well-known antimalarial drug, posses pleitropic effects as well: antiinflammatory, anticoagulant and vascular actions. The effects of chloroquine on renal function may involve significant increase in urine flow rate, glomerular filtration rate and sodium excretion, as well as stimulation of nitric oxide synthase. However, its role in experimental models of renal I/R injury is unknown. We aimed to analyze the acute effects of a single-dose intravenous chloroquine administered at three different times in the experimental model of I/R injury in rat. Methods Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion with saline lasting 4 hours. Chloroquine was administered in doses of 0.3 mg/kg i.v. and 3 mg/kg i.v. 30 min before ischemia, 30 min before reperfusion and 5 min before reperfusion. Selected a hemodynamic, biochemical and morphological parameters were followed in the Sham-operated animals and rats subjected to I/R injury and pretreated with saline or chloroquine. Results Chloroquine (0.3 and 3 mg/kg, i.v.) protected the I/R injured kidney in an U-shaped manner. Both doses were protective regarding biochemical and histological markers of the I/R injury (serum urea, creatinine and fractional excretion of sodium, as well as total histological score, tubular necrosis score and KIM-1 staining score) (P<0.05 vs. corresponding controls, i.e. rats subjected to I/R injury and treated with saline only). The protective effects of the lower dose of chloroquine were more profound. Time-related differences between pretreatments were not observed (P>0.05, all). Conclusion Our study shows for the first time that a single dose of chloroquine (0.3 mg/kg i.v.) could afford significant protection of the injured rat kidney. PMID:24681567

Influence of Acute Kidney Injury Defined by the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease Score on the Clinical Course of PICU Patients.

PubMed

Cabral, Felipe Cezar; Ramos Garcia, Pedro Celiny; Mattiello, Rita; Dresser, Daiane; Fiori, Humberto Holmer; Korb, Cecilia; Dalcin, Tiago Chagas; Piva, Jefferson Pedro

2015-10-01

To evaluate the predictive value of the pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease criteria for disease course severity in patients with or without acute kidney injury admitted to a PICU. Retrospective cohort study. A 12-bed PICU at a tertiary referral center in Southern Brazil. All patients admitted to the study unit over a 1-year period. A database of all eligible patients was analyzed retrospectively. Patients were classified by pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease score at admission and worst pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease score during PICU hospitalization. The outcomes of interest were length of PICU stay, duration of mechanical ventilation, duration of vasoactive drug therapy, and mortality. The Pediatric Index of Mortality 2 was used to assess overall disease severity at the time of PICU admission. Of 375 patients, 169 (45%) presented acute kidney injury at the time of admission and 37 developed acute kidney injury during PICU stay, for a total of 206 of 375 patients (55%) diagnosed with acute kidney injury during the study period. The median Pediatric Index of Mortality 2 score predicted a mortality rate of 9% among non-acute kidney injury patients versus a mortality rate of 16% among acute kidney injury patients (p = 0.006). The mortality of patients classified as pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease F was double that predicted by Pediatric Index of Mortality 2 (7 vs 3.2). Patients classified as having severe acute kidney injury (pediatric-modified Risk, Injury, Failure, Loss, End-stage renal disease I + F) exhibited higher mortality (14.1%; p = 0.001) and prolonged PICU length of stay (median, 7 d; p = 0.001) when compared with other patients. Acute kidney injury is a very frequent occurrence among patients admitted to PICUs. The degree of acute kidney injury severity, as assessed by the pediatric-modified Risk

Xenon Preconditioning Protects against Renal Ischemic-Reperfusion Injury via HIF-1α Activation

PubMed Central

Ma, Daqing; Lim, Ta; Xu, Jing; Tang, Haidy; Wan, Yanjie; Zhao, Hailin; Hossain, Mahmuda; Maxwell, Patrick H.; Maze, Mervyn

2009-01-01

The mortality rate from acute kidney injury after major cardiovascular operations can be as high as 60%, and no therapies have been proved to prevent acute kidney injury in this setting. Here, we show that preconditioning with the anesthetic gas xenon activates hypoxia-inducible factor 1α (HIF-1α) and its downstream effectors erythropoietin and vascular endothelial growth factor in a time-dependent manner in the kidneys of adult mice. Xenon increased the efficiency of HIF-1α translation via modulation of the mammalian target of rapamycin pathway. In a model of renal ischemia-reperfusion injury, xenon provided morphologic and functional renoprotection; hydrodynamic injection of HIF-1α small interfering RNA demonstrated that this protection is HIF-1α dependent. These results suggest that xenon preconditioning is a natural inducer of HIF-1α and that administration of xenon before renal ischemia can prevent acute renal failure. If these data are confirmed in the clinical setting, then preconditioning with xenon may be beneficial before procedures that temporarily interrupt renal perfusion. PMID:19144758

Severe hypertriglyceridemia and hypercholesterolemia accelerating renal injury: a novel model of type 1 diabetic hamsters induced by short-term high-fat / high-cholesterol diet and low-dose streptozotocin.

PubMed

He, Liang; Hao, Lili; Fu, Xin; Huang, Mingshu; Li, Rui

2015-04-11

Hyperlipidemia is thought to be a major risk factor for the progression of renal diseases in diabetes. Recent studies have shown that lipid profiles are commonly abnormal early on type 2 diabetes mellitus (T2DM) with diabetic nephropathy. However, the early effects of triglyceride and cholesterol abnormalities on renal injury in type 1 diabetes mellitus (T1DM) are not fully understood and require reliable animal models for exploration of the underlying mechanisms. Hamster models are important tools for studying lipid metabolism because of their similarity to humans in terms of lipid utilization and high susceptibility to dietary cholesterol and fat. Twenty-four male Golden Syrian hamsters (100-110 g) were rendered diabetes by intraperitoneal injections of streptozotocin (STZ) on consecutive 3 days at dose of 30 mg/kg, Ten days after STZ injections, hamsters with a plasma Glu concentration more than 12 mmol/L were selected as insulin deficient ones and divided into four groups (D-C, D-HF, D-HC, and D-HFHC), and fed with commercially available standard rodent chow, high-fat diet, high-cholesterol diet, high-fat and cholesterol diet respectively, for a period of four weeks. After an induction phase, a stable model of renal injury was established with the aspects of early T1DM kidney disease, These aspects were severe hypertriglyceridemia, hypercholesterolemia, proteinuria with mesangial matrix accumulation, upgraded creatinine clearance, significant cholesterol and triglyceride deposition, and increasing glomerular surface area, thickness of basement membrane and mesangial expansion. The mRNA levels of sterol regulatory element binding protein-1c, transforming growth factors-β, plasminogen activator inhibitor-1, tumor necrosis factor-α and interleukin-6 in the D-HFHC group were significantly up-regulated compared with control groups. This study presents a novel, non-transgenic, non-surgical method for induction of renal injury in hamsters, which is an important

DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells.

PubMed

Ma, Zhengwei; Wei, Qingqing; Dong, Guie; Huo, Yuqing; Dong, Zheng

2014-07-01

Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or "reperfusion" of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death. Copyright © 2014 Elsevier B.V. All rights reserved.

DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells

PubMed Central

Ma, Zhengwei; Wei, Qingqing; Dong, Guie; Huo, Yuqing; Dong, Zheng

2014-01-01

Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or “reperfusion” of renal proximal tubular cells (RPTCs) after ATP-depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP-depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death. PMID:24726884

ERK phosphorylation plays an important role in the protection afforded by hypothermia against renal ischemia-reperfusion injury.

PubMed

Choi, Dae Eun; Jeong, Jin Young; Choi, Hyunsu; Chang, Yoon Kyung; Ahn, Moon Sang; Ham, Young Rok; Na, Ki Ryang; Lee, Kang Wook

2017-02-01

Although hypothermia attenuates the renal injury induced by ischemia-reperfusion, the detailed molecular pathway(s) involved remains unknown. ERK phosphorylation is known to protect against ischemia-reperfusion injury. Also, it has been reported that hypothermia may induce ERK phosphorylation in the heart and brain. We evaluated the role played by ERK in hypothermic protection against renal ischemia-reperfusion injury. C57Bl/6 mice were divided into the following groups: sham-operated (cold, 32°C) vs normal temperature (37°C); ischemia-reperfusion mice (32°C vs 37°C); and PD98059- or vehicle-treated ischemia-reperfusion mice (32°C). Kidneys were harvested 10 and 27 minutes after induction of renal ischemia and 24 hours after ischemia-reperfusion injury. Functional and molecular markers of kidney injury were evaluated. To explore the molecular mechanism involved the expression levels of renal HIF-1 and associated proteins were evaluated. The blood urea nitrogen (BUN) and serum creatinine (s-Cr) levels and the histologic renal injury scores were significantly lower in 32°C ischemia-reperfusion than 37°C ischemia-reperfusion kidneys (all P values < .05). The expression levels of Bax and caspase-3 and the extent of TUNEL and 8-OHdG cell positivity decreased, whereas the renal Bcl-2 level increased, in 32°C ischemia-reperfusion compared to 37°C ischemia-reperfusion mice. The extent of renal ERK phosphorylation was significantly higher in ischemia-reperfusion than sham-operated kidneys. Also, ERK phosphorylation was significantly increased in the kidneys of 32°C compared to 37°C ischemia-reperfusion mice. PD98059 treatment of 32°C ischemia-reperfusion mice significantly decreased the renal HIF-1 level (P < .05) and increased the BUN, s-Cr, renal Bax, and caspase-3 expression levels; the tissue injury score; and the proportions of TUNEL- and 8-OHdG-positive cells. PD98059 also increased the renal Bcl-2 level in such mice. Hypothermia attenuates the renal

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

PubMed

Rong, Song; Hueper, Katja; Kirsch, Torsten; Greite, Robert; Klemann, Christian; Mengel, Michael; Meier, Matthias; Menne, Jan; Leitges, Michael; Susnik, Nathan; Meier, Martin; Haller, Hermann; Shushakova, Nelli; Gueler, Faikah

2014-09-15

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H(2b) PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H(2d) recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI. Copyright © 2014 the American Physiological Society.

Regional traumatic limb hypothermia attenuates distant hepatic and renal injury following blast limb trauma in rats.

PubMed

Zhao, Hongzhi; Ning, Jiaolin; Duan, Jiaxiang; Gu, Jianteng; Yi, Bin; Lu, Kaizhi; Mo, Liwen; Lai, Xinan; Hennah, Lindsay; Ma, Daqing

2014-09-01

Blast limb injury was reported to result in distant organ injury including the lungs, which can be attenuated with transient regional hypothermia (RH) to the injured limb. We aimed to further study hepatic and renal injuries following blast limb trauma and also to evaluate the protective effects of regional traumatic limb hypothermia on such injuries in rats. Blast limb trauma (BLT) was created using chartaceous electricity detonators in anesthetized male Sprague-Dawley rats. The BLT rats were randomly allocated to undergo regional traumatic limb hypothermic treatment (RH) for 30 minutes, 60 minutes, or 6 hours immediately after the onset of blast or without RH (n = 8 per group). The severity of hepatic and renal injury was assessed through histologic examination and water content (wet/dry weight) in all animals 6 hours later. The level of plasma tumor necrosis factor α (TNF-α), interleukin 6, hydrogen sulfide (H2S), and myeloperoxidase (MPO) together with hepatic and renal MPO, malondialdehyde (MDA), superoxide dismutase, and total antioxidant capacity were measured 6 hours after the blast injury. Following BLT, hepatic injury was evidenced by histopathologic changes, increased water content, as well as plasma alanine aminotransferase and aspartate aminotransferase. Renal histopathologic but not functional changes were also found. RH treatment for all durations attenuated this distant renal injury, but only RH treatment for 60 minutes and 6 hours attenuated distant hepatic injury following BLT. RH treatment for all durations decreased plasma TNF-α and interleukin 6, reduced liver and kidney MPO activity and kidney MDA, and elevated superoxide dismutase and total antioxidant capacity in both liver and kidneys. RH treatment for 60 minutes is the most effective duration to reduce hepatic MPO activity, plasma TNF-α, and kidney MDA. This study indicates that BLT-induced distant renal and hepatic injury could be attenuated by RH treatment through reduction of

Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease.

PubMed

Kelsen, Silvia; Hall, John E; Chade, Alejandro R

2011-07-01

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.

Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease

PubMed Central

Kelsen, Silvia; Hall, John E.

2011-01-01

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg−1·day−1) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD. PMID:21478482

The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury

PubMed Central

Kim, Mihwa; Ham, Ahrom; Kim, Joo Yun; Brown, Kevin M.; D’Agati, Vivette D.; Lee, H. Thomas

2013-01-01

The volatile anesthetic isoflurane protects against renal ischemia and reperfusion injury by releasing renal tubular TGF-β1. Since adenosine is a powerful cytoprotective molecule, we tested whether TGF-β1 generated by isoflurane induces renal tubular ecto-5′-nucleotidase (CD73) and adenosine to protect against renal ischemia and reperfusion injury. Isoflurane induced new CD73 synthesis and increased adenosine generation in cultured kidney proximal tubule cells and in mouse kidney. Moreover, a TGF-β1 neutralizing antibody prevented isoflurane-mediated induction of CD73 activity. Mice anesthetized with isoflurane after renal ischemia and reperfusion had significantly reduced plasma creatinine and decreased renal tubular necrosis, neutrophil infiltration and apoptosis compared to pentobarbital-anesthetized mice. Isoflurane failed to protect against renal ischemia and reperfusion injury in CD73 deficient mice, in mice pretreated with a selective CD73 inhibitor or mice treated with an adenosine receptor antagonist. The TGF-β1 neutralizing antibody or the CD73 inhibitor attenuated isoflurane-mediated protection against HK-2 cell apoptosis. Thus, isoflurane causes TGF-β1-dependent induction of renal tubular CD73 and adenosine generation to protect against renal ischemia and reperfusion injury. Modulation of this pathway may have important therapeutic implications to reduce morbidity and mortality arising from ischemic acute kidney injury. PMID:23423261

Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

PubMed Central

Maicas, Nuria; van der Vlag, Johan; Bublitz, Janin; Florquin, Sandrine; Bakker-van Bebber, Marinka; Dinarello, Charles A.; Verweij, Vivienne; Masereeuw, Roos; Joosten, Leo A.

2017-01-01

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions. PMID:28235038

Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury.

PubMed

Peters, Esther; Ergin, Bülent; Kandil, Asli; Gurel-Gurevin, Ebru; van Elsas, Andrea; Masereeuw, Rosalinde; Pickkers, Peter; Ince, Can

2016-12-15

Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial. Copyright © 2016. Published by Elsevier Inc.

Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation.

PubMed

Prowle, John R; Molan, Maurice P; Hornsey, Emma; Bellomo, Rinaldo

2012-06-01

In septic patients, decreased renal perfusion is considered to play a major role in the pathogenesis of acute kidney injury. However, the accurate measurement of renal blood flow in such patients is problematic and invasive. We sought to overcome such obstacles by measuring renal blood flow in septic patients with acute kidney injury using cine phase-contrast magnetic resonance imaging. Pilot observational study. University-affiliated general adult intensive care unit. Ten adult patients with established septic acute kidney injury and 11 normal volunteers. Cine phase-contrast magnetic resonance imaging measurement of renal blood flow and cardiac output. The median age of the study patients was 62.5 yrs and eight were male. At the time of magnetic resonance imaging, eight patients were mechanically ventilated, nine were on continuous hemofiltration, and five required vasopressors. Cine phase-contrast magnetic resonance imaging examinations were carried out without complication. Median renal blood flow was 482 mL/min (range 335-1137) in septic acute kidney injury and 1260 mL/min (range 791-1750) in healthy controls (p = .003). Renal blood flow indexed to body surface area was 244 mL/min/m2 (range 165-662) in septic acute kidney injury and 525 mL/min/m2 (range 438-869) in controls (p = .004). In patients with septic acute kidney injury, median cardiac index was 3.5 L/min/m2 (range 1.6-8.7), and median renal fraction of cardiac output was only 7.1% (range 4.4-10.8). There was no rank correlation between renal blood flow index and creatinine clearance in patients with septic acute kidney injury (r = .26, p = .45). Cine phase-contrast magnetic resonance imaging can be used to noninvasively and safely assess renal perfusion during critical illness in man. Near-simultaneous accurate measurement of cardiac output enables organ blood flow to be assessed in the context of the global circulation. Renal blood flow seems consistently reduced as a fraction of cardiac output in

Oxidized phosphatidylcholines are produced in renal ischemia reperfusion injury

PubMed Central

Solati, Zahra; Edel, Andrea L.; Shang, Yue; O, Karmin

2018-01-01

Background The aim of this study was to determine the individual oxidized phosphatidylcholine (OxPC) molecules generated during renal ischemia/ reperfusion (I/R) injury. Methods Kidney ischemia was induced in male Sprague–Dawley rats by clamping the left renal pedicle for 45 min followed by reperfusion for either 6h or 24h. Kidney tissue was subjected to lipid extraction. Phospholipids and OxPC species were identified and quantitated using liquid chromatography coupled to electrospray ionization tandem mass spectrometry using internal standards. Result We identified fifty-five distinct OxPC in rat kidney following I/R injury. These included a variety of fragmented (aldehyde and carboxylic acid containing species) and non-fragmented products. 1-stearoyl-2-linoleoyl-phosphatidylcholine (SLPC-OH), which is a non-fragmented OxPC and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), which is a fragmented OxPC, were the most abundant OxPC species after 6h and 24 h I/R respectively. Total fragmented aldehyde OxPC were significantly higher in 6h and 24h I/R groups compared to sham operated groups (P = 0.03, 0.001 respectively). Moreover, levels of aldehyde OxPC at 24h I/R were significantly greater than those in 6h I/R (P = 0.007). Fragmented carboxylic acid increased significantly in 24h I/R group compared with sham and 6h I/R groups (P = 0.001, 0.001). Moreover, levels of fragmented OxPC were significantly correlated with creatinine levels (r = 0.885, P = 0.001). Among non-fragmented OxPC, only isoprostanes were elevated significantly in 6h I/R group compared with sham group but not in 24h I/R group (P = 0.01). No significant changes were observed in other non-fragmented OxPC including long chain products and terminal furans. Conclusion We have shown for the first time that bioactive OxPC species are produced in renal I/R and their levels increase with increasing time of reperfusion in a kidney model of I/R and correlate with severity of I/R injury. Given the

The impact of seat belts and airbags on high grade renal injuries and nephrectomy rate in motor vehicle collisions.

PubMed

Bjurlin, Marc A; Fantus, Richard Jacob; Fantus, Richard Joseph; Mellett, Michele M; Villines, Dana

2014-10-01

Motor vehicle collisions are the most common cause of blunt genitourinary trauma. We compared renal injuries with no protective device to those with seat belts and/or airbags using NTDB. Our primary end point was a decrease in high grade (grades III-V) renal injuries with a secondary end point of a nephrectomy rate reduction. The NTDB research data sets for hospital admission years 2010, 2011 and 2012 were queried for motor vehicle collision occupants with renal injury. Subjects were stratified by protective device and airbag deployment. The AIS was converted to AAST renal injury grade and nephrectomy rates were evaluated. Intergroup comparisons were analyzed for renal injury grades, nephrectomy, length of stay and mortality using the chi-square test or 1-way ANOVA. The relative risk reduction of protective devices was determined. A review of 466,028 motor vehicle collisions revealed a total of 3,846 renal injuries. Injured occupants without a protective device had a higher rate of high grade renal injuries (45.1%) than those with seat belts (39.9%, p = 0.008), airbags (42.3%, p = 0.317) and seat belts plus airbags (34.7%, p <0.001). Seat belts (20.0%), airbags (10.5%) and seat belts plus airbags (13.3%, each p <0.001) decreased the nephrectomy rate compared to no protective device (56.2%). The combination of seatbelts and airbags also decreased total hospital length of stay (p <0.001) and intensive care unit days (p = 0.005). The relative risk reductions of high grade renal injuries (23.1%) and nephrectomy (39.9%) were highest for combined protective devices. Occupants of motor vehicle collisions with protective devices show decreased rates of high grade renal injury and nephrectomy. Reduction appears most pronounced with the combination of seat belts and airbags. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney.

PubMed

Duan, Xiaolu; Kong, Zhenzhen; Mai, Xin; Lan, Yu; Liu, Yang; Yang, Zhou; Zhao, Zhijian; Deng, Tuo; Zeng, Tao; Cai, Chao; Li, Shujue; Zhong, Wen; Wu, Wenqi; Zeng, Guohua

2018-06-01

Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time. Copyright © 2018. Published by Elsevier B.V.

Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity

PubMed Central

Leonard, Ellen C.; Beal, Alisa G.; Schleuter, Devin; Friedrich, Jessica

2012-01-01

ANG II is a potent renal vasoconstrictor and profibrotic factor and its activity is enhanced by oxidative stress. We sought to determine whether renal oxidative stress was persistent following recovery from acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) injury in rats and whether this resulted in increased ANG II sensitivity. Rats were allowed to recover from bilateral renal I/R injury for 5 wk and renal blood flow responses were measured. Post-AKI rats showed significantly enhanced renal vasoconstrictor responses to ANG II relative to sham-operated controls and treatment of AKI rats with apocynin (15 mM, in the drinking water) normalized these responses. Recovery from AKI for 5 wk resulted in sustained oxidant stress as indicated by increased dihydroethidium incorporation in renal tissue slices and was normalized in apocynin-treated rats. Surprisingly, the renal mRNA expression for common NADPH oxidase subunits was not altered in kidneys following recovery from AKI; however, mRNA screening using PCR arrays suggested that post-AKI rats had decreased renal Gpx3 mRNA and an increased expression other prooxidant genes such as lactoperoxidase, myeloperoxidase, and dual oxidase-1. When rats were infused for 7 days with ANG II (100 ng·kg−1·min−1), renal fibrosis was not apparent in sham-operated control rats, but it was enhanced in post-AKI rats. The profibrotic response was significantly attenuated in rats treated with apocynin. These data suggest that there is sustained renal oxidant stress following recovery from AKI that alters both renal hemodynamic and fibrotic responses to ANG II, and may contribute to the transition to chronic kidney disease following AKI. PMID:22442209

Incidence and management of penetrating renal trauma in patients with multiorgan injury: extended experience at an inner city trauma center.

PubMed

Kansas, Bryan T; Eddy, Michael J; Mydlo, Jack H; Uzzo, Robert G

2004-10-01

Patients with penetrating trauma often have multiorgan involvement that may complicate the management of any single organ system. Here we review the incidence of associated injuries in patients with penetrating renal trauma and our extended experience treating these patients at a busy inner city trauma center. All trauma cases presenting to Temple University Trauma Center during a 6-year period were identified through our institutional databases and were reviewed (5,276). Penetrating trauma represented 41% of all cases (2,163). Of these we identified 123 patients with penetrating renal trauma (5.7%). A total of 93 cases were available for review. Multiorgan injury was staged in the operating room if patients were hemodynamically unstable or radiographically if they were stable. Renal injuries were staged by high dose, single shot excretory urogram in patients taken immediately to surgery or by computerized tomography if stable. Renal injuries were classified using the American Association for Surgery of Trauma (AAST) grading system. AAST classifications were subcategorized for purposes of streamlining. Grade 1 and 2 injuries were grouped as low grade, grades 3 and 4 nonvascular injuries were grouped as intermediate grade, and AAST grade 4 vascular and grade 5 injuries were grouped as high grade. Demographic, clinical and intraoperative variables, as well as number and severity of associated injuries, were then assessed to determine the relationship with various renal surgical outcomes including the requirement of surgical intervention, type of surgical intervention, need for nephrectomy and associated adverse outcomes. The median age of injured patients was 28 years (range 14 to 80). The majority of victims were male (93%). The mechanism of injury was predominantly gunshot wound (GSW, 86%) while 14% were due to stab wounds. Renal injuries were low grade (19%), intermediate grade (44%) and high grade (37%). Nearly all patients with penetrating renal injury had

Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion

PubMed Central

Zhou, Xiaoxu; Liu, Lirong; Masucci, Monica V.; Tang, Jinhua; Li, Xuezhu; Liu, Na; Bayliss, George; Zhao, Ting C.; Zhuang, Shougang

2017-01-01

Activation of Src kinase has been implicated in the pathogenesis of acute brain, liver, and lung injury. However, the role of Src in acute kidney injury (AKI) remains unestablished. To address this, we evaluated the effects of Src inhibition on renal dysfunction and pathological changes in a murine model of AKI induced by ischemia/reperfusion (I/R). I/R injury to the kidney resulted in increased Src phosphorylation at tyrosine 416 (activation). Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved renal function and ameliorated renal pathological damage. PP1 treatment also suppressed renal expression of neutrophil gelatinase-associated lipocalin and reduced apoptosis in the injured kidney. Moreover, Src inhibition prevented downregulation of several adherens and tight junction proteins, including E-cadherin, ZO-1, and claudins-1/−4 in the kidney after I/R injury as well as in cultured renal proximal tubular cells following oxidative stress. Finally, PP1 inhibited I/R–induced renal expression of matrix metalloproteinase-2 and -9, phosphorylation of extracellular signal–regulated kinases1/2, signal transducer and activator of transcription-3, and nuclear factor-κB, and the infiltration of macrophages into the kidney. These data indicate that Src is a pivotal mediator of renal epithelial injury and that its inhibition may have a therapeutic potential to treat AKI. PMID:28415724

Our paper 20 years later: from acute renal failure to acute kidney injury--the metamorphosis of a syndrome.

PubMed

Druml, Wilfred; Lenz, Kurt; Laggner, Anton N

2015-11-01

More than 20 years ago we reported an analysis of a case series of elderly critically ill patients with acute kidney injury (AKI)--then termed acute renal failure. At that time, AKI was regarded as a "simple" complication, but has since undergone a fundamental change and actually has become one of the central syndromes in the critically ill patient. We have analyzed elderly patients above 65 years of age with an AKI defined as serum creatinine above 3 mg/dl corresponding to modern KDIGO stage 3, most of them requiring renal replacement therapy (RRT). Using an extremely complete data set the diagnosis differentiated the underlying disease entity, the dominant cause of AKI, acute and chronic risk factors (comorbidities). Special aspects such as severity of disease, early AKI at admission versus late AKI, early versus later start of RRT, AKI not treated by RRT in spite of indication for RRT, various measures of short-term and long-term prognosis, renal outcome, patients dying with resolved AKI, and causes of death were evaluated. Crude mortality was 61% which corresponds to modern studies with gross variation among the different subgroups. Age per se was not a determinant of survival either within the group of elderly patients or as compared to younger age groups. Despite an increase in mean age and disease severity during the observation period prognosis improved. A total of 17% of patients developed a chronic kidney disease. Long-term survival as compared to the general population was low. A look back at the last two decades illustrates a remarkable evolution or rather metamorphosis of a syndrome. AKI has evolved as a central syndrome in intensive care patients, a systemic disease process associated with multiple systemic sequels and extra-renal organ injury and exerting a pronounced effect on the course of disease and short- and long-term prognosis not only of the patient but also of the kidney. Moreover, the "non-renal-naïve" elderly patient with multiple

Protective role of curcumin on renal ischemia reperfusion injury via attenuating the inflammatory mediators and Caspase-3.

PubMed

Liu, F-H; Ni, W-J; Wang, G-K; Zhang, J-J

2016-09-30

Renal ischemia/reperfusion (I/R) damage may arise due to nephron sparing surgery in patient with a solitary kidney of restricted renal parenchymas. Apoptosis, inflammation and oxidative stress play a significant role in the expansion of renal dysfunction following renal I/R. The aim of the current investigation was to particularize the potential effect of curcumin against hypoxia induced renal injury. The albino Wistar rats divided into groups and each group contains six rats. They groups are normal control; disease control; curcumin (5 mg/kg per day) and another group orally treated with curcumin (10 mg/kg per day) for two weeks before induction of renal I/R. The renal and serum samples were collected and used for the biochemical estimation. The renal tissue was further used for the histopathological estimation. The result of the current investigation demonstrated that the curcumin significantly (P<0.01) attenuated I/R induced renal injury in a dose-dependent way. It also causes significant (P<0.01) reduction in the serum creatinine, blood urea nitrogen level and also suppressed the kidney injury molecules-1. Additionally, it also causes significant inhibition of the malonaldehyde, caspase-3, myeloperoxide, lactose dehydrogenase and interferon-gamma together with enhanced interlukin-10 content.

βENaC acts as a mechanosensor in renal vascular smooth muscle cells that contributes to renal myogenic blood flow regulation, protection from renal injury and hypertension.

PubMed

Drummond, Heather A; Stec, David E

2015-06-01

Pressure-induced constriction (also known as the "myogenic response") is an important mechanodependent response in small renal arteries and arterioles. The response is initiated by vascular smooth muscle cell (VSMC) stretch due to an increase in intraluminal pressure and leads to vasoconstriction. The myogenic response has two important roles as a mechanism of local blood flow autoregulation and protection against systemic blood pressure-induced microvascular damage. However, the molecular mechanisms underlying initiation of myogenic response are unresolved. Although several molecules have been considered initiators of the response, our laboratory has focused on the role of degenerin proteins because of their strong evolutionary link to mechanosensing in the nematode. Our laboratory has addressed the hypothesis that certain degenerin proteins act as mechanosensors in VSMCs. This article discusses the importance of a specific degenerin protein, β Epithelial Na + Channel (βENaC), in pressure-induced vasoconstriction, renal blood flow and susceptibility to renal injury. We propose that loss of the renal myogenic constrictor response delays the correction of renal blood flow that occurs with fluctuations in systemic pressure, which allows pressure swings to be transmitted to the microvasculature, thus increasing the susceptibility to renal injury and hypertension. The role of βENaC in myogenic regulation is independent of tubular βENaC and thus represents a non-tubular role for βENaC in renal-cardiovascular homeostasis.

Prospective observational study with an abbreviated protocol in the management of blunt renal injury in children.

PubMed

Graziano, Kathleen D; Juang, David; Notrica, David; Grandsoult, Victoria L; Acosta, Juan; Sharp, Susan W; Murphy, J Patrick; St Peter, Shawn D

2014-01-01

There are no published management schemes for blunt renal injuries. We are conducting a 2-center prospective observational study with a fixed management scheme. Children with CT proven renal injuries were enrolled with permission. Ambulation is allowed when able regardless of grade. Discharge occurs when tolerating a diet and pain is controlled regardless of hematuria. Urinalysis occurs at follow up in 2-4weeks and repeated as indicated. Between 9/2008 and 9/2012, 70 patients were enrolled. Mean age was 11.8years (3-17), and 70% were male. The mean grade of injury was 2.8±1.1 [1-5]. One nephrectomy (1.4%) was performed for a grade 5 injury. Other renal interventions included an embolization for the hilar bleed and one cystotomy for a clot. Mean LOS was 2.9days±2.4days. In patients without other major injury, LOS was 1.9±1.7days (0.4-8days). There were 5 (7%) readmissions: 3 for pain, 1 for hematuria, and 1 for a bladder clot. 58 patients (83%) gave urinalysis samples at initial follow up (med 18days), where 31 (53%) were positive for blood. Children with blunt renal injury may benefit from management without strict bedrest guidelines. Hematuria appears to have little influence on recovery. © 2014.

Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance

PubMed Central

Jin, Jianliang; Lv, Xianhui; Chen, Lulu; Zhang, Wei; Li, Jinbo; Wang, Qian; Wang, Rong; Lu, Xiang; Miao, Dengshun

2014-01-01

To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1-/- mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL−1) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg−1 diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1-/- and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1-/- mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1-/- mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury. PMID:24915841

Grape seed proanthocyanidins prevent DOCA-salt hypertension-induced renal injury and its mechanisms in rats.

PubMed

Lan, Chao-Zong; Ding, Ling; Su, Yi-Lin; Guo, Kun; Wang, Li; Kan, Hong-Wei; Ou, Yu-Rong; Gao, Shan

2015-07-01

Renal dysfunction is one of the major effects of DOCA (deoxycorticosterone acetate)-salt hypertension and there is an increasing amount of evidence that oxidative stress damages the function of the kidney. Grape seed proanthocyanidins (GSPE) have been reported to be potent anti-oxidants and free radical scavengers. The present study sought to investigate the ability of GSPE to prevent renal injury in DOCA-salt hypertensive rats and to explore the molecular mechanisms underlying its protective effects. A total of 54 Sprague Dawley (SD) rats were randomly divided into 7 groups: Sham group (n = 7), UnX-sham group (n = 8), DOCA-salt group (n = 8), GSPE150 group (150 mg kg(-1), n = 7), GSPE240 group (240 mg kg(-1), n = 8), GSPE384 group (384 mg kg(-1), n = 8) and ALM (amlodipine besylate tablets) group (5 mg kg(-1), n = 8), and treated for 4 weeks. Compared to sham group rats, renal injury was observed in DOCA-salt hypertensive group rats as the urine protein, KW/BW (kidney weight/body weight), degree of renal fibrosis, renal MDA (malondialdehyde) and Hyp (hydroxyproline) contents significantly increased (P < 0.01). Moreover, SOD (Superoxide Dismutase) activities decreased in the model group (P < 0.01). In contrast, DOCA-salt hypertensive rats treated with different dose of GSPE or ALM showed a significant improvement of renal injury with decreased urine protein, KW/BW, degree of renal fibrosis, renal total MDA and Hyp contents compared to the untreated group. In addition, SOD activities increased in the treatment group. Since the experimental modeling time was short, kidney damage occurs to a lesser extent. BUN (Blood Urea Nitrogen), Scr (Serum Creatinine) and UA (Uric Acid) contents did not appear significantly changed in all groups. Finally, the activation of JNK and p38 kinases in the kidney was suppressed in rats treated with GSPEs or ALM compared to the untreated group, suggesting that the inhibition of these kinase pathways by GSPE contributes to the improvement

Protective role of silymarin in a mouse model of renal Ischemia-Reperfusion injury.

PubMed

Tan, Jian; Hu, Jianpeng; He, Yonghui; Cui, Feilun

2015-10-31

We investigated the mechanism of action of silymarin in a mouse model of renal ischemia-reperfusion injury (I/R) to ascertain its role in the treatment of I/R injury. Twenty-four C57BL/6 male mice were divided randomly into three groups: control (sham); ischemia-reperfusion (I/R); silymarin + ischemia-reperfusion (silymarin + I/R). In sham mice, an abdominal incision was made, followed by dissection of the bilateral renal pedicle, with no further cross-clamping of arteries. Silymarin + I/R mice were administered 100 mg/kg silymarin daily for 7 consecutive days before surgery, whereas I/R mice were administered (i.g.) 0.9 % saline + 0.1 % (v/v) ethanol daily for 7 consecutive days before surgery. Silymarin + I/R and I/R mice were subjected to renal ischemia to induce acute kidney injury after 45-min clamping of bilateral renal arteries. Serum levels of creatinine and blood urea nitrogen levels were measured. Periodic acid-Schiff (PAS) staining was undertaken to detect damaged renal tissue. Myeloperoxidase (MPO) activity and immunofluorescent detection of CD68 expression was undertaken for each group. Levels of inflammatory cytokines secreted by renal tissue were monitored by ELISA. Apoptosis was detected by TUNEL staining. Expression of cleaved-caspase-3, Bcl-2 and Bax was detected by western blotting. Serum creatinine and blood urea nitrogen levels were elevated in silymarin + I/R and I/R groups compared with sham mice (p < 0.05), whereas those in the I/R group were significantly higher than in the silymarin + I/R group (p < 0.05). Number of damaged renal tubule cells and apoptotic cells in sham and silymarin + I/R groups was significantly lower than in I/R mice. MPO activity and secretion of inflammatory cytokines in silymarin + I/R and I/R groups was reduced (p < 0.05), and CD68 expression in silymarin + I/R mice was lower than in I/R mice (p < 0.05). Expression of cleaved-caspase-3 and Bax in the I/R group

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury.

PubMed

Kölling, Malte; Genschel, Celina; Kaucsar, Tamas; Hübner, Anika; Rong, Song; Schmitt, Roland; Sörensen-Zender, Inga; Haddad, George; Kistler, Andreas; Seeger, Harald; Kielstein, Jan T; Fliser, Danilo; Haller, Hermann; Wüthrich, Rudolf; Zörnig, Martin; Thum, Thomas; Lorenzen, Johan

2018-02-21

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Non-coding RNAs are crucially involved in its pathophysiology. We identified hypoxia-induced long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) to be upregulated in renal I/R injury. We here elucidated the functional role of Malat1 in vitro and its potential contribution to kidney injury in vivo. Malat1 was upregulated in kidney biopsies and plasma of patients with AKI, in murine hypoxic kidney tissue as well as in cultured and ex vivo sorted hypoxic endothelial cells and tubular epithelial cells. Malat1 was transcriptionally activated by hypoxia-inducible factor 1-α. In vitro, Malat1 inhibition reduced proliferation and the number of endothelial cells in the S-phase of the cell cycle. In vivo, Malat1 knockout and wildtype mice showed similar degrees of outer medullary tubular epithelial injury, proliferation, capillary rarefaction, inflammation and fibrosis, survival and kidney function. Small-RNA sequencing and whole genome expression analysis revealed only minor changes between ischemic Malat1 knockout and wildtype mice. Contrary to previous studies, which suggested a prominent role of Malat1 in the induction of disease, we did not confirm an in vivo role of Malat1 concerning renal I/R-injury.

Acquired resistance to rechallenge injury in rats recovered from subclinical renal damage with uranyl acetate-Importance of proliferative activity of tubular cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Yuan; Fujigaki, Yoshihide, E-mail: yf0516@hama-med.ac.j; Sakakima, Masanori

Animals recovered from acute renal failure are resistant to subsequent insult. We investigated whether rats recovered from mild proximal tubule (PT) injury without renal dysfunction (subclinical renal damage) acquire the same resistance. Rats 14 days after recovering from subclinical renal damage, which was induced by 0.2 mg/kg of uranyl acetate (UA) (sub-toxic dose), were rechallenged with 4 mg/kg of UA (nephrotoxic dose). Fate of PT cells and renal function were examined in response to nephrotoxic dose of UA. All divided cells after sub-toxic dose of UA insult were labeled with bromodeoxyuridine (BrdU) for 14 days then the number of PTmore » cells with or without BrdU-labeling was counted following nephrotoxic dose of UA insult. Rats recovered from subclinical renal damage gained resistance to nephrotoxic dose of UA with reduced renal dysfunction, less severity of peak damage (necrotic and TUNEL+ apoptotic cells) and accelerated PT cell proliferation, but with earlier peak of PT damage. The decrease in number of PT cells in the early phase of rechallenge injury with nephrotoxic UA was more in rats pretreated with sub-toxic dose of UA than vehicle pretreated rats. The exaggerated loss of PT cells was mainly caused by the exaggerated loss of BrdU+ divided cells. In contrast, accelerated cell proliferation in rats recovered from sub-toxic dose of UA was observed mainly in BrdU- non-divided cells. The findings suggest that rats recovered from subclinical renal damage showed partial acquired resistance to nephrotoxic insult. Accelerated recovery with increased proliferative activity of non-divided PT cells after subclinical renal damage may mainly contribute to acquired resistance.« less

Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats.

PubMed

Quesada, Andrés; Vargas, Félix; Montoro-Molina, Sebastián; O'Valle, Francisco; Rodríguez-Martínez, María Dolores; Osuna, Antonio; Prieto, Isabel; Ramírez, Manuel; Wangensteen, Rosemary

2012-01-01

This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r(2)>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.

PubMed

Koo, Tai Yeon; Lee, Jae-Ghi; Yan, Ji-Jing; Jang, Joon Young; Ju, Kyung Don; Han, Miyeun; Oh, Kook-Hwan; Ahn, Curie; Yang, Jaeseok

2017-08-01

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69 + CD4 + , and CD44 + CD4 + T cells was attenuated, but renal Foxp3 + CD4 + Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3 + CD4 + Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

PubMed Central

Besenhofer, Lauren M.; Cain, Marie C.; Dunning, Cody

2012-01-01

Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalate-induced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol–treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate’s interaction with, and retention by, the kidney epithelium. PMID:23138489

Ischemic preconditioning provides both acute and delayed protection against renal ischemia and reperfusion injury in mice.

PubMed

Joo, Jin Deok; Kim, Mihwa; D'Agati, Vivette D; Lee, H Thomas

2006-11-01

Acute as well as delayed ischemic preconditioning (IPC) provides protection against cardiac and neuronal ischemia reperfusion (IR) injury. This study determined whether delayed preconditioning occurs in the kidney and further elucidated the mechanisms of renal IPC in mice. Mice were subjected to IPC (four cycles of 5 min of ischemia and reperfusion) and then to 30 min of renal ischemia either 15 min (acute IPC) or 24 h (delayed IPC) later. Both acute and delayed renal IPC provided powerful protection against renal IR injury. Inhibition of Akt but not extracellular signal-regulated kinase phosphorylation prevented the protection that was afforded by acute IPC. Neither extracellular signal-regulated kinase nor Akt inhibition prevented protection that was afforded by delayed renal IPC. Pretreatment with an antioxidant, N-(2-mercaptopropionyl)-glycine, to scavenge free radicals prevented the protection that was provided by acute but not delayed renal IPC. Inhibition of protein kinase C or pertussis toxin-sensitive G-proteins attenuated protection from both acute and delayed renal IPC. Delayed renal IPC increased inducible nitric oxide synthase (iNOS) as well as heat-shock protein 27 synthesis, and the renal protective effects of delayed preconditioning were attenuated by a selective inhibitor of iNOS (l-N(6)[1-iminoethyl]lysine). Moreover, delayed IPC was not observed in iNOS knockout mice. Both acute and delayed IPC were independent of A(1) adenosine receptors (AR) as a selective A(1)AR antagonist failed to block preconditioning and acute and delayed preconditioning occurred in mice that lacked A(1)AR. Therefore, this study demonstrated that acute or delayed IPC provides renal protection against IR injury in mice but involves distinct signaling pathways.

Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertension

PubMed Central

Graciano, Miguel L.; Nishiyama, Akira; Jackson, Keith; Seth, Dale M.; Ortiz, Rudy M.; Prieto-Carrasquero, Minolfa C.; Kobori, Hiroyuki; Navar, L. Gabriel

2008-01-01

Chronic ANG II infusions lead to increases in intrarenal ANG II levels, hypertension, and tissue injury. Increased blood pressure also elicits increases in renal interstitial fluid (RIF) ATP concentrations that stimulate cell proliferation. We evaluated the contribution of purinergic receptor activation to ANG II-induced renal injury in rats by treating with clopidogrel, a P2Y12 receptor blocker, or with PPADS, a nonselective P2 receptor blocker. α-Actin expression in mesangial cells, afferent arteriolar wall thickness (AAWT), cortical cell proliferation, and macrophage infiltration were used as early markers of renal injury. Clopidogrel and PPADS did not alter blood pressure, renin or kidney ANG II content. α-Actin expression increased from control of 0.6 ± 0.4% of mesangial area to 6.3 ± 1.9% in ANG II-infused rats and this response was prevented by clopidogrel (0.4 ± 0.2%) and PPADS. The increase in AAWT from 4.7 ± 0.1 to 6.0 ± 0.1 mm in ANG II rats was also prevented by clopidogrel (4.8 ± 0.1 mm) and PPADS. ANG II infusion led to interstitial macrophage infiltration (105 ± 16 vs. 62 ± 4 cell/mm2) and tubular proliferation (71 ± 15 vs. 20 ± 4 cell/mm2) and these effects were prevented by clopidogrel (52 ± 4 and 36 ± 3 cell/mm2) and PPADS. RIF ATP levels were higher in ANG II-infused rats than in control rats (11.8 ± 1.9 vs. 5.6 ± 0.6 nmol/l, P < 0.05). The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation, renal inflammation, and vascular hypertrophy observed in ANG II-dependent hypertension. PMID:17989111

Mechanisms of HO-1 mediated attenuation of renal immune injury: a gene profiling study.

PubMed

Duann, Pu; Lianos, Elias A

2011-10-01

Using a mouse model of immune injury directed against the renal glomerular vasculature and resembling human forms of glomerulonephritis (GN), we assessed the effect of targeted expression of the cytoprotective enzyme heme oxygenase (HO)-1. A human (h) HO-1 complementary DNAN (cDNA) sequence was targeted to glomerular epithelial cells (GECs) using a GEC-specific murine nephrin promoter. Injury by administration of antibody against the glomerular basement membrane (anti-GBM) to transgenic (TG) mice with GEC-targeted hHO-1 was attenuated compared with wild-type (WT) controls. To explore changes in the expression of genes that could mediate this salutary effect, we performed gene expression profiling using a microarray analysis of RNA isolated from the renal cortex of WT or TG mice with or without anti-GBM antibody-induced injury. Significant increases in expression were detected in 9 major histocompatibility complex (MHC)-class II genes, 2 interferon-γ (IFN-γ)-inducible guanosine triphosphate (GTP)ases, and 3 genes of the ubiquitin-proteasome system. The increase in MHC-class II and proteasome gene expression in TG mice with injury was validated by real-time polymerase chain reaction (PCR) or Western blot analysis. The observations point to novel mechanisms underlying the cytoprotective effect of HO-1 in renal immune injury. Copyright © 2011. Published by Mosby, Inc.

Mild zinc deficiency in male and female rats: early postnatal alterations in renal nitric oxide system and morphology.

PubMed

Tomat, Analia Lorena; Veiras, Luciana Cecilia; Aguirre, Sofía; Fasoli, Héctor; Elesgaray, Rosana; Caniffi, Carolina; Costa, María Ángeles; Arranz, Cristina Teresa

2013-03-01

Fetal and postnatal zinc deficiencies induce an increase in arterial blood pressure and impair renal function in male adult rats. We therefore hypothesized that these renal alterations are present in early stages of life and that there are sexual differences in the adaptations to this nutritional injury. The aim was to study the effects of moderate zinc deficiency during fetal life and lactation on renal morphology, oxidative stress, apoptosis, and the nitric oxide system in male and female rats at 21 d of life. Female Wistar rats received low (8 ppm) or control (30 ppm) zinc diets from the beginning of pregnancy to weaning. Glomerulus number, morphology, oxidative stress, apoptotic cells, nitric oxide synthase activity, and protein expression were evaluated in the kidneys of offspring at 21 d. Zinc deficiency decreased the nephron number, induced glomerular hypertrophy, increased oxidative damage, and decreased nitric oxide synthase activity in the male and female rat kidneys. Nitric oxide synthase activity was not affected by inhibitors of the neuronal or inducible isoforms, so nitric oxide was mainly generated by the endothelial isoenzyme. Gender differences were observed in glomerular areas and antioxidant enzyme activities. Zinc deficiency during fetal life and lactation induces an early decrease in renal functional units, associated with a decrease in nitric oxide activity and an increase in oxidative stress, which would contribute to increased arterial blood pressure and renal dysfunction in adulthood. The sexual differences observed in this model may explain the dissimilar development of hypertension and renal diseases in adult life. Copyright © 2013 Elsevier Inc. All rights reserved.

Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat

PubMed Central

Maric-Bilkan, Christine; Flynn, Elizabeth R.

2012-01-01

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and 125I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function. PMID:22031855

PREVENTING AUTOIMMUNITY PROTECTS AGAINST THE DEVELOPMENT OF HYPERTENSION AND RENAL INJURY

PubMed Central

Mathis, Keisa W.; Wallace, Kedra; Flynn, Elizabeth R.; Maric-Bilkan, Christine; LaMarca, Babbette; Ryan, Michael J.

2015-01-01

Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production and the prevalence of hypertension is markedly increased in this patient population compared to normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or IgG antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein -1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation is an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus. PMID:25024282

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury.

PubMed

Ahmad, Tariq; Jackson, Keyanna; Rao, Veena S; Tang, W H Wilson; Brisco-Bacik, Meredith A; Chen, Horng H; Felker, G Michael; Hernandez, Adrian F; O'Connor, Christopher M; Sabbisetti, Venkata S; Bonventre, Joseph V; Wilson, F Perry; Coca, Steven G; Testani, Jeffrey M

2018-05-08

Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N -acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N -acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P >0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P <0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin ( P =0.21), N -acetyl-β-d-glucosaminidase ( P =0.46), or kidney injury molecule 1 ( P =0.22). Increases in neutrophil gelatinase-associated lipocalin, N -acetyl

[Plasma cell dyscrasias and renal damage].

PubMed

Pasquali, Sonia; Iannuzzella, Francesco; Somenzi, Danio; Mattei, Silvia; Bovino, Achiropita; Corradini, Mattia

2012-01-01

Kidney damage caused by immunoglobulin free light chains in the setting of plasma cell dyscrasias is common and may involve all renal compartments, from the glomerulus to the tubulointerstitium, in a wide variety of histomorphological and clinical patterns. The knowledge of how free light chains can promote kidney injury is growing: they can cause functional changes, be processed and deposited, mediate inflammation, apoptosis and fibrosis, and obstruct nephrons. Each clone of the free light chain is unique and its primary structure and post-translation modification can determine the type of renal disease. Measurement of serum free light chain concentrations and calculation of the serum kappa/lambda ratio, together with renal biopsy, represent essential diagnostic tools. An early and correct diagnosis of renal lesions due to plasma cell dyscrasias will allow early initiation of disease-specific treatment strategies. The treatment of free light chain nephropathies is evolving and knowledge of the pathways that promote renal damage should lead to further therapeutic developments.

Tauroursodeoxycholic Acid Attenuates Renal Tubular Injury in a Mouse Model of Type 2 Diabetes

PubMed Central

Zhang, Jing; Fan, Ying; Zeng, Chuchu; He, Li; Wang, Niansong

2016-01-01

Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology. These changes were associated with a significant decreased expression of ER stress markers. At the same time, diabetic db/db mice had more TUNEL-positive nuclei in the renal tubule, which were attenuated by TUDCA treatment, along with decreases in ER stress–associated apoptotic markers in the kidneys. In summary, the effect of TUDCA on tubular injury, in part, is associated with inhibition of ER stress in the kidneys of diabetic db/db mice. TUDCA shows potential as a therapeutic target for the prevention and treatment of DN. PMID:27669287

Early renal dysfunction after contrast media administration despite prophylactic hydration.

PubMed

Burchardt, Pawel; Guzik, Przemyslaw; Tabaczewski, Piotr; Synowiec, Tomasz; Bogdan, Monika; Faner, Paula; Chmielarz-Sobocińska, Anna; Palasz, Anna

2013-06-01

The actual incidence of renal dysfunction after contrast media administration seems to be underestimated, especially in the context of epidemiological data. There are only few data concerning the monitoring of impaired kidney function within a few hours after iodine contrast medium application. Hence, the purpose of this study is to observe the incidence of early renal function deterioration within 12-18 h after administration of iodine contrast media in patients scheduled for elective coronary angiography, who were intravenously and orally hydrated. In addition, the project aims to reclassify the contrast induced nephropathy phenomenon, by identification of early markers of renal dysfunction. Morphology, electrolytes, blood urea nitrogen (BUN), creatinine, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein, and total cholesterol levels were assessed with the use of typical laboratory techniques in 319 patients referred for coronary angiography. We demonstrated that early deterioration of renal function in patients 12-18 h after administration of contrast during imaging tests (even when appropriate prophylactic hydration was used), may occurred just as an increase (or no change) of serum creatinine level and BUN level and a decrease of creatinine clearance and glomerular filtration rate. Depending on the parameter, the phenomenon can be found in 13-28 % of all respondents. Early renal function impairment defined as above was almost 2 and 2.22 × 10(3) times (respectively) more frequently observed in our study than contrast induced nephropathy defined by current definitions.

Selective Rac1 inhibition protects renal tubular epithelial cells from oxalate-induced NADPH oxidase-mediated oxidative cell injury

PubMed Central

Thamilselvan, Vijayalakshmi; Menon, Mani

2013-01-01

Oxalate-induced oxidative cell injury is one of the major mechanisms implicated in calcium oxalate nucleation, aggregation and growth of kidney stones. We previously demonstrated that oxalate-induced NADPH oxidase-derived free radicals play a significant role in renal injury. Since NADPH oxidase activation requires several regulatory proteins, the primary goal of this study was to characterize the role of Rac GTPase in oxalate-induced NADPH oxidase-mediated oxidative injury in renal epithelial cells. Our results show that oxalate significantly increased membrane translocation of Rac1 and NADPH oxidase activity of renal epithelial cells in a time-dependent manner. We found that NSC23766, a selective inhibitor of Rac1, blocked oxalate-induced membrane translocation of Rac1 and NADPH oxidase activity. In the absence of Rac1 inhibitor, oxalate exposure significantly increased hydrogen peroxide formation and LDH release in renal epithelial cells. In contrast, Rac1 inhibitor pretreatment, significantly decreased oxalate-induced hydrogen peroxide production and LDH release. Furthermore, PKC α and δ inhibitor, oxalate exposure did not increase Rac1 protein translocation, suggesting that PKC resides upstream from Rac1 in the pathway that regulates NADPH oxidase. In conclusion, our data demonstrate for the first time that Rac1-dependent activation of NADPH oxidase might be a crucial mechanism responsible for oxalate-induced oxidative renal cell injury. These findings suggest that Rac1 signaling plays a key role in oxalate-induced renal injury, and may serve as a potential therapeutic target to prevent calcium oxalate crystal deposition in stone formers and reduce recurrence. PMID:21814770

Tempol Protects Against Acute Renal Injury by Regulating PI3K/Akt/mTOR and GSK3β Signaling Cascades and Afferent Arteriolar Activity.

PubMed

Zhang, Gensheng; Wang, Qin; Wang, Wenwen; Yu, Minghua; Zhang, Suping; Xu, Nan; Zhou, Suhan; Cao, Xiaoyun; Fu, Xiaodong; Ma, Zufu; Liu, Ruisheng; Mao, Jianhua; Lai, En Yin

2018-05-30

Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3β (GSK3β) pathways as well as the coordinating apoptosis and inflammation related proteins. The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3β pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice. The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O2.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3β, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole. Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3β pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity. © 2018 The Author(s). Published by S. Karger AG, Basel.

Early impact of robot-assisted partial nephrectomy on renal function as assessed by renal scintigraphy.

PubMed

Luciani, Lorenzo G; Chiodini, Stefano; Donner, Davide; Cai, Tommaso; Vattovani, Valentino; Tiscione, Daniele; Giusti, Guido; Proietti, Silvia; Chierichetti, Franca; Malossini, Gianni

2016-06-01

To measure the early impact of robot-assisted partial nephrectomy (RAPN) on renal function as assessed by renal scan (Tc 99m-DTPA), addressing the issue of risk factors for ischemic damage to the kidney. All patients undergoing RAPN for cT1 renal masses between June 2013 and May 2014 were included in this prospective study. Renal function as expressed by glomerular filtration rate (GFR) was assessed by Technetium 99m-diethylenetriaminepentaacetic acid (Tc 99m-DTPA) renal scan preoperatively and postoperatively at 1 month in every patient. A multivariable analysis was used for the determination of independent factors predictive of GFR decrease of the operated kidney. Overall, 32 patients underwent RAPN in the time interval. Median tumor size, blood loss, and ischemia time were 4 cm, 200 mL, and 24 min, respectively. Two grade III complications occurred (postoperative bleeding in the renal fossa, urinoma). The GFR of the operated kidney decreased significantly from 51.7 ± 15.1 mL/min per 1.73 m(2) preoperatively to 40, 12 ± 12.4 mL/min per 1.73 m(2) 1 month postoperatively (p = 0.001) with a decrease of 22.4 %. On multivariable analysis, only tumor size (p = 0.05) was a predictor of GFR decrease of the operated kidney. Robotic-assisted partial nephrectomy had a detectable impact on early renal function in a series of relatively large tumors and prevailing intermediate nephrometric risk. A mean decrease of 22 % of GFR as assessed by renal scan in the operated kidney was found at 1 month postoperatively. In multivariable analysis, tumor size only was a significant predictor of renal function loss.

The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.

PubMed

Calvier, Laurent; Martinez-Martinez, Ernesto; Miana, Maria; Cachofeiro, Victoria; Rousseau, Elodie; Sádaba, J Rafael; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

2015-01-01

This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside-binding lectin, is increased in heart failure and kidney injury. Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats.

PubMed

Sakai, Mariko; Uchii, Masako; Myojo, Kensuke; Kitayama, Tetsuya; Kunori, Shunji

2015-08-15

Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury. Copyright © 2015 Elsevier B.V. All rights reserved.

Study on the effect of black cumin (Nigella sativa Linn.) on experimental renal ischemia-reperfusion injury in rats.

PubMed

Mousavi, Ghafour

2015-08-01

To evaluate the effect of Black cumin (Nigella sativa Linn.) pre-treatment on renal ischemia/reperfusion (I/R) induced injury in the rats. A total of 40 male Wistar rats were randomly allocated into five equal groups including Sham, I/R model and three I/R+ Black cumin (0.5, 1 and 2%)-treated groups. I/R groups' kidneys were subjected to 60 min of global ischemia at 37°C followed by 24 h of reperfusion. At the end of reperfusion period, the rats were euthanized. Superoxide dismutase, catalase and glutathione peroxidase activities as well as reduced glutathione and renal malondialdehyde contents were determined in renal tissues. Kidney function tests and histopathological examination were also performed. High serum creatinine, blood urea nitrogen and uric acid as well as malondialhehyde (MDA) levels, and low antioxidant enzyme activities were observed in I/R rats compared to the sham rats. Pre-treatment with Black cumin for three weeks prior to IR operation improved renal function and reduced I/R induced renal inflammation and oxidative injury. These biochemical observations were supported by histopathological test of kidney sections. Black cumin significantly prevented renal ischemia/reperfusion induced functional and histological injuries.

Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury.

PubMed

Garcia-Martinez, Rita; Noiret, Lorette; Sen, Sambit; Mookerjee, Rajeshwar; Jalan, Rajiv

2015-02-01

In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury. Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both groups were treated with intravenous albumin infusion, 40-60 g/days over 3-4 days. Cardiac and renal haemodynamics were measured. Endothelial activation/dysfunction was assessed using von Willebrand factor and serum nitrite levels. F2α Isoprostanes, resting neutrophil burst and noradrenaline levels were quantified as markers of oxidative stress, endotoxemia and sympathetic activation respectively. Albumin infusion leads to a shift in the renal blood flow autoregulation curve towards normalization, which resulted in a significant increase in renal blood flow. Accordingly, improvement of renal function was observed. In parallel, a significant decrease in sympathetic activation, inflammation/oxidative stress and endothelial activation/dysfunction was documented. Improvement of renal blood flow correlated with improvement in endothelial activation (r = 0.741, P < 0.001). The data suggest that albumin infusion improves renal function in acutely decompensated cirrhotic patients with acute kidney injury by impacting on renal blood flow autoregulation. This is possibly achieved through endothelial stabilization and a reduction in the sympathetic tone, endotoxemia and oxidative stress. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice.

PubMed

Wang, Hui; Zhang, Jia-Xiang; Ye, Liang-Ping; Li, Shu-Long; Wang, Feng; Zha, Wan-Sheng; Shen, Tong; Wu, Changhao; Zhu, Qi-Xing

2016-07-01

Trichloroethylene (TCE) is a major environmental pollutant. An immunological response is a newly-recognized mechanism for TCE-induced kidney damage. However, the role of the plasma kallikrein-kinin system (KKS) in immune-mediated kidney injury has never been examined. This study aimed to explore the role of the key components of the KKS, i.e. plasma kallikrein (PK), bradykinin (BK) and its receptors B1R and B2R, in TCE-induced kidney injury. A mouse model of skin sensitization was used to explore the mechanism of injury with or without a PK inhibitor PKSI. Kidney function was evaluated by measuring blood urea nitrogen (BUN) and creatinine (Cr) in conjunction with histopathologic characterization. Plasma BK was determined by ELISA; Renal C5b-9 membrane attack complex was evaluated by immunohistochemistry. Expression of BK and PK in the kidney was detected by immunofluorescence. mRNA and protein levels of B1R and B2R were assessed by real-time qPCR and Western blot. As expected, numerous inflammatory cell infiltration and tubular epithelial cell vacuolar degeneration were observed in TCE-sensitized mice. Moreover, serum BUN and Cr and plasma BK were increased. In addition, deposition of BK, PK and C5b-9 were observed and B1R and B2R mRNA and proteins levels were up-regulated. Pre-treatment with PKSI, a highly selective inhibitor of PK, alleviated TCE-induced renal damage. In addition, PKSI attenuated TCE-induced up-regulation of BK, PK and its receptors and C5b-9. These results provided the first evidence that activation of the KKS contributed to immune-mediated renal injury induced by TCE and also helped to identify the KKS as a potential therapeutic target for mitigating chemical sensitization-induced renal damage.

'Biologic memory' in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease.

PubMed

Zager, Richard A

2013-08-01

Following the induction of ischemic or toxin-mediated acute kidney injury (AKI), cellular adaptations occur that 're-program' how the kidney responds to future superimposed insults. This re-programming is not simply a short-lived phenomenon; rather it can persist for many weeks, implying that a state of 'biologic memory' has emerged. These changes can be both adaptive and maladaptive in nature and they can co-exist in time. A beneficial adaptation is the emergence of acquired cytoresistance, whereby a number of physiologic responses develop that serve to protect the kidney against further ischemic or nephrotoxic attack. Conversely, some changes are maladaptive, such as a predisposition to Gram-negative or Gram-positive bacteremia due to a renal tubular up-regulation of toll-like receptor responses. This latter change culminates in exaggerated cytokine production, and with efflux into the systemic circulation, extra-renal tissue injury can result (so-called 'organ cross talk'). Another maladaptive response is a persistent up-regulation of pro-inflammatory, pro-fibrotic and vasoconstrictive genes, culminating in progressive renal injury and ultimately end-stage renal failure. The mechanisms by which this biologic re-programming, or biologic memory, is imparted remain subjects for considerable debate. However, injury-induced, and stable, epigenetic remodeling at pro-inflammatory/pro-fibrotic genes seems likely to be involved. The goal of this editorial is to highlight that the so-called 'maintenance phase' of acute renal failure is not a static one, somewhere between injury induction and the onset of repair. Rather, this period is one in which the induction of 'biologic memory' can ultimately impact renal functional recovery, extra-renal injury and the possible transition of AKI into chronic, progressive renal disease.

Stem cells and their role in renal ischaemia reperfusion injury.

PubMed

Bagul, Atul; Frost, Jodie H; Drage, Martin

2013-01-01

Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC. Copyright © 2012 S. Karger AG, Basel.

Biomarker for early renal microvascular and diabetic kidney diseases.

PubMed

Futrakul, Narisa; Futrakul, Prasit

2017-11-01

Recognition of early stage of diabetic kidney disease, under common practice using biomarkers, namely microalbuminuria, serum creatinine level above 1 mg/dL and accepted definition of diabetic kidney disease associated with creatinine clearance value below 60 mL/min/1.73 m 2 , is unlikely. This would lead to delay treatment associated with therapeutic resistance to vasodilator due to a defective vascular homoeostasis. Other alternative biomarkers related to the state of microalbuminuria is not sensitive to screen for early diabetic kidney disease (stages I, II). In this regard, a better diagnostic markers to serve for this purpose are creatinine clearance, fractional excretion of magnesium (FE Mg), cystatin C. Recently, renal microvascular disease and renal ischemia have been demonstrated to correlate indirectly with the development of diabetic kidney disease and its function. Among these are angiogenic and anti-angiogenic factors, namely VEGF, VEGF receptors, angiopoietins and endostatin. With respect to therapeutic prevention, implementation of treatment at early stage of diabetic and nondiabetic kidney disease is able to restore renal perfusion and function.

Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.

PubMed

Eirin, Alfonso; Zhu, Xiang-Yang; Ferguson, Christopher M; Riester, Scott M; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

2015-01-19

Percutaneous transluminal renal angioplasty (PTRA) fails to fully improve cardiac injury and dysfunction in patients with renovascular hypertension (RVH). Mesenchymal stem cells (MSCs) restore renal function, but their potential for attenuating cardiac injury after reversal of RVH has not been explored. We hypothesized that replenishment of MSCs during PTRA would improve cardiac function and oxygenation, and decrease myocardial injury in porcine RVH. Pigs were studied after 16 weeks of RVH, RVH treated 4 weeks earlier with PTRA with or without adjunct intra-renal delivery of MSC (10^6 cells), and controls. Cardiac structure, function (fast-computed tomography (CT)), and myocardial oxygenation (Blood-Oxygen-Level-Dependent- magnetic resonance imaging) were assessed in-vivo. Myocardial microvascular density (micro-CT) and myocardial injury were evaluated ex-vivo. Kidney venous and systemic blood levels of inflammatory markers were measured and their renal release calculated. PTRA normalized blood pressure, yet stenotic-kidney glomerular filtration rate, similarly blunted in RVH and RVH + PTRA, normalized only in PTRA + MSC-treated pigs. PTRA attenuated left ventricular remodeling, whereas myocardial oxygenation, subendocardial microvascular density, and diastolic function remained decreased in RVH + PTRA, but normalized in RVH + PTRA-MSC. Circulating isoprostane levels and renal release of inflammatory cytokines increased in RVH and RVH + PTRA, but normalized in RVH + PTRA-MSC, as did myocardial oxidative stress, inflammation, collagen deposition, and fibrosis. Intra-renal MSC delivery during PTRA preserved stenotic-kidney function, reduced systemic oxidative stress and inflammation, and thereby improved cardiac function, oxygenation, and myocardial injury four weeks after revascularization, suggesting a therapeutic potential for adjunctive MSC delivery to preserve cardiac function and structure after reversal of experimental RVH.

Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Xiangjun; Yao, Qisheng, E-mail: yymcyqs@126.com; Sun, Xinbo

Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treatedmore » with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells

Readmission after treatment of Grade 3 and 4 renal injuries at a Level I trauma center: Statewide assessment using the Comprehensive Hospital Abstract Reporting System.

PubMed

Winters, Brian; Wessells, Hunter; Voelzke, Bryan B

2016-03-01

One criticism of the existing renal trauma research is the limited outpatient follow-up after index hospitalization. We assessed readmission rates following treatment for American Association for the Surgery of Trauma (AAST) Grade 3 and 4 renal injury using the Comprehensive Hospital Abstract Reporting System (CHARS). We evaluated all patients with AAST Grade 3 and 4 renal injuries admitted to Harborview Medical Center (HMC) between 1998 and 2010, the only Level 1 trauma center in Washington state. Grade 4 renal injuries were stratified by collecting system laceration (CSL) or segmental vascular injury. Data were abstracted from the CHARS database for readmissions to any Washington state hospital within 6 months of renal injury. Clinical variables, diagnoses, and procedures were queried based on DRG International Classification of Diseases-9th Rev. codes. A total of 477 Grade 3 and 159 Grade 4 renal injuries were initially treated at HMC. On admission, 111 patients required intervention: 75 (16%) of 477 Grade 3 and 36 (23%) of 159 Grade 4 injuries. Within 6 months of index hospitalization, 86 (18%) of 477 Grade 3 and 38 (24%) of 159 Grade 4 patients were readmitted to any Washington state hospital. Eighty percent of Grade 3 injuries and 66% of Grade 4 injuries returned to HMC compared with secondary hospitals (p = 0.08). At readmission, 19 (22%) of 86 Grade 3 and 16 (42%) of 38 Grade 4 injuries had a urologic diagnosis. Subsequent procedural intervention was required on readmission in 6 (7%) of 86 Grade 3 and 5 (13%) of 38 Grade 4 renal injuries (all CSL injuries). A subset of patients treated for Grade 3 and 4 renal trauma will be readmitted for further management. While urologic diagnoses and additional procedures may be low overall, readmission to outside hospitals may preclude accurate determination of renal trauma outcomes. Based on these data, patients with Grade 4 CSL injuries seem to be at the highest risk for readmission and to require a subsequent

Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

PubMed

Liu, Xue-Jing; Wu, Xiao-Yue; Wang, Huan; Wang, Su-Xia; Kong, Wei; Zhang, Ling; Liu, George; Huang, Wei

2018-05-08

Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue (AT) and could lead to renal failure in humans. However, the effect of Seipin on renal function is poorly understood. Here we report that Seipin knockout (SKO) mice exhibited impaired renal function, enlarged glomerular and mesangial surface areas, renal depositions of lipid, and advanced glycation end products. Elevated glycosuria and increased electrolyte excretion were also detected. Relative renal gene expression in fatty acid oxidation and reabsorption pathways were impaired in SKO mice. Elevated glycosuria might be associated with reduced renal glucose transporter 2 levels. To improve renal function, AT transplantation or leptin administration alone was performed. Both treatments effectively ameliorated renal injury by improving all of the parameters that were measured in the kidney. The treatments also rescued insulin resistance and low plasma leptin levels in SKO mice. Our findings demonstrate for the first time that Seipin deficiency induces renal injury, which is closely related to glucolipotoxicity and impaired renal reabsorption in SKO mice, and is primarily caused by the loss of AT and especially the lack of leptin. AT transplantation and leptin administration are two effective treatments for renal injury in Seipin-deficient mice.-Liu, X.-J., Wu, X.-Y., Wang, H., Wang, S.-X., Kong, W., Zhang, L., Liu, G., Huang, W. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Changing picture of renal cortical necrosis in acute kidney injury in developing country

PubMed Central

Prakash, Jai; Singh, Vijay Pratap

2015-01-01

Renal cortical necrosis (RCN) is characterized by patchy or diffuse ischemic destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. In addition, direct endothelial injury particularly in setting of sepsis, eclampsia, haemolytic uremic syndrome (HUS) and snake bite may lead to endovascular thrombosis with subsequent renal ischemia. Progression to end stage renal disease is a rule in diffuse cortical necrosis. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients with AKI. In contrast, RCN incidence is higher in developing countries ranging between 6%-7% of all causes of AKI. Obstetric complications (septic abortion, puerperal sepsis, abruptio placentae, postpartum haemorrhage and eclampsia) are the main (60%-70%) causes of RCN in developing countries. The remaining 30%-40% cases of RCN are caused by non-obstetrical causes, mostly due to sepsis and HUS. The incidence of RCN ranges from 10% to 30% of all cases of obstetric AKI compared with only 5% in non-gravid patients. In the developed countries, RCN accounts for 2% of all cases of AKI in adults and more than 20% of AKI during the third trimester of pregnancy. The reported incidence of RCN in obstetrical AKI varies between 18%-42.8% in different Indian studies. However, the overall incidence of RCN in pregnancy related AKI has decreased from 20%-30% to 5% in the past two decades in India. Currently RCN accounts for 3% of all causes of AKI. The incidence of RCN in obstetrical AKI was 1.44% in our recent study. HUS is most common cause of RCN in non-obstetrical group, while puerperal sepsis is leading cause of RCN in obstetric group. Because of the catastrophic sequelae of RCN, its prevention and aggressive management should always be important for the better renal outcome and prognosis of the patients. PMID:26558184

Effect of novel vitamin D receptor activator paricalcitol on renal ischaemia/reperfusion injury in rats

PubMed Central

Huddam, B; Haberal, N; Koçak, G; Ortabozkoyun, L; Şenes, M; Akdoğan, MF; Denizli, N; Duranay, M

2013-01-01

Introduction Despite the developments in modern medicine, acute renal injury is still a challenging and common health problem. It is well known that ischaemia and reperfusion takes place in pathological mechanisms. Efforts to clarify the pathophysiology and interventions to improve outcomes are essential. Our study aimed to investigate whether the prophylactic use of paricalcitol is beneficial in renal ischaemia/reperfusion (I/R) injury. Methods Twenty-four Wistar albino rats were assigned randomly to four groups. Right nephrectomies were performed at the time of renal arterial clamping. Sham surgery was performed on the rats in group 1. For the rats in group 2, the left renal artery was clamped for 45 minutes. The rats in group 3 received paricalcitol for seven days (0.2µg/kg/day); following this, a right nephrectomy and left renal arterial clamping were not performed. The rats in group 4 received paricalcitol for seven days (0.2µg/ kg/day); following this, a right nephrectomy and left renal arterial clamping for 45 minutes were performed. Tissue thiobarbituric acid reactive substances (TBARS), superoxide dismutase, sulfhydryl groups as well as nitric oxide metabolites, serum urea and creatinine levels were measured for all four groups. Results In group 4, there were some improvements in terms of TBARS, nitrite, nitrate, superoxide dismutase and creatinine levels. In the histopathological evaluation, paricalcitol therapy improved tubular necrosis and medullar congestion but there was no significant difference in terms of tubular cell swelling, cellular vacuolisation or general damage. Immunohistopathological examination revealed lower scores for vascular endothelial growth factor in the group 4 rats than in group 2. Conclusions Paricalcitol therapy improved renal I/R injury in terms of serum and histopathological parameters. These potential beneficial effects need to be further investigated. PMID:24112495

miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

PubMed Central

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J.; Liang, Mingyu; Ding, Xiaoqiang

2015-01-01

Background MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Results Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. Conclusions These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning. PMID:23681145

miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice.

PubMed

Jia, Ping; Teng, Jie; Zou, Jianzhou; Fang, Yi; Zhang, Xiaoyan; Bosnjak, Zeljko J; Liang, Mingyu; Ding, Xiaoqiang

2013-09-01

MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti-miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti-miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.

Epidemiology and Outcome of Acute Kidney Injury According to Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease: Improving Global Outcomes Criteria in Critically Ill Children-A Prospective Study.

PubMed

Volpon, Leila C; Sugo, Edward K; Consulin, Julio C; Tavares, Tabata L G; Aragon, Davi C; Carlotti, Ana P C P

2016-05-01

We aimed to investigate the epidemiology, risk factors, and short- and medium-term outcome of acute kidney injury classified according to pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease, and Kidney Disease: Improving Global Outcomes criteria in critically ill children. Prospective observational cohort study. Two eight-bed PICUs of a tertiary-care university hospital. A heterogeneous population of critically ill children. None. Demographic, clinical, laboratory, and outcome data were collected on all patients admitted to the PICUs from August 2011 to January 2012, with at least 24 hours of PICU stay. Of the 214 consecutive admissions, 160 were analyzed. The prevalence of acute kidney injury according to pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease: Improving Global Outcomes criteria was 49.4% vs. 46.2%, respectively. A larger proportion of acute kidney injury episodes was categorized as Kidney Disease: Improving Global Outcomes stage 3 (50%) compared with pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease F (39.2%). Inotropic score greater than 10 was a risk factor for acute kidney injury severity. About 35% of patients with acute kidney injury who survived were discharged from the PICU with an estimated creatinine clearance less than 75 mL/min/1.73 m and one persisted with altered renal function 6 months after PICU discharge. Age 12 months old or younger was a risk factor for estimated creatinine clearance less than 75 mL/min/1.73 m at PICU discharge. Acute kidney injury and its severity were associated with increased PICU length of stay and longer duration of mechanical ventilation. Eleven patients died; nine had acute kidney injury (p < 0.05). The only risk factor associated with death after multivariate adjustment was Pediatric Risk of Mortality score greater than or equal to 10. Acute kidney injury defined by both pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease

Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study.

PubMed

Bragadottir, Gudrun; Redfors, Bengt; Ricksten, Sven-Erik

2012-08-17

Acute kidney injury (AKI), which is a major complication after cardiovascular surgery, is associated with significant morbidity and mortality. Diuretic agents are frequently used to improve urine output and to facilitate fluid management in these patients. Mannitol, an osmotic diuretic, is used in the perioperative setting in the belief that it exerts reno-protective properties. In a recent study on uncomplicated postcardiac-surgery patients with normal renal function, mannitol increased glomerular filtration rate (GFR), possibly by a deswelling effect on tubular cells. Furthermore, experimental studies have previously shown that renal ischemia causes an endothelial cell injury and dysfunction followed by endothelial cell edema. We studied the effects of mannitol on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO2), and extraction (RO2Ex) in early, ischemic AKI after cardiac surgery. Eleven patients with AKI were studied during propofol sedation and mechanical ventilation 2 to 6 days after complicated cardiac surgery. All patients had severe heart failure treated with one (100%) or two (73%) inotropic agents and intraaortic balloon pump (36%). Systemic hemodynamics were measured with a pulmonary artery catheter. RBF and renal filtration fraction (FF) were measured by the renal vein thermo-dilution technique and by renal extraction of chromium-51-ethylenediaminetetraacetic acid (51Cr-EDTA), respectively. GFR was calculated as the product of FF and renal plasma flow RBF × (1-hematocrit). RVO2 and RO2Ex were calculated from arterial and renal vein blood samples according to standard formulae. After control measurements, a bolus dose of mannitol, 225 mg/kg, was given, followed by an infusion at a rate of 75 mg/kg/h for two 30-minute periods. Mannitol did not affect cardiac index or cardiac filling pressures. Mannitol increased urine flow by 61% (P < 0.001). This was accompanied by a 12% increase in RBF (P < 0.05) and a 13

Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study

PubMed Central

2012-01-01

Introduction Acute kidney injury (AKI), which is a major complication after cardiovascular surgery, is associated with significant morbidity and mortality. Diuretic agents are frequently used to improve urine output and to facilitate fluid management in these patients. Mannitol, an osmotic diuretic, is used in the perioperative setting in the belief that it exerts reno-protective properties. In a recent study on uncomplicated postcardiac-surgery patients with normal renal function, mannitol increased glomerular filtration rate (GFR), possibly by a deswelling effect on tubular cells. Furthermore, experimental studies have previously shown that renal ischemia causes an endothelial cell injury and dysfunction followed by endothelial cell edema. We studied the effects of mannitol on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO2), and extraction (RO2Ex) in early, ischemic AKI after cardiac surgery. Methods Eleven patients with AKI were studied during propofol sedation and mechanical ventilation 2 to 6 days after complicated cardiac surgery. All patients had severe heart failure treated with one (100%) or two (73%) inotropic agents and intraaortic balloon pump (36%). Systemic hemodynamics were measured with a pulmonary artery catheter. RBF and renal filtration fraction (FF) were measured by the renal vein thermo-dilution technique and by renal extraction of chromium-51-ethylenediaminetetraacetic acid (51Cr-EDTA), respectively. GFR was calculated as the product of FF and renal plasma flow RBF × (1-hematocrit). RVO2 and RO2Ex were calculated from arterial and renal vein blood samples according to standard formulae. After control measurements, a bolus dose of mannitol, 225 mg/kg, was given, followed by an infusion at a rate of 75 mg/kg/h for two 30-minute periods. Results Mannitol did not affect cardiac index or cardiac filling pressures. Mannitol increased urine flow by 61% (P < 0.001). This was accompanied by a 12% increase in

Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

PubMed Central

Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

2016-01-01

Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

PubMed Central

Doi, Kent; Okamoto, Koji; Negishi, Kousuke; Suzuki, Yoshifumi; Nakao, Akihide; Fujita, Toshiro; Toda, Akiko; Yokomizo, Takehiko; Kita, Yoshihiro; Kihara, Yasuyuki; Ishii, Satoshi; Shimizu, Takao; Noiri, Eisei

2006-01-01

Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells. PMID:16651609

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

[Cardio-Pulmonary-Renal interactions].

PubMed

Samoni, Sara; Husain-Syed, Faeq; De Rosa, Silvia; Ronco, Claudio

2017-03-01

Over the past decade, understanding about feedback mechanisms involving the heart, lung and kidney is significantly improved. Each organ injury may trigger hemodynamic, neuro-hormonal and cellular pathway that may damage diverse organs. Recurrent acute on chronic injury may lead to the advanced stage of disease. On the other hand, chronic pathological conditions may decrease functional reserve leading to a high susceptibility to acute injury. Assessment of functional reserve and dosage of novel biomarkers may allow an early diagnosis and treatment. This review summarizes the current state-of-the-art understanding of cardio-pulmonary-renal interactions. Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.

Magnolol Reduces Renal Ischemia and Reperfusion Injury via Inhibition of Apoptosis.

PubMed

Tang, Chia-Yu; Lai, Chang-Chi; Huang, Po-Hsun; Yang, An-Han; Chiang, Shu-Chiung; Huang, Po-Chao; Tseng, Kuo-Wei; Huang, Cheng-Hsiung

2017-01-01

Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003[Formula: see text]mg/kg and 0.006[Formula: see text]mg/kg 10[Formula: see text]min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-[Formula: see text], IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-[Formula: see text] production and the modulation of pro- and anti-apoptotic signaling elements.

Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II): RenalGuard System in high-risk patients for contrast-induced acute kidney injury.

PubMed

Briguori, Carlo; Visconti, Gabriella; Focaccio, Amelia; Airoldi, Flavio; Valgimigli, Marco; Sangiorgi, Giuseppe Massimo; Golia, Bruno; Ricciardelli, Bruno; Condorelli, Gerolama

2011-09-13

The RenalGuard System, which creates high urine output and fluid balancing, may be beneficial in preventing contrast-induced acute kidney injury. The Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II) trial is a randomized, multicenter, investigator-driven trial addressing the prevention of contrast-induced acute kidney injury in high-risk patients. Patients with an estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 m(-2) and/or a risk score ≥11 were randomly assigned to sodium bicarbonate solution and N-acetylcysteine (control group) or hydration with saline and N-acetylcysteine controlled by the RenalGuard System and furosemide (RenalGuard group). The primary end point was an increase of ≥0.3 mg/dL in the serum creatinine concentration at 48 hours after the procedure. The secondary end points included serum cystatin C kinetics and rate of in-hospital dialysis. Contrast-induced acute kidney injury occurred in 16 of 146 patients in the RenalGuard group (11%) and in 30 of 146 patients in the control group (20.5%; odds ratio, 0.47; 95% confidence interval, 0.24 to 0.92). There were 142 patients (48.5%) with an estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 and 149 patients (51.5%) with only a risk score ≥11. Subgroup analysis according to inclusion criteria showed a similarly lower risk of adverse events (estimated glomerular filtration rate ≤30 mL · min(-1) · 1.73 m(-2): odds ratio, 0.44; risk score ≥11: odds ratio, 0.45; P for interaction=0.97). Changes in cystatin C at 24 hours (0.02±0.32 versus -0.08±0.26; P=0.002) and 48 hours (0.12±0.42 versus 0.03±0.31; P=0.001) and the rate of in-hospital dialysis (4.1% versus 0.7%; P=0.056) were higher in the control group. RenalGuard therapy is superior to sodium bicarbonate and N-acetylcysteine in preventing contrast-induced acute kidney injury in high-risk patients. URL: http://www.clinicaltrial.gov. Unique identifier: NCT01098032.

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure.

PubMed

Yaqoob, Noreen; Evans, Andrew; Foster, John R; Lock, Edward A

2014-09-02

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500mg/kg/day) or TCE-OH at (100mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism

Retinoid agonist isotretinoin ameliorates obstructive renal injury.

PubMed

Schaier, Matthias; Jocks, Thomas; Grone, Hermann-Josef; Ritz, Eberhard; Wagner, Juergen

2003-10-01

Interstitial fibrosis is a major cause of end stage renal failure. Retinoids, which are involved in tissue repair and fibrosis, inhibit inflammatory and proliferative pathways. Therefore, we studied the dose dependent effects of the retinoid receptor agonist isotretinoin 13-cis retinoic acid in the unilateral ureteral obstruction model (UUO). Sham operated control rats were compared with UUO rats treated with vehicle (UUO-Veh), or low (5 mg/kg body weight (UUO-LD) or high (25 mg/kg) (UUO-HD) dose isotretinoin. Kidneys were evaluated using reverse transcriptase-polymerase chain reaction and immunohistology 7 days after UUO. Renal injury and fibrosis were quantified by immunostaining and expression measurements of the genes involved in renal fibrosis. In UUO-Veh kidneys the interstitial area was expanded 5-fold but only 3-fold in UUO-HD and 3.5-fold in UUO-LD rats. Interstitial cell counts were 3-fold higher in UUO-Veh rats but significantly less in UUO-HD or UUO-LD animals. Tubular and interstitial cell proliferation was significantly higher in UUO-Veh rats compared with sham operated control plus vehicle animals but less so in UUO-LD and UUO-HD rats. In UUO-Veh rats interstitial infiltration by monocytes/macrophages was higher compared with unobstructed controls. It was significantly less after isotretinoin treatment. In UUO-Veh rats mRNA for procollagen I, and transforming growth factor-beta1 and II receptor was significantly increased. It was significantly less after treatment with isotretinoin. Fibronectin and collagen I immunostaining was also decreased by isotretinoin. Since isotretinoin limits proliferation, inflammation and fibrosis after UUO, retinoids should be further investigated as potentially promising therapeutic agents for renal disease.

Blunt splenic injury: are early adverse events related to trauma, nonoperative management, or surgery?

PubMed Central

Frandon, Julien; Rodiere, Mathieu; Arvieux, Catherine; Vendrell, Anne; Boussat, Bastien; Sengel, Christian; Broux, Christophe; Bricault, Ivan; Ferretti, Gilbert; Thony, Frédéric

2015-01-01

PURPOSE We aimed to compare clinical outcomes and early adverse events of operative management (OM), nonoperative management (NOM), and NOM with splenic artery embolization (SAE) in blunt splenic injury (BSI) and identify the prognostic factors. METHODS Medical records of 136 consecutive patients with BSI admitted to a trauma center from 2005 to 2010 were retrospectively reviewed. Patients were separated into three groups: OM, NOM, and SAE. We focused on associated injuries and early adverse events. Multivariate analysis was performed on 23 prognostic factors to find predictors. RESULTS The total survival rate was 97.1%, with four deaths all occurred in the OM group. The spleen salvage rate was 91% in NOM and SAE. At least one adverse event was observed in 32.8%, 62%, and 96% of patients in NOM, SAE, and OM groups, respectively (P < 0.001). We found significantly more deaths, infectious complications, pleural drainage, acute renal failures, and pancreatitis in OM and more pseudocysts in SAE. Six prognostic factors were statistically significant for one or more adverse events: simplified acute physiology score 2 ≥25 for almost all adverse events, age ≥50 years for acute respiratory syndrome, limb fracture for secondary bleeding, thoracic injury for pleural drainage, and at least one associated injury for pseudocyst. Adverse events were not related to the type of BSI management. CONCLUSION Patients with BSI present worse outcome and more adverse events in OM, but this is related to the severity of injury. The main predictor of adverse events remains the severity of injury. PMID:26081719

Blunt splenic injury: are early adverse events related to trauma, nonoperative management, or surgery?

PubMed

Frandon, Julien; Rodiere, Mathieu; Arvieux, Catherine; Vendrell, Anne; Boussat, Bastien; Sengel, Christian; Broux, Christophe; Bricault, Ivan; Ferretti, Gilbert; Thony, Frédéric

2015-01-01

We aimed to compare clinical outcomes and early adverse events of operative management (OM), nonoperative management (NOM), and NOM with splenic artery embolization (SAE) in blunt splenic injury (BSI) and identify the prognostic factors. Medical records of 136 consecutive patients with BSI admitted to a trauma center from 2005 to 2010 were retrospectively reviewed. Patients were separated into three groups: OM, NOM, and SAE. We focused on associated injuries and early adverse events. Multivariate analysis was performed on 23 prognostic factors to find predictors. The total survival rate was 97.1%, with four deaths all occurred in the OM group. The spleen salvage rate was 91% in NOM and SAE. At least one adverse event was observed in 32.8%, 62%, and 96% of patients in NOM, SAE, and OM groups, respectively (P < 0.001). We found significantly more deaths, infectious complications, pleural drainage, acute renal failures, and pancreatitis in OM and more pseudocysts in SAE. Six prognostic factors were statistically significant for one or more adverse events: simplified acute physiology score 2 ≥25 for almost all adverse events, age ≥50 years for acute respiratory syndrome, limb fracture for secondary bleeding, thoracic injury for pleural drainage, and at least one associated injury for pseudocyst. Adverse events were not related to the type of BSI management. Patients with BSI present worse outcome and more adverse events in OM, but this is related to the severity of injury. The main predictor of adverse events remains the severity of injury.

Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress.

PubMed

Yang, Ting; Zhang, Xing-Mei; Tarnawski, Laura; Peleli, Maria; Zhuge, Zhengbing; Terrando, Niccolo; Harris, Robert A; Olofsson, Peder S; Larsson, Erik; Persson, A Erik G; Lundberg, Jon O; Weitzberg, Eddie; Carlstrom, Mattias

2017-10-01

Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0mmol/kg/day) or standard chow for two weeks prior to 30min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1β, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The Mitochondria-Targeted Antioxidant Mitoquinone Protects against Cold Storage Injury of Renal Tubular Cells and Rat Kidneys

PubMed Central

Mitchell, Tanecia; Rotaru, Dumitru; Saba, Hamida; Smith, Robin A. J.; Murphy, Michael P.

2011-01-01

The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4°C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 μM in vitro; 100 μM ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production ∼2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation. PMID:21159749

The mitochondria-targeted antioxidant mitoquinone protects against cold storage injury of renal tubular cells and rat kidneys.

PubMed

Mitchell, Tanecia; Rotaru, Dumitru; Saba, Hamida; Smith, Robin A J; Murphy, Michael P; MacMillan-Crow, Lee Ann

2011-03-01

The majority of kidneys used for transplantation are obtained from deceased donors. These kidneys must undergo cold preservation/storage before transplantation to preserve tissue quality and allow time for recipient selection and transport. However, cold storage (CS) can result in tissue injury, kidney discardment, or long-term renal dysfunction after transplantation. We have previously determined mitochondrial superoxide and other downstream oxidants to be important signaling molecules that contribute to CS plus rewarming (RW) injury of rat renal proximal tubular cells. Thus, this study's purpose was to determine whether adding mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to University of Wisconsin (UW) preservation solution could offer protection against CS injury. CS was initiated by placing renal cells or isolated rat kidneys in UW solution alone (4 h at 4°C) or UW solution containing MitoQ or its control compound, decyltriphenylphosphonium bromide (DecylTPP) (1 μM in vitro; 100 μM ex vivo). Oxidant production, mitochondrial function, cell viability, and alterations in renal morphology were assessed after CS exposure. CS induced a 2- to 3-fold increase in mitochondrial superoxide generation and tyrosine nitration, partial inactivation of mitochondrial complexes, and a significant increase in cell death and/or renal damage. MitoQ treatment decreased oxidant production ~2-fold, completely prevented mitochondrial dysfunction, and significantly improved cell viability and/or renal morphology, whereas DecylTPP treatment did not offer any protection. These findings implicate that MitoQ could potentially be of therapeutic use for reducing organ preservation damage and kidney discardment and/or possibly improving renal function after transplantation.

Multiphoton imaging for assessing renal disposition in acute kidney injury

NASA Astrophysics Data System (ADS)

Liu, Xin; Liang, Xiaowen; Wang, Haolu; Roberts, Darren M.; Roberts, Michael S.

2016-11-01

Estimation of renal function and drug renal disposition in acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but is challenging due to fluctuations in kidney function. Multiphoton microscopy has been shown to be a useful tool in studying drug disposition in liver and can reflect dynamic changes of liver function. We extend this imaging technique to investigate glomerular filtration rate (GFR) and tubular transporter functional change in various animal models of AKI, which mimic a broad range of causes of AKI such as hypoxia (renal ischemia- reperfusion), therapeutic drugs (e.g. cisplatin), rhabdomyolysis (e.g. glycerol-induced) and sepsis (e.g. LPSinduced). The MPM images revealed acute injury of tubular cells as indicated by reduced autofluorescence and cellular vacuolation in AKI groups compared to control group. In control animal, systemically injected FITC-labelled inulin was rapidly cleared from glomerulus, while the clearance of FITC-inulin was significantly delayed in most of animals in AKI group, which may reflect the reduced GFR in AKI. Following intravenous injection, rhodamine 123, a fluorescent substrate of p-glycoprotein (one of tubular transporter), was excreted into urine in proximal tubule via p-glycoprotein; in response to AKI, rhodamine 123 was retained in tubular cells as revealed by slower decay of fluorescence intensity, indicating P-gp transporter dysfunction in AKI. Thus, real-time changes in GFR and transporter function can be imaged in rodent kidney with AKI using multiphoton excitation of exogenously injected fluorescent markers.

Urinary podocalyxin, the novel biomarker for detecting early renal change in obesity.

PubMed

Suwanpen, Chayanut; Nouanthong, Phonethipsavanh; Jaruvongvanich, Veeravich; Pongpirul, Krit; Pongpirul, Wannarat Amornnimit; Leelahavanichkul, Asada; Kanjanabuch, Talerngsak

2016-02-01

The prevalence of obesity is increasing during the past decade along with obesity-related glomerulopathy (ORG), glomeruli injury due to the obesity. The major pathogenesis of ORG is the shedding of podocytes from the glomerular cell barrier into urine. Podocalyxin (PCX), a main surface antigen of podocyte, correlates well with glomerulosclerosis progression and glomerular injury severity, and might be a potential biomarker for early renal alteration in obesity. In addition, vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA) also play a role in promoting glomerulosclerosis. The aim of this study was to explore whether obese subjects without other diseases excrete more PCX-positive (PCX+) cells than non-obese individuals, in comparison with urine protein-creatinine ratio (UPCR) and glomerular filtration rate (GFR) as traditional renal markers. Moreover, the effect of body mass index (BMI) on urinary VEGF, PCX or α-SMA positive cells was also investigated. Forty-eight obese and 13 non-obese adults were included. Exfoliated cells from fresh first void morning urine were harvested, stained with PCX, VEGF, and α-SMA antibody, and quantified by flow cytometry. Correlation between interested urinary biomarkers (cells positive for PCX, VEGF plus PCX and α-SMA), UPCR and GFR with BMI and metabolic risk factors were analyzed. Obese patients had significantly higher PCX+ cells than non-obese [0.62 (0.00-13.13) vs. 0.15 (0.00-0.72) cells/ml × mg cr, p < 0.05]. There was no significant difference in GFR and UPCR between the groups. Of interest, BMI demonstrated a correlation with PCX+ cells (r = 0.343, p = 0.008) and cells positive for PCX plus VEGF (r = 0.374, p = 0.004). Obese subjects without other diseases and with normal UPCR and GFR showed evidence of renal alteration through the detection of a higher number of PCX+ cells. Increasing BMI also resulted in higher number of PCX+ cells.

End-Stage Renal Disease From Cast Nephropathy in a Teenager With Neuroendocrine Carcinoma.

PubMed

Butani, Lavjay; Ducore, Jonathan

2016-07-01

Cast nephropathy is the most common manifestation of renal injury in patients with multiple myeloma but is rarely reported in other conditions. We are reporting our experience in caring for a teenager with a metastatic neuroendocrine carcinoma who developed rapidly progressive kidney injury that advanced to end-stage renal disease. On renal biopsy extensive tubular necrosis and intratubular eosinophilic casts were noted. This previously unreported finding should prompt oncologists to closely monitor for such a complication in patients with secretory tumors. Whether early plasmapheresis could be of benefit, as has been tried in multiple myeloma, remains to be determined.

Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation

PubMed Central

Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

2016-01-01

Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment. PMID:27999546

Potentiating Tissue-Resident Type 2 Innate Lymphoid Cells by IL-33 to Prevent Renal Ischemia-Reperfusion Injury.

PubMed

Cao, Qi; Wang, Yiping; Niu, Zhiguo; Wang, Chengshi; Wang, Ruifeng; Zhang, Zhiqiang; Chen, Titi; Wang, Xin Maggie; Li, Qing; Lee, Vincent W S; Huang, Qingsong; Tan, Jing; Guo, Minghao; Wang, Yuan Min; Zheng, Guoping; Yu, Di; Alexander, Stephen I; Wang, Hui; Harris, David C H

2018-03-01

The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33-treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo -expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of amphiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo -expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33-ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy. Copyright © 2018 by the American Society of Nephrology.

The Urine Proteome as a Biomarker of Radiation Injury: Submitted to Proteomics- Clinical Applications Special Issue: "Renal and Urinary Proteomics (Thongboonkerd)"

PubMed

Sharma, Mukut; Halligan, Brian D; Wakim, Bassam T; Savin, Virginia J; Cohen, Eric P; Moulder, John E

2008-06-18

Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up of such individuals. However, no such biomarkers have yet been proven to exist. We tested the potential of high throughput proteomics to identify protein biomarkers of radiation injury after total body X-ray irradiation in a rat model. Subtle functional changes in the kidney are suggested by an increased glomerular permeability for macromolecules measured within 24 hours after TBI. Ultrastructural changes in glomerular podocytes include partial loss of the interdigitating organization of foot processes. Analysis of urine by LC-MS/MS and 2D-GE showed significant changes in the urine proteome within 24 hours after TBI. Tissue kallikrein 1-related peptidase, cysteine proteinase inhibitor cystatin C and oxidized histidine were found to be increased while a number of proteinase inhibitors including kallikrein-binding protein and albumin were found to be decreased post-irradiation. Thus, TBI causes immediately detectable changes in renal structure and function and in the urinary protein profile. This suggests that both systemic and renal changes are induced by radiation and it may be possible to identify a set of biomarkers unique to radiation injury.

Tenofovir-induced kidney injury.

PubMed

Gitman, Michael D; Hirschwerk, David; Baskin, Cindy H; Singhal, Pravin C

2007-03-01

Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor with activity against both HIV and the hepatitis B virus. It has had minimal nephrotoxic effects in early clinical trials, but as clinical use has widened, case reports describing tenofovir-induced renal tubular damage, Fanconi's syndrome and diabetes insipidus have been described. The authors review the pharmacokinetics, mechanism of action and clinical uses of tenofovir disoproxil fumarate. The large clinical trials, as well as the case reports of tenofovir-induced kidney injury, are also reviewed. The potential mechanism of renal damage is discussed and recommendations for evaluation and treatment of tenofovir-induced kidney injury are given.

Autophagy activation promotes removal of damaged mitochondria and protects against renal tubular injury induced by albumin overload.

PubMed

Tan, Jin; Wang, Miaohong; Song, Shuling; Miao, Yuyang; Zhang, Qiang

2018-01-10

Proteinuria (albuminuria) is an important cause of aggravating tubulointerstitial injury. Previous studies have shown that autophagy activation can alleviate renal tubular epithelial cell injury caused by urinary protein, but the mechanism is not clear. Here, we investigated the role of clearance of damaged mitochondria in this protective effect. We found that albumin overload induces a significant increase in turnover of LC3-II and decrease in p62 protein level in renal proximal tubular (HK-2) cells in vitro. Albumin overload also induces an increase in mitochondrial damage. ALC, a mitochondrial torpent, alleviates mitochondrial damage induced by albumin overload and also decreases autophagy, while mitochondrial damage revulsant CCCP further increases autophagy. Furthermore, pretreatment of HK-2 cells with rapamycin reduced the amount of damaged mitochondria and the level of apoptosis induced by albumin overload. In contrast, blocking autophagy with chloroquine exerted an opposite effect. Taken together, our results indicated autophagy activation promotes removal of damaged mitochondria and protects against renal tubular injury caused by albumin overload. This further confirms previous research that autophagy activation is an adaptive response in renal tubular epithelial cells after urinary protein overload.

Vascular Smooth Muscle-Specific EP4 Receptor Deletion in Mice Exacerbates Angiotensin II-Induced Renal Injury.

PubMed

Thibodeau, Jean-Francois; Holterman, Chet E; He, Ying; Carter, Anthony; Cron, Gregory O; Boisvert, Naomi C; Abd-Elrahman, Khaled S; Hsu, Karolynn J; Ferguson, Stephen S G; Kennedy, Christopher R J

2016-10-20

Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs is contraindicated in hypertension, as it may reduce glomerular filtration rate (GFR) and renal blood flow. However, the identity of the specific eicosanoid and receptor underlying these effects is not known. We hypothesized that vascular smooth muscle prostaglandin E2 (PGE2) E-prostanoid 4 (EP4) receptor deletion predisposes to renal injury via unchecked vasoconstrictive actions of angiotensin II (AngII) in a hypertension model. Mice with inducible vascular smooth muscle cell (VSMC)-specific EP4 receptor deletion were generated and subjected to AngII-induced hypertension. EP4 deletion was verified by PCR of aorta and renal vessels, as well as functionally by loss of PGE2-mediated mesenteric artery relaxation. Both AngII-treated groups became similarly hypertensive, whereas albuminuria, foot process effacement, and renal hypertrophy were exacerbated in AngII-treated EP4 VSMC-/- but not in EP4 VSMC+/+ mice and were associated with glomerular scarring, tubulointerstitial injury, and reduced GFR. AngII-treated EP4 VSMC-/- mice exhibited capillary damage and reduced renal perfusion as measured by fluorescent bead microangiography and magnetic resonance imaging, respectively. NADPH oxidase 2 (Nox2) expression was significantly elevated in AngII-treated EP4 -/- mice. EP4-receptor silencing in primary VSMCs abolished PGE2 inhibition of AngII-induced Nox2 mRNA and superoxide production. These data suggest that vascular EP4 receptors buffer the actions of AngII on renal hemodynamics and oxidative injury. EP4 agonists may, therefore, protect against hypertension-associated kidney damage. Antioxid. Redox Signal. 25, 642-656.

Renal blood flow, fractional excretion of sodium and acute kidney injury: time for a new paradigm?

PubMed

Prowle, John; Bagshaw, Sean M; Bellomo, Rinaldo

2012-12-01

Global renal blood flow is considered pivotal to renal function. Decreased global renal blood flow (decreased perfusion) is further considered the major mechanism of reduced glomerular filtration rate responsible for the development of acute kidney injury (AKI) in critically ill patients. Additionally, urinary biochemical tests are widely taught to allow the differential diagnosis of prerenal (functional) AKI and intrinsic [structural AKI (so-called acute tubular necrosis)]. In this review we will examine recent evidence regarding these two key clinical paradigms. Recent animal experiments and clinical studies in humans using cine-phase contrast magnetic resonance technology are not consistent with the decreased perfusion paradigm. They suggest instead that changes in the intra-renal circulation including modification in efferent arteriolar function and intra-renal shunting are much more likely to be responsible for AKI, especially in sepsis. Similarly, recent human studies indicate the urinary biochemistry has limited diagnostic or prognostic ability and is dissociated form biomarker and microscopic evidence of tubular injury. Intra-renal microcirculatory changes are likely more important than changes in global blood flow in the development of AKI. Urinary biochemistry is not a clinically useful diagnostic or prognostic tool in critically ill patients at risk of or with AKI.

Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model.

PubMed

Karahan, M A; Yalcin, S; Aydogan, H; Büyükfirat, E; Kücük, A; Kocarslan, S; Yüce, H H; Taskın, A; Aksoy, N

2016-06-01

Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p <  0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model.

Oxidized LDL accumulation in experimental renal ischemia reperfusion injury model.

PubMed

Kulah, Eyup; Tascilar, Oge; Acikgoz, Serefden; Tekin, Ishak Ozel; Karadeniz, Guldeniz; Can, Murat; Gun, Banu; Barut, Figen; Comert, Mustafa

2007-01-01

The aim of this study was to identify oxidative damage of kidney during ischemia reperfusion injury (IRI) by evaluating changes in lipid peroxidation markers in tissue and blood by an experimental model. Oxidized LDL (ox-LDL) was used as an oxidative stress biomarker, whereas paraoxonase (PON-1) activity was used as an antioxidative biomarker. Sixty-three male Wistar rats were randomly assigned into three groups: renal IRI, sham, and control. In the renal IRI group, the right kidney was removed and the artery and vein of the left kidney were clamped for 90 minutes. The presence of ox-LDL in the kidney tissue sections was determined by using an immunofluorescent staining method. The plasma ox-LDL levels did not increase significantly at the 24th hour following IRI, made a peak at the 48th hour, and declined at the 72nd hour. Accumulation of ox-LDL was detected in the kidney tissue on the 24th, 48th, and 72nd hours of the renal IRI. Serum PON-1 levels have peaked on the 24th hour and then declined. This study demonstrates the accumulation of ox-LDL molecules in the renal tissues of the IRI model. Future strategies aimed to reduce the lipid peroxidation during the initial hours of renal IRI may be useful to prevent complications of ischemia.

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury

PubMed Central

Huang, Qingsong; Niu, Zhiguo; Tan, Jing; Yang, Jun; Liu, Yun; Ma, Haijun; Lee, Vincent W.S.; Sun, Shuming; Song, Xiangfeng; Guo, Minghao; Wang, Yiping

2015-01-01

IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPPtype2) cells in kidney. IL-25–responsive ILC2 and MPPtype2 cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPPtype2 cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPPtype2 cells regulate macrophage phenotype in kidney and prevent renal IRI. PMID:25556172

Allopurinol attenuates rhabdomyolysis-associated acute kidney injury: Renal and muscular protection.

PubMed

Gois, Pedro H F; Canale, Daniele; Volpini, Rildo A; Ferreira, Daniela; Veras, Mariana M; Andrade-Oliveira, Vinicius; Câmara, Niels O S; Shimizu, Maria H M; Seguro, Antonio C

2016-12-01

Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF 2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion.

PubMed

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.

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

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. Copyright © 2013. Published by Elsevier Ltd.

Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury.

PubMed

García-Arroyo, Fernando E; Cristóbal, Magdalena; Arellano-Buendía, Abraham S; Osorio, Horacio; Tapia, Edilia; Soto, Virgilia; Madero, Magdalena; Lanaspa, Miguel A; Roncal-Jiménez, Carlos; Bankir, Lise; Johnson, Richard J; Sánchez-Lozada, Laura-Gabriela

2016-07-01

Recurrent dehydration, such as commonly occurs with manual labor in tropical environments, has been recently shown to result in chronic kidney injury, likely through the effects of hyperosmolarity to activate both vasopressin and aldose reductase-fructokinase pathways. The observation that the latter pathway can be directly engaged by simple sugars (glucose and fructose) leads to the hypothesis that soft drinks (which contain these sugars) might worsen rather than benefit dehydration associated kidney disease. Recurrent dehydration was induced in rats by exposure to heat (36°C) for 1 h/24 h followed by access for 2 h to plain water (W), a 11% fructose-glucose solution (FG, same composition as typical soft drinks), or water sweetened with noncaloric stevia (ST). After 4 wk plasma and urine samples were collected, and kidneys were examined for oxidative stress, inflammation, and injury. Recurrent heat-induced dehydration with ad libitum water repletion resulted in plasma and urinary hyperosmolarity with stimulation of the vasopressin (copeptin) levels and resulted in mild tubular injury and renal oxidative stress. Rehydration with 11% FG solution, despite larger total fluid intake, resulted in greater dehydration (higher osmolarity and copeptin levels) and worse renal injury, with activation of aldose reductase and fructokinase, whereas rehydration with stevia water had opposite effects. In animals that are dehydrated, rehydration acutely with soft drinks worsens dehydration and exacerbates dehydration associated renal damage. These studies emphasize the danger of drinking soft drink-like beverages as an attempt to rehydrate following dehydration. Copyright © 2016 the American Physiological Society.

Renal oxygenation and hemodynamics in acute kidney injury and chronic kidney disease

PubMed Central

Singh, Prabhleen; Ricksten, Sven-Erik; Bragadottir, Gudrun; Redfors, Bengt; Nordquist, Lina

2013-01-01

Summary 1. Acute kidney injury (AKI) puts a major burden on health systems that may arise from multiple initiating insults, including ischemia-reperfusion injury, cardiovascular surgery, radio-contrast administration as well as sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage kidney disease (ESRD). 2. Although the mechanisms for development of AKI and progression of CKD remain poorly understood, initial impairment of oxygen balance is likely to constitute a common pathway, causing renal tissue hypoxia and ATP starvation that will in turn induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop-diuretics, inducible nitric oxide synthase inhibitors and atrial natriuretic peptide, substances that target kidney oxygen consumption and regulators of renal oxygenation such as nitric oxide and heme oxygenase-1. PMID:23360244

Anemia and Long-Term Renal Prognosis in Patients with Post-Renal Acute Kidney Injury of Nonmalignant Cause.

PubMed

Sasaki, Sho; Kawarazaki, Hiroo; Hasegawa, Takeshi; Shima, Hideaki; Naganuma, Toshihide; Shibagaki, Yugo

2017-01-01

The renal prognosis of post-renal acute kidney injury (PoR-AKI) has not been verified so far. The objective of this study was to assess the association of baseline anemia with long-term renal prognosis in patients with PoR-AKI. We performed a multicenter retrospective cohort study. Consecutive adult patients from December 2006 to February 2010, who met the requirements as mentioned in the definition of PoR-AKI, were included. Patients without data on baseline renal function and at 6 months after PoR-AKI were excluded. We set baseline hemoglobin (Hb) level (g/dl) as the main exposure to be tested. The main outcome measure was long-term renal prognosis as determined by the difference between proximate estimated glomerular filtration rate (eGFR) at 6 months after diagnosis of PoR-AKI and baseline eGFR prior to the occurrence of the present PoR-AKI (ΔeGFR after 6 months) using the general linear model. We included 136 patients with PoR-AKI. The most frequent cause of PoR-AKI was malignancy, accounting for 39.0% (n = 53) of cases. Multivariate analysis adjusted for possible confounders showed that ΔeGFR after 6 months significantly changed by -4.28 ml/min/1.73 m2 for every 1 g/dl lower Hb at diagnosis (95% CI 1.86-6.69, p < 0.01). An additional multivariate analysis that was stratified by the presence or absence of malignancy as the cause of PoR-AKI yielded the same significant result only in the stratum of the nonmalignant cause of PoR-AKI. Patients with a nonmalignant cause of PoR-AKI who have baseline anemia may have poor long-term renal prognosis. In these cases, close observation of renal function after renal recovery may be required. © 2016 S. Karger AG, Basel.

Cystatin C as an early marker of acute kidney injury in septic shock.

PubMed

Ortuño-Andériz, F; Cabello-Clotet, N; Vidart-Simón, N; Postigo-Hernández, C; Domingo-Marín, S; Sánchez-García, M

2015-03-01

To describe the utility of determining plasma cystatinC concentrations in the diagnosis of acute incident kidney injury in septic shock. Prospective series of 50 patients with septic shock and plasma creatinine levels <2mg/dL hospitalized in an intensive care unit. Clinical and laboratory follow-ups were conducted, with measurements of cystatinC, urea and plasma creatinine levels from the diagnosis of septic shock to 5days later. The severity of the septic shock was assessed with the RIFLE scale. Twenty patients (40%) developed acute kidney injury: 8 (16%) were categorized as RIFLE-R, 5 (10%) as RIFLE-I and 7 (14%) as RIFLE-F. All patients categorized as RIFLE-F required extracorporeal renal clearance. Eighteen (36%) patients died, 8 (20%) of whom had developed acute kidney injury in their evolution. There was poor correlation between plasma creatinine and cystatin C levels (r=.501; P=.001), which disappeared upon reaching any degree of renal impairment on the RIFLE scale. CystatinC levels increased earlier and were better able to identify patients who would develop serious renal function impairment (RIFLE-F) than creatinine and urea levels. The initial cystatinC levels were related to mortality at 30days (OR=1.16; 95%CI: 03-.85). For patients who developed acute septic kidney injury, the plasma cystatinC levels increased before the classical markers of renal function. CystatinC also constitutes a severity biomarker that correlates with progression to RIFLE-F, the need for extrarenal clearance and, ultimately, mortality. This precocity could be useful for starting measures that prevent the progression of renal dysfunction. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Medicare Program; End-Stage Renal Disease Prospective Payment System, Payment for Renal Dialysis Services Furnished to Individuals With Acute Kidney Injury, and End-Stage Renal Disease Quality Incentive Program. Final rule.

PubMed

2017-11-01

This rule updates and makes revisions to the end-stage renal disease (ESRD) prospective payment system (PPS) for calendar year (CY) 2018. It also updates the payment rate for renal dialysis services furnished by an ESRD facility to individuals with acute kidney injury (AKI). This rule also sets forth requirements for the ESRD Quality Incentive Program (QIP), including for payment years (PYs) 2019 through 2021.

Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.

PubMed

Akbas, Alpaslan; Silan, Coskun; Gulpinar, Murat Tolga; Sancak, Eyup Burak; Ozkanli, Sidika Seyma; Cakir, Dilek Ulker

2015-12-01

Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.

Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat.

PubMed

Azari, Omid; Kheirandish, Reza; Azizi, Shahrzad; Farajli Abbasi, Mohammad; Ghahramani Gareh Chaman, Shahin; Bidi, Masoud

2015-01-01

Renal ischemia reperfusion injury may occur in a variety of clinical situations, following a transient drop in total or regional blood flow to the kidney. This study was performed to investigate the protective effects of different antioxidants such as vitamin C, vitamin E, hydrocortisone and combination of these agents against experimental renal ischemia-reperfusion injury. Thirty male rats were divided into six groups. Group Sham, Group I/R: (45 min of ischemia followed by 1h of reperfusion), Group I/R+Vit C: (50 mg/kg Vit C, IV, immediately after reperfusion), Group I/R+Vit E: (20 mg/kg Vit E, IM, 15 min before reperfusion), Group I/R+Hydrocortisone: (50 mg/kg, IV, immediately after reperfusion), and Group Combination: Ischemia-reperfusion plus combination of Vit C, E and hydrocortisone. After the experiments, the left kidney was removed and the tissues were processed for histopathological examination. Severe injuries such as necrosis of tubules, atrophy of glomerulus, and hemorrhage were observed in group I/R. Histological scores indicating tissue injury significantly decreased in all treatment groups compared to the group I/R. The renal tissue in group treatment was preserved in comparison with the group I/R. Comparison between the treatment groups showed that group combination was more effective and group vit E was less effective in protecting of renal tissue against I/R injuries. The results demonstrated simultaneous administration of combination of Vit C, E and hydrocortisone before reperfusion of blood flow to the ischemic tissue could show a synergy against deleterious effects of I/R injuries in kidney.

The effect of prolonged of warm ischaemic injury on renal function in an experimental ex vivo normothermic perfusion system.

PubMed

Hosgood, Sarah A; Shah, K; Patel, M; Nicholson, M L

2015-06-30

Donation after circulatory death (DCD) kidney transplants inevitably sustain a degree of warm ischaemic injury, which is manifested clinically as delayed graft function. The aim of this study was to define the effects of prolonged periods of warm ischaemic injury on renal function in a normothermic haemoperfused kidney model. Porcine kidneys were subjected to 15, 60, 90 (n = 6 per group) and 120 min (n = 4) of in situ warm ischaemia (WI) and then retrieved, flushed with cold preservation fluid and stored in ice for 2 h. Kidneys then underwent 3 h of normothermic reperfusion with a whole blood-based perfusate using an ex vivo circuit developed from clinical grade cardiopulmonary bypass technology. Creatinine clearance, urine output and fractional excretion of sodium deteriorated sequentially with increasing warm time. Renal function was severely compromised after 90 or 120 min of WI but haemodynamic, metabolic and histological parameters demonstrated the viability of kidneys subjected to prolonged warm ischaemia. Isolated kidney perfusion using a warm, oxygenated, red cell-based perfusate allows an accurate ex vivo assessment of the potential for recovery from warm ischaemic injury. Prolonged renal warm ischaemic injury caused a severe decrement in renal function but was not associated with tissue necrosis.

Omega-3 attenuates high fat diet-induced kidney injury of female rats and renal programming of their offsprings.

PubMed

Shamseldeen, Asmaa Mohammed; Ali Eshra, Mohammed; Ahmed Rashed, Laila; Fathy Amer, Marwa; Elham Fares, Amal; Samir Kamar, Samaa

2018-05-09

Maternal diet composition could influence fetal organogenesis. We investigated effects of high fat diet (HFD) intake alone or combined with omega 3 during pregnancy, lactation and early days of weaning on nephrogenesis of pups and maternal renal function and morphology. Mothers and their pups included in each group were supplied with the same diet composition. Rats were divided into group I, II and III supplied with chow of either 10 kcal%, 45 kcal% or 45 kcal% from fat together with omega-3 respectively. Group II showed increased serum urea and creatinine, renal TNF-α, IL1β. Structural injury was observed in mothers and their pups as Bowman's capsule and tubular dilatation and increased expression of PCNA that were decreased following omega-3 supplementation added to down regulation of Wnt4, Pax2 gene and podocin expression. Omega-3 supplementation improves lipid nephrotoxicity observed in mothers and their pups.

Following specific podocyte injury captopril protects against progressive long term renal damage.

PubMed

Zhou, Yu S; Ihmoda, Ihmoda A; Phelps, Richard G; Bellamy, Christopher Os; Turner, A Neil

2015-01-01

Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model. We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group. After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05). Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury.

Reduction of high-energy shock-wave-induced renal tubular injury by selenium.

PubMed

Strohmaier, W L; Lahme, S; Weidenbach, P M; Bichler, K H

1999-10-01

In shock-wave-induced renal injury cavitation-generated free radicals play an important role. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of selenium, a free radical scavenger, in shock-wave-induced tubular cell injury. Suspensions of MDCK cells (33 x 10(6) cells/ml) were placed in small containers (volume 1.1 ml) for shock wave exposure. Two groups of 12 containers each were examined: (1) control (no medication), (2) selenium (0.4 microg/ml nutrient medium). Six containers in each group were exposed to shock waves (impulse rate 256, frequency 60 Hz, generator voltage 18 kV), while the other six containers in each group served as a control. After shock wave exposure, the concentration of cellular enzymes such as lactate dehydrogenase (LDH), N-acetyl-beta-glucosaminidase (NAG), glutamate oxaloacetate transaminase (GOT) and glutamate lactate dehydrogenase (GLDH) in the nutrient medium was examined. Following shock wave exposure there was a significant rise in LDH, NAG, GOT and GLDH concentrations. Selenium reduced this enzyme leakage significantly. Thus we conclude that selenium protects renal tubular cells against shock-wave-induced injury. Since selenium is an essential part of glutathione peroxidase, this effect seems to be mediated by a reduction in reactive oxygen species.

Effect of Regular Exercise on the Histochemical Changes of d-Galactose-Induced Oxidative Renal Injury in High-Fat Diet-Fed Rats

PubMed Central

Park, Sok; Kim, Chan-Sik; Lee, Jin; Suk Kim, Jung; Kim, Junghyun

2013-01-01

Renal lipid accumulation exhibits slowly developing chronic kidney disease and is associated with increased oxidative stress. The impact of exercise on the obese- and oxidative stress-related renal disease is not well understood. The purpose of this study was to investigate whether a high-fat diet (HFD) would accelerate d-galactose-induced aging process in rat kidney and to examine the preventive effect of regular exercise on the obese- and oxidative stress-related renal disease. Oxidative stress was induced by an administration of d-galactose (100 mg/kg intraperitoneally injected) for 9 weeks, and d-galactose-treated rats were also fed with a high-fat diet (60% kcal as fat) for 9 weeks to induce obesity. We investigated the efficacy of regular exercise in reducing renal injury by analyzing Nε-carboxymethyllysine (CML), 8-hydroxygluanine (8-OHdG) and apoptosis. When rats were fed with a HFD for 9 weeks in d-galactose-treated rats, an increased CML accumulation, oxidative DNA damage and renal podocyte loss were observed in renal glomerular cells and tubular epithelial cells. However, the regular exercise restored all these renal changes in HFD plus d-galactose-treated rats. Our data suggested that long-term HFD may accelerate the deposition of lipoxidation adducts and oxidative renal injury in d-galactose-treated rats. The regular exercise protects against obese- and oxidative stress-related renal injury by inhibiting this lipoxidation burden. PMID:24023395

Silymarin protects against renal injury through normalization of lipid metabolism and mitochondrial biogenesis in high fat-fed mice.

PubMed

Bin Feng; Meng, Ran; Bin Huang; Bi, Yan; Shen, Shanmei; Zhu, Dalong

2017-09-01

Obesity is associated with an increased risk of chronic kidney diseases and the conventional treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors is not enough to prevent renal injury and prolong the progression of disease. Recently, silymarin has shown protective effects on renal tissue injury, but the underlying mechanisms remain elusive. The goal of this study was to investigate the potential capacity of silymarin to prevent renal injury during obesity induced by high fat diet (HFD) in mice. In vivo, male C57BL/6 mice received HFD (60% of total calories) for 12 weeks, randomized and treated orally with vehicle saline or silymarin (30mg/kg body weight/d) for 4 weeks. In vitro, human proximal tubular epithelial cells (HK2) were exposed to 300μM palmitic acid (PA) for 36h followed by silymarin administration at different concentrations. The administration of silymarin significantly ameliorated HFD induced glucose metabolic disorders, oxidative stress and pathological alterations in the kidney. Silymarin significantly mitigated renal lipid accumulation, fatty acid β-oxidation and mitochondrial biogenesis in HFD mice and PA treated HK2 cells. Furthermore, silymarin partly restored mitochondrial membrane potential of HK2 cells after PA exposure. In conclusion, silymarin can improve oxidative stress and preserve mitochondrial dysfunction in the kidney, potentially via preventing accumulation of renal lipids and fatty acid β-oxidation. Copyright © 2017. Published by Elsevier Inc.

A randomised controlled trial evaluating renal protective effects of selenium with vitamins A, C, E, verapamil, and losartan against extracorporeal shockwave lithotripsy-induced renal injury.

PubMed

El-Nahas, Ahmed R; Elsaadany, Mohamed M; Taha, Diaa-Eldin; Elshal, Ahmed M; El-Ghar, Mohamed Abo; Ismail, Amani M; Elsawy, Essam A; Saleh, Hazem H; Wafa, Ehab W; Awadalla, Amira; Barakat, Tamer S; Sheir, Khaled Z

2017-01-01

To evaluate the protective effects of selenium with vitamins A, C and E (selenium ACE, i.e. antioxidants), verapamil (calcium channel blocker), and losartan (angiotensin receptor blocker) against extracorporeal shockwave lithotripsy (ESWL)-induced renal injury. A randomised controlled trial was conducted between August 2012 and February 2015. Inclusion criteria were adult patients with a single renal stone (<2 cm) suitable for ESWL. Patients with diabetes, hypertension, congenital renal anomalies, moderate or marked hydronephrosis, or preoperative albuminuria (>300 mg/L) were excluded. ESWL was performed using the electromagnetic DoLiS lithotripter. Eligible patients were randomised into one of four groups using sealed closed envelopes: Group1, control; Group 2, selenium ACE; Group 3, losartan; and Group 4, verapamil. Albuminuria and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were estimated after 2-4 h and 1 week after ESWL. The primary outcome was differences between albuminuria and uNGAL. Dynamic contrast-enhanced magnetic resonance imaging was performed before ESWL, and at 2-4 h and 1 week after ESWL to compare changes in renal perfusion. Of 329 patients assessed for eligibility, the final analysis comprised 160 patients (40 in each group). Losartan was the only medication that showed significantly lower levels of albuminuria after 1 week (P < 0.001). For perfusion changes, there was a statistically significant decrease in the renal perfusion in patients with obstructed kidneys in comparison to before ESWL (P = 0.003). These significant changes were present in the control or antioxidant group, whilst in the losartan and verapamil groups renal perfusion was not significantly decreased. Losartan was found to protect the kidney against ESWL-induced renal injury by significantly decreasing post-ESWL albuminuria. Verapamil and losartan maintained renal perfusion in patients with post-ESWL renal obstruction. © 2016 The Authors BJU International �

Hibiscus sabdariffa Linnaeus aqueous extracts attenuate the progression of renal injury in 5/6 nephrectomy rats.

PubMed

Seujange, Yuyen; Leelahavanichkul, Asada; Yisarakun, Waranurin; Khawsuk, Witoon; Meepool, Ardool; Phamonleatmongkol, Ponlapat; Saechau, Walai; Onlamul, Winita; Tantiwarattanatikul, Pansa; Oonsook, Worapong; Eiam-Ong, Somchai; Eiam-Ong, Somchit

2013-01-01

Hibiscus sabdariffa Linn. (HS) is a tropical wild plant with antioxidant, antibacterial, antihypertensive, and lipid-lowering properties. In several animal models, HS aqueous extracts reduced the severity of the multi-organ injuries such as hypertension and diabetic nephropathy. One of the multiorgan injuries is chronic kidney disease (CKD), which results from the loss of nephron function. HS was used in a 5/6 nephrectomy (5/6 Nx) rat model to determine if it could attenuate the progression of CKD. HS (250 mg/kg/day) or placebo was orally administered to 5/6 Nx male Sprague-Dawley rats. The Nx+HS group had fewer renal injuries as measured by blood urea nitrogen, serum creatinine, creatinine clearance, and renal pathology when compared with the Nx group. In order to determine which property of HS, either vasodilatory and/or antioxidant, was important in attenuating the progression of CKD, systolic blood pressure (SBP) and serum levels of malondialdehyde (MDA) were assessed. In the Nx+HS group, the SBP and the serum levels of MDA were significantly lower at Week 7. In conclusion, through either antihypertensive and/or antioxidant properties, HS was able to attenuate the progression of renal injury after 5/6 Nx. Hence, HS should be considered as one of the new, promising drugs that can be used to attenuate the progression of CKD.

Early Focal Segmental Glomerulosclerosis as a Cause of Renal Allograft Primary Nonfunction

PubMed Central

Griffin, Emma J.; Thomson, Peter C.; Kipgen, David; Clancy, Marc; Daly, Conal

2013-01-01

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered. PMID:23781382

The Identification of Novel Potential Injury Mechanisms and Candidate Biomarkers in Renal Allograft Rejection by Quantitative Proteomics*

PubMed Central

Sigdel, Tara K.; Salomonis, Nathan; Nicora, Carrie D.; Ryu, Soyoung; He, Jintang; Dinh, Van; Orton, Daniel J.; Moore, Ronald J.; Hsieh, Szu-Chuan; Dai, Hong; Thien-Vu, Minh; Xiao, Wenzhong; Smith, Richard D.; Qian, Wei-Jun; Camp, David G.; Sarwal, Minnie M.

2014-01-01

Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a “hub” protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

PubMed

Stevens, R Brian; Lane, James T; Boerner, Brian P; Miles, Clifford D; Rigley, Theodore H; Sandoz, John P; Nielsen, Kathleen J; Skorupa, Jill Y; Skorupa, Anna J; Kaplan, Bruce; Wrenshall, Lucile E

2012-01-01

Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia. Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed. Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus). © 2011 John Wiley & Sons A/S.

Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced nephropathy.

PubMed

Arias, Simone Costa Alarcon; Valente, Carla Perez; Machado, Flavia Gomes; Fanelli, Camilla; Origassa, Clarice Silvia Taemi; de Brito, Thales; Camara, Niels Olsen Saraiva; Malheiros, Denise Maria Avancini Costa; Zatz, Roberto; Fujihara, Clarice Kazue

2013-01-01

Treatments that effectively prevent chronic kidney disease (CKD) when initiated early often yield disappointing results when started at more advanced phases. We examined the long-term evolution of renal injury in the 5/6 nephrectomy model (Nx) and the effect of an association between an AT-1 receptor blocker, losartan (L), and hydrochlorothiazide (H), shown previously to be effective when started one month after Nx. Adult male Munich-Wistar rats underwent Nx, being divided into four groups: Nx+V, no treatment; Nx+L, receiving L monotherapy; Nx+LH, receiving the L+H association (LH), and Nx+AHHz, treated with the calcium channel blocker, amlodipine, the vascular relaxant, hydralazine, and H. This latter group served to assess the effect of lowering blood pressure (BP). Rats undergoing sham nephrectomy (S) were also studied. In a first protocol, treatments were initiated 60 days after Nx, when CKD is at a relatively early stage. In a second protocol, treatments were started 120 days after Nx, when glomerulosclerosis and interstitial fibrosis are already advanced. In both protocols, L treatment promoted only partial renoprotection, whereas LH brought BP, albuminuria, tubulointerstitial cell proliferation and plasma aldosterone below pretreatment levels, and completely detained progression of renal injury. Despite normalizing BP, the AHHz association failed to prevent renal damage, indicating that the renoprotective effect of LH was not due to a systemic hemodynamic action. These findings are inconsistent with the contention that thiazides are innocuous in advanced CKD. In Nx, LH promotes effective renoprotection even at advanced stages by mechanisms that may involve anti-inflammatory and intrarenal hemodynamic effects, but seem not to require BP normalization.

Biomarkers-a potential route for improved diagnosis and management of ongoing renal damage.

PubMed

Oberbauer, R

2008-12-01

Currently, the identification and validation of biomarkers of kidney injury is among the top priorities of many diagnostic biotechnology companies as well as academic research institutes. Specifically, in renal transplantation, validated biomarkers of tissue injury with good discriminatory power between the various renal compartments and the underlying pathophysiology are desired, because sequential allograft biopsies are limited in number and cannot be used as a screening tool. Given the high demands on these markers, it is not surprising that none of those currently under evaluation has been thoroughly validated for a specific entity. Published biomarker candidates for early tubular damage include neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, soluble CD30, perforin, and granzyme B. Recently, C4d flow panel reactive antibodies were evaluated as biomarkers for humoral alloimmune responses. Additional biomarkers such as FOXP3 and kidney injury molecule 1 have been studied in the maintenance phase of renal transplantation. Given the complex prerequisites, it is not surprising that no biomarker panel has been sufficiently validated for clinical use. However, in the near future a biomarker for use as an indicator of renal tubule cell injury will be available. Troponin T or transaminase of the kidney may then at least be used to differentiate between functional renal failure (equivalent to a rise in creatinine) and intrinsic kidney injury.

Obstructive renal injury: from fluid mechanics to molecular cell biology.

PubMed

Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

2010-04-22

Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

Obstructive uropathy and severe acute kidney injury from renal calculi due to adenine phosphoribosyltransferase deficiency.

PubMed

Chong, Siew Le; Ng, Yong Hong

2016-05-01

Adenine phosphoribosyltransferase (APRT) deficiency is an uncommon genetic cause of chronic kidney disease due to crystalline nephropathy. A case of a Chinese boy with APRT deficiency presenting with severe acute kidney injury secondary to obstructive uropathy from multiple renal calculi was reviewed. The patient underwent staged removal of the calculi. Infrared spectrometry of the renal calculi showed 2,8-dihydroxyadenine. APRT deficiency was confirmed with abolished APRT enzyme activity in red blood cells. He was started on allopurinol and low purine diet with complete resolution of the residual calculi. APRT deficiency should be considered in patients with multiple radiolucent renal calculi.

Exaggerated Liver Injury Induced by Renal Ischemia Reperfusion in Diabetes: Effect of Exenatide

PubMed Central

Vaghasiya, Jitendra D.; Sheth, Navin R.; Bhalodia, Yagnik S.; Jivani, Nurudin P.

2010-01-01

Background/Aim: This study was designed to investigate the possible effect of exenatide (Glucagon like Peptide-1 receptor agonist) on liver injury (distant organ) induced by renal ischemia reperfusion (IR) in diabetic rats. Materials and Methods: In vivo renal IR was performed in both type 2 diabetic and normal rats. Each protocol comprised ischemia for 30 minutes followed by reperfusion for 24 hours and a treatment period of 14 days before induction of ischemia. Results: Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in liver tissue were significantly increased (P < 0.01, P < 0.001, P < 0.001, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Antioxidant enzymes like glutathione, superoxide dismutase, catalase and glutathione peroxidase were significantly reduced (P < 0.05, P < 0.05, P < 0.01, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Exenatide treatment significantly normalized (P < 0.01), these biochemical parameters in treated rats compared to diabetic IR rats. Serum creatinine phosphokinase activity and liver function enzymes were also significantly normalized (P < 0.001, P < 0.001, respectively), after administration of exenatide. Conclusion: Exenatide exerted protective effect on exaggerated remote organ (liver) injury induced by renal IR in diabetes. PMID:20616412

MicroRNA-125b as a new potential biomarker on diagnosis of renal ischemia-reperfusion injury.

PubMed

Güçlü, Aydın; Koçak, Cengiz; Koçak, Fatma E; Akçılar, Raziye; Dodurga, Yavuz; Akçılar, Aydın; Elmas, Levent

2017-01-01

Acute renal failure is commonly seen in the perioperative period. Ischemia-reperfusion (IR) injury plays a major role in acute renal failure and delayed graft function. MicroRNAs (miRs), which are pivotal modulators of cell activities, offer a major opportunity for affective diagnosis and treatment strategies because they are tissue specific and in the center of gene expression modulation. The effect of bardoxolone methyl (BM) on miR-21, miR-223-5p, and miR-125b in renal IR injury was evaluated in this study. Wistar-Albino rats (12-16 wk old, weighing 300-350 g) were used in the study. Rats (n = 6) were randomized into three groups (control, IR, and BM + IR). Tissue levels of miRs were analyzed with reverse transcription polymerase chain reaction. Significant reduction of urea and total oxidant status, increase of total antioxidant status, and oxidative stress index were identified in the IR + BM group compared with the IR group. Significant increases of miR-21 (2842.82-fold) and miR-125b (536.8-fold) were identified in the IR group compared with the control group; however, miR-223-5p levels did not show any significant difference. Also, miR-21 and miR-125b were significantly reduced in the IR + BM group compared with the IR group. Reduced histopathologic changes were observed in the IR + BM group. A significant decrease in the number of tunel-positive cells was identified in the IR + BM group compared with the IR group. miR-125b was significantly increased in IR injury; thus, miR-125b can be a potential novel marker that can be used in diagnosis and treatment of renal IR injury. BM reduces miR-21 and miR-125b in case of IR injury and makes functional and histopathologic repairs. Copyright © 2016 Elsevier Inc. All rights reserved.

The central role of renal microcirculatory dysfunction in the pathogenesis of acute kidney injury.

PubMed

Ince, Can

2014-01-01

Acute kidney injury (AKI) is a rapidly developing condition often associated with critical illness, with a high degree of morbidity and mortality, whose pathophysiology is ill understood. Recent investigations have identified the dysfunction of the renal microcirculation and its cellular and subcellular constituents as being central to the etiology of AKI. Injury is caused by inflammatory activation involving endothelial leucocyte interactions in combination with dysregulation of the homeostatis between oxygen, nitric oxide, and reactive oxygen species. Effective therapies expected to resolve AKI will have to control inflammation and restore this homeostasis. In order to apply and guide these therapies effectively, diagnostic tools aimed at physiological biomarkers of AKI for monitoring renal microcirculatory function in advance of changes in pharmacological biomarkers associated with structural damage of the kidney will need to be developed. 2014 S. Karger AG, Basel.

Urinary NGAL and hematic ADMA levels: an early sign of cardio-renal syndrome in young adults born preterm?

PubMed

Bassareo, Pier Paolo; Fanos, Vassilios; Mussap, Michele; Flore, Giovanna; Noto, Antonio; Puddu, Melania; Saba, Luca; Mercuro, Giuseppe

2013-10-01

Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 ± 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. Urinary NGAL levels were higher in ex- ELBW subjects compared to C (p < 0.05), as well as hematic ADMA concentrations (p < 0.05). A statistically significant correlation was found between urinary NGAL and ADMA (r = -0.60, p < 0.04). Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.

A new electromagnetic shock-wave generator "SLX-F2" with user-selectable dual focus size: ex vivo evaluation of renal injury.

PubMed

Leistner, Rasmus; Wendt-Nordahl, Gunnar; Grobholz, Rainer; Michel, Maurice Stephan; Marlinghaus, Ernst; Köhrmann, Kai Uwe; Alken, Peter; Häcker, Axel

2007-08-01

Storz Medical AG (Kreutzlingen/Switzerland) has developed a new electromagnetic shockwave (SW) generator, the "SLX-F2", which allows the user to choose between a small-focus, high-pressure treatment regime or a wide-focus, low-pressure option. The aim of this study was to investigate, under standardized conditions, the impact of these two different treatment regimes on SW-induced renal injury. SW-induced renal injury was investigated by using the standardized model of the perfused ex vivo kidney. SWs were applied under ultrasound control in the parenchyma of a kidney pole. Different SW numbers (20, 50, 125, 250, 500, 1,000) were applied in three groups: group A was treated with a wider focus (80 MPa), groups B (60 MPa) and C (120 MPa) with a smaller focus (each parameter setting was repeated ten-fold). Disintegration capacity (measured by crater volume in cubes of plaster of Paris) was the same in groups A and C. After SW exposure, barium sulphate suspension was perfused through the renal artery. The maximum diameter (mm) of the extravasation in the cortex, representing the extent of vascular injury, was measured on X-ray mammography films. H&E staining was performed. In all three groups (A, B, C) a higher number of SWs caused the diameter of the extravasate to increase, with statistical significance appearing at 1,000 shots versus 20 shots (p < 0.05). Vascular injury was not influenced by the focal size and positive peak pressure at identical SW numbers applied. Histology of the focal area showed gap-like defects. Our ex vivo data show that renal vascular injury is independent of the focal diameter of the SW generator at the same peak positive pressure and disintegration power. This confirms the in vivo findings that show renal injury caused by SW as being related to the number of SWs administered. Clinical studies are needed to investigate whether there is any advantage to offering both treatment regimes in one SW machine-for example, by using the "wide

CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.

PubMed

Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing; Thomson, Angus W; Isenberg, Jeffrey S

2016-08-01

Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

The renoprotective effects of mannitol and udenafil in renal ischemia-reperfusion injury model.

PubMed

Özlülerden, Yusuf; Toktaş, Cihan; Aybek, Hülya; Küçükatay, Vural; Şen Türk, Nilay; Zumrutbas, Ali Ersin

2017-07-01

The aim of this study was to investigate and compare the effects of udenafil and mannitol in an experimental renal ischemia-reperfusion (I/R) injury model. A total of 64 female Wister Albino rats were used. Right nephrectomy was performed in all groups. In the control group; I/R injury was not performed. In the I/R group; left renal pedicle was clamped for 45 minutes and then underwent 60 minutes and 24 hours of reperfusion. In the mannitol group; 1 mL 20% mannitol was given intravenously 15 minutes before clamping. In the udenafil group; 10-mg/kg udenafil was given orally 1 hour before clamping. Creatinine (Cr), blood urea nitrogen (BUN), Cr clearance, malondialdehyde, neutrophil gelatinase associated lipocalin (NGAL), histological examination and DNA damage (Comet Assay method) levels were compared in tissue, serum and urine samples. Udenafil had a better protective effect than mannitol according to biochemical parameters (Cr, BUN, Cr clearance, and NGAL levels) and histopathological findings when compared with the I/R group. In the Comet sampling analysis no significant difference was detected. Udenafil has a better renoprotective effect than mannitol against I/R injury and this effect supports more functional improvements. Further clinical trials are needed to demonstrate those effects and clinical utility of udenafil for that purpose in humans.

Long-term verification of functional and structural renal damage after renal sympathetic denervation.

PubMed

Dörr, Oliver; Liebetrau, Christoph; Möllmann, Helge; Gaede, Luise; Troidl, Christian; Wiebe, Jens; Renker, Matthias; Bauer, Timm; Hamm, Christian; Nef, Holger

2016-06-01

Previous studies of renal sympathetic denervation (RSD) excluded patients with impaired renal function to avoid potential RSD-related renal damage. Measurement of the highly sensitive biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) has shown that RSD does not aggravate renal damage during the early post-procedural period. The aim of the present study was to examine the effect of RSD on blood pressure (BP) reduction and renal function after a long-term follow-up. A total of 62 consecutive patients undergoing RSD were included in this study. Serum NGAL and KIM-1 were collected prior to RSD and at 24 hr, 48 hr, and 3 months after RSD. BP measurements, antihypertensive medication use, and safety events were followed over a three-year period. Follow-up data were available over 36.9[±3.4] months in 47 of 62 (75.8%) of the initially included patients. At this time point a significant systolic BP reduction of 23 mm Hg (P > 0.001) was documented, and there were no significant changes in serum creatinine (P = 0.14), blood urea nitrogen (P = 0.33), or estimated glomerular filtration rate (eGFR) (P = 0.2) values. There were also no significant changes documented in patients with impaired renal function (eGFR < 45 mL/min) during the early post- procedural period or the long-term follow-up (P = 0.34). The results of the present study show a sustained effect of RSD on BP reduction after a three-year follow-up, and there was no evidence of renal failure. These results provide verification of the long-term safety and effectiveness of RSD, even in patients with impaired renal function. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Renal ultrasound provides low utility in evaluating cardiac surgery associated acute kidney injury.

PubMed

Young, Allen; Crawford, Todd; Pierre, Alejandro Suarez; Trent Magruder, J; Fraser, Charles; Conte, John; Whitman, Glenn; Sciortino, Christopher

2017-09-02

Renal ultrasonography is part of the algorithm in assessing acute kidney injury (AKI). The purpose of this study was to assess the clinical utility of renal US in postoperative cardiac patients who develop AKI. We conducted a retrospective study of 90 postoperative cardiac surgery patients at a single institution from 1/19/2010 to 3/19/2016 who underwent renal US for AKI. We reviewed provider documentation to determine whether renal US changed management. We defined change as: administration of crystalloid or colloid, addition of inotropic or vasopressor, or procedural interventions on the renal system. Mean age of study patients was 68 ± 13 years. 48/90 patients (53.3%) had pre-existing chronic kidney disease of varying severity. 48 patients (53.3%) had normal renal US with incidental findings and 31 patients (34.4%) had US evidence of medical kidney disease. 10 patients (11.1%) had limited US results due to poor visualization and 1 patient (1.1%) had mild right-sided hydronephrosis. No patients were found to have obstructive uropathy or renal artery stenosis. Clinical management was altered in only 4/90 patients (4.4%), which included 3 patients that received a fluid bolus and 1 patient that received a fluid bolus and inotropes. No vascular or urologic procedures resulted from US findings. Although renal ultrasound is often utilized in the work-up of AKI, our study shows that renal US provides little benefit in managing postoperative cardiac patients. This diagnostic modality should be scrutinized rather than viewed as a universal measure in the cardiac surgery population.

Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice.

PubMed

Xiao, Tangli; Guan, Xu; Nie, Ling; Wang, Song; Sun, Lei; He, Ting; Huang, Yunjian; Zhang, Jingbo; Yang, Ke; Wang, Junping; Zhao, Jinghong

2014-09-01

The aim was to explore the effects of rapamycin on autophagy and injury of podocytes in streptozocin (STZ)-induced type 1 diabetic mice, and its role in delaying progression of diabetic nephropathy. In this study, male Balb/c mice were divided into three groups: control (n = 12), STZ-induced diabetic (n = 12), and rapamycin-treated diabetic (DM + Rapa) (n = 12), which received intraperitoneal injection of rapamycin (2 mg/kg/48 h) after induction of DM. Levels of urinary albumin (UA), blood urea nitrogen, serum creatinine, and kidney weight/body weight were measured at week 12. Renal pathologic changes, number of podocytes autophagy, and organelles injury were investigated by PAS staining, transmission electron microscopy, and immunofluorescence staining, respectively. Western blot was performed to determine the expression of LC3 (a podocyte autophagy marker), phosphorylated mammalian target of rapamycin, p-p70S6K, bax, and caspase-3 protein. Podocytes count was evaluated by immunofluorescence staining and Wilms tumor 1 immunohistochemistry, and Western blot of nephrin and podocin. The results indicated that rapamycin could reduce the kidney weight/body weight and UA secretion. It could alleviate podocyte foot process fusion, glomerular basement membrane thickening, and matrix accumulation, and increase the number of autophagosomes, and LC3-expressing podocytes. Down-regulation of bax and caspase-3 protein, and up-regulation of nephrin and podocin protein were observed in the glomeruli of diabetic mice after administration of rapamycin. In conclusion, rapamycin can ameliorate renal injury in diabetic mice by increasing the autophagy activity and inhibition of apoptosis of podocytes.

Protective effect of Bu-zhong-yi-qi decoction, the water extract of Chinese traditional herbal medicine, on 5-fluorouracil-induced renal injury in mice.

PubMed

Xiong, Ying; Shang, Bingzhen; Xu, Siying; Zhao, Ran; Gou, He; Wang, Chun

2016-09-01

Drug-induced renal injury is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-zhong-yi-qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in Asia as an alternative treatment to reduce the side effects of chemotherapy and also improve cancer survival. However, the mechanism is unknown. This study is designed to investigate the protective effect of BZYQD on 5-FU-induced renal injury in mice. Mice were divided into four groups: the control, 5-FU, 5-FU + low, and high BZYQD group. Mice in the three latter groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for six days, and in the 5-FU + low and high BZYQD groups were given BZYQD (1 or 2 g raw herb/kg/day, intragastrically) beginning four days before 5-FU and continuing until the termination of the experiment. The right kidney fixed in formalin for histological examination and the left was homogenized to measure the levels of apoptosis-related proteins and activities of oxidative stress-related biomarkers. Blood samples were collected for measuring renal function-related biochemical indices. Renal morphology injury, increased urea nitrogen and creatinine concentration, and decreased SOD, CAT, and GSH-Px were all observed in 5-FU-administrated mice. However, BZYQD almost reversed the morphological injury as well as renal function-related indices and antioxidant enzyme activity. These results suggest that BZYQD inhibits 5-FU-induced renal injury, possibly through the reduction of apoptosis and necrosis in renal tubular epithelial cells via the antioxidant mechanism. Henceforth, BZYQD may be a potential antioxidant against drug-induced oxidative stress.

[Pathologic changes and expression of Heme oxygenase-1 in paraquat-induced renal injury].

PubMed

Tian, Ying-ping; Liu, Fu-rong; Tong, Fei; Shi, Han-wen; Yao, Dong-qi

2009-08-01

To study the mechanism of paraquat-induced renal injury in rats. Adult healthy Sprague-Dawley (SD) rats (female and male in half) were randomly divided into two groups, the control group and the paraquat poisoned group. The rats in the paraquat poisoned group were treated with PQ (25 mg/kg) intraperitoneally while the rats in the control group were treated with the same dose of normal saline. Its histopathological change was observed and the expression of HO-1 and the mRNA expression of HO-1 were detected by RT-PCR at 3rd h, 6th h, 12th h, on 1st d, 2nd d, 3rd d and 5th d. (1) In the control group, the tissue structure was clear without edema, vacuolar degeneration, cloudy swelling and necrosis. In the paraquat poisoned group, there were obvious lesions in the renal tubule of cortical part, including cellular swelling, the narrow cannula, the mesenchymal congestion and edema. These pathologic changes gradually became more severe, reached the peak on the 1st day, and did not relieve until the end of this study; there was the karyopyknosis and the cyto-architecture disappeared in some severe cases; Some glomerulus and medulla were also involved. (2) In the control group, there was no or weak expression of HO-1 and HO-1 mRNA. At the 3rd hour, the expressions of HO-1 in the paraquat poisoned group were observed in the membrane and cytoplasm of renal tubular epithelial cell of cortical part. Immunohistochemistry score (IHS) in the paraquat poisoned group was higher than that in the control group (P<0.05), except the HIS of the 5th day. At the 3rd hour, the expression of HO-1 mRNA increased, reached the peak on the 1st day, and then decreased. The expression of HO-1 mRNA was (0.53 +/- 0.21), (0.55 +/- 0.31), (0.56 +/- 0.22), (0.64 +/- 0.14) and (0.43 +/- 0.25) at the time point other than on the 3rd and 5th day. It showed statistical difference between the paraquat poisoned group and the control group from the 3rd hour to the 2nd day (P<0.05). The mechanism of paraquat

Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait.

PubMed

Kim, Lisa; Garfinkel, Marc R; Chang, Anthony; Kadambi, Pradeep V; Meehan, Shane M

2011-07-01

Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of complete hilar versus only renal artery clamping on renal histomorphology following ischemia/reperfusion injury in an experimental model.

PubMed

Umul, M; Cal, A C; Turna, B; Oktem, G; Aydın, H H

2016-01-01

To evaluate the effect of temporary complete hilar versus only renal artery clamping with different duration of warm ischemia on renal functions, and possibly identify a "safe" clamping type and duration of renal ischemia. Fifty male rabbits have been incorporated to study. Rabbits were subjected to ischemia/reperfusion injury by temporary vascular clamping. Reagents were randomized to 3 experimental groups (only renal artery clamping, complete hilar clamping, sham surgery) and sub-groups were determined according to different clamping times (30 and 60 minutes). Median laparotomy and left renal hilus dissection were performed to sham group. Only artery or complete hilar clamping was performed for 30 or 60 minutes by microvascular bulldog clamps to other reagents. Rabbits were sacrificed 10 days after primary surgery and left nephrectomy performed. Nephrectomy materials were evaluated for the level of nitric-oxide synthase (NOS) immunoreactivity, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity and an electron microscopic examination was performed. NOS immunoreactivity was correlated with the temporary clamping time. We also observed that complete hilar vascular clamping entails an increase on NOS immunoreactivity. MDA levels were similar for all experimental surgery groups (p = 0.42). The SOD activity was decreased among all subgroups compared with sham surgery. But the significant decrease occurred in 30 minutes only artery and 30 minutes complete hilar clamping groups in proportion to sham surgery (p = 0.026 and p = 0.019, respectively). This current study suggested that only renal artery clamping under 30 minutes is more appropriate during renal surgical procedures requiring temporary vascular clamping.

Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study.

PubMed

Schneeweiss, Sebastian; Carver, Peggy L; Datta, Kausik; Galar, Alicia; Johnson, Melissa D; Johnson, Matthew G; Marty, Francisco M; Nagel, Jerod; Najdzinowicz, Maryann; Saul, Melissa; Shoham, Shmuel; Silveira, Fernanda P; Varughese, Christy A; Wilck, Marissa; Weatherby, Lisa; Auton, Tim; Walker, Alexander M

2016-10-01

Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Pink1/Parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury.

PubMed

Zhao, Chuanyan; Chen, Zhuyun; Xu, Xueqiang; An, Xiaofei; Duan, Suyan; Huang, Zhimin; Zhang, Chengning; Wu, Lin; Zhang, Bo; Zhang, Aihua; Xing, Changying; Yuan, Yanggang

2017-01-15

Cisplatin often causes acute kidney injury (AKI) in the treatment of a wide variety of malignancies. Mitochondrial dysfunction is one of the main reasons for cisplatin nephrotoxicity. Previous study showed that Pink1 and Parkin play central roles in regulating the mitophagy, which is a key protective mechanism by specifically eliminating dysfunctional or damaged mitochondria. However, the mechanisms that modulate mitophagy in cisplatin induced nephrotoxicity remain to be elucidated. The purpose of this study was to investigate the effects of Pink1/Parkin pathway in mitophagy, mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. In cultured human renal proximal tubular cells, we found that knockdown of Pink1/Parkin induced the aggravation of mitochondrial function, leading to the increase of cell injury through inhibition of mitophagy. Additionally, the overexpression of Pink1/Parkin protected against cisplatin-induced mitochondrial dysfunction and cell injury by promoting mitophagy. Our results provide clear evidence that Pink1/Parkin-dependent mitophagy has identified potential targets for the treatment of cisplatin-induced AKI. Copyright © 2016 Elsevier Inc. All rights reserved.

Early Detection of Postoperative Acute Kidney Injury in Acute Stanford Type A Aortic Dissection With Doppler Renal Resistive Index.

PubMed

Qin, Huai; Wu, Haibo; Chen, Yi; Zhang, Nan; Fan, Zhanming

2017-10-01

This study aimed to evaluate the early efficiency of Doppler renal resistive index (DRRI) in prediction of acute kidney injury (AKI) after surgery in acute Stanford Type A aortic dissection (AAAD) patients. Sixty-one AAAD patients who planned to receive Sun's surgical management were prospectively enrolled. The DRRI was measured by ultrasonography Doppler on the day before surgery (DRRI pre ), on admission to the intensive care unit (DRRI T0 ), 6 hours after surgery (DRRI T6 ), 24 hours after surgery (DRRI T24 ), and 48 hours after surgery (DRRI T48 ). The maximum DRRI value (DRRI max ) was recorded. The AKI was evaluated according to the classifications of the Acute Kidney Injury Network. The DRRI and serum creatinine (sCr) were compared between the pre- and postoperative time stations, as well as between the AKI and no-AKI groups. Thirty-nine (63.9%) patients suffered from AKI, and 12 (19.6%) patients received dialysis. No significant difference was found in DRRI pre (0.63 ± 0.04 versus 0.65 ± 0.06, P = .059) and sCr pre (84.13 ± 23.77 versus 94.29 ± 51.11, P = .383) between the two groups with and without AKI. Both the DRRI and sCr increased significantly after surgery in the AKI groups (P < .001). However, the DRRI reached its maximum 6 hours after surgery, whereas the sCr reached its maximum after 24 hours. Both the DRRI and sCr improved 48 hours after surgery. The area under the receiver operating characteristic curve for DRRI max (0.864, 95% confidence interval: 0.770-0.957) and DRRI T6 (0.861, 95% confidence interval: 0.766-0.957) was larger than the other three DRRIs measured at different time points. The cutoff value of DRRI max was 0.71, a sensitivity of 76.9% and specificity of 95.5%. Postoperative DRRI predicts the AKI earlier than sCr after AAAD surgery. The best time to detect DRRI was 6 hours after surgery. © 2017 by the American Institute of Ultrasound in Medicine.

Short-term menhaden oil rich diet changes renal lipid profile in acute kidney injury.

PubMed

Ossani, Georgina P; Denninghoff, Valeria C; Uceda, Ana M; Díaz, Maria L; Uicich, Raúl; Monserrat, Alberto J

2015-01-01

Weanling male Wistar rats fed a choline-deficient diet develop acute kidney injury. Menhaden oil, which is a very important source of omega-3 fatty acids, has a notorious protective effect. The mechanism of this protection is unknown; one possibility could be that menhaden oil changes renal lipid profile, with an impact on the functions of biological membranes. The aim of this work was to study the renal lipid profile in rats fed a choline-deficient diet with menhaden oil or vegetable oil as lipids. Rats were divided into 4 groups and fed four different diets for 7 days: choline-deficient or choline-supplemented diets with corn and hydrogenated oils or menhaden oil. Serum homocysteine, vitamin B12, and folic acid were analyzed. Renal lipid profile, as well as the fatty acid composition of the three oils, was measured. Choline-deficient rats fed vegetable oils showed renal cortical necrosis. Renal omega-6 fatty acids were higher in rats fed a cholinedeficient diet and a choline-supplemented diet with vegetable oils, while renal omega-3 fatty acids were higher in rats fed a choline-deficient diet and a choline-supplemented diet with menhaden oil. Rats fed menhaden oil diets had higher levels of renal eicosapentaenoic and docosahexaenoic acids. Renal myristic acid was increased in rats fed menhaden oil. The lipid renal profile varied quickly according to the type of oil present in the diet.

Injury - kidney and ureter

MedlinePlus

... injury of the kidney; Bruised kidney; Ureteral injury; Pre-renal failure - injury, Post-renal failure - injury; Kidney ... or falling blood pressure Signs of kidney failure Tests that may be done include: Abdominal CT scan ...

Novel urinary biomarkers and the early detection of acute kidney injury after open cardiac surgeries.

PubMed

Elmedany, Said M; Naga, Salah S; Elsharkawy, Rania; Mahrous, Rabab S; Elnaggar, Ahmed I

2017-08-01

Acute kidney injury (AKI) is a common complication after cardiac surgery, recently, several biomarkers have been used to facilitate early detection of AKI, including Neutrophil-gelatinase-associated-lipocalin (NGAL) and Kidney-injury-molecule-1 (KIM-1).This study was carried out to study the efficacy of urinary KIM-1 and NGAL separately and in combination in relation to early detection and assessment of severity of AKI after cardiac surgeries. This prospective study was carried out on 45 adult patients, of both sexes, Cleveland score(CCS) (0-5) and scheduled for elective coronary artery bypass graft (CABG) surgery in Alexandria Main University Hospital, after approval of the ethical committee and having an informed written consent from every patient. Patients were screened for renal function tests before surgery and every day for 3 day after surgery. Freshly urine samples were taken from all patients and centrifuged for microscopic examination of the sediment: preoperative, 2, 12, 24, and 48 hr after cardiopulmonary bypass (CPB) and for measurement of NGAL and KIM-1; after induction, 2, 6, 12, and 24 hr after CPB. The primary end point was the incidence of AKI defined by the AKIN criteria of serum creatinine. 11 patients developed AKI. Patients with AKI had a higher AKIN stages and CCS. CPB time and cross clamp time were significantly higher in the AKI group with a mean of (90.5±16.2) and (60.9±8.1) minutes respectively. Serum creatinine started to be significantly higher in AKI group from the second postoperative day with a mean value of 1.56±0.28 mg/dl compared to a mean value of 0.85±0.14 mg/dl in non-AKI group. Urine sediment score(USS) 1 and 2 were higher in the AKI group than in the non-AKI group 2 hrs after CPB and till the end of the 2nd day with area under the curve (AUC) average of (0.865). Urinary NGAL significantly rise in AKI patients 2 and 6 hr after CPB with corresponding AUC of (0.710 and 0.700) but uKIM-1 was higher in the AKI group 12 and 24

[Early detection, prevention and management of renal failure in liver transplantation].

PubMed

Castells, Lluís; Baliellas, Carme; Bilbao, Itxarone; Cantarell, Carme; Cruzado, Josep Maria; Esforzado, Núria; García-Valdecasas, Juan Carlos; Lladó, Laura; Rimola, Antoni; Serón, Daniel; Oppenheimer, Federico

2014-10-01

Renal failure is a frequent complication in liver transplant recipients and is associated with increased morbidity and mortality. A variety of risk factors for the development of renal failure in the pre- and post-transplantation periods have been described, as well as at the time of surgery. To reduce the negative impact of renal failure in this population, an active approach is required for the identification of those patients with risk factors, the implementation of preventive strategies, and the early detection of progressive deterioration of renal function. Based on published evidence and on clinical experience, this document presents a series of recommendations on monitoring RF in LT recipients, as well as on the prevention and management of acute and chronic renal failure after LT and referral of these patients to the nephrologist. In addition, this document also provides an update of the various immunosuppressive regimens tested in this population for the prevention and control of post-transplantation deterioration of renal function. Copyright © 2013 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

The renoprotective effects of mannitol and udenafil in renal ischemia-reperfusion injury model

PubMed Central

Toktaş, Cihan; Aybek, Hülya; Küçükatay, Vural; Şen Türk, Nilay; Zumrutbas, Ali Ersin

2017-01-01

Purpose The aim of this study was to investigate and compare the effects of udenafil and mannitol in an experimental renal ischemia-reperfusion (I/R) injury model. Materials and Methods A total of 64 female Wister Albino rats were used. Right nephrectomy was performed in all groups. In the control group; I/R injury was not performed. In the I/R group; left renal pedicle was clamped for 45 minutes and then underwent 60 minutes and 24 hours of reperfusion. In the mannitol group; 1 mL 20% mannitol was given intravenously 15 minutes before clamping. In the udenafil group; 10-mg/kg udenafil was given orally 1 hour before clamping. Creatinine (Cr), blood urea nitrogen (BUN), Cr clearance, malondialdehyde, neutrophil gelatinase associated lipocalin (NGAL), histological examination and DNA damage (Comet Assay method) levels were compared in tissue, serum and urine samples. Results Udenafil had a better protective effect than mannitol according to biochemical parameters (Cr, BUN, Cr clearance, and NGAL levels) and histopathological findings when compared with the I/R group. In the Comet sampling analysis no significant difference was detected. Conclusions Udenafil has a better renoprotective effect than mannitol against I/R injury and this effect supports more functional improvements. Further clinical trials are needed to demonstrate those effects and clinical utility of udenafil for that purpose in humans. PMID:28681040

14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia/reperfusion injury.

PubMed

Tian, Haibin; Lu, Yan; Shah, Shraddha P; Wang, Quansheng; Hong, Song

2012-05-01

Bone marrow mesenchymal stem cells (MSCs) have shown potential to improve treatment of renal failure. The prohealing functions of MSCs have been found to be enhanced by treatment with the lipid mediator, 14S,21R-dihydroxy-docosa4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA). In this article, using a murine model of renal ischemia/reperfusion (I/R) injury, we found that treatment with 14S,21R-diHDHA enhanced MSC amelioration of renal I/R injury. Treated MSCs more efficiently inhibited I/R-induced elevation of serum creatinine levels, reduced renal tubular cell death, and inhibited infiltration of neutrophils, macrophages, and dendritic cells in kidneys. Conditioned medium from treated MSCs reduced the generation of tumor necrosis factor-α and reactive oxygen species by macrophages under I/R conditions. Infusion of treated MSCs more efficiently reduced I/R-damage to renal histological structures compared with untreated MSCs (injury score: 7.9±0.4 vs. 10.5±0.5). Treated MSCs were resistant to apoptosis in vivo when transplanted under capsules of I/R-injured kidneys (active caspase-3+ MSCs: 4.2%±2.8% vs. 11.7%±2.4% of control) and in vitro when cultured under I/R conditions. Treatment with 14S,21R-diHDHA promoted viability of MSCs through a mechanism involving activation of the phosphoinositide 3-kinase -Akt signaling pathway. Additionally, treatment of MSCs with 14S,21R-diHDHA promoted secretion of renotrophic hepatocyte growth factor and insulin growth factor-1. Similar results were obtained when 14S,21RdiHDHA was used to inhibit apoptosis of human MSCs (hMSCs) and to increase the generation of renotrophic cytokines from hMSCs. These findings provide a lead for new strategies in the treatment of acute kidney injury with MSCs.

Functional MRI detects perfusion impairment in renal allografts with delayed graft function.

PubMed

Hueper, Katja; Gueler, Faikah; Bräsen, Jan Hinrich; Gutberlet, Marcel; Jang, Mi-Sun; Lehner, Frank; Richter, Nicolas; Hanke, Nils; Peperhove, Matti; Martirosian, Petros; Tewes, Susanne; Vo Chieu, Van Dai; Großhennig, Anika; Haller, Hermann; Wacker, Frank; Gwinner, Wilfried; Hartung, Dagmar

2015-06-15

Delayed graft function (DGF) after kidney transplantation is not uncommon, and it is associated with long-term allograft impairment. Our aim was to compare renal perfusion changes measured with noninvasive functional MRI in patients early after kidney transplantation to renal function and allograft histology in biopsy samples. Forty-six patients underwent MRI 4-11 days after transplantation. Contrast-free MRI renal perfusion images were acquired using an arterial spin labeling technique. Renal function was assessed by estimated glomerular filtration rate (eGFR), and renal biopsies were performed when indicated within 5 days of MRI. Twenty-six of 46 patients had DGF. Of these, nine patients had acute rejection (including borderline), and eight had other changes (e.g., tubular injury or glomerulosclerosis). Renal perfusion was significantly lower in the DGF group compared with the group with good allograft function (231 ± 15 vs. 331 ± 15 ml·min(-1)·100 g(-1), P < 0.001). Living donor allografts exhibited significantly higher perfusion values compared with deceased donor allografts (P < 0.001). Renal perfusion significantly correlated with eGFR (r = 0.64, P < 0.001), resistance index (r = -0.57, P < 0.001), and cold ischemia time (r = -0.48, P < 0.01). Furthermore, renal perfusion impairment early after transplantation predicted inferior renal outcome and graft loss. In conclusion, noninvasive functional MRI detects renal perfusion impairment early after kidney transplantation in patients with DGF. Copyright © 2015 the American Physiological Society.

[Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases].

PubMed

Le Vaillant, J; Pellerin, L; Brouard, J; Eckart, P

2013-06-01

Renal failure secondary to acetaminophen poisoning is rare and occurs in approximately 1-2 % of patients with acetaminophen overdose. The pathophysiology is still being debated, and renal acetaminophen toxicity consists of acute tubular necrosis, without complication if treated promptly. Renal involvement can sometimes occur without prior liver disease, and early renal manifestations usually occur between the 2nd and 7th day after the acute acetaminophen poisoning. While therapy is exclusively symptomatic, sometimes serious metabolic complications can be observed. The monitoring of renal function should therefore be considered as an integral part of the management of children with acute, severe acetaminophen intoxication. We report 3 cases of adolescents who presented with acute renal failure as a result of voluntary drug intoxication with acetaminophen. One of these 3 girls developed severe renal injury without elevated hepatic transaminases. None of the 3 girls' renal function required hemodialysis, but one of the 3 patients had metabolic complications after her acetaminophen poisoning. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Early Complementopathy after Multiple Injuries in Humans

PubMed Central

Burk, Anne-Maud; Martin, Myriam; Flierl, Michael A.; Rittirsch, Daniel; Helm, Matthias; Lampl, Lorenz; Bruckner, Uwe; Stahl, Gregory L.; Blom, Anna M.; Perl, Mario; Gebhard, Florian; Huber-Lang, Markus

2012-01-01

After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study we hypothesized that multiple trauma results in immediate activation, consumption and dysfunction of the complement cascade and that the resulting severe “complementopathy” may be associated with morbidity and mortality. Therefore a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score [ISS] = 30.3 ± 2.9) was performed. After polytrauma serum was collected as early as possible at the scene, upon admission to the emergency room and 4, 12, 24, 120 and 240 hours post trauma and analysed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma and discriminated between lethal and non-lethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin (MBL) showed a biphasic response after trauma. Key fluid phase inhibitors of complement, such as C4b-binding protein (C4BP) and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronically rapid activation and dysfunction of complement suggesting a trauma-induced “complementopathy” early after injury. These events may participate to the impairment of the innate immune response observed after severe trauma. PMID:22258234

Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice.

PubMed

Zeng, Yi; Wang, Ping-Han; Zhang, Mao; Du, Jun-Rong

2016-02-01

The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls. The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.

RenalGuard system to prevent contrast-induced acute kidney injury in Japanese patients with renal dysfunction; RESPECT KIDNEY study.

PubMed

Katoh, Hiromasa; Nozue, Tsuyoshi; Horie, Kazuki; Sozu, Takashi; Inoue, Naoto; Michishita, Ichiro

2018-05-05

Increasing the urine flow rate (UFR) reduces the toxic effect of contrast media. Use of the RenalGuard system enables the achievement of a high UFR by maintaining intravascular volume and prevents the development of contrast-induced acute kidney injury (CI-AKI). However, the efficacy and safety of RenalGuard system have not yet been evaluated in Japan. This multicenter prospective study evaluated the efficacy and safety of the RenalGuard therapy in preventing CI-AKI development in 60 Japanese patients with renal dysfunction [estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m 2 ] undergoing catheter procedures. Baseline eGFR and Mehran's CIN (contrast-induced nephropathy) risk score were 35.1 ± 8.5 mL/min/1.73 m 2 and 11.7 ± 4.3, respectively. Regardless of this high-risk profile, the incidence of CI-AKI was 8.6% (5/58) compared with the 26.1% incidence estimated by the CIN risk score. Moreover, two-sided 95% (Fisher's) exact confidence interval was 2.9-19.0 and its upper limit (i.e., 19.0) was less than the prespecified threshold incidence of 25.0. Univariate logistic regression analysis demonstrated that the UFR during catheter procedure was one of the most important factor associated with CI-AKI (odds ratio 0.99, confidence interval 0.98-1.00, p = 0.03). In conclusion, RenalGuard therapy may prevent CI-AKI development in Japanese patients with renal dysfunction. Further large-scale prospective multicenter studies are necessary to confirm our findings.

Mesenchymal stem cells in renal function recovery after acute kidney injury: use of a differentiating agent in a rat model.

PubMed

La Manna, Gaetano; Bianchi, Francesca; Cappuccilli, Maria; Cenacchi, Giovanna; Tarantino, Lucia; Pasquinelli, Gianandrea; Valente, Sabrina; Della Bella, Elena; Cantoni, Silvia; Claudia, Cavallini; Neri, Flavia; Tsivian, Matvey; Nardo, Bruno; Ventura, Carlo; Stefoni, Sergio

2011-01-01

Acute kidney injury (AKI) is a major health care condition with limited current treatment options. Within this context, stem cells may provide a clinical approach for AKI. Moreover, a synthetic compound previously developed, hyaluronan monoesters with butyric acid (HB), able to induce metanephric differentiation, formation of capillary-like structures, and secretion of angiogenic cytokines, was tested in vitro. Thereafter, we investigated the effects of human mesenchymal stem cells from fetal membranes (FMhMSCs), both treated and untreated with HB, after induction of ischemic AKI in a rat model. At reperfusion following 45-min clamping of renal pedicles, each rat was randomly assigned to one of four groups: CTR, PBS, MSC, and MSC-HB. Renal function at 1, 3, 5, and 7 days was assessed. Histological samples were analyzed by light and electron microscopy and renal injury was graded. Cytokine analysis on serum samples was performed. FMhMSCs induced an accelerated renal functional recovery, demonstrated by biochemical parameters and confirmed by histology showing that histopathological alterations associated with ischemic injury were less severe in cell-treated kidneys. HB-treated rats showed a minor degree of inflammation, both at cytokine and TEM analyses. Better functional and morphological recovery were not associated to stem cells' regenerative processes, but possibly suggest paracrine effects on microenvironment that induce retrieval of renal damaged tissues. These results suggest that FMhMSCs could be useful in the treatment of AKI and the utilization of synthetic compounds could enhance the recovery induction ability of cells.

Cardiac surgery-associated acute kidney injury.

PubMed

Vives, Marc; Wijeysundera, Duminda; Marczin, Nandor; Monedero, Pablo; Rao, Vivek

2014-05-01

Acute kidney injury develops in up to 30% of patients who undergo cardiac surgery, with up to 3% of patients requiring dialysis. The requirement for dialysis after cardiac surgery is associated with an increased risk of infection, prolonged stay in critical care units and long-term need for dialysis. The development of acute kidney injury is independently associated with substantial short- and long-term morbidity and mortality. Its pathogenesis involves multiple pathways. Haemodynamic, inflammatory, metabolic and nephrotoxic factors are involved and overlap each other leading to kidney injury. Clinical studies have identified predictors for cardiac surgery-associated acute kidney injury that can be used effectively to determine the risk for acute kidney injury in patients undergoing cardiac surgery. High-risk patients can be targeted for renal protective strategies. Nonetheless, there is little compelling evidence from randomized trials supporting specific interventions to protect or prevent acute kidney injury in cardiac surgery patients. Several strategies have shown some promise, including less invasive procedures in those at greatest risk, natriuretic peptide, fenoldopam, preoperative hydration, preoperative optimization of anaemia and postoperative early use of renal replacement therapy. The efficacy of larger-scale trials remains to be confirmed.

Tangeretin attenuates cisplatin-induced renal injury in rats: Impact on the inflammatory cascade and oxidative perturbations.

PubMed

Arab, Hany H; Mohamed, Wafaa R; Barakat, Bassant M; Arafa, El-Shaimaa A

2016-10-25

Despite the efficacy of cisplatin as a chemotherapeutic agent against various cancers, its clinical utility is limited by serious adverse reactions including nephrotoxicity. The current study aims to investigate the protective potential of tangeretin, a citrus flavone with marked antioxidant actions, against cisplatin-induced renal injury in rats. Tangeretin was administered at 50 and 100 mg/kg p.o. for 1 week starting one day before cisplatin (7.5 mg/kg i.p.) injection. Likewise, silymarin was administered at 100 mg/kg orally. Renal function tests, histopathology, oxidative stress and inflammatory events were investigated. Tangeretin mitigated the increased levels of serum creatinine, blood urea nitrogen and histopathologic alterations evoked by cisplatin. It alleviated renal oxidative stress due to cisplatin by lowering lipid peroxides, nitric oxide and Nrf2 levels with concomitant enhancement of GSH and GPx. Tangeretin also suppressed the upregulated inflammatory response seen with cisplatin treatment by downregulation of activated NF-κB p65 protein expression together with its downstream effectors e.g., iNOS and TNF-α, with restoration of the anti-inflammatory interleukin IL-10. Additionally, it down-regulated the expression of caspase-3, an apoptotic marker, thus favoring renal cell survival. Importantly, tangeretin enhanced the cytotoxic actions of cisplatin in Hep3B and HCT-116 human cancer cell lines. Together, these findings accentuate the dual benefit of tangeretin: mitigation of renal injury-induced by cisplatin and enhancement of its cytotoxic effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The effect of discharge voltage on renal injury and impairment caused by lithotripsy in the pig.

PubMed

Connors, B A; Evan, A P; Willis, L R; Blomgren, P M; Lingeman, J E; Fineberg, N S

2000-02-01

The present study was designed to determine the effects of shock wave voltage (kV) on lesion size and renal function induced by shock wave lithotripsy (SWL) in the 6- to 8-wk-old pig. Each SWL-treated pig received 2000 shock waves at 12, 18, or 24 kV to the lower pole calyx of one kidney. A group of sham SWL pigs served as time controls. Bilateral GFR, renal plasma flow (RPF), and para-aminohippurate (PAH) extraction were measured 1 h before and 1 and 4 h after SWL in all treated and sham animals. The kidneys were removed at the end of each experiment for morphometric analysis. The SWL-induced lesion increased significantly in size as shock wave energy was increased from 12 to 24 kV. PAH extraction, a measure of tubular function, was not significantly affected at 12 kV, was transiently reduced at 18 kV, and was reduced for the duration of the experiment at 24 kV. GFR and RPF, however, were significantly and similarly reduced at the 1 h post-SWL period at all three kilovolt levels. At the 4-h post-SWL period, both GFR and RPF had returned to baseline levels. Lesion size and tubular injury were correlated with changes in kilovoltage, while changes in renal hemodynamics were already maximal at the lowest discharge voltage. These findings suggest that renal microvessels are highly sensitive to shock waves and that frank injury to tubules and vessels may be more closely related to discharge energy than is renal blood flow.

A simple football injury leading to a grade 4 renal trauma.

PubMed

Fanning, Deirdre Mary; Forde, James C; Mohan, Ponnusamy

2012-03-08

This case highlights the need for cautious management and serial regular examination of trauma patients. A 22-year-old Caucasian male presented to the emergency department 4 h following an injury sustained during football training. He complained of the immediate onset of severe left upper quadrant and left flank pain. He subsequently developed frank haematuria. On initial review, he was haemodynamically stable. CT of the abdomen and pelvis showed a grade 4 renal trauma. Over the following 36 h, he remained haemodynamically stable. On serial abdominal examinations however, he developed a rigid abdomen and was noted to have a haemoglobin drop. Interval CT scan showed a progression of his injury and the presence of a haemoperitoneum. An emergency laparotomy was performed resulting in a left nephrectomy. He made an uneventful recovery.

Effects of apigenin on the expression levels of B-cell lymphoma-2, Fas and Fas ligand in renal ischemia-reperfusion injury in rats.

PubMed

Liu, Yang; Liu, Xiuheng; Wang, Lei; Du, Yang; Chen, Zhiyuan; Chen, Hui; Guo, Jia; Weng, Xiaodong; Wang, Xiao; Wang, Ming; Wang, Zhishun

2017-12-01

The aim of the present study was to investigate the effect and possible mechanism of apigenin on renal ischemia-reperfusion (I/R) injury in rats, as well as in in vitro experiments. In total, 36 rats were subjected to 45 min of renal ischemia, with or without treatment prior to ischemia with different concentrations of apigenin (2, 10 and 50 mg/kg) administered intravenously. All rats were sacrificed at 24 h after I/R injury. The serum creatinine (Cr) and blood urea nitrogen (BUN) levels were analyzed, and histological examination was conducted. In addition, the expression levels of B-cell lymphoma 2 (Bcl-2) and Fas/Fas ligand (FasL) were detected by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analysis. For in vitro experiments, the NRK-52E cell line was employed. The viability, apoptosis and expression levels of Fas, FasL and Bcl-2 were examined in the culture of NRK-52E cells following the I/R. The results indicated that apigenin significantly decreased the levels of serum Cr and BUN induced by renal I/R, demonstrating an improvement in renal function. The histological evidence of renal damage associated with I/R was also mitigated by apigenin in vivo . Furthermore, apigenin increased the cell viability and decreased cell apoptosis in the culture of NRK52E after I/R in vitro . Compared with the I/R group, the expression of Bcl-2 was upregulated and the expression levels of Fas and FasL were downregulated by apigenin at the mRNA and protein levels in vivo and in vitro . In conclusion, apigenin appeared to increase the expression of Bcl-2 and reduce Fas/FasL expression in renal I/R injury, providing evident protection against renal I/R injury in rats.

Effects of apigenin on the expression levels of B-cell lymphoma-2, Fas and Fas ligand in renal ischemia-reperfusion injury in rats

PubMed Central

Liu, Yang; Liu, Xiuheng; Wang, Lei; Du, Yang; Chen, Zhiyuan; Chen, Hui; Guo, Jia; Weng, Xiaodong; Wang, Xiao; Wang, Ming; Wang, Zhishun

2017-01-01

The aim of the present study was to investigate the effect and possible mechanism of apigenin on renal ischemia-reperfusion (I/R) injury in rats, as well as in in vitro experiments. In total, 36 rats were subjected to 45 min of renal ischemia, with or without treatment prior to ischemia with different concentrations of apigenin (2, 10 and 50 mg/kg) administered intravenously. All rats were sacrificed at 24 h after I/R injury. The serum creatinine (Cr) and blood urea nitrogen (BUN) levels were analyzed, and histological examination was conducted. In addition, the expression levels of B-cell lymphoma 2 (Bcl-2) and Fas/Fas ligand (FasL) were detected by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analysis. For in vitro experiments, the NRK-52E cell line was employed. The viability, apoptosis and expression levels of Fas, FasL and Bcl-2 were examined in the culture of NRK-52E cells following the I/R. The results indicated that apigenin significantly decreased the levels of serum Cr and BUN induced by renal I/R, demonstrating an improvement in renal function. The histological evidence of renal damage associated with I/R was also mitigated by apigenin in vivo. Furthermore, apigenin increased the cell viability and decreased cell apoptosis in the culture of NRK52E after I/R in vitro. Compared with the I/R group, the expression of Bcl-2 was upregulated and the expression levels of Fas and FasL were downregulated by apigenin at the mRNA and protein levels in vivo and in vitro. In conclusion, apigenin appeared to increase the expression of Bcl-2 and reduce Fas/FasL expression in renal I/R injury, providing evident protection against renal I/R injury in rats. PMID:29285062

Inhibition of plasma kallikrein-kinin system to alleviate renal injury and arthritis symptoms in rats with adjuvant-induced arthritis.

PubMed

Zhu, Jie; Wang, Hui; Chen, Jingyu; Wei, Wei

2018-04-01

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Impairment of kidney functions in RA was observed. However, the mechanism of kidney injury of RA has not been clear. Plasma kallikrein-kinin system (KKS) was involved in inflammatory processes in kidney disease. This study aimed to explore the role of plasma KKS in immune reactions and kidney injury of RA. The paw of AA rats appeared to be swelling and redness, the arthritis index was significantly increased on the 18, 21 and 24 d after injection and secondary inflammation in multi-sites was observed. Kidney dysfunction accompanied with inflammatory cell infiltration, tubular epithelial cell mitochondrial swelling and vacuolar degeneration, renal glomerular foot process fusions and glomerular basement membrane thickening were observed in AA rats. The expressions of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) in kidney of AA rats were increased. In addition, expressions of BK, PK, B1R and B2R in the renal tissue of AA rats were up-regulated. Pro-inflammatory cytokines IL-2, IFN-γ and TNF-α were increased and anti-inflammatory cytokines IL-4 and IL-10 were low in kidney. Plasma kallikrein (PK) inhibitor PKSI-527 attenuated arthritis signs and renal damage, and inhibited BK, PK, B1R and B2R expressions. The protein expressions of P38, p-P38 and p-JNK and IFN-γ and TNF-α were inhibited by PKSI-527. These findings demonstrate that plasma KKS activation contributed to the renal injury of AA rats through MAPK signaling pathway. Plasma KKS might be a potential target for RA therapy.

Effect of antisense oligodeoxynucleotides for ICAM-1 on renal ischaemia–reperfusion injury in the anaesthetised rat

PubMed Central

Kiew, Lik Voon; Munavvar, Abdul Sattar; Law, Chung Hiong; Azizan, Abdullah Nor; Nazarina, Abdul Rahman; Sidik, Khalifah; Johns, Edward J

2004-01-01

An antisense oligodeoxynucleotide (As-ODN) to the 3′ untranslated region of the mRNA sequence expressing the intracellular adhesion molecule-1 (ICAM-1) was employed to determine ICAM-1's role in renal ischaemia–reperfusion injury in the rat. Wistar-Kyoto rats receiving i.v. either lipofectin–As-ODN (As-ODN group), lipofectin–reverse ODN (Rv-ODN group) or lipofectin (ischaemia control group) 8 h prior to study were anaesthetized and subjected to 30 min of renal artery occlusion. Renal haemodynamic and excretory parameters were monitored before and after renal ischaemia. On termination of the study renal tissue was subjected to histological and Western blot analysis. Renal blood flow decreased in the 3 h post-ischaemia period in the ischaemia control and Rv-ODN groups, but was maintained in the As-ODN group. Glomerular filtration rate was depressed initially but gradually increased to 10% above basal levels in the ischaemia control and Rv-ODN groups, but was below basal levels (20%) in the As-ODN group. There was a three- to fourfold increase in sodium and water excretion following ischaemia in the ischaemia control and reverse-ODN groups but not in the As-ODN treated group. The As-ODN ameliorated the histological evidence of ischaemic damage and reduced ICAM-1 protein levels to a greater extent in the medulla than cortex. These observations suggested that in the post-ischaemic period afferent and efferent arteriolar tone was increased with a loss of reabsorptive capacity which was in part due to ICAM-1. The possibility arises that the action of ICAM-1 at vascular and tubular sites in the deeper regions of the kidney contributes to the ischaemia–reperfusion injury. PMID:15047774

[Renal decapsulation for the treatment of anuria : A "forgotten" treatment from the early 20th century].

PubMed

Dräger, D L; Protzel, C; Hakenberg, O W

2017-01-01

In the early 20th century, Harrison first performed renal decapsulation in anuric children with scarlet fever and observed improvement in renal function postoperatively. The pathophysiological explanation was seen in intraparenchymal renal pressure due to edema which was improved by surgical decapsulation. The technique of decapsulation was simple excision after incision and blunt dissection of the renal parenchyma. Renal decapsulation then became a procedure commonly used for many indications in inflammatory renal conditions; indications were renal angioneurosis, hydronephrosis, toxic, bacterial and chronic nephritis, renal abscess and even eclampsia. With the beginning of the antibiotic era, renal decapsulation became obsolete and has disappeared from the urological spectrum completely.

Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis

PubMed Central

Simon, Noémie; Hertig, Alexandre

2015-01-01

Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research. PMID:26301223

Silencing of p53 RNA through transarterial delivery ameliorates renal tubular injury and downregulates GSK-3β expression after ischemia-reperfusion injury.

PubMed

Fujino, Takayuki; Muhib, Sharifi; Sato, Nobuyuki; Hasebe, Naoyuki

2013-12-01

p53, a pivotal protein in the apoptotic pathway, has been identified as a mediator of transcriptional responses to ischemia-reperfusion (IR) injury. The characteristics and functional significance of the p53 response in vivo are largely unknown in IR-induced kidney injury. Therapeutic opportunities of delivering small interfering RNA (siRNA) via venous injection have gained recognition; however, systemic adverse effects of siRNA therapy should be considered. To prevent IR-induced kidney injury, we tested the efficacy of transarterial administration of siRNA targeting p53 (p53 siRNA). Female C57BL/6 mice underwent unilateral renal artery ischemia for 30 min, followed by reperfusion. siRNA experiments utilized short hairpin (sh) RNA plasmid-based approaches. Transfection of shRNA was performed using cationic polymer transfection reagent. Injection of synthetic p53 shRNA into the left renal artery just after ischemia improved tubular injury, apoptosis, and the swelling of mitochondria in cells of the thick ascending limb of Henle (mTALH) at the outer medullary regions. Staining of upregulated p53 was colocalized with the inducible expression of glycogen synthase kinase-3β (GSK-3β) at mTALH after IR injury. p53 shRNA inhibited GSK-3β expression and restored β-catenin expression at mTALH. For IR-induced kidney injury, transarterial delivery of p53 siRNA is an effective pharmacological intervention. Targeting siRNA to p53 leads to an attenuation of apoptosis and mitochondrial damage through the downregulation of GSK-3β expression and upregulation of β-catenin. Local delivery of vectors such as p53 siRNA through a transaortic catheter is clinically useful in reducing the adverse effect of siRNA-related therapy.

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

Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury.

PubMed

Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

2016-01-01

Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury.

Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury

PubMed Central

Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

2016-01-01

Introduction Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. Methods We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. Results We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). Conclusion The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury. PMID:27642395

Mining the human urine proteome for monitoring renal transplant injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sigdel, Tara K.; Gao, Yuqian; He, Jintang

The human urinary proteome reflects systemic and inherent renal injury perturbations and can be analyzed to harness specific biomarkers for different kidney transplant injury states. 396 unique urine samples were collected contemporaneously with an allograft biopsy from 396 unique kidney transplant recipients. Centralized, blinded histology on the graft was used to classify matched urine samples into categories of acute rejection (AR), chronic allograft nephropathy (CAN), BK virus nephritis (BKVN), and stable graft (STA). Liquid chromatography–mass spectrometry (LC-MS) based proteomics using iTRAQ based discovery (n=108) and global label-free LC-MS analyses of individual samples (n=137) for quantitative proteome assessment were used inmore » the discovery step. Selected reaction monitoring (SRM) was applied to identify and validate minimal urine protein/peptide biomarkers to accurately segregate organ injury causation and pathology on unique urine samples (n=151). A total of 958 proteins were initially quantified by iTRAQ, 87% of which were also identified among 1574 urine proteins detected in LC-MS validation. 103 urine proteins were significantly (p<0.05) perturbed in injury and enriched for humoral immunity, complement activation, and lymphocyte trafficking. A set of 131 peptides corresponding to 78 proteins were assessed by SRM for their significance in an independent sample cohort. A minimal set of 35 peptides mapping to 33 proteins, were modeled to segregate different injury groups (AUC =93% for AR, 99% for CAN, 83% for BKVN). Urinary proteome discovery and targeted validation identified urine protein fingerprints for non-invasive differentiation of kidney transplant injuries, thus opening the door for personalized immune risk assessment and therapy.« less

Mixed organic solvents induce renal injury in rats.

PubMed

Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

2012-01-01

To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli.

Mixed Organic Solvents Induce Renal Injury in Rats

PubMed Central

Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

2012-01-01

To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2∶2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5–6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli. PMID:23029287

Effects of dexpanthenol and N-acetylcysteine pretreatment in rats before renal ischemia/reperfusion injury.

PubMed

Sen, Huseyin; Deniz, Suleyman; Yedekci, A Erturk; Inangil, Gokhan; Muftuoglu, Tuba; Haholu, Aptullah; Ozkan, Sezai

2014-11-01

We investigated the anti-inflammatory and protective effects of concomitant use of dexpanthenol (DXP) and N-acetylcysteine (NAC) induced ischemia/reperfusion (I/R) injury of kidney. Forty rats were randomly divided into 5 groups. In all groups except for Group 1(Sham), renal arteries bilaterally occluded with vascular clamp for IR injury. Group 1(Sham), received a single dose of 10 mL/kg isotonic saline daily by intraperitoneal (IP) injection for three days. Group 2(IR), received a single dose of 10 mL/kg isotonic saline daily by IP injection for three days. Group 3(IR + NAC), received 300 mg/kg NAC daily by IP injection for three days. Group 4(IR + DXP), received 500 mg/kg DXP daily by IP injection for three days. Group 5(IR + NAC + DXP), received 500 mg/kg DXP and 300 mg/kg NAC daily by IP injection for three days. Serum urea (BUN), creatinine (Cr) and neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2, siderocalin) levels were measured as kidney function tests. TNF-α levels were measured as inflammatory marker. Tissue sections were evaluated histopathologically under light microscopy. IR + NAC + DXP group received both NAC and DXP before induction of renal I/R and as the biochemical and histopathological data revealed the results of the IR + NAC + DXP group and sham group were similar. Biochemically and histopathologically, combined use of NAC and DXP has better results when each of them used alone. We concluded that concomitant use of DXP and NAC plays a major role against I/R injury and may be useful in acute treatment of I/R induced renal failure.

Impact of early screening for reflux in siblings on the detection of renal damage.

PubMed

Houle, Anne-Marie; Cheikhelard, Alaa; Barrieras, Diego; Rivest, Marie-Christine; Gaudreault, Valérie

2004-07-01

To assess the impact of screening siblings after detecting significant vesico-ureteric reflux (VUR) and renal scarring, as such screening might identify patients with VUR before urinary tract infections develop, but might also detect clinically insignificant VUR. We used a previously reported screening protocol to assess the clinical characteristics of patients, including the incidence of renal scarring, and their siblings, and compared the results. In all, 123 children were screened and 44 (36%) had VUR on voiding cystography. The median (range) age at screening was 9 (1-90) months. The grades of VUR detected were < III in 61% and > or = III in 39%; VUR was bilateral in 48%. In all, 37 siblings with VUR were assessed by ultrasonography; 70% were normal, including 12 (32%) children with VUR of grade > or = III. When used, renal scintigraphy was normal in 74% of siblings, vs 18% of index patients. However, when screened after 2 years old, siblings had twice the risk of already having renal damage on renal scintigraphy (P = 0.04). Early screening (< or = 2 years) appears to be more protective for avoiding renal damage than screening older patients. Thus we propose early screening in asymptomatic siblings to detect VUR before it becomes clinically significant.

WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors.

PubMed

Motamedi, Fariba Jian; Badro, Danielle A; Clarkson, Michael; Lecca, M Rita; Bradford, Stephen T; Buske, Fabian A; Saar, Kathrin; Hübner, Norbert; Brändli, André W; Schedl, Andreas

2014-07-17

Kidney organogenesis requires the tight control of proliferation, differentiation and apoptosis of renal progenitor cells. How the balance between these cellular decisions is achieved remains elusive. The Wilms' tumour suppressor Wt1 is required for progenitor survival, but the molecular cause for renal agenesis in mutants is poorly understood. Here we demonstrate that lack of Wt1 abolishes fibroblast growth factor (FGF) and induces BMP/pSMAD signalling within the metanephric mesenchyme. Addition of recombinant FGFs or inhibition of pSMAD signalling rescues progenitor cell apoptosis induced by the loss of Wt1. We further show that recombinant BMP4, but not BMP7, induces an apoptotic response within the early kidney that can be suppressed by simultaneous addition of FGFs. These data reveal a hitherto unknown sensitivity of early renal progenitors to pSMAD signalling, establishes FGF and pSMAD signalling as antagonistic forces in early kidney development and places WT1 as a key regulator of pro-survival FGF signalling pathway genes.

Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension.

PubMed

Papazova, Diana A; Friederich-Persson, Malou; Joles, Jaap A; Verhaar, Marianne C

2015-01-01

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (Po2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney Qo2, cortical Po2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 ± 3.3 vs. 0.9 ± 0.4 pmol O2 · s(-1)· mg protein(-1), P < 0.05) and increased whole kidney Qo2 (55 ± 16 vs. 33 ± 10 μmol O2/min, P < 0.05). Corticomedullary Po2 was lower in TX compared with 1K-CON (30 ± 13 vs. 47 ± 4 μM, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Qo2, Po2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage. Copyright © 2015 the American Physiological Society.

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation.

PubMed

Park, Ji Hyeon; Jang, Hye Ryoun; Kim, Do Hee; Kwon, Ghee Young; Lee, Jung Eun; Huh, Wooseong; Choi, Soo Jin; Oh, Wonil; Oh, Ha Young; Kim, Yoon-Goo

2017-10-01

Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu. Copyright © 2017 the American Physiological Society.

[Correlation between serum uric acid level and acute renal injury after coronary artery bypass grafting].

PubMed

Xu, D Q; Du, J; Zheng, Z; Tang, Y; Zou, L; Zhang, Y H; Zhang, H T

2017-07-11

Objective: To evaluate whether early postoperative serum uric acid level can predict postoperative acute renal injury (AKI) among patients undergoing coronary artery bypass grafting (CABG). Methods: The study retrospectively enrolled 1 306 patients undergoing CABG in Fuwai Hospital between September 2012 and December 2013. The patients were divided into 5 groups by the concentrations of serum uric acid measured on the morning of the first postoperative day, and uric acid categories were as follow: less than 195 μmol/L (Q1 group, 262 cases), 195-236 μmol/L (Q2 group, 263 cases), 237-280 μmol/L (Q3 group, 260 cases), 281-336 μmol/L (Q4 group, 261 cases), more than 336 μmol/L (Q5 group, 260 cases). The primary end points were AKI (RIFLE criteria), severe AKI (AKI≥stage Ⅰ), postoperative continuous renal replacement therapy (CRRT) requirement, in-hospital death, length of stay in hospital and intensive care unit(ICU). The area under the receiver-operating characteristic (ROC) curve (AUC) was used to determine the ability of the early postoperative serum uric acid level as a risk factor for postoperative AKI prediction. Results: Among the 1 306 patients enrolled in the study, AKI was found in 335 patients (25.65%). After adjusting for variables that were different between the 5 groups, the Q5 group had significantly higher risk of AKI, AKI≥ stage Ⅰ and the requirement of CRRT ( P <0.01). The ROC for the outcome of postoperative AKI had an AUC of 0.648 (95% CI: 0.612-0.683) when serum creatinine levels alone were used and 0.722 (95% CI: 0.688-0.755) when serum uric acid levels alone were used (both P <0.001). Early postoperative serum uric acid was a better predictor than serum creatinine( P <0.001). Conclusion: The serum uric acid concentration within 12 hours after operation is an independent predictor of postoperative AKI in patients undergoing CABG, which could be used to identify patients at high risk for AKI.

The management of neonatal acute and chronic renal failure: A review.

PubMed

Coulthard, Malcolm G

2016-11-01

Most babies with chronic renal failure are identified antenatally, and over half that are treated with peritoneal dialysis receive kidney transplants before school age. Most infants that develop acute renal failure have hypotension following cardiac surgery, or multiple organ failure. Sometimes the falls in glomerular filtration and urine output are physiological and reversible, and sometimes due to kidney injury, but (illogically) it is now common to define them all as having 'acute kidney injury'. Contrary to widespread opinion, careful interpretation of the plasma creatinine concentrations can provide sensitive evidence of early acute renal failure. Conservative management frequently leads to under-nutrition or fluid overload. Acute peritoneal dialysis is often technically fraught in very small patients, and haemotherapies have been limited by vascular access and anticoagulation requirements, the need to blood-prime circuits, and serious limitations in regulating fluid removal. Newer devices, including the Nidus, have been specifically designed to reduce these difficulties. Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.

Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats.

PubMed

Yang, Ming; Liu, Changjin; Jiang, Jian; Zuo, Guowei; Lin, Xuemei; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

2014-05-27

The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys. The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR. In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1. The present results

Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats

PubMed Central

2014-01-01

Background The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys. Methods The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR. Results In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1

Can renal dysfunction after infra-renal aortic aneurysm repair be modified by multi-antioxidant supplementation?

PubMed

Wijnen, M H W A; Vader, H L; Van Den Wall Bake, A W L; Roumen, R M H

2002-08-01

Renal failure after lower torso ischemia is a serious problem, partly caused by hypotension and indirect reperfusion injury. This injury is partly due to the formation of oxygen free radicals by activated neutrophils. This injury results in albuminuria and renal function impairment. There are indications that free radical damage in indirect reperfusion injury can be diminished by administering extra antioxidants before and during reperfusion. In this prospective randomised study we have looked at the influence of a multi-antioxidant supplementation on renal function in patients undergoing an elective open infrarenal abdominal aneurysm repair. The patients received either standard treatment (n=22) or standard treatment with additional antioxidants perioperatively (Allopurinol, vitamin E and C, N-acetylcysteine and mannitol). For renal function we have looked at the albumin/creatinine ratio in urine and 24 hr creatinine clearance. Despite significantly increased serum total antioxidant capacity, the group receiving extra antioxidants showed no decrease in the albumin/creatinine ratio in urine. There was however a significantly higher creatinine clearance in this group at day 2. The results indicate that the diminished renal function after infrarenal aneurysm repair may be influenced by antioxidant therapy.

Kid-1, a putative renal transcription factor: regulation during ontogeny and in response to ischemia and toxic injury.

PubMed Central

Witzgall, R; O'Leary, E; Gessner, R; Ouellette, A J; Bonventre, J V

1993-01-01

We have identified a new putative transcription factor from the rat kidney, termed Kid-1 (for kidney, ischemia and developmentally regulated gene 1). Kid-1 belongs to the C2H2 class of zinc finger genes. Its mRNA accumulates with age in postnatal renal development and is detected predominantly in the kidney. Kid-1 mRNA levels decline after renal injury secondary to ischemia or folic acid administration, two insults which result in epithelial cell dedifferentiation, followed by regenerative hyperplasia and differentiation. The low expression of Kid-1 early in postnatal development, and when renal tissue is recovering after injury, suggests that the gene product is involved in establishment of a differentiated phenotype and/or regulation of the proliferative response. The deduced protein contains 13 C2H2 zinc fingers at the COOH end in groups of 4 and 9 separated by a 32-amino-acid spacer. There are consensus sites for phosphorylation in the NH2 terminus non-zinc finger region as well as in the spacer region between zinc fingers 4 and 5. A region of the deduced protein shares extensive homology with a catalytic region of Raf kinases, a feature shared only with TFIIE among transcription factors. To determine whether Kid-1 can modulate transcription, a chimeric construct encoding the Kid-1 non-zinc finger region (sense or antisense) and the DNA-binding region of GAL4 was transfected into COS and LLC-PK1 cells together with a chloramphenicol acetyltransferase (CAT) reporter plasmid containing GAL4 binding sites, driven by either a minimal promoter or a simian virus 40 enhancer. CAT activity was markedly inhibited in cells transfected with the sense construct compared with the activity in cells transfected with the antisense construct. To our knowledge, this pattern of developmental regulation, kidney expression, and regulation of transcription is unique among the C2H2 class of zinc finger-containing DNA-binding proteins. Images PMID:8382778

Curcumin-carrying nanoparticles prevent ischemia-reperfusion injury in human renal cells.

PubMed

Xu, Yong; Hu, Ning; Jiang, Wei; Yuan, Hong-Fang; Zheng, Dong-Hui

2016-12-27

Renal ischemia-reperfusion injury (IRI) is a major complication in clinical practice. However, despite its frequency, effective preventive/treatment strategies for this condition are scarce. Curcumin possesses antioxidant properties and is a promising potential protective agent against renal IRI, but its poor water solubility restricts its application. In this study, we constructed curcumin-carrying distearoylphosphatidylethanolamine-polyethylene glycol nanoparticles (Cur-NPs), and their effect on HK-2 cells exposed to IRI was examined in vitro. Curcumin encapsulated in NPs demonstrated improved water solubility and slowed release. Compared with the IRI and Curcumin groups, Cur-NP groups displayed significantly improved cell viability, downregulated protein expression levels of caspase-3 and Bax, upregulated expression of Bcl-2 protein, increased antioxidant superoxide dismutase level, and reduced apoptotic rate, reactive oxygen species level, and malondialdehyde content. Results clearly showed that Cur-NPs demonstrated good water solubility and slow release, as well as exerted protective effects against oxidative stress in cultured HK-2 cells exposed to IRI.

[Diagnostic and prognostic value of heart-type fatty acid-binding protein (H-FABP), an early biochemical marker of myocardial injury].

PubMed

Bertinchant, J P; Polge, A

2005-12-01

Heart-type fatty acid-binding protein (H-FABP) is a 132 amino acids soluble protein, with general characteristics resembling myoglobin. Because of its low molecular weight (15 kd) and cytoplasmic location, it constitutes a biologic marker readily released into the circulation after myocardial injury. Despite the development of various immunoassays to measure H-FABP, few are currently easy to perform, quantitative and applicable in emergency. Most studies have shown the diagnostic sensitivity of H-FABP (i.e. its ability to detect the presence of a myocardial infarction) to be high, above that of myoglobin in patients presenting within 3 to 6 h of after the onset of chest pain. This superiority is attributable to an earlier and more rapid rise in H-FABP than in myoglobin. After thrombolysis, the serum concentrations of H-FABP peak at approximately 4 h after the onset of chest pain, and return to normal values within 24 h. Because of this rapid return of its blood concentration to baseline, H-FABP can contribute to an early biologic diagnosis of post-thrombolysis reperfusion and re-infarction. In absence of renal insufficiency, H-FABP also provides a reliable estimate of infarct size associated with ST segment elevation. When myocardial injury occurs after cardiac surgery, the second peak in H-FABP concentration precedes that of myoglobin, CK-MB or troponins. In addition, H-FABP peaks earlier and is more sensitive than troponins in the detection of subtle myocardial injury in patients presenting with acute coronary syndrome without ST segment elevation, and in patients with severe heart failure, thus offering early prognostic information. Limitations of H-FABP include a limited cardio-specificity, a narrow diagnostic window (20 to 30 h), and a nearly exclusive renal elimination.

Disparate effects of single endothelin A and B receptor blocker therapy on the progression of renal injury in advanced renovascular disease

PubMed Central

Chade, Alejandro R.; Stewart, Nicholas J.; Peavy, Patrick R.

2013-01-01

We hypothesized that chronic specific endothelin (ET)-A receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed-tomography. All pigs with renovascular disease were divided such that 7 were untreated, 7 were treated with ET-A blockers, and 5 were treated with ET-B blockers. Four weeks later, all pigs were re-studied in vivo, then euthanized and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. RBF, GFR, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation and fibrosis in the stenotic kidney. These effects were functionally consequential since ET-A blockade improved single kidney microvascular endothelial function, RBF, and GFR, and decreased albuminuria. PMID:24352153

Baicalin Inhibits Renal Cell Apoptosis and Protects Against Acute Kidney Injury in Pediatric Sepsis

PubMed Central

Zhu, Yanping; Fu, Yanxia; Lin, Hairong

2016-01-01

Background Pediatric sepsis has high morbidity in children, may lead to acute kidney injury (AKI), and further aggravate the disease. Baicalin is a kind of flavonoid in Scutellaria baicalensis Georgi and has been reported to protect against several diseases, but its roles in septic AKI remain unclear. This study aimed to uncover the effects of baicalin in AKI during pediatric sepsis. Material/Methods Blood urea nitrogen (BUN) and serum creatinine (Cr) levels were detected in 50 pediatric patients, who underwent basic therapy with or without baicalin adjunctive therapy. Mouse sepsis models were constructed by cecal ligation and puncture (CLP) and treated with baicalin intragastrically, after which BUN and Cr examination, TUNEL apoptosis assay, and expression analyses of BAX and BCL2 were performed. Results Baicalin adjunctive therapy significantly decreased BUN and Cr levels in pediatric sepsis patients (P<0.05). CLP led to elevated BUN and Cr levels in the mouse model (P<0.01), indicating kidney injury accompanied by sepsis. Baicalin decreased BUN and Cr levels (P<0.05), and reduced the apoptotic cell percent in the renal tissue (P<0.05) of the CLP model. It inhibited BAX and promoted BCL2 in the renal tissue, which was consistent with cell apoptosis changes. Conclusions Baicalin is capable of suppressing renal cell apoptosis and protecting against AKI in pediatric sepsis. This study provides a potential adjunctive therapy for treating AKI in pediatric sepsis, and further research is necessary to reveal its deeper mechanisms. PMID:28013315

Baicalin Inhibits Renal Cell Apoptosis and Protects Against Acute Kidney Injury in Pediatric Sepsis.

PubMed

Zhu, Yanping; Fu, Yanxia; Lin, Hairong

2016-12-25

BACKGROUND Pediatric sepsis has high morbidity in children, may lead to acute kidney injury (AKI), and further aggravate the disease. Baicalin is a kind of flavonoid in Scutellaria baicalensis Georgi and has been reported to protect against several diseases, but its roles in septic AKI remain unclear. This study aimed to uncover the effects of baicalin in AKI during pediatric sepsis. MATERIAL AND METHODS Blood urea nitrogen (BUN) and serum creatinine (Cr) levels were detected in 50 pediatric patients, who underwent basic therapy with or without baicalin adjunctive therapy. Mouse sepsis models were constructed by cecal ligation and puncture (CLP) and treated with baicalin intragastrically, after which BUN and Cr examination, TUNEL apoptosis assay, and expression analyses of BAX and BCL2 were performed. RESULTS Baicalin adjunctive therapy significantly decreased BUN and Cr levels in pediatric sepsis patients (P<0.05). CLP led to elevated BUN and Cr levels in the mouse model (P<0.01), indicating kidney injury accompanied by sepsis. Baicalin decreased BUN and Cr levels (P<0.05), and reduced the apoptotic cell percent in the renal tissue (P<0.05) of the CLP model. It inhibited BAX and promoted BCL2 in the renal tissue, which was consistent with cell apoptosis changes. CONCLUSIONS Baicalin is capable of suppressing renal cell apoptosis and protecting against AKI in pediatric sepsis. This study provides a potential adjunctive therapy for treating AKI in pediatric sepsis, and further research is necessary to reveal its deeper mechanisms.

Intraperitoneal curcumin decreased lung, renal and heart injury in abdominal aorta ischemia/reperfusion model in rat.

PubMed

Aydin, Mehmet Salih; Caliskan, Ahmet; Kocarslan, Aydemir; Kocarslan, Sezen; Yildiz, Ali; Günay, Samil; Savik, Emin; Hazar, Abdussemet; Yalcin, Funda

2014-01-01

Previous studies have demonstrated that curcumin (CUR) has protective effects against ischemia reperfusion injury to various organs. We aimed to determine whether CUR has favorable effects on tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. Thirty rats were divided into three groups as sham, control and treatment (CUR) group. Control and CUR groups underwent abdominal aorta ischemia for 60 min followed by a 120 min period of reperfusion. In the CUR group, CUR was given 5 min before reperfusion at a dose of 200 mg/kg via an intraperitoneal route. Total antioxidant capacity (TAC), total oxidative status (TOS), and oxidative stress index (OSI) in blood serum were measured, and lung, renal and heart tissue histopathology were evaluated with light microscopy. TOS and OSI activity in blood samples were statistically decreased in sham and CUR groups compared to the control group (p < 0.001 for TOS and OSI). Renal, lung, heart injury scores of sham and CUR groups were statistically decreased compared to control group (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in CUR group than in the control group. CUR administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta I/R rat model. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Salubrious effect of C-phycocyanin against oxalate-mediated renal cell injury.

PubMed

Farooq, Shukkur Muhammed; Asokan, Devarajan; Sakthivel, Ramasamy; Kalaiselvi, Periandavan; Varalakshmi, Palaninathan

2004-10-01

. Thus, the present analysis reveals that the antioxidant nature of C-phycocyanin protects the renal cell against oxalate-induced injury and may be a nephroprotective agent.

Astaxanthin attenuates early acute kidney injury following severe burns in rats by ameliorating oxidative stress and mitochondrial-related apoptosis.

PubMed

Guo, Song-Xue; Zhou, Han-Lei; Huang, Chun-Lan; You, Chuan-Gang; Fang, Quan; Wu, Pan; Wang, Xin-Gang; Han, Chun-Mao

2015-04-13

Early acute kidney injury (AKI) is a devastating complication in critical burn patients, and it is associated with severe morbidity and mortality. The mechanism of AKI is multifactorial. Astaxanthin (ATX) is a natural compound that is widely distributed in marine organisms; it is a strong antioxidant and exhibits other biological effects that have been well studied in various traumatic injuries and diseases. Hence, we attempted to explore the potential protection of ATX against early post burn AKI and its possible mechanisms of action. The classic severe burn rat model was utilized for the histological and biochemical assessments of the therapeutic value and mechanisms of action of ATX. Upon ATX treatment, renal tubular injury and the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were improved. Furthermore, relief of oxidative stress and tubular apoptosis in rat kidneys post burn was also observed. Additionally, ATX administration increased Akt and Bad phosphorylation and further down-regulated the expression of other downstream pro-apoptotic proteins (cytochrome c and caspase-3/9); these effects were reversed by the PI3K inhibitor LY294002. Moreover, the protective effect of ATX presents a dose-dependent enhancement. The data above suggested that ATX protects against early AKI following severe burns in rats, which was attributed to its ability to ameliorate oxidative stress and inhibit apoptosis by modulating the mitochondrial-apoptotic pathway, regarded as the Akt/Bad/Caspases signalling cascade.

Astaxanthin Attenuates Early Acute Kidney Injury Following Severe Burns in Rats by Ameliorating Oxidative Stress and Mitochondrial-Related Apoptosis

PubMed Central

Guo, Song-Xue; Zhou, Han-Lei; Huang, Chun-Lan; You, Chuan-Gang; Fang, Quan; Wu, Pan; Wang, Xin-Gang; Han, Chun-Mao

2015-01-01

Early acute kidney injury (AKI) is a devastating complication in critical burn patients, and it is associated with severe morbidity and mortality. The mechanism of AKI is multifactorial. Astaxanthin (ATX) is a natural compound that is widely distributed in marine organisms; it is a strong antioxidant and exhibits other biological effects that have been well studied in various traumatic injuries and diseases. Hence, we attempted to explore the potential protection of ATX against early post burn AKI and its possible mechanisms of action. The classic severe burn rat model was utilized for the histological and biochemical assessments of the therapeutic value and mechanisms of action of ATX. Upon ATX treatment, renal tubular injury and the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were improved. Furthermore, relief of oxidative stress and tubular apoptosis in rat kidneys post burn was also observed. Additionally, ATX administration increased Akt and Bad phosphorylation and further down-regulated the expression of other downstream pro-apoptotic proteins (cytochrome c and caspase-3/9); these effects were reversed by the PI3K inhibitor LY294002. Moreover, the protective effect of ATX presents a dose-dependent enhancement. The data above suggested that ATX protects against early AKI following severe burns in rats, which was attributed to its ability to ameliorate oxidative stress and inhibit apoptosis by modulating the mitochondrial-apoptotic pathway, regarded as the Akt/Bad/Caspases signalling cascade. PMID:25871290

Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis.

PubMed

Humphreys, Benjamin D; Xu, Fengfeng; Sabbisetti, Venkata; Grgic, Ivica; Movahedi Naini, Said; Wang, Ningning; Chen, Guochun; Xiao, Sheng; Patel, Dhruti; Henderson, Joel M; Ichimura, Takaharu; Mou, Shan; Soeung, Savuth; McMahon, Andrew P; Kuchroo, Vijay K; Bonventre, Joseph V

2013-09-01

Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1(RECtg)) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1(RECtg) mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1(RECtg) kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1-dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.

Anti-Inflammatory Effects of Ang-(1-7) in Ameliorating HFD-Induced Renal Injury through LDLr-SREBP2-SCAP Pathway.

PubMed

Zheng, Yaning; Tang, Lin; Huang, Wenhan; Yan, Ruyu; Ren, Feifeng; Luo, Lei; Zhang, Ling

2015-01-01

The angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis (ACE2-Ang-(1-7)-Mas axis) is reported to participate in lipid metabolism in kidney, but its precise effects and underlying mechanisms remain unknown. We hypothesized that Ang-(1-7) reduces lipid accumulation and improves renal injury through the low density lipoprotein receptor-sterol regulatory element binding proteins 2-SREBP cleavage activating protein (LDLr-SREBP2-SCAP) system by suppressing inflammation in high fat diet (HFD)-fed mice. In this study, male C57BL/6 mice were randomized into four groups: STD (standard diet)+saline, HFD+saline, HFD+Ang-(1-7) and STD+Ang-(1-7). After 10 weeks of feeding, mice were administered Ang-(1-7) or saline for two weeks. We found that high inflammation status induced by HFD disrupted the LDLr-SREBP2-SCAP feedback system. Treatment of mice fed a high-fat diet with Ang-(1-7) induced significant improvement in inflammatory status, following the downregulation of LDLr, SREBP2 and SCAP, and then, decreased lipid deposition in kidney and improved renal injury. In conclusion, the anti-inflammatory effect of Ang-(1-7) alleviates renal injury triggered by lipid metabolic disorders through a LDLr- SREBP2-SCAP pathway.

Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

PubMed Central

Khalifa, Hesham A.; Al-Quraishy, Saleh A.

2017-01-01

The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID:28819543

Limitation of HIF-1α with pentoxifillyne on renal tubular ischemia result of hiperoxaluria and ESWL.

PubMed

Erturhan, Sakip; Bayrak, Omer; Seckiner, Ilker; Celik, Mehmet; Karakok, Metin

2014-03-01

To evaluate hypoxia-inducible factor 1 subunit α (HIF-1α) expression during the performance of extracorporeal shock wave lithotripsy (ESWL) and to investigate the effects of pentoxyphylline on HIF-1α expression. One hundred New Zealand Albino rabbit were used in the study divided in 5 groups. There were 20 rabbits in each group. The groups were divided in two parts: early (7 days) and late period (14 days) according to follow up duration. Immunohistochemical analyses were performed using nuclear staining to show HIF-1α expression in rabbit renal tissue sample. HIF-1α expression was higher in rabbits undergoing ESWL (group 4). In the hyperoxaluria group taking pentoxyphylline before ESWL (group 5), HIF-1α expression was lower in both early and late period subgroups (p < 0.05) CONCLUSION: In this study we evaluated HIF-1α expression and showed that ESWL may cause renal cell injury. Our results suggest that pentoxyphylline, as a circulatory regulator agent, may prevent renal cell injury induced by ESWL.

Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study.

PubMed

Bragadottir, Gudrun; Redfors, Bengt; Ricksten, Sven-Erik

2013-10-01

Acute kidney injury develops in a large proportion of patients after cardiac surgery because of the low cardiac output syndrome. The inodilator levosimendan increases cardiac output after cardiac surgery with cardiopulmonary bypass, but a detailed analysis of its effects on renal perfusion, glomerular filtration, and renal oxygenation in this group of patients is lacking. We therefore evaluated the effects of levosimendan on renal blood flow, glomerular filtration rate, renal oxygen consumption, and renal oxygen demand/supply relationship, i.e., renal oxygen extraction, early after cardiac surgery with cardiopulmonary bypass. Prospective, placebo-controlled, and randomized trial. Cardiothoracic ICU of a tertiary center. Postcardiac surgery patients (n=30). The patients were randomized to receive levosimendan, 0.1 µg/kg/min after a loading dose of 12 µg/kg (n=15), or placebo (n=15). The experimental procedure started 4-6 hours after surgery in the ICU during propofol sedation and mechanical ventilation. Systemic hemodynamic were evaluated by a pulmonary artery thermodilution catheter. Renal blood flow and glomerular filtration rate were measured by the renal vein retrograde thermodilution technique and by renal extraction of Cr-EDTA, respectively. Central venous pressure was kept constant by colloid/crystalloid infusion. Compared to placebo, levosimendan increased cardiac index (22%), stroke volume index (15%), and heart rate (7%) and decreased systemic vascular resistance index (21%), whereas mean arterial pressure was not affected. Levosimendan induced significant increases in renal blood flow (12%, p<0.05) and glomerular filtration rate (21%, p<0.05), decreased renal vascular resistance (18%, p<0.05) but caused no significant changes in filtration fraction, renal oxygen consumption, or renal oxygen extraction, compared to placebo. After cardiac surgery with cardiopulmonary bypass, levosimendan induces a vasodilation, preferentially of preglomerular resistance

Relationship between histopathological changes in post partum renal biopsies and renal function tests of African women with early onset pre-eclampsia.

PubMed

Khedun, S M; Naicker, T; Moodley, J

2000-05-01

To improve the diagnostic accuracy of concurrent renal disease in hypertension of pregnancy, biopsy evaluation is essential. In addition, establishing underlying renal disease is important for prognosis on future pregnancies. We therefore designed a study to determine the diagnostic yield of postpartum renal biopsy and the nature and frequency of complications associated with this procedure. Also, to determine relationships, if any, between renal function tests and ultrastructural and histopathological findings. Fifty renal biopsies were performed in the immediate postpartum period in black African women with early onset pre-eclampsia. Each biopsy specimen was placed in a separate container and coded so that sampling was unknown to the electron microscopist. Each biopsy specimen was divided into three parts, and processed and stained for light, fluorescent and transmission electron microscopy using conventional techniques. Renal tissue biopsies were adequate for diagnostic purposes in all cases. There were no complications in any of the 50 patients studied. Ultrastructural examination confirmed the light microscopy findings. In addition the ultrastructural findings showed intramembranous deposits, foot process fusion and mesangial deposits. In 16 patients with normal renal function tests; the biopsies evaluation from these patients showed ultrastructural changes. In the remaining 34 patients with abnormal renal function tests of varying severity; biopsy evaluation from these patients showed both ultrastructural and histopathological changes. Renal biopsy procedure is safe, and ultrastructural and histological findings obtained from postpartum renal biopsies are more informative than the routine renal function tests.

High Endogenous Accumulation of ω-3 Polyunsaturated Fatty Acids Protect against Ischemia-Reperfusion Renal Injury through AMPK-Mediated Autophagy in Fat-1 Mice.

PubMed

Gwon, Do Hyeong; Hwang, Tae Woong; Ro, Ju-Ye; Kang, Yoon-Joong; Jeong, Jin Young; Kim, Do-Kyung; Lim, Kyu; Kim, Dong Woon; Choi, Dae Eun; Kim, Jwa-Jin

2017-09-30

Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). Fat-1 transgenic mice produce ω3-Polyunsaturated fatty acids (ω3-PUFAs) from ω6-Polyunsaturated fatty acids (ω6-PUFAs) without a dietary ω3-PUFAs supplement, leading to a high accumulation of omega-3 in various tissues. ω3-PUFAs show protective effects against various renal injuries and it has recently been reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated its associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham ( n = 10), fat-1 sham ( n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI ( n = 15). Kidneys and blood were harvested 24 h after IRI and renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7; lower amounts of p62; and, higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more adenosine monophosphate-activated protein kinase (AMPK) activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

Notch3 orchestrates epithelial and inflammatory responses to promote acute kidney injury.

PubMed

Kavvadas, Panagiotis; Keuylian, Zela; Prakoura, Niki; Placier, Sandrine; Dorison, Aude; Chadjichristos, Christos E; Dussaule, Jean-Claude; Chatziantoniou, Christos

2018-07-01

Acute kidney injury is a major risk factor for subsequent chronic renal and/or cardiovascular complications. Previous studies have shown that Notch3 was de novo expressed in the injured renal epithelium in the early phases of chronic kidney disease. Here we examined whether Notch3 is involved in the inflammatory response and the epithelial cell damage that typifies ischemic kidneys using Notch3 knockout mice and mice with short-term activated Notch3 signaling (N3ICD) in renal epithelial cells. After ischemia/reperfusion, N3ICD mice showed exacerbated infiltration of inflammatory cells and severe tubular damage compared to control mice. Inversely, Notch3 knockout mice were protected against ischemia/reperfusion injury. Renal macrophages derived from Notch3 knockout mice failed to activate proinflammatory cytokines. Chromatin immunoprecipitation analysis of the Notch3 promoter identified NF-κB as the principal inducer of Notch3 in ischemia/reperfusion. Thus, Notch3 induced by NF-κB in the injured epithelium sustains a proinflammatory environment attracting activated macrophages to the site of injury leading to a rapid deterioration of renal function and structure. Hence, targeting Notch3 may provide a novel therapeutic strategy against ischemia/reperfusion and acute kidney injury by preservation of epithelial structure and disruption of proinflammatory signaling. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Urinary exosomal transcription factors, a new class of biomarkers for renal disease

PubMed Central

Zhou, Hua; Cheruvanky, Anita; Hu, Xuzhen; Matsumoto, Takayuki; Hiramatsu, Noriyuki; Cho, Monique E.; Berger, Alexandra; Leelahavanichkul, Asada; Doi, Kent; Chawla, Lakhmir S.; Illei, Gabor G.; Kopp, Jeffrey B.; Balow, James E.; Austin, Howard A.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Urinary exosomes are excreted from all nephron segments and are a rich source of kidney injury biomarkers. Because exosomes contain intracellular proteins, we asked if transcription factors (TF) can be measured in urinary exosomes. We collected urine from two acute kidney injury (AKI) models (cisplatin or ischemia/reperfusion) and two podocyte injury models (puromycin-treated rats and podocin/Vpr transgenic mice). Human urine was obtained from patients with AKI, focal segmental glomerulosclerosis (FSGS), and matched controls. After isolating urine exosomes by differential centrifugation, activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) were detected by western blot. ATF3 was continuously detected in urine exosomes 2–24 hr after ischemia/reperfusion and in a biphasic pattern after cisplatin. In both models, urinary ATF3 was detected earlier than serum creatinine. Urinary ATF3 was detected in AKI patients but not in normal subjects or patients with chronic kidney disease (CKD). Urinary WT-1 was detected in animal models before significant glomerular sclerosis. Urinary WT-1 was detected in 9/10 FSGS patients, but not in 8 controls. Transcription factors can be detected in urine exosomes, but not in whole urine. Urinary ATF3 may be a novel renal tubular cell injury biomarker for detecting early AKI, whereas urinary WT-1 may detect early podocyte injury. Urinary exosomal TFs represent a new class of biomarkers for acute and chronic renal diseases and may offer insight into cellular regulatory pathways. PMID:18509321

Ischemia and reperfusion injury in renal transplantation: hemodynamic and immunological paradigms

PubMed Central

Requião-Moura, Lúcio Roberto; Durão, Marcelino de Souza; de Matos, Ana Cristina Carvalho; Pacheco-Silva, Alvaro

2015-01-01

Ischemia and reperfusion injury is an inevitable event in renal transplantation. The most important consequences are delayed graft function, longer length of stay, higher hospital costs, high risk of acute rejection, and negative impact of long-term follow-up. Currently, many factors are involved in their pathophysiology and could be classified into two different paradigms for education purposes: hemodynamic and immune. The hemodynamic paradigm is described as the reduction of oxygen delivery due to blood flow interruption, involving many hormone systems, and oxygen-free radicals produced after reperfusion. The immune paradigm has been recently described and involves immune system cells, especially T cells, with a central role in this injury. According to these concepts, new strategies to prevent ischemia and reperfusion injury have been studied, particularly the more physiological forms of storing the kidney, such as the pump machine and the use of antilymphocyte antibody therapy before reperfusion. Pump machine perfusion reduces delayed graft function prevalence and length of stay at hospital, and increases long-term graft survival. The use of antilymphocyte antibody therapy before reperfusion, such as Thymoglobulin™, can reduce the prevalence of delayed graft function and chronic graft dysfunction. PMID:25993079

Temporary renal ischemia during nephron sparing surgery is associated with short-term but not long-term impairment in renal function.

PubMed

Yossepowitch, Ofer; Eggener, Scott E; Serio, Angel; Huang, William C; Snyder, Mark E; Vickers, Andrew J; Russo, Paul

2006-10-01

The emergence of laparoscopic nephron sparing surgery has rekindled interest in the impact of warm renal ischemia on renal function. To provide data with which warm renal ischemia can be compared we analyzed short-term and long-term changes in the glomerular filtration rate after temporary cold renal ischemia. In patients undergoing open nephron sparing surgery the estimated glomerular filtration rate was assessed preoperatively, early in the postoperative hospital stay, and 1 and 12 months after surgery using the abbreviated Modification of Diet in Renal Disease Study equation. We separately analyzed 70 patients with a solitary kidney and 592 with 2 functioning kidneys. The end point was the percent change from the baseline glomerular filtration rate. A linear regression model was used to test the association between the glomerular filtration rate change, and ischemia time, patient age, tumor size, estimated blood loss and intraoperative fluid administration. Median cold ischemia time was 31 minutes in patients with a solitary kidney and 35 minutes in those with 2 kidneys. Compared to patients with 2 kidneys those with a solitary kidney had a significantly lower preoperative estimated glomerular filtration rate (p < 0.001), which decreased a median of 30% during the early postoperative period, and 15% and 32% 1 and 12 months after surgery, respectively. In patients with 2 kidneys the corresponding glomerular filtration rate decreases were 16%, 13% and 14%, respectively. On multivariate analyses in each group cold ischemia duration and intraoperative blood loss were significantly associated with early glomerular filtration rate changes. However, 12 months after surgery age was the only independent predictor of a glomerular filtration rate decrease in patients with 2 kidneys. Cold renal ischemia during nephron sparing surgery is a significant determinant of the short-term postoperative glomerular filtration rate. Longer clamping time is particularly detrimental in

The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats.

PubMed

Vogelaar, Pieter C; Roorda, Maurits; de Vrij, Edwin L; Houwertjes, Martin C; Goris, Maaike; Bouma, Hjalmar; van der Graaf, Adrianus C; Krenning, Guido; Henning, Robert H

2018-04-11

Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 µg/kg/h) undergoing H/R at 15°C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed. H/R injury in vitro lowered cell viability by 94 ± 1%, which was counteracted dose-dependently by multiple 6-hydroxychomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 5'-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols

Dietary docosahexaenoic acid ameliorates, but rapeseed oil and safflower oil accelerate renal injury in stroke-prone spontaneously hypertensive rats as compared with soybean oil, which is associated with expression for renal transforming growth factor-beta, fibronectin and renin.

PubMed

Miyazaki, M; Takemura, N; Watanabe, S; Hata, N; Misawa, Y; Okuyama, H

2000-01-03

We have noted that n-3 fatty acid-rich oils, such as fish oil, perilla oil and flaxseed oil as well as ethyl docosahexaenoate (DHA) prolonged the survival time of stroke-prone spontaneously hypertensive rats (SHRSP) rats by approximately 10% as compared with linoleate (n-6)-rich safflower oil. Rapeseed oil with a relatively low n-6/n-3 ratio unusually shortened the survival time by approximately 40%, suggesting the presence of minor components unfavorable to SHRSP rats. This study examined the effects of dietary oils and DHA on renal injury and gene expression related to renal injury in SHRSP rats. Rats fed rapeseed oil- and safflower oil-supplemented diets developed more severe proteinuria than those fed soybean oil-supplemented diet used as a control, but there were no significant differences in blood pressure. In contrast, the DHA-supplemented diet inhibited the development of proteinuria and suppressed hypertension. The mRNA levels for renal TGF-beta, fibronectin and renin were higher in the rapeseed oil and safflower oil groups after 9 weeks of feeding of the experimental diet than in the soybean oil and DHA groups. The fatty acid composition of kidney phospholipids was markedly affected by these diets. These results indicate that the renal injury observed in the groups fed safflower oil with a high n-6/n-3 ratio and rapeseed oil with presumed minor components is accompanied by increased expression of the TGF-beta, renin and fibronectin genes, and that dietary DHA suppresses renal injury and gene expression as compared with soybean oil.

Predictors of post-hospitalization recovery of renal function among patients with acute kidney injury requiring dialysis.

PubMed

Pajewski, Russell; Gipson, Patrick; Heung, Michael

2018-01-01

Acute kidney injury (AKI) requiring dialysis complicates 1% of all hospital admissions, and up to 30% of survivors will still require dialysis at hospital discharge. There is a paucity of data to describe the postdischarge outcomes or to guide evidence-based dialysis management of this vulnerable population. Single-center, retrospective analysis of 100 consecutive patients with AKI who survived to hospital discharge and required outpatient dialysis. Data collection included baseline characteristics, hospitalization characteristics, and outpatient dialysis treatment variables. Primary outcome was dialysis independence 90 days after discharge. Overall, 43% of patients recovered adequate renal function to discontinue dialysis, with the majority recovering within 30 days post discharge. Worse baseline renal function was associated with lower likelihood of renal recovery. In the first week postdischarge, patients with subsequent nonrecovery of renal function had greater net fluid removal (5.3 vs. 4.1 L, P = 0.037), higher ultrafiltration rates (6.0 vs. 4.7 mL/kg/h, P = 0.041) and more frequent intradialytic hypotension (24.6% vs. 9.3% with 3 or more episodes, P = 0.049) compared to patients that later recovered. A significant proportion of AKI survivors will recover renal function following discharge. Outpatient intradialytic factors may influence subsequent renal function recovery. © 2017 International Society for Hemodialysis.

High risk of rhabdomyolysis and acute kidney injury after traumatic limb compartment syndrome.

PubMed

Tsai, Wei-Hsuan; Huang, Shih-Tsai; Liu, Wen-Chung; Chen, Lee-Wei; Yang, Kuo-Chung; Hsu, Kuei-Chang; Lin, Cheng-Ta; Ho, Yen-Yi

2015-05-01

Rhabdomyolysis often occurs after traumatic compartment syndrome, and high morbidity and mortality have been reported with the acute kidney injury that develops subsequently. We focused on the risk factors for rhabdomyolysis and acute kidney injury in patients with traumatic compartment syndrome. We also analyzed the relation between renal function and rhabdomyolysis in these patients. A retrospective chart review was conducted from January 2006 to March 2012. Inpatients with traumatic compartment syndrome were included. We evaluated patients' demographics, history of illicit drugs use or alcohol consumption, mechanism of injury, symptoms, serum creatine kinase levels, and kidney function. A total of 52 patients with a mean age of 40.9 years were included; 23 patients had rhabdomyolysis (44.2%), of which 9 patients developed acute kidney injury (39.1%). Significant predictive factors for rhabdomyolysis were history of illicit drugs or alcohol use (P=0.039; odds ratio, 5.91) and ischemic injury (P=0.005). We found a moderate correlation between serum creatine kinase levels and serum creatinine levels (R=0.57; P<0.0001). The correlation coefficient (R) between serum creatine kinase levels and the estimated creatinine clearance rate was -0.45. Rhabdomyolysis was a predisposing factor for acute kidney injury (P=0.011; odds ratio, 8.68). Four patients with rhabdomyolysis required a short period of renal replacement therapy. A high percentage of patients with traumatic compartment syndrome developed rhabdomyolysis (44.2%). Patients with rhabdomyolysis had a higher possibility of developing acute kidney injury (39.1%), and rhabdomyolysis was correlated to renal function. Early diagnosis, frequent monitoring, and aggressive treatment are suggested once compartment syndrome is suspected. The overall prognosis is good with early diagnosis and proper treatment.

Hypertensive renal disease: susceptibility and resistance in inbred hypertensive rat lines.

PubMed

Braun, Michael C; Herring, Stacy M; Gokul, Nisha; Monita, Monique; Bell, Rebecca; Hicks, M John; Wenderfer, Scott E; Doris, Peter A

2013-10-01

Spontaneously hypertensive rat (SHR) lines differ in their susceptibility to hypertensive end-organ disease and may provide an informative model of genetic risk of disease. Lines derived from the original SHR-B and SHR-C clades are highly resistant to hypertensive end-organ disease, whereas lines derived from the SHR-A clade were selected for stroke susceptibility and experience hypertensive renal disease. Here we characterize the temporal development of progressive renal injury in SHR-A3 animals consuming 0.3% sodium in the diet and drinking water. SHR-A3 rats demonstrate albuminuria, glomerular damage, tubulointerstitial injury, and renal fibrosis that emerge at 18 weeks of age and progress. Mortality of SHR-A3 animals was 50% at 40 weeks of age, and animals surviving to this age had reduced renal function. In contrast SHR-B2, which are 87% genetically identical to SHR-A3, are substantially protected from renal injury and demonstrate only moderate changes in albuminuria and renal histological injury over this time period. At 40 weeks of age, electron microscopy of the renal glomerulus revealed severe podocyte effacement in SHR-A3, but slit diaphragm architecture in SHR-B2 at this age was well preserved. Renal injury traits in the F1 and F2 progeny of an intercross between SHR-A3 and SHR-B2 were measured to determine heritability of renal injury in this model. Heritability of albuminuria, glomerular injury, and tubulointerstitial injury were estimated at 48.9, 66.5 and 58.6%, respectively. We assessed the relationship between blood pressure and renal injury measures in the F2 animals and found some correlation between these variables that explain up to 26% of the trait variation. Quantitative trait locus (QTL) mapping was performed using over 200 single nucleotide polymorphism markers distributed across the 13% of the genome that differs between these two closely related lines. Mapping of albuminuria, tubulointerstitial injury, and renal fibrosis failed to

Early post-splenectomy sepsis after missile injury in adults.

PubMed Central

Ellias, Y. A.; Elias, M. A.; Gorey, T. F.

1991-01-01

Early septic complications were studied in 292 patients operated on for penetrating missile injury of the abdomen with involvement of either the spleen or the liver, at Basrah Teaching Hospital between January 1983 and April 1986. Depending on associated injuries, patients with splenectomy were divided into three groups, the first with isolated splenic injury, the second with splenic and associated extra-intestinal organ injury, and the third with splenic and intestinal injuries with or without extra-intestinal organ injury. Patients with hepatic injury were classified similarly. Splenectomy was carried out for any degree of splenic injury. Grade I hepatic injuries were managed by débridement and suturing while major grades II-IV underwent segmentectomy or lobectomy. Patients were considered septic if they had any three of four clinical criteria: temperature higher than 39 degrees C; significant haemodynamic deterioration; respiratory alkalosis, or oliguria. Of the total, 79 were excluded due to: early transfer 51, incomplete records 8, perioperative death 11, and having combined splenic and hepatic injuries 9 (excluded by definition), leaving 104 (74.8%) patients with splenectomy and 109 (71.1%) with hepatic injury available for study. Sepsis developed in 48 (46.1%) of patients after splenectomy and in 28 (25.7%) with hepatic injury. This difference was significant (P greater than 0.005). In patients with isolated splenic injury, eight (25.8%) were septic while three (13.6%) of those with isolated hepatic injury developed sepsis. This was not significant (P = 0.32, Fisher's exact test). When either was associated with an injury to an extra-intestinal organ, 15 (50%) of the splenectomy group developed sepsis compared to five (23.8%) of the hepatic injury group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2042899

Pediatric Acute Kidney Injury.

PubMed

Fragasso, Tiziana; Ricci, Zaccaria; Goldstein, Stuart L

2018-01-01

Acute kidney injury (AKI) in children is a serious condition with an important impact on morbidity and mortality. Onset can be insidious and it is frequently unrecognized in the early phase when the therapeutic opportunities are theoretically more effective. The present review focuses on the most recent epidemiology studies and the progress in pediatric AKI (pAKI) research. Standardization of definition (presented in the Kidney Disease: Improving Global Outcomes) and novel biomarkers have been developed to help clinicians recognize kidney injury in a timely manner, both in adult and pediatric populations. Strengths and weaknesses of these diagnostic tools are discussed and the clinical scoring system (Renal Angina Index), which aims to provide a rational context for biomarker utilization, is also presented. Even if effective treatments are not currently available for established AKI, specific preventive approaches and some promising pharmacological treatments will be detailed. Renal replacement therapy is currently considered the most effective way to manage fluid balance when severe AKI occurs. Key Messages: Great efforts in pAKI research have today led to new strategies for early AKI detection and prevention strategies. Further studies have to be conducted in the next future in order to definitely improve the outcomes of pediatric patients experiencing this deadly syndrome. © 2018 S. Karger AG, Basel.

Effects of early overnutrition on the renal response to Ang II and expression of RAAS components in rat renal tissue.

PubMed

Granado, M; Amor, S; Fernández, N; Carreño-Tarragona, G; Iglesias-Cruz, M C; Martín-Carro, B; Monge, L; García-Villalón, A L

2017-10-01

The aim of this study was to analyze the effects of early overnutrition (EON) on the expression of the renin angiotensin aldosterone system (RAAS) components in renal cortex, renal arteries and renal perivascular adipose tissue (PVAT), as well as the vascular response of renal arteries to Angiotensin II (Ang II). On birth day litters were adjusted to twelve (L12-control) or three (L3-overfed) pups per mother. Half of the animals were sacrificed at weaning (21 days old) and the other half at 5 months of age. Ang II-induced vasoconstriction of renal artery segments increased in young overfed rats and decreased in adult overfed rats. EON decreased the gene expression of angiotensinogen (Agt), Ang II receptors AT1 and AT2 and eNOS in renal arteries of young rats, while it increased the mRNA levels of AT-2 and ET-1 in adult rats. In renal PVAT EON up-regulated the gene expression of COX-2 and TNF-α in young rats and the mRNA levels of renin receptor both in young and in adult rats. On the contrary, Ang II receptors mRNA levels were downregulated at both ages. Renal cortex of overfed rats showed increased gene expression of Agt in adult rats and of AT1 in young rats. However the mRNA levels of AT1 were decreased in the renal cortex of overfed adult rats. EON is associated with alterations in the vascular response of renal arteries to Ang II and changes in the gene expression of RAAS components in renal tissue. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Predictors and Outcomes of Postcontrast Acute Kidney Injury after Endovascular Renal Artery Intervention.

PubMed

Takahashi, Edwin A; Kallmes, David F; Fleming, Chad J; McDonald, Robert J; McKusick, Michael A; Bjarnason, Haraldur; Harmsen, William S; Misra, Sanjay

2017-12-01

To determine incidence, predictors, and clinical outcomes of postcontrast acute kidney injury (PC-AKI) following renal artery stent placement for atherosclerotic renal artery stenosis. This retrospective study reviewed 1,052 patients who underwent renal artery stent placement for atherosclerotic renal artery stenosis; 437 patients with follow-up data were included. Mean age was 73.6 years ± 8.3. PC-AKI was defined as absolute serum creatinine increase ≥ 0.3 mg/dL or percentage increase in serum creatinine ≥ 50% within 48 hours of intervention. Logistic regression analysis was performed to identify risk factors for PC-AKI. The cumulative proportion of patients who died or went on to hemodialysis was determined using Kaplan-Meier survival analysis. Mean follow-up was 71.1 months ± 68.4. PC-AKI developed in 26 patients (5.9%). Patients with PC-AKI had significantly higher levels of baseline proteinuria compared with patients without PC-AKI (odds ratio = 1.38; 95% confidence interval, 1.11-1.72; P = .004). Hydration before intervention, chronic kidney disease stage, baseline glomerular filtration rate, statin medications, contrast volume, and iodine load were not associated with higher rates of PC-AKI. Dialysis-free survival and mortality rates were not significantly different between patients with and without PC-AKI (P = .50 and P = .17, respectively). Elevated baseline proteinuria was the only predictor for PC-AKI in patients undergoing renal artery stent placement. Patients who developed PC-AKI were not at greater risk for hemodialysis or death. Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.

Use of early tactile stimulation in rehabilitation of digital nerve injuries.

PubMed

Cheng, A S

2000-01-01

Digital nerves are the most frequently injured peripheral nerve. To improve the recovery of functional sensibility of digital nerve injuries, a prospective randomized controlled study was conducted to see the effect of using early tactile stimulation in rehabilitation of digital nerve injuries. Two specific tactile stimulators were made and prescribed for patients with digital nerve-injury. Twenty-four participants with 32 digital nerve injuries received the prescribed tactile stimulators (experimental group), and another 25 participants with 33 digital nerve injuries received only routine conventional therapy (control group). A significant difference (p < .05) was seen in the experimental group, although there were some variations between the different classes of associated injuries, with least benefit observed in the combined nerve, tendon, and bone injury class. Use of early tactile stimulation as described in this study can be considered an effective way to improve both quality and quantity of recovery of functional sensibility in digital nerve injuries without combined nerve, tendon, and bone injuries.

[Effect of Cordyceps sinensis on the expression of HIF-1α and NGAL in rats with renal ischemia-reperfusion injury].

PubMed

Yu, Honglei; Zhou, Qiaoling; Huang, Renfa; Yuan, Mingxia; Ao, Xiang; Yang, Jinghua

2012-01-01

To observe the level of urinary neutrophil gelatinase-associated lipocalin (NGAL), the expression of hypoxia inducible factor-1α (HIF-1α) and NGAL in rat kidney after renal ischemia and reperfusion (I/R), before and after the treatment with Cordyceps Sinensis (C. sinensis), and to explore the mechanism of C. sinensis against I/R injury. A total of 45 healthy male Sprague-Dawley rats were randomly divided into a sham group, a renal I/R model group, and a C. sinensis group (15 in each group).The rats in the sham group and the renal I/R model group were intragastrically administered saline (2 mL/d), and rats in the treatment group were intragastricabby administered of C. sinensis [5.0 g/(kg.d)]. The rats were sacrificed at 24, 48, and 72 h, respectively after the reperfusion and urinary N-acetyl-β-D-glucosaminidase (NAG) level was measured, renal function in rats was detected, and the pathological changes were observed with HE staining. We determined the urinary NGAL levels in the rats by ELISA, the expression of HIF-1α mRNA by RT-PCR, and the expressions of HIF-1α and NGAL proteins by confocal immunofluorescence. Compared with the sham group, the levels of BUN, SCr, levels of NAG and NGAL in urine were increased in the I/R group and the C. sinensis group, reached a peak at 24 h after the reperfusion and slowly declined at 48 and 72 h. Glomerular and tubulointerstitial areas in the sham group did not show any pathological change. Induced pathological changes included tubular cell necrosis, focal areas of proximal tubular dilation, distal tubular casts, effacement and loss of proximal tubule brush border, etc. Compared with the sham group, the expression of HIF-1α and NGAL in the kidney tissues of the I/R group and the C. sinensis group increased. C. sinensis can lower the level of NAG and NGAL in the urine and the expression of NGAL protein in the kidney tissues. It up-regulated the expression of HIF-1α mRNA and protein in the kidney tissues whilst attenuated

Plasma NGAL predicts early acute kidney injury no earlier than s-creatinine or cystatin C in severely burned patients.

PubMed

Rakkolainen, Ilmari; Vuola, Jyrki

2016-03-01

Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker used in acute kidney injury (AKI) diagnostics. Studies on burn patients have highlighted it as a promising biomarker for early detection of AKI. This study was designed to discover whether plasma NGAL is as a biomarker superior to serum creatinine and cystatin C in detecting AKI in severely burned patients. Nineteen subjects were enrolled from March 2013 to September 2014 in the Helsinki Burn Centre. Serum creatinine, cystatin C, and plasma NGAL were collected from the patients at admission and every 12h during the first 48h and thereafter daily until seven days following admission. AKI was defined by acute kidney injury network criteria. Nine (47%) developed AKI during their intensive care unit stay and two (11%) underwent renal replacement therapy. All biomarkers were significantly higher in the AKI group but serum creatinine- and cystatin C values reacted more rapidly to changes in kidney function than did plasma NGAL. Plasma NGAL tended to rise on average 72h±29h (95% CI) later in patients with early AKI than did serum creatinine. Area-under-the-curve values calculated for each biomarker were 0.92 for serum creatinine, 0.87 for cystatin C, and 0.62 for plasma NGAL predicting AKI by the receiver-operating-characteristic method. This study demonstrated serum creatinine and cystatin C as faster and more reliable biomarkers than plasma NGAL in detecting early AKI within one week of injury in patients with severe burns. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy.

PubMed

Ellery, Stacey J; LaRosa, Domenic A; Cullen-McEwen, Luise A; Brown, Russell D; Snow, Rod J; Walker, David W; Kett, Michelle M; Dickinson, Hayley

2017-04-01

Acute kidney injury affects ~70% of asphyxiated newborns, and increases their risk of developing chronic kidney disease later in life. Acute kidney injury is driven by renal oxygen deprivation during asphyxia, thus we hypothesized that creatine administered antenatally would protect the kidney from the long-term effects of birth asphyxia. Pregnant spiny mice were fed standard chow or chow supplemented with 5% creatine from 20-d gestation (midgestation). One day prior to term (37-d gestation), pups were delivered by caesarean or subjected to intrauterine asphyxia. Litters were allocated to one of two time-points. Kidneys were collected at 1 mo of age to estimate nephron number (stereology). Renal function (excretory profile and glomerular filtration rate) was measured at 3 mo of age, and kidneys then collected for assessment of glomerulosclerosis. Compared with controls, at 1 mo of age male (but not female) birth-asphyxia offspring had 20% fewer nephrons (P < 0.05). At 3 mo of age male birth-asphyxia offspring had 31% lower glomerular filtration rate (P < 0.05) and greater glomerular collagen IV content (P < 0.01). Antenatal creatine prevented these renal injuries arising from birth asphyxia. Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced acute kidney injury and the emergence of chronic kidney disease.

Early detection and prevention of diabetic nephropathy: a challenge calling for mandatory action for Mexico and the developing world.

PubMed

Correa-Rotter, Ricardo; González-Michaca, Luis

2005-09-01

During the last decades, developing countries have experienced an epidemiologic transition characterized by a reduction of infectious diseases and an increase of chronic degenerative diseases. This situation is generating tormenting public health, financial, and social consequences. Of particular relevance is type 2 diabetes mellitus and its chronic complications, particularly cardiovascular disease and diabetic nephropathy, because mortality of the patient with diabetes is, in most instances, related to these complications. There is a clear need to implement diagnostic and treatment strategies to reduce risk factors for development of diabetes (primary prevention), to detect risk factors of chronic complications in early stages of diabetes (secondary prevention), and to prevent further progression of those that already have renal injury (tertiary prevention). Microalbuminuria is an early marker of renal injury in diabetes, and its early detection can help the timely use of renal preventive measures, which would avoid the extremely high costs of renal replacement treatment for end-stage renal disease as well as that of other cardiovascular complications. Preventive strategies are of very little or no impact, if the primary physician has limited knowledge about the natural history of diabetic nephropathy, the beneficial effect of early preventive maneuvers for delaying its progression, and the social and economic impact of end-stage renal disease. It is therefore imperative to assure in our health systems that general practitioners have the ability and commitment to detect early diabetes complications, in order to promote actions that support regression or retard highly morbid cardiovascular and renal conditions.

Early Application of High Cut-Off Haemodialysis for de-Novo Myeloma Nephropathy is Associated with Long-Term Dialysis-Independency and Renal Recovery

PubMed Central

Khalafallah, Alhossain A.; Loi, Sie Wuong; Love, Sarah; Mohamed, Muhajir; Mace, Rose; Khalil, Ramy; Girgs, Miriam; Raj, Rajesh; Mathew, Mathew

2013-01-01

Background Multiple myeloma (MM) is a haematological malignancy associated with kidney injury resulting from cast nephropathy, which can be caused by monoclonal free light chains (FLC). It has been demonstrated that early reduction of FLC can lead to a higher proportion of patients recovering renal function with a better outcome, especially if high cut-off haemodialysis (HCO-HD) combined with chemotherapy is used. Patients and Methods In this study, four cases with MM nephropathy were treated with HCO-HD and chemotherapy at a single institution during the period from August 2009 to August 2011. All of the patients presented with acute renal failure and high serum FLC. All patients underwent a bone marrow biopsy to confirm the diagnosis of MM, according to the WHO criteria. Three patients had de novo MM and one patient had relapsed light chain myeloma disease. All patients underwent HCO-HD concomitantly with specific myeloma therapy once the diagnosis or relapse of MM was established. Results After a medial follow up of 26 months, (range, 13–36) our data showed that all patients had a significant decrease in serum FLC through HCO-HD, proving the effectiveness of HCO-HD in managing MM. De-novo MM patients restored their renal function and achieved low-level FLC early in the treatment and became dialysis-independent. One patient with relapsed myeloma remained dialysis-dependent. Conclusion In summary, our study suggests that in myeloma nephropathy associated with light-chain MM, HCO-HD should be initiated as early as possible. At the same time a specific MM treatment should be initiated to gain control of the disease and salvage the kidneys in order to achieve dialysis-independency. Further randomized trials to confirm our results are warranted. PMID:23350020

Resilience in mathematics after early brain injury: The roles of parental input and early plasticity.

PubMed

Glenn, Dana E; Demir-Lira, Özlem Ece; Gibson, Dominic J; Congdon, Eliza L; Levine, Susan C

2018-04-01

Children with early focal unilateral brain injury show remarkable plasticity in language development. However, little is known about how early brain injury influences mathematical learning. Here, we examine early number understanding, comparing cardinal number knowledge of typically developing children (TD) and children with pre- and perinatal lesions (BI) between 42 and 50 months of age. We also examine how this knowledge relates to the number words children hear from their primary caregivers early in life. We find that children with BI, are, on average, slightly behind TD children in both cardinal number knowledge and later mathematical performance, and show slightly slower learning rates than TD children in cardinal number knowledge during the preschool years. We also find that parents' "number talk" to their toddlers predicts later mathematical ability for both TD children and children with BI. These findings suggest a relatively optimistic story in which neural plasticity is at play in children's mathematical development following early brain injury. Further, the effects of early number input suggest that intervening to enrich the number talk that children with BI hear during the preschool years could narrow the math achievement gap. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Staphylococcus aureus Sepsis Induces Early Renal Mitochondrial DNA Repair and Mitochondrial Biogenesis in Mice

PubMed Central

Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.

2014-01-01

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection. PMID:24988481

Early onset primary pulmonary cryptococcosis in a renal transplant patient.

PubMed

Tarai, B; Kher, V; Kotru, P; Sabhikhi, A; Barman, P; Rattan, A

2010-01-01

We report a case of primary pulmonary cryptococcosis in a post-renal transplant patient. A 65-year-old male renal transplant patient was admitted to the hospital with a low grade fever of 1 month, radiologically mimicking tuberculosis (TB). Broncho-alveolar fluid (BAL) shows capsulated yeast, and Cryptococcus neoformans was grown on culture supported by cytology and histopathological examination. Cryptococcal antigen was positive (32-fold) in serum and was negative in cerebrospinal fluid (CSF). The patient was given amphotericin B and 5-flucytosine and clinical improvement was seen on a weekly follow up. The serum cryptococcal antigen test might contribute to the early detection and treatment of pulmonary cryptococcosis. The results of antifungal susceptibility were aid in selecting the drug of choice for treatment.

A study of Semen Strychni-induced renal injury and herb-herb interaction of Radix Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of strychnine and brucine in rats.

PubMed

Gu, Liqiang; Wang, Xiaofan; Liu, Zhenzhen; Ju, Ping; Zhang, Lunhui; Zhang, Yuanyuan; Ma, Bingjie; Bi, Kaishun; Chen, Xiaohui

2014-06-01

Recently, the renal injury caused by Semen strychni and its major toxic constituents, strychnine and brucine, was reported in many clinical cases. Hence, this study was conducted to investigate the renal injury induced by Semen Strychni and the protective effects of Radix Glycyrrhizae and Rhizoma Ligustici. The protective mechanisms were related to the comparative toxicokinetics of strychnine and brucine. Serum and urine uric acid and creatinine were used as renal function markers to evaluate the condition of kidney, and renal injury was directly reflected by histopathological changes. Compared with rats in blank group and protective herb groups, rats in Semen Strychni high-dose group showed significant differences in the results of renal function markers, and various glomerular and tubular degenerations were found in the histopathological study. The decreased AUC (only strychnine) and Cmax, the increased Tmax by Radix Glycyrrhizae and the decreased T1/2 by Radix Glycyrrhizae and Rhizoma Ligustici were found in model groups. Results indicated that high dose of Semen Strychni might induce renal injury. Radix Glycyrrhizae and Rhizoma Ligustici might work together and have effects on the elimination of strychnine and brucine. The protective effects of Radix Glycyrrhizae might also be explained by the slow absorption of the alkaloids. Copyright © 2014 Elsevier Ltd. All rights reserved.

Renal impairment and heart failure with preserved ejection fraction early post-myocardial infarction

PubMed Central

Jorapur, Vinod; Lamas, Gervasio A; Sadowski, Zygmunt P; Reynolds, Harmony R; Carvalho, Antonio C; Buller, Christopher E; Rankin, James M; Renkin, Jean; Steg, Philippe Gabriel; White, Harvey D; Vozzi, Carlos; Balcells, Eduardo; Ragosta, Michael; Martin, C Edwin; Srinivas, Vankeepuram S; Wharton III, William W; Abramsky, Staci; Mon, Ana C; Kronsberg, Shari S; Hochman, Judith S

2010-01-01

AIM: To study if impaired renal function is associated with increased risk of peri-infarct heart failure (HF) in patients with preserved ejection fraction (EF). METHODS: Patients with occluded infarct-related arteries (IRAs) between 1 to 28 d after myocardial infarction (MI) were grouped into chronic kidney disease (CKD) stages based on estimated glomerular filtration rate (eGFR). Rates of early post-MI HF were compared among eGFR groups. Logistic regression was used to explore independent predictors of HF. RESULTS: Reduced eGFR was present in 71.1% of 2160 patients, with significant renal impairment (eGFR < 60 mL/min every 1.73 m2) in 14.8%. The prevalence of HF was higher with worsening renal function: 15.5%, 17.8% and 29.4% in patients with CKD stages 1, 2 and 3 or 4, respectively (P < 0.0001), despite a small absolute difference in mean EF across eGFR groups: 48.2 ± 10.0, 47.9 ± 11.3 and 46.2 ± 12.1, respectively (P = 0.02). The prevalence of HF was again higher with worsening renal function among patients with preserved EF: 10.1%, 13.6% and 23.6% (P < 0.0001), but this relationship was not significant among patients with depressed EF: 27.1%, 26.2% and 37.9% (P = 0.071). Moreover, eGFR was an independent correlate of HF in patients with preserved EF (P = 0.003) but not in patients with depressed EF (P = 0.181). CONCLUSION: A significant proportion of post-MI patients with occluded IRAs have impaired renal function. Impaired renal function was associated with an increased rate of early post-MI HF, the association being strongest in patients with preserved EF. These findings have implications for management of peri-infarct HF. PMID:20885993

Renal excretion of ingested gastrografin: clinical relevance in early postoperative treatment of patients who have undergone gastric surgery.

PubMed

Sohn, Kyung-Myung; Lee, Sung-Yong; Kwon, Oh-Han

2002-05-01

We performed this study to evaluate the clinical relevance of renal excretion of ingested Gastrografin (methylglucamine diatrizoate) revealed on CT in the early treatment of patients who have undergone gastric surgery. Unenhanced abdominal CT was performed before and then 1 hr to 1 hr 30 min after Gastrografin ingestion in 30 patients 7 days after gastric surgery and in 19 healthy adults who served as the control group. CT scans were reviewed for the opacification of the renal collecting system or urinary bladder after Gastrografin ingestion, a finding that represents renal excretion of the ingested contrast medium. In the control group, four (21 %) of the 19 healthy adults showed renal excretion of ingested Gastrografin visualized as opacification of the urinary tract on CT scans obtained 1 hr to 1 hr 30 min after ingestion of the substance. Renal excretion of the ingested Gastrografin was seen in 19 (63%) of the 30 patients, a significantly larger percentage than in the control group (z score, p < 0.01). No patient showed either radiologic or clinical evidence of leakage from the anastomotic site. Renal excretion of ingested Gastrografin is frequently visualized on CT in patients without anastomotic leakage during the early postoperative period after gastric surgery, and this phenomenon is not rare, even in healthy adults. Therefore, renal excretion seen on CT should not be regarded as a sign of anastomotic leakage in early postoperative patients.

Disruption of gap junctions attenuates aminoglycoside-elicited renal tubular cell injury.

PubMed

Yao, Jian; Huang, Tao; Fang, Xin; Chi, Yuan; Zhu, Ying; Wan, Yigang; Matsue, Hiroyuki; Kitamura, Masanori

2010-08-01

Gap junctions play important roles in the regulation of cell phenotype and in determining cell survival after various insults. Here, we investigated the role of gap junctions in aminoglycoside-induced injury to renal tubular cells. Two tubular epithelial cell lines NRK-E52 and LLC-PK1 were compared for gap junction protein expression and function by immunofluorescent staining, Western blot and dye transfer assay. Cell viability after exposure to aminoglycosides was evaluated by WST assay. Gap junctions were modulated by transfection of the gap junction protein, connexin 43 (Cx43), use of Cx43 siRNA and gap junction inhibitors. NRK-E52 cells expressed abundant Cx43 and were functionally coupled by gap junctional intercellular communication (GJIC). Exposure of NRK-E52 cells to aminoglycosides, G418 and hygromycin, increased Cx43 phosphorylation and GJIC. The aminoglycosides also decreased cell viability that was prevented by gap junction inhibitors and Cx43 siRNA. LLC-PK1 cells were gap junction-deficient and resistant to aminoglycoside-induced cytotoxicity. Over-expression of a wild-type Cx43 converted LLC-PK1 cells to a drug-sensitive phenotype. The gap junction inhibitor alpha-glycyrrhetinic acid (alpha-GA) activated Akt in NRK-E52 cells. Inhibition of the Akt pathway enhanced cell toxicity to G418 and abolished the protective effects of alpha-GA. In addition, gentamycin-elicited cytotoxicity in NRK-E52 cells was also significantly attenuated by alpha-GA. Gap junctions contributed to the cytotoxic effects of aminoglycosides. Modulation of gap junctions could be a promising approach for prevention and treatment of aminoglycoside-induced renal tubular cell injury.

CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis.

PubMed

Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin; Entman, Mark L; Wang, Yanlin

2014-07-01

Recent studies have shown that angiotensin II (Ang II) plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms are poorly understood. In this study, we investigated the role of CXCR6 in Ang II-induced renal injury and fibrosis. Wild-type and CXCR6-green fluorescent protein (GFP) knockin mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg per minute after unilateral nephrectomy for ≤ 4 weeks. Wild-type and CXCR6-GFP knockin mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that was similar between wild-type and CXCR6-GFP knockin mice. CXCR6-GFP knockin mice were protected from Ang II-induced renal dysfunction, proteinuria, and fibrosis. CXCR6-GFP knockin mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts and produced less extracellular matrix protein in the kidneys after Ang II treatment. Furthermore, CXCR6-GFP knockin mice exhibited fewer F4/80(+) macrophages and CD3(+) T cells and expressed less proinflammatory cytokines in the kidneys after Ang II treatment. Finally, wild-type mice engrafted with CXCR6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts, macrophages, and T cells in the kidney after Ang II treatment when compared with wild-type mice engrafted with CXCR6(+/+) bone marrow cells. Our results indicate that CXCR6 plays a pivotal role in the development of Ang II-induced renal injury and fibrosis through regulation of macrophage and T-cell infiltration and bone marrow-derived fibroblast accumulation. © 2014 American Heart Association, Inc.

CXCR6 Plays a Critical Role in Angiotensin II-induced Renal Injury and Fibrosis

PubMed Central

Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin; Entman, Mark L.; Wang, Yanlin

2014-01-01

Objective Recent studies have shown that angiotensin II (Ang II) plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms are poorly understood. In this study, we investigated the role of CXCR6 in Ang II-induced renal injury and fibrosis. Approach and Results Wild-type and CXCR6-GFP knockin mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg/min after unilateral nephrectomy for up to 4 weeks. WT and CXCR6-GFP knockin mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that was similar between WT and CXCR6-GFP knockin mice. CXCR6-GFP knockin mice were protected from Ang II-induced renal dysfunction, proteinuria, and fibrosis. CXCR6-GFP knockin mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts and produced less extracellular matrix protein in the kidneys following Ang II treatment. Furthermore, CXCR6-GFP knockin mice exhibited fewer F4/80+ macrophages and CD3+ T cells and expressed less proinflammatory cytokines in the kidneys after Ang II treatment. Finally, wild-type mice engrafted with CXCR6−/− bone marrow cells displayed fewer bone marrow-derived fibroblasts, macrophages, and T cells in the kidney after Ang II treatment compared with wild-type mice engrafted with CXCR6+/+ bone marrow cells. Conclusions Our results indicate that CXCR6 plays a pivotal role in the development of Ang II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation. PMID:24855055

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice.

PubMed

Jia, Yingli; He, Jinzhao; Wang, Liang; Su, Limin; Lei, Lei; Huang, Wei; Geng, Xiaoqiang; Zhang, Shun; Meng, Xiaolu; Zhou, Hong; Yang, Baoxue

2018-01-01

A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson's trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis. © 2018 The Author(s). Published by S. Karger AG, Basel.

Effect of Γ-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats: Gender-related difference.

PubMed

Vafapour, Marzieh; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Talebi, Nahid; Shirdavani, Soheyla

2015-01-01

The most important cause of kidney injury is renal ischemia/reperfusion injury (IRI), which is gender-related. This study was designed to investigate the protective role of Γ-aminobutyric acid (GABA (against IRI in male and female rats. Thirty-six female and male wistar rats were assigned to six experimental groups. The IRI was induced by clamping renal vessels for 45 min then was performed reperfusion for 24 h. The group sex posed to IRI were pretreated with GABA and were compared with the control groups. Serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score increased in the IRI alone groups, (P < 0.05), while GABA decreased these parameters in female significantly (P < 0.05), but not in male rats. Uterus weight decreased significantly in female rats treated with GABA. Testis weight did not alter in male rats. Serum level of nitrite and kidney level of malondialdehyde (MDA) had no significant change in both female and male rats. Kidney level of nitrite increased significantly in female rats experienced IRI and serum level of MDA increased significantly in males that were exposed to IRI (P < 0.05). GABA could ameliorate kidney injury induced by renal IRI in a gender dependent manner.

Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial

PubMed Central

Nadkarni, Girish N.; Rao, Veena; Ismail-Beigi, Faramarz; Fonseca, Vivian A.; Shah, Sudhir V.; Simonson, Michael S.; Cantley, Lloyd; Devarajan, Prasad; Parikh, Chirag R.

2016-01-01

Background and objectives Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome. Design, setting, participants, & measurements We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with ≥40% sustained eGFR decline over the 5-year follow-up period to 190 participants with ≤10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 μg/mg, and baseline eGFR within 10 ml/min per 1.73 m2), with ≤10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression. Results Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-to-creatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio. Conclusions Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2

Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial.

PubMed

Nadkarni, Girish N; Rao, Veena; Ismail-Beigi, Faramarz; Fonseca, Vivian A; Shah, Sudhir V; Simonson, Michael S; Cantley, Lloyd; Devarajan, Prasad; Parikh, Chirag R; Coca, Steven G

2016-08-08

Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome. We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with ≥40% sustained eGFR decline over the 5-year follow-up period to 190 participants with ≤10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 μg/mg, and baseline eGFR within 10 ml/min per 1.73 m(2)), with ≤10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression. Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-to-creatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio. Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2 diabetes with preserved renal function. Copyright © 2016 by the American Society of

Attenuation of Cisplatin-Induced Renal Injury by Inhibition of Soluble Epoxide Hydrolase Involves Nuclear Factor κB Signaling

PubMed Central

Liu, Yingmei; Webb, Heather K.; Fukushima, Hisayo; Micheli, Janine; Markova, Svetlana; Olson, Jean L.

2012-01-01

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(−/−) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(−/−) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy. PMID:22414856

RenalGuard System for the prevention of acute kidney injury in patients undergoing transcatheter aortic valve implantation.

PubMed

Visconti, Gabriella; Focaccio, Amelia; Donahue, Michael; Golia, Bruno; Marzano, Antonio; Donnarumma, Elvira; Ricciardelli, Bruno; Selvetella, Lucio; Marino, Luigi; Briguori, Carlo

2016-04-08

We aimed to assess whether the RenalGuard™ System is effective in preventing acute kidney injury (AKI) following transcatheter aortic valve implantation (TAVI). Forty-eight consecutive patients with chronic kidney disease (CKD) scheduled for TAVI were assigned to: 1) hydration with sodium bicarbonate solution (Control group), or 2) hydration with RenalGuard Therapy (RenalGuard group). Hypotension was defined as periprocedural mean blood pressure <55 mmHg. The primary endpoint was the occurrence of AKI (i.e., an increase of ≥0.3 mg/dL in the serum creatinine concentration at seven days). AKI occurred in 10/26 (38.5%) patients in the Control group and in 1/22 (4.5%) patients in the RenalGuard group (p=0.005, odds ratio [OR] 0.076, 95% confidence interval [CI]: 0.009-0.66). RenalGuard Therapy protected against AKI (OR 0.71, 95% CI: 0.07-0.775, p=0.026), whereas post-procedural hypotension (OR 3.88, 95% CI: 1.06-14.24, p=0.040), and contrast media volume (OR 3.65, 95% CI: 1.15-5.75, p=0.043) increased the risk of AKI. This non-randomised pilot study suggests that RenalGuard Therapy may be effective in preventing AKI in CKD patients undergoing TAVI.

Development and Validation of a Simplified Renal Replacement Therapy Suitable for Prolonged Field Care in a Porcine (Sus scrofa) Model of Acute Kidney Injury

DTIC Science & Technology

2018-03-01

of a Simplified Renal Replacement Therapy Suitable for Prolonged Field Care in a Porcine (Sus scrofa) Model of Acute Kidney Injury. PRINCIPAL...and methods, results - include tables/figures, and conclusions/applications.) Objectives/Background: Acute kidney injury (AKI) is a serious

Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy.

PubMed

Moore, Jeremy K; Chen, Junjie; Pan, Hua; Gaut, Joseph P; Jain, Sanjay; Wickline, Samuel A

2018-06-01

To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine-chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico-medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after

Bilateral renal milk of calcium masquerading as nephrolithiasis in patients with spinal cord injury.

PubMed

Vaidyanathan, Subramanian; Hughes, Peter L; Soni, Bakul M

2007-01-01

Milk of calcium is a viscous colloidal suspension of calcium carbonate, calcium phosphate, or calcium oxalate, or a mixture of these compounds. The calcific material gravitates to the dependent portion of a cystic cavity. Crescent- or hemisphere-shaped calcium density with a sharp horizontal upper border at the milk of calcium-clear fluid interface confirms the diagnosis. Bilateral milk of calcium in the renal pelvis or in dilated calyces is very rare and has not been reported in patients with spinal cord injury. A 63-year-old male patient with T-10 paraplegia presented with recurrent urinary tract infections. X-ray of the kidneys, taken with the vertical beam while the patient lay supine, revealed a poorly defined opacity overlying the lower pole of the right kidney. Findings on ultrasonography of the kidneys were interpreted as a large, staghorn-type calculus in the dilated lower pole calyx of the right kidney. Because x-ray of the kidneys showed a poorly defined opacity overlying the lower pole of the right kidney, milk of calcium was suspected, and computed tomography (CT) of the kidneys was performed. Calcific debris with horizontal layering in the lower pole calyces of both kidneys was seen; this confirmed the diagnosis of milk of calcium. A 62-year-old female patient with C-7 tetraplegia underwent ileal conduit urinary diversion. Subsequently, she developed calculi in the right kidney, which were treated with shock wave lithotripsy. Follow-up x-ray revealed faintly opaque shadows with indistinct margins in the region of both kidneys. Intravenous urography showed cortical thinning at the upper poles and blunting of the calyces, suggestive of chronic pyelonephritis. The right renal pelvis was bulky, and bilateral renal calculi were diagnosed during ultrasonography; however, the presence of faintly radio-opaque shadows with indistinct margins raised suspicions of renal milk of calcium. A CT scan of the kidneys, which was performed in the supine and subsequently

Bcl-2 protects tubular epithelial cells from ischemia reperfusion injury by inhibiting apoptosis.

PubMed

Suzuki, Chigure; Isaka, Yoshitaka; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Takabatake, Yoshitsugu; Ito, Takahito; Takahara, Shiro; Imai, Enyu

2008-01-01

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of graft dysfunction in kidney transplantation subjected to ischemia. The mechanism that triggers inflammation and renal injury after ischemia remains to be elucidated; however, cellular stress may induce apoptosis during the first hours and days after transplantation, which might play a crucial role in early graft dysfunction. Bcl-2 is known to inhibit apoptosis induced by the etiological factors promoting ischemia and reperfusion injury. Accordingly, we hypothesized that an augmentation of the antiapoptotic factor Bcl-2 may thus protect tubular epithelial cells by inhibiting apoptosis, thereby ameliorating the subsequent tubulointerstitial injury. We examined the effects of Bcl-2 overexpression on ischemia-reperfusion (I/R) injury using Bcl-2 transgenic mice (Bcl-2 TG) and their wild-type littermates (WT). To investigate the effects of I/R injury, the left renal artery and vein were clamped for 45 min, followed by reperfusion for 0-96 h. Bcl-2 TG exhibited decreased active caspase protein in the tubular cells, which led to a reduction in TUNEL-positive apoptotic cells. Consequently, interstitial fibrosis and phenotypic changes were ameliorated in Bcl-2 TG. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R, and subsequent interstitial injury by inhibiting tubular apoptosis.

Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury.

PubMed

Han, Sang Jun; Kim, Jee In; Park, Jeen-Woo; Park, Kwon Moo

2015-09-01

Progression of acute kidney injury to chronic kidney disease (CKD) is associated with inadequate recovery of damaged kidney. Hydrogen sulfide (H2S) regulates a variety of cellular signals involved in cell death, differentiation and proliferation. This study aimed to identify the role of H2S and its producing enzymes in the recovery of kidney following ischemia/reperfusion (I/R) injury. Mice were subjected to 30 min of bilateral renal ischemia. Some mice were administered daily NaHS, an H2S donor, and propargylglycine (PAG), an inhibitor of the H2S-producing enzyme cystathionine gamma-lyase (CSE), during the recovery phase. Cell proliferation was assessed via 5'-bromo-2'-deoxyuridine (BrdU) incorporation assay. Ischemia resulted in decreases in CSE and cystathionine beta-synthase (CBS) expression and activity, and H2S level in the kidney. These decreases did not return to sham level until 8 days after ischemia when kidney had fibrotic lesions. NaHS administration to I/R-injured mice accelerated the recovery of renal function and tubule morphology, whereas PAG delayed that. Furthermore, PAG increased mortality after ischemia. NaHS administration to I/R-injured mice accelerated tubular cell proliferation, whereas it inhibited interstitial cell proliferation. In addition, NaHS treatment reduced post-I/R superoxide formation, lipid peroxidation, level of GSSG/GSH and Nox4 expression, whereas it increased catalase and MnSOD expression. Our findings demonstrate that H2S accelerates the recovery of I/R-induced kidney damage, suggesting that the H2S-producing transsulfuration pathway plays an important role in kidney repair after acute injury. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy

PubMed Central

Jheng, Huei-Fen; Tsai, Pei-Jane; Chuang, Yi-Lun; Shen, Yi-Ting; Tai, Ting-An; Chen, Wen-Chung; Chou, Chuan-Kai; Ho, Li-Chun; Tang, Ming-Jer; Lai, Kuei-Tai A.; Sung, Junne-Ming; Tsai, Yau-Sheng

2015-01-01

ABSTRACT Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4−/− mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN. PMID:26398934

Oxidative Stress and Modification of Renal Vascular Permeability Are Associated with Acute Kidney Injury during P. berghei ANKA Infection

PubMed Central

Elias, Rosa Maria; Correa-Costa, Matheus; Barreto, Claudiene Rodrigues; Silva, Reinaldo Correia; Hayashida, Caroline Y.; Castoldi, Ângela; Gonçalves, Giselle Martins; Braga, Tarcio Teodoro; Barboza, Renato; Rios, Francisco José; Keller, Alexandre Castro; Cenedeze, Marcos Antonio; Hyane, Meire Ioshie; D'Império-Lima, Maria Regina; Figueiredo-Neto, Antônio Martins; Reis, Marlene Antônia; Marinho, Cláudio Romero Farias; Pacheco-Silva, Alvaro; Câmara, Niels Olsen Saraiva

2012-01-01

Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA. PMID:22952850

Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3β Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats.

PubMed

Shen, Xiaohua; Hu, Bo; Xu, Guangtao; Chen, Fengjuan; Ma, Ruifen; Zhang, Nenghua; Liu, Jie; Ma, Xiaoqin; Zhu, Jia; Wu, Yuhong; Shen, Ruilin

2017-01-01

Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3β inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model. STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-κB in the renal tissue were measured by qRT-PCR and western blotting. I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-κB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats. These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms. © 2017 The Author(s). Published by S. Karger AG, Basel.

Cutaneous and renal glomerular vasculopathy as a cause of acute kidney injury in dogs in the UK

PubMed Central

Hawkins, I.; Robin, C.; Newton, R. J.; Jepson, R.; Stanzani, G.; McMahon, L. A.; Pesavento, P.; Carr, T.; Cogan, T.; Couto, C. G.; Cianciolo, R.; Walker, D. J.

2015-01-01

To describe the signalment, clinicopathological findings and outcome in dogs presenting with acute kidney injury (AKI) and skin lesions between November 2012 and March 2014, in whom cutaneous and renal glomerular vasculopathy (CRGV) was suspected and renal thrombotic microangiopathy (TMA) was histopathologically confirmed. The medical records of dogs with skin lesions and AKI, with histopathologically confirmed renal TMA, were retrospectively reviewed. Thirty dogs from across the UK were identified with clinicopathological findings compatible with CRGV. These findings included the following: skin lesions, predominantly affecting the distal extremities; AKI; and variably, anaemia, thrombocytopaenia and hyperbilirubinaemia. Known causes of AKI were excluded. The major renal histopathogical finding was TMA. All thirty dogs died or were euthanised. Shiga toxin was not identified in the kidneys of affected dogs. Escherichia coli genes encoding shiga toxin were not identified in faeces from affected dogs. CRGV has previously been reported in greyhounds in the USA, a greyhound in the UK, without renal involvement, and a Great Dane in Germany. This is the first report of a series of non-greyhound dogs with CRGV and AKI in the UK. CRGV is a disease of unknown aetiology carrying a poor prognosis when azotaemia develops. PMID:25802439

Rifampicin-Induced Concomitant Renal Injury and Hepatitis

PubMed Central

Chogtu, Bharti; Surendra, Vyshak Uddur; Acharya, Preetam Rajgopal; Yerrapragada, Devesh Bhaskar

2016-01-01

Adverse drug reactions are not unusual during Anti-Tubercular Therapy (ATT). One of the common complications of anti-tubercular treatment is drug induced hepatitis and renal insufficiency has also been reported. Renal failure and/or hepatitis encountered during treatment of tuberculosis can have varied aetiologies: drug induced, concomitant viral infection, pre-existing co-morbidities or a combination of these. Since, hepatitis and/or renal insufficiency can be life threatening a prompt diagnosis is warranted, where drugs should be kept as one of the important cause. Identifying the drug helps in treating hepatitis and/or renal insufficiency along with helping the physician to change the combination of ATT regimen. Rifampicin is one of the most important first line drugs in the treatment of tuberculosis. Hepatitis, epigastric distress, anaemia, thrombocytopenia, and interstitial nephritis are reported adverse drug reactions to rifampicin. As per literature rifampicin induced renal toxicity is usually seen on rifampicin re-exposure, or rifampicin administration on alternate days, both being present in this case. Here we are reporting a case of ATT induced renal failure with concomitant hepatitis where rifampicin was suspected to be the cause. PMID:27790502