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Sample records for human renal allograft

  1. Human renal allograft blood flow and early renal function.

    PubMed Central

    Anderson, C B; Etheredge, E E

    1977-01-01

    Renal allograft blood flow (RBF) was measured at operation by electromagnetic flow meter and probes in 45 patients (34 cadaver donors and 11 living related donors). Mean RBF in 26 patients without acute tubular necrosis (ATN), was 412 +/- 80 ml/min and in 19 patients with ATN, 270 +/- 100 ml/min (p less than .001). Only two of 24 transplants (8%) with RBF greater than 350 ml/min had ATN; whereas, 17 of 21 transplants (81 per cent) with RBF less than 350 ml/min had ATN (p less than .001). In cadaver donor transplants, RBF did not correlate with duration of ATN, warm ischemia time, total ischemia time, pulsatile perfusion time or renal vascular resistance during perfusion. Measurement of renal allograft blood flow can predict presence or absence of postoperative ATN in 87% of patients. PMID:335986

  2. Expression of growth arrest-specific gene 6 and its receptors in dysfunctional human renal allografts.

    PubMed

    Yin, Jian L; Hambly, Brett D; Bao, Shi S; Painter, Dorothy; Bishop, G Alex; Eris, Josette M

    2003-09-01

    Growth arrest-specific gene 6 (Gas6) and its receptors Rse, Axl and Mer have recently been found to be involved in a rat model of chronic allograft nephropathy (CAN). Thus, in this study we investigated the function of Gas6 and its receptors in human renal allograft dysfunction. Expression of Gas6 and its receptors was detected by immunohistochemical staining. Gas6 and its receptors were widely expressed in glomeruli, tubules and vessels of renal allografts. Gas6 expression was detected in normal-functioning allografts and was increased in acute rejection ( P<0.05), acute tubular necrosis ( P<0.05) and CAN ( P<0.01). Gas6 receptors were not upregulated in any of the allograft groups, except for the Axl receptor, which increased only in acute tubular necrosis ( P<0.01). Gas6 expression was also found to correspond with the expression of alpha-smooth muscle actin, a general marker of CAN ( r(2)=0.21, P<0.01). These findings suggest that Gas6, acting as a growth factor, is increased in the process of kidney allograft dysfunction and in CAN.

  3. Nitration and Inactivation of Manganese Superoxide Dismutase in Chronic Rejection of Human Renal Allografts

    NASA Astrophysics Data System (ADS)

    MacMillan-Crow, L. A.; Crow, John P.; Kerby, Jeffrey D.; Beckman, Joseph S.; Thompson, John A.

    1996-10-01

    Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 μ M) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.

  4. Human papillomavirus type 18 infection in a female renal allograft recipient: a case report.

    PubMed

    Cistjakovs, Maksims; Sultanova, Alina; Jermakova, Olga; Chapenko, Svetlana; Lesina-Korne, Baiba; Rozental, Rafail; Razeberga, Dace; Murovska, Modra; Ziedina, Ieva

    2016-11-09

    Human papillomavirus type 18 is the second most common cause of cervical cancer and is found in 7 to 20 % of cases of cervical cancer. The oncogenic potential of high-risk human papillomavirus is associated with expression of early proteins E6 and E7. Due to long-term immunosuppressive therapy, renal transplant recipients have a higher risk of developing persistent human papillomavirus infection. A 29-year-old white woman from Latvia with chronic focal segmental glomerulosclerosis received renal allograft transplantation and was prescribed immunosuppressive therapy with cyclosporine, prednisolone, and mycophenolate mofetil. Two weeks after renal transplantation, her cervical swab was positive for human papillomavirus consensus sequences. After 6 months, quantitative polymerase chain reaction showed a high viral load of 3,630,789 copies/10(5) cells of high-risk human papillomavirus type 18 and expression of E6 and E7 oncogenes in her cervical swab and urine sample. One year after renal transplantation, the viral load in her cervical swab increased significantly to 7,413,102 copies/10(5) cells. Messenger ribonucleic acid of human papillomavirus type 18 E6 and E7 oncogenes were also detected. Shortly after this, she had an unsuccessful pregnancy which resulted in a spontaneous abortion at 6/7 weeks. Two months after the abortion her viral load sharply decreased to 39 copies/10(5) cells. Oncogenes E6 and E7 messenger ribonucleic acid expression was not observed in this period. This case report represents data which show that immunosuppressive therapy may increase the risk of developing persistent high-risk human papillomavirus infection with expression of E6 and E7 oncogenes in renal transplant recipients. However, even during this therapy the immune status of a recipient can improve and contribute to human papillomavirus viral load reduction. Spontaneous abortion can be considered a possible contributory factor in human papillomavirus clearance.

  5. Assessment of the cellular immune response to HL-A antigens in human renal allograft recipients

    PubMed Central

    Falk, R. E.; Guttmann, R. D.; Falk, J. A.; Beaudoin, J. G.; Deveber, G.; Morehouse, D. D.; Wilson, D. R.

    1973-01-01

    The cellular response to HL-A antigens has been studied in thirty-one patients who had received a renal allograft from either a cadaveric or living donor, utilizing the leucocyte migration technique. The results indicate that inhibition of migration develops prior to or during the onset of a clinical rejection episode. This inhibition of migration reverts to non-inhibition in autologous serum when the rejection crisis is reversed. Inhibition of migration is still noted in allogeneic serum following this clinical reversal, but after varying time intervals the inhibition reaction also decreases in this serum. The abrogation of inhibition in autologous serum is specific to the HL-A antigens of the donor. These observations suggest that survival of human renal allografts depends on a blocking substance in the serum initially; subsequently, the loss of inhibition of migration with HL-A antigens in both autologous and allogeneic serum suggests an inactivation of specific antigen sensitive cells to the histocompatibility antigens of the donor. PMID:4577287

  6. Monocyte procoagulant activity and plasminogen activator. Role in human renal allograft rejection

    SciTech Connect

    Cole, E.H.; Cardella, C.J.; Schulman, J.; Levy, G.A.

    1985-10-01

    Currently the mechanism of renal allograft rejection is not well understood. This study was designed to determine whether induction of monocyte procoagulant activity (MCPA) is important in the pathogenesis of renal allograft rejection. The MPCA assay was performed utilizing a one stage clotting assay both in normal and in factor-VII-deficient plasma. There was no increase in spontaneous MPCA in 20 patients with endstage renal failure and in 10 patients following abdominal or orthopedic operation, as compared with 20 normal controls. MPCA was assessed daily in 18 patients who had received renal allografts. Rejection episodes (RE) were predicted on the basis of persistent elevation in MPCA as compared with pretransplant levels. Rejection was diagnosed clinically and treated on the basis of standard criteria. Treated RE were compared with those predicted by elevated MPCA, and 3 patients were assessed as having no RE by MPCA and by standard criteria. In 8 RE, MPCA correlated temporally with RE (same day) when compared with standard criteria. In 12 RE, MPCA was predictive of rejection preceding standard criteria by at least 24 hr. There were 7 false-positive predictions on the basis of MPCA; however, there was only 1 false negative. MPCA was shown to be a prothrombinase by its dependence only on prothrombin and fibrinogen for full activity. MPCA may be important in the pathogenesis of allograft rejection, and additionally it may be a useful adjunct in the clinical management of this disease.

  7. Emphysema in the renal allograft

    SciTech Connect

    Potter, J.L.; Sullivan, B.M.; Fluornoy, J.G.; Gerza, C.

    1985-04-01

    Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.

  8. Perioperative release of pro-regenerative biochemical signals from human renal allografts subjected to ischemia-reperfusion injury.

    PubMed

    Błogowski, Wojciech; Dolegowska, Barbara; Budkowska, Marta; Sałata, Daria; Domański, Leszek; Starzynska, Teresa

    2014-02-01

    Complement-derived molecules modulate the intensity of renal ischemia-reperfusion injury and may lead to the generation of biochemical signals [such as stromal-derived factor-1 (SDF-1) or sphingosine-1-phosphate (S1P)], which stimulate tissue/organ regeneration after injury. We tested the association between perioperative C5b-9/membrane attack complex (MAC) levels and intensified erythrocyte lysis, and asked whether significant changes in the levels of pro-regenerative substances occur during the early phase of renal allograft reperfusion. Seventy-five recipients were enrolled and divided into the early, slow, and delayed graft function (DGF) groups. Perioperative blood samples were collected from the renal vein during consecutive minutes of reperfusion. Extracellular hemoglobin (eHb), albumin (plasma S1P transporter), 8-iPF2α-III isoprostane, SDF-1 and S1P concentrations were measured. Throughout the reperfusion period, erythrocyte lysis intensified and was most pronounced in the DGF group. However, perioperative eHb levels did not correlate significantly with C5b-9/MAC values, but rather with the intensity of oxidative stress. No significant changes were observed in S1P, its plasma transporter (albumin) or SDF-1 levels, which were relatively low in all groups throughout the reperfusion period. Our study therefore demonstrates that no known biochemical signal for bone marrow-derived stem cell mobilization is released from human renal allografts to the periphery during the early phase of reperfusion.

  9. Renal expression of Toll-like receptor 2 and 4: dynamics in human allograft injury and comparison to rodents.

    PubMed

    Stribos, Elisabeth G D; van Werkhoven, Maaike B; Poppelaars, Felix; van Goor, Harry; Olinga, Peter; van Son, Willem J; Damman, Jeffrey; Seelen, Marc A

    2015-03-01

    Activation of the innate immunity through Toll-like receptors (TLRs) has been postulated to play an important role in the pathophysiology of renal allograft dysfunction. TLR2 and TLR4 dynamics in different human post-transplant pathological entities has never been studied. Therefore, we evaluated pre- and post-transplantation protein expression of TLR2 and TLR4 in human kidney biopsies. Human kidney biopsies obtained from living kidney donors and patients with acute tubular necrosis, acute cellular and vascular rejection and interstitial fibrosis/tubular atrophy (IF/TA) were used. Translating results from animal studies to the clinical situation is highly important considering the upcoming clinical studies with TLR inhibitors in human renal transplantation. Hence, the TLR2 and TLR4 expression in healthy mouse and rat kidneys was analyzed and compared with human kidneys. In healthy human kidneys, TLR2 is expressed on the endothelium and Bowman's capsule, while TLR4 is expressed on the endothelium only. No tubular staining was found for both receptors in human kidneys. In contrast to human biopsies, TLR2 and TLR4 expression in rodents was observed on tubular epithelial cells. In all acute rejection human biopsies, increased infiltration of TLR4(+) leukocytes was observed. In conclusion, a discrepancy exists between human and rodent renal TLR expression, which suggests careful attention when translating results from rodent studies to the human situation. Additionally, this study revealed human TLR2 and TLR4 expression dynamics in human biopsies pre- and post-transplantation.

  10. Computational Biology: Modeling Chronic Renal Allograft Injury

    PubMed Central

    Stegall, Mark D.; Borrows, Richard

    2015-01-01

    New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using mathematical modeling to analyze predictors of graft loss using both clinical and experimental data and how we plan to expand this approach to investigate specific mechanisms of chronic renal allograft injury. PMID:26284070

  11. Active haemorrhage of a renal allograft detected on portable ultrasound

    PubMed Central

    Ricketts, James; Pang, Chun Lap; Dissanayake, Prageeth; Hutchinson, Rachel; Gutteridge, Catherine

    2013-01-01

    Function of a renal allograft relies on the integrity of its vascular anatomy. Renal biochemistry, ultrasound and percutaneous biopsy are used in combination to determine allograft function. Biopsy is not without risk, and in this case study we demonstrate a rare but a potentially life-threatening complication of renal allograft biopsy. PMID:23682093

  12. Renal allograft rejection: sonography and scintigraphy

    SciTech Connect

    Singh, A.; Cohen, W.N.

    1980-07-01

    A total of 30 renal allograft patients who had sonographic B scanning and radionuclide studies of the transplant was studied as to whether: (1) the allograft rejection was associated with any consistent and reliable sonographic features and (2) the sonograms complemented the radionuclide studies. Focal areas of decreased parenchymal echogenicity were the most striking and consistent sonographic finding in chymal echogenicity were the most striking and consistens sonographic finding in allograft rejection. This was observed in most of the patients exhibiting moderate or severe rejection, but was frequently absent with mild rejection. Areas of decreased parenchymal echogenicity were not seen during episodes of acute tubular necrosis. Therefore, sonography showing zones of decreased parenchymal echogenicity was complementary to radionuclide studies in the diagnosis of allograft rejection versus acute tubular necrosis. Corticomedullary demarcation was difficult to interpret because of technical variables, and was inconsistently related to rejection in this series.

  13. Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

    PubMed

    Wang, Ying-Ying; Jiang, Hong; Pan, Jun; Huang, Xiao-Ru; Wang, Yu-Cheng; Huang, Hong-Feng; To, Ka-Fai; Nikolic-Paterson, David J; Lan, Hui-Yao; Chen, Jiang-Hua

    2017-02-16

    Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68(+)/α-SMA(+) cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA(+) myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

  14. Recurrent Focal Segmental Glomerulosclerosis in Renal Allograft Recipients: Role of Human Leukocyte Antigen Mismatching and Other Clinical Variables

    PubMed Central

    Sharief, Shimi; Mahesh, Shefali; Del Rio, Marcela; Telis, Vivian; Woroniecki, Robert P.

    2011-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation impacts long-term graft survival and limits access to transplantation. We hypothesized that HLA donor/recipient matching could be used as a surrogate marker of recurrence. In a retrospective study of 42 pediatric and 77 adult subjects with primary FSGS, transplanted from 1990 to 2007 at a single center, we analyzed the degree of donor/recipient HLA compatibility and other clinical variables associated with FSGS recurrence. There were total of 131 allografts for primary FSGS (11 subjects were transplanted twice, and 1 had a third allograft) with 20 cases of FSGS recurrence (17 children) in the primary allograft, and two children who had FSGS recurrence in the second allograft. Fifty-two subjects (40%) were African American, and 66 (50%) Caucasians. Recurrent FSGS and controls were not different for age at transplant, gender, donor source, acute/chronic rejection episodes, and HLA matches. Recurrent FSGS was not associated with HLA mismatches; power equals 83%. Immunosuppressive regimen had no effect on recurrence of FSGS, P = .75. Recurrent FSGS is not associated with HLA mismatching, acute cellular or vascular rejection, and occurs primarily in the pediatric population. PMID:21755058

  15. Renal allograft eosinophilia: An unusual presentation of sudden graft dysfunction

    PubMed Central

    Yuvaraj, A.; Ghosh, S.; Abraham, G.; Koshy, P.

    2017-01-01

    We present a case of sudden allograft dysfunction 11 months after renal transplantation which presented as severe peripheral and allograft eosinophilia and was managed as a case of an acute cellular rejection with significant interstitial graft eosinophilic infiltration. Patient had partial response to antirejection therapy and eventually ended up in a chronic allograft dysfunction. PMID:28356665

  16. Immunohistochemical detection of hypoxia-inducible factor-1alpha in human renal allograft biopsies.

    PubMed

    Rosenberger, Christian; Pratschke, Johann; Rudolph, Birgit; Heyman, Samuel N; Schindler, Ralf; Babel, Nina; Eckardt, Kai-Uwe; Frei, Ulrich; Rosen, Seymour; Reinke, Petra

    2007-01-01

    Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

  17. Focal posttransplantation lymphoproliferative disorder at the renal allograft hilum.

    PubMed

    Lopez-Ben, R; Smith, J K; Kew, C E; Kenney, P J; Julian, B A; Robbin, M L

    2000-11-01

    This report describes the imaging characteristics of focal posttransplantation lymphoproliferative disorder. Posttransplantation lymphoproliferative disorder may be limited to the allograft. A focal complex mass in the renal allograft hilum surrounding the main renal blood vessels is a common finding and can be visualized with sonography. MR imaging can help increase diagnostic confidence.

  18. Diagnostic Value of Monitoring Human Cytomegalovirus Late pp67 mRNA Expression in Renal-Allograft Recipients by Nucleic Acid Sequence-Based Amplification

    PubMed Central

    Blok, Marinus J.; Goossens, Valere J.; Vanherle, Sabina J. V.; Top, Bert; Tacken, Nicole; Middeldorp, Jaap M.; Christiaans, Maarten H. L.; van Hooff, Johannes P.; Bruggeman, Cathrien A.

    1998-01-01

    The diagnostic value of monitoring human cytomegalovirus (HCMV) late pp67 mRNA expression by nucleic acid sequence-based amplification (NASBA) after renal-allograft transplantation was evaluated. RNAs were isolated from 489 whole-blood specimens of 42 patients for the specific amplification of the late pp67 (UL65) mRNA. NASBA results were compared to results from the pp65 antigenemia assay, virus isolation by cell culture, and serology. The sensitivity value for NASBA proved to be higher than that for the antigenemia assay (50 versus 35%) for the detection of HCMV infection, while the sensitivity values of cell culture and NASBA were comparable (54 and 50%, respectively). NASBA detected the onset of HCMV infection simultaneously with cell culture and the antigenemia assay. Both the antigenemia assay and NASBA are very specific (100%) and highly predictive (100%) for the onset of HCMV infection. Antiviral therapy with ganciclovir resulted in negative results for cell culture, the antigenemia assay, and NASBA. In conclusion, monitoring HCMV pp67 mRNA expression by NASBA is a highly specific method for the detection of HCMV infection in renal-allograft recipients and is more sensitive than the antigenemia assay. Furthermore, NASBA can be used to monitor the progression of HCMV infections and the effect of antiviral therapy on viral activity. PMID:9574702

  19. Multiplexed color-coded probe-based gene expression assessment for clinical molecular diagnostics in formalin-fixed paraffin-embedded human renal allograft tissue.

    PubMed

    Adam, Benjamin; Afzali, Bahman; Dominy, Katherine M; Chapman, Erin; Gill, Reeda; Hidalgo, Luis G; Roufosse, Candice; Sis, Banu; Mengel, Michael

    2016-03-01

    Histopathologic diagnoses in transplantation can be improved with molecular testing. Preferably, molecular diagnostics should fit into standard-of-care workflows for transplant biopsies, that is, formalin-fixed paraffin-embedded (FFPE) processing. The NanoString(®) gene expression platform has recently been shown to work with FFPE samples. We aimed to evaluate its methodological robustness and feasibility for gene expression studies in human FFPE renal allograft samples. A literature-derived antibody-mediated rejection (ABMR) 34-gene set, comprised of endothelial, NK cell, and inflammation transcripts, was analyzed in different retrospective biopsy cohorts and showed potential to molecularly discriminate ABMR cases, including FFPE samples. NanoString(®) results were reproducible across a range of RNA input quantities (r = 0.998), with different operators (r = 0.998), and between different reagent lots (r = 0.983). There was moderate correlation between NanoString(®) with FFPE tissue and quantitative reverse transcription polymerase chain reaction (qRT-PCR) with corresponding dedicated fresh-stabilized tissue (r = 0.487). Better overall correlation with histology was observed with NanoString(®) (r = 0.354) than with qRT-PCR (r = 0.146). Our results demonstrate the feasibility of multiplexed gene expression quantification from FFPE renal allograft tissue. This represents a method for prospective and retrospective validation of molecular diagnostics and its adoption in clinical transplantation pathology.

  20. Phase I trial of a humanized, Fc receptor nonbinding anti-CD3 antibody, hu12F6mu in patients receiving renal allografts

    PubMed Central

    Du, Li; Tan, Min; Hou, Sheng; Qian, Weizhu; Li, Bohua; Zhang, Dapeng; Dai, Jianxin; Wang, Hao; Zhang, Xu

    2010-01-01

    Hu12F6mu is an Fc-mutated, humanized anti-CD3 antibody developed in our lab. The aim of this study was to assess single dose escalation pharmacokinetics (PK) and safety profile of hu12F6mu and to measure the effects of the antibody on levels of circulating T cells over time. Twenty-seven patients receiving renal allografts were randomized to receive hu12F6mu intravenously at a single-dose of 2.5, 5 or 10 mg. The concentration-time data obtained by a validated ELISA method were subjected to non-compartmental PK analysis by DAS 2.1 software. Subgroups of CD2+, CD3+, CD4+ and CD8+ lymphocytes were monitored periodically by flow cytometry. Our results showed that hu12F6mu exhibited linear PK over the dose range of 2.5–10 mg. A significant decline in the proportion of T cells was observed immediately after the infusion, followed by a progressive increase occurring over the ensuing days of therapy. A significant negative correlation was observed between serum concentration of hu12F6mu and CD3+ cell proportion. Intravenous infusion of hu12F6mu was well-tolerated in patients receiving renal allografts. These results suggest that hu12F6mu may have potential as a therapeutic agent, although further studies are needed. PMID:20519962

  1. Asymptomatic bacteriuria and urinary tract infections among renal allograft recipients.

    PubMed

    Singh, Ramandeep; Geerlings, Suzanne E; Bemelman, Frederike J

    2015-02-01

    Bacteriuria is common among renal allograft recipients. It can be categorized into asymptomatic bacteriuria (ASB) and urinary tract infection (UTI). However, in medical literature, the classifications of bacteriuria are often not clear or ASB is also classified as a UTI. This contributes to difficulties in interpretation of the incidence and risk factors of these two entities. In this review, we describe the epidemiology, risk factors, management and the impact on renal allograft function of these two entities separately according to the recent literature. Risk factors for ASB are not completely comparable to the risk factors of UTIs. Persistent ASB has been associated with development of acute rejection and allograft pyelonephritis. The available data suggest that treatment of ASB is not very effective. Prophylaxis with trimethoprim-sulfamethoxazole does not prevent UTIs such as allograft pyelonephritis. Blood stream infections and emphysematous allograft pyelonephritis are associated with renal allograft loss. ASB is the most common manifestation of bacteriuria after renal transplantation. More effective interventions are needed to prevent bacteriuria. Renal allograft recipients with persistent ASB should be closely monitored since they could be at risk for developing not only UTIs, such as allograft pyelonephritis, but also acute rejection.

  2. Multifocal bacterial osteomyelitis in a renal allograft recipient following urosepsis.

    PubMed

    Valson, A T; David, V G; Balaji, V; John, G T

    2014-05-01

    Non-tubercular bacterial osteomyelitis is a rare infection. We report on a renal allograft recipient with osteomyelitis complicating urosepsis, manifesting as a multifocal infection poorly responsive to appropriate antibiotics and surgical intervention and culminating in graft loss.

  3. Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts.

    PubMed

    Gorbacheva, Victoria; Fan, Ran; Fairchild, Robert L; Baldwin, William M; Valujskikh, Anna

    2016-11-01

    Despite advances in immunosuppression, antibody-mediated rejection is a serious threat to allograft survival. Alloreactive memory helper T cells can induce potent alloantibody responses and often associate with poor graft outcome. Nevertheless, the ability of memory T cells to elicit well characterized manifestations of antibody-mediated rejection has not been tested. We investigated helper functions of memory CD4 T cells in a mouse model of renal transplantation. Whereas the majority of unsensitized C57Bl/6 recipients spontaneously accepted fully MHC-mismatched A/J renal allografts, recipients containing donor-reactive memory CD4 T cells rapidly lost allograft function. Increased serum creatinine levels, high serum titers of donor-specific alloantibody, minimal T cell infiltration, and intense C4d deposition in the grafts of sensitized recipients fulfilled all diagnostic criteria for acute renal antibody-mediated rejection in humans. IFNγ neutralization did not prevent the renal allograft rejection induced by memory helper T cells, and CD8 T cell depletion at the time of transplantation or depletion of both CD4 and CD8 T cells also did not prevent the renal allograft rejection induced by memory helper T cells starting at day 4 after transplantation. However, B cell depletion inhibited alloantibody generation and significantly extended allograft survival, indicating that donor-specific alloantibodies (not T cells) were the critical effector mechanism of renal allograft rejection induced by memory CD4 T cells. Our studies provide direct evidence that recipient T cell sensitization may result in antibody-mediated rejection of renal allografts and introduce a physiologically relevant animal model with which to investigate mechanisms of antibody-mediated rejection and novel therapeutic approaches for its prevention and treatment. Copyright © 2016 by the American Society of Nephrology.

  4. RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

    PubMed Central

    Van Aelst, L. N. L.; Summer, G.; Li, S.; Gupta, S. K.; Heggermont, W.; De Vusser, K.; Carai, P.; Naesens, M.; Van Cleemput, J.; Van de Werf, F.; Vanhaecke, J.; Thum, T.; Waer, M.; Papageorgiou, A.‐P.; Schroen, B.

    2015-01-01

    Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR‐21, ‐142‐3p, ‐142‐5p, ‐146a, ‐146b, ‐155, ‐222, ‐223, and ‐494 increased during ACR in humans and mice, whereas miR‐149‐5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune‐related diseases. Interestingly, 33 of 70 transcripts function downstream of IL‐6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR‐155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR‐155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR‐155, and transcripts, in particular those related to the IL‐6 pathway, are promising therapeutic targets to prevent acute allograft rejection. PMID:26249758

  5. Targeting Sirtuin-1 prolongs murine renal allograft survival and function.

    PubMed

    Levine, Matthew H; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R; Hancock, Wayne W; Beier, Ulf H

    2016-05-01

    Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3(+) T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3(+) T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1(fl/fl)CD4(cre)) or mice treated with a Sirtuin-1-specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1(fl/fl)CD4(cre) recipients showed markedly longer survival and improved kidney function. Sirt1(fl/fl)CD4(cre) recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell-mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration.

  6. Carcinoembryonic antigen in renal allograft recipients and immunosuppressed renal patients.

    PubMed

    Myers, J B; Frost, M; Coates, A S; Mathews, J D; Kincaid-Smith, P

    1977-02-01

    Carcinoembryonic antigen (CEA) was estimated in plasma from 70 patients with a renal transplant, 105 patients with glomerulonephritis who had received immunosuppressive therapy, and 124 healthy controls. There were raised levels in 30% of those with a renal transplant, 10% of those with glomerulonephritis and 2% of controls, and levels were higher in current smokers. CEA levels did not correlate with pre-transplant dialysis time nor with serum creatinine levels, but tended to fall with increasing time after transplantation, especially in non-smokers. CEA levels did not correlate with prednisolone dosage nor with number of rejection episodes, after allowing for time after transplantation and smoking habit. Nine of 70 patients with a renal transplant and three of 105 with glomerulonephritis had cancer, of skin in seven, cervix uteri in four, and colon in one. CEA was raised in all four transplant recipients with a visceral cancer (cervix three and colon one), but in none of the five with cutaneous cancer. Raised CEA levels occurring late after a renal allograft should prompt a careful search for visceral cancer.

  7. Tuberculosis in a renal allograft: a successful outcome.

    PubMed

    George, Pratish; Pawar, Basant; Calton, Nalini

    2008-09-01

    Tuberculosis is endemic in most South-East Asian countries including India. It causes significant morbidity and mortality in renal transplant recipients and often, it is not diagnosed early, due to its innocuous clinical presentations. A high index of suspicion and proactive management in the early phase of presentation can reduce allograft nephropathy, graft nephrectomy and mortality. A patient with an unusual presentation of tuberculosis localized to the allograft and successful management with anti-tuberculosis medications is described.

  8. Effects of growth hormone administration in pediatric renal allograft recipients.

    PubMed

    Bartosh, S; Kaiser, B; Rezvani, I; Polinsky, M; Schulman, S; Palmer, J; Baluarte, H J

    1992-01-01

    The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2 +/- 2.0 years) all of whom had bone ages less than or equal to 12 years (10.0 +/- 1.4 years), a height standard deviation score of less than -2.5 (-4.9 +/- 1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40 ml/min per 1.73 m2 (51 +/- 6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7 +/- 2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5 +/- 1.6 cm/year pre therapy, 8.5 +/- 1.4 cm/year post therapy, P less than 0.001) and percentage of expected growth velocity for bone age (67 +/- 31% pre therapy, 163 +/- 27% post therapy, P less than 0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Rare Presentations of Cytomegalovirus Infection in Renal Allograft Recipients

    PubMed Central

    Ardalan, Mohammadreza

    2012-01-01

    Cytomegalovirus is the most common viral infection after kidney transplantation. Clinical presentations of cytomegalovirus infection range from asymptomatic infection to organ-specific involvement. Most symptomatic infections manifest as fever and cytopenia. The gastrointestinal tract is the most common site of tissue-invasive infection, often presenting as diarrhea or gastrointestinal bleeding. Gastrointestinal obstruction, perforation, thrombosis of large gastrointestinal veins, splenic artery thrombosis, and pancreatitis are rare gastrointestinal presentations of cytomegalovirus infection. Renal-allograft ureteral stricture and skin involvement are other rare presentations of cytomegalovirus infection. hemophagocytic syndrome, thrombotic microangiopathy, adrenal insufficiency, and renal allograft artery stenosis are other rare symptoms of cytomegalovirus infection. PMID:23573461

  10. Postransplant lymphoproliferative disorder localized near the allograft in renal transplantation.

    PubMed

    Kew, C E; Lopez-Ben, R; Smith, J K; Robbin, M L; Cook, W J; Gaston, R S; Deierhoi, M H; Julian, B A

    2000-03-15

    Posttransplant lymphoproliferative disorder (PTLD), a complication of immunosuppression, develops in approximately 1% of renal allograft recipients. Typically, PTLD is a proliferation of B-cells associated with Epstein-Barr virus (EBV) infection; it is said to be most often a systemic disease. Involvement occasionally is localized near the allograft. This is a retrospective analysis of all cases of PTLD in recipients of 1474 renal transplants performed at University of Alabama at Birmingham between 1993 and 1997. Of 14 patients developing PTLD, 10 had disease localized near the allograft. The mean interval from transplantation to diagnosis was 221 +/- 70 days. All patients presented with renal dysfunction; an ultrasound examination revealed a hilar mass, with hydronephrosis in five and stenosis of renal vessels in eight. No patient had lymphadenopathy, according to computerized tomographic or magnetic resonance imaging findings. After reduction of immunosuppressive therapy, seven required a nephrectomy because of rejection, progressive dysfunction, or mass enlargement. Tissue recovered in four patients was consistent with PTLD; the tumors in the remaining three patients were unresectable and regressed. One patient died 1 month after a nephrectomy, and another died 4 years after surgery; neither had evidence of PTLD when they died. Three patients retain functional grafts without clinical or radiographical evidence of progression. All patients with disseminated disease died. In a large cohort of renal allograft recipients, PTLD affected 1%. Disease localized near the allograft was the most common variant. For most patients with localized disease, the outcome was graft loss, and the mortality was low. Localized PTLD should be considered in the differential diagnosis of allograft dysfunction in the 1st posttransplant year.

  11. Incidence, risk factors, and the impact of allograft pyelonephritis on renal allograft function.

    PubMed

    Singh, R; Geerlings, S E; Peters-Sengers, H; Idu, M M; Hodiamont, C J; Ten Berge, I J M; Bemelman, F J

    2016-10-01

    The impact of allograft pyelonephritis (AGPN) on renal allograft function is controversial. In this study, we evaluated the incidence, risk factors, and the impact of AGPN on renal allograft function. Retrospective cohort study in adult renal allograft recipients with 1-year follow-up after transplantation (Tx). Renal allograft function was evaluated by estimated glomerular filtration rate (eGFR) (by Modification of Diet in Renal Disease formula) and 24-h urine protein excretion. A total of 431 renal allograft recipients were analyzed; 57 (13.2%) developed AGPN within 1 year after Tx. Median time between Tx and AGPN was 50 days. Risk factors for AGPN were the presence of a urological catheter (odds ratio [OR] = 18.93, 95% confidence interval [CI] = 8.00-44.81, P < 0.001) and preceding asymptomatic bacteriuria (ASB) (OR = 2.16, 95% CI = 1.20-3.90, P = 0.009). In 72.7%, the causative microorganism of ASB was identical to that of the succeeding AGPN episode. Multivariable linear regression analysis showed that experiencing AGPN did not decrease the eGFR (P = 0.61) nor did increased proteinuria (P = 0.29) 1 year after Tx. For the eGFR, an interaction was found between AGPN/bacteriuria (BU) and acute rejection (AR): the group experiencing BU preceding AR had significantly (P < 0.001) lower eGFR compared with the group that experienced only AR (21 mL/min/1.73 m(2) vs. 48 mL/min/1.73 m(2) ), as a result of increased prevalence of combined rejections within the BU group. Indwelling urological catheters and preceding ASB are associated with developing AGPN. An incident of AGPN itself does not impair renal allograft function 1 year after Tx. However, a relevant interaction occurs between BU and AR, in which the sequence of occurrence of these 2 events synergistically impairs the eGFR. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Recurrence of Acute Page Kidney in a Renal Transplant Allograft

    PubMed Central

    Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft. PMID:27725836

  13. Recurrence of Acute Page Kidney in a Renal Transplant Allograft.

    PubMed

    Kapoor, Rajan; Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft.

  14. Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes.

    PubMed

    Adam, B A; Smith, R N; Rosales, I A; Matsunami, M; Afzali, B; Oura, T; Cosimi, A B; Kawai, T; Colvin, R B; Mengel, M

    2017-04-26

    Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10-fold cross-validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (area under the curve = 0.92). This three-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39-0.63, p < 0.001). Principal component analysis confirmed the association between three-gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell-mediated rejection (TCMR). Elevated three-gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  15. Pilot Study of Renal Diffusion Tensor Imaging as a Correlate to Histopathology in Pediatric Renal Allografts.

    PubMed

    Li, Yi; Lee, Marsha M; Worters, Pauline W; MacKenzie, John D; Laszik, Zoltan; Courtier, Jesse L

    2017-06-01

    Fractional anisotropy (FA) is a measure of molecular motion obtained from diffusion tensor imaging (DTI). The objective of this study was to assess the use of FA as a noninvasive correlate of renal allograft histopathology. Sixteen pediatric renal allograft recipients were imaged using DTI in a prospective study, between October 2014 and January 2016, before a same-day renal allograft biopsy. The Kendall tau correlation coefficient was used to assess the relationship between cortical and medullary FA values and several clinically important Banff renal allograft histopathology scores. The Mann-Whitney U test was also used to compare cortical and medullary FA values in the region of biopsy in patients whose biopsy results did and in those whose biopsy results did not change clinical management. Medullary FA values had direct inverse correlation with several histopathology scores: tubulitis (designated "t" score in Banff pathologic classification, p < 0.04), interstitial inflammation (i score, p < 0.005), tubular atrophy (ct score, p < 0.002), and interstitial fibrosis (ci score, p < 0.007). Cortical FA values inversely correlated with peritubular capillaritis (ptc score, p < 0.02). Neither medullary nor cortical FA values correlated with glomerulitis (g score). At a b value of 800 s/mm(2), medullary FA values of pediatric renal allograft recipients whose renal biopsies prompted a change in clinical management (mean ± SD at a b value of 800 s/mm(2) = 0.262 ± 0.07; n = 9) were statistically different compared with the group whose biopsy results did not change clinical management (mean ± SD at a b value of 800 s/mm(2) = 0.333 ± 0.06; n = 7) (p < 0.006). FA is a noninvasive correlate of several important renal allograft histopathology scores and a potential noninvasive method of assessing renal allograft health in pediatric allograft recipients.

  16. Renal allograft rejection: possible involvement of lymphokine-activated killer cells.

    PubMed Central

    Kirby, J A; Forsythe, J L; Proud, G; Taylor, R M

    1989-01-01

    Human renal allograft tissue was recovered at transplant nephrectomy from three patients with irreversible loss of graft function. This tissue was disaggregated and separated into two fractions on the basis of particle size. Fraction 1 contained glomeruli and developed a mixed outgrowth containing adherent epithelial and mesangial cells after a limited period of culture. Fraction 2 contained fragments of renal tubules and produced monolayers of tubular epithelial cells during culture. A population of lymphoid cells was observed to grow from the primary disaggregate into medium supplemented with recombinant human interleukin-2 (IL-2). After culture for 5 days these lymphoid cells were predominantly CD3-positive and carried both class II major histocompatibility antigens (MHC) and the CD25 IL-2 receptor. Culture of peripheral blood-derived mononuclear cells with IL-2 caused the generation of lymphokine-activated killer (LAK) cells; these cells were able to lyse both glomerular and tubular cells grown from nephrectomy tissue without showing MHC antigen restriction. The lymphoid cells grown from renal allograft tissue showed a similar lytic potential for both renal cells prepared from the same nephrectomy specimen and from third party renal tissue. It is possible that any LAK cells formed within a renal allograft by the action of IL-2 may contribute to the tissue destruction observed during graft rejection. Images Figure 2 PMID:2661417

  17. Renal Cell Carcinoma in the Allograft: What Is the Role of Polyomavirus?

    PubMed Central

    Neirynck, Valerie; Claes, Kathleen; Naesens, Maarten; De Wever, Liesbeth; Pirenne, Jacques; Kuypers, Dirk; Vanrenterghem, Yves; Poppel, Hendrik Van; Kabanda, Andre; Lerut, Evelyne

    2012-01-01

    BK virus (BKV) is known to cause subclinical infection in childhood. The virus remains latent in the human body, mainly in the urinary tract epithelium. After initiation of an immunosuppressive treatment, reactivation can occur in renal transplant recipients. BKV can cause hemorrhagic cystitis, ureteral stenosis and BKV nephropathy in immunocompromised patients. Furthermore, a number of case reports suggest an association between BKV infection and the development of urinary tract cancer. So far, an oncogenic potential of BKV has been observed in vitro and in animal models; however, its oncogenic capacity in humans remains unclear. We report the case of a 59-year-old patient who developed a poorly differentiated renal cell carcinoma in her renal allograft, with pulmonary and abdominal metastasis. Surgical removal of the allograft and cessation of the immunosuppressive therapy resulted in complete resolution of the metastatic disease. PMID:23197968

  18. [Tubulointerstitial rejection of renal allografts].

    PubMed

    Malušková, Jana; Honsová, Eva

    2015-01-01

    Tubulo-intersticial rejection represents T-cell mediated rejection of kidney allografts with the morphology of immune-mediated interstitial nephritis. Diagnosis is dependent on the histopathological evaluation of a graft biopsy sample. The key morphological features are interstitial inflammatory infiltrate and damage to tubular epithelial cell which in severe cases can result in the ruptures of the tubular basement membranes. The differential diagnosis of tubulo-interstitial rejection includes acute interstitial nephritis and viral inflammatory kidney diseases, mainly polyomavirus nephropathy.

  19. Recurrent renal allograft dysfunction due to ureteric stenosis in a patient with the BK virus infection.

    PubMed

    Reddy, Yogesh N V; Trabert, Johannes; Wunderer, Florian; Abraham, Georgi; Reddy, Yuvaram N V

    2014-01-01

    Diseases of the genitourinary tract in association with the BK virus (BKV) infection are increasing among renal allograft recipients. We herewith report a young, female renal transplant recipient who presented with allograft dysfunction secondary to proximal ureteric stenosis. The allograft function improved dramatically after correction and stenting of the stenosis. Our case suggests that screening for BKV infection should be an integral part of evaluation of allograft dysfunction.

  20. Successful treatment of verruca vulgaris with Thuja occidentalis in a renal allograft recipient.

    PubMed

    Joseph, R; Pulimood, S A; Abraham, P; John, G T

    2013-09-01

    Human papillomavirus-driven verruca vulgaris infection is common in solid organ transplant recipients and increases the risk for squamous cell carcinoma. The available treatment modalities have limited response. We report a renal allograft recipient who presented with multiple warts not responding to cryotherapy and radiosurgery with one turning malignant, needing amputation of the finger. An extract from Thuja occidentalis (White cedar tree) cured the resistant warts on the other fingers, leaving only superficial scars and without affecting allograft function. We have reviewed the pharmacological and clinical properties of T. occidentalis.

  1. Renal allograft tuberculosis with infected lymphocele transmitted from the donor.

    PubMed

    Al-Nesf, Maryam Ali; Al-Ani, Omar Isam; Al-Ani, Ahmed Abdul-Rahman; Rashed, Awad Hamed

    2014-03-01

    Transmission of tuberculosis (TB) from a donor through renal transplantation is a rare incident. We are reporting a 53-year-old Qatari woman diagnosed with renal allograft TB infection. The disease was confirmed by isolation of Mycobacterium tuberculosis from fluid from the lymphocele and demonstration of caseating granuloma in graft biopsy with acid-fast bacilli seen on Ziehl-Neelsen staining. The diagnosis was made quite early post-transplantation. The presence of the granuloma, which is unusual with patients on intensive immunosuppressant medications, suggests that transmission of the infection occurred from the donor rather than from the activation of latent infection. In reviewing the literature, we found ten case reports of TB in transplanted kidney with transmission of TB infection from the donor. The presence of TB in lymphocele in association with the infected transplant by TB, to the best of our knowledge, was reported only once in the literature. Our case had unfavorable outcome and ended by renal allograft nephrectomy and hemodialysis. We are presenting this case of TB infection of renal allograft and lymphocele diagnosed early post-transplantation transmitted from the donor and pertinent review from the literature.

  2. Imaging-based diagnosis of acute renal allograft rejection

    PubMed Central

    Thölking, Gerold; Schuette-Nuetgen, Katharina; Kentrup, Dominik; Pawelski, Helga; Reuter, Stefan

    2016-01-01

    Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the “gold-standard”. However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods. PMID:27011915

  3. Xenon treatment attenuates early renal allograft injury associated with prolonged hypothermic storage in rats.

    PubMed

    Zhao, Hailin; Yoshida, Akira; Xiao, Wei; Ologunde, Rele; O'Dea, Kieran P; Takata, Masao; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

    2013-10-01

    Prolonged hypothermic storage elicits severe ischemia-reperfusion injury (IRI) to renal grafts, contributing to delayed graft function (DGF) and episodes of acute immune rejection and shortened graft survival. Organoprotective strategies are therefore needed for improving long-term transplant outcome. The aim of this study is to investigate the renoprotective effect of xenon on early allograft injury associated with prolonged hypothermic storage. Xenon exposure enhanced the expression of heat-shock protein 70 (HSP-70) and heme oxygenase 1 (HO-1) and promoted cell survival after hypothermia-hypoxia insult in human proximal tubular (HK-2) cells, which was abolished by HSP-70 or HO-1 siRNA. In the brown Norway to Lewis rat renal transplantation, xenon administered to donor or recipient decreased the renal tubular cell death, inflammation, and MHC II expression, while delayed graft function (DGF) was therefore reduced. Pathological changes associated with acute rejection, including T-cell, macrophage, and fibroblast infiltration, were also decreased with xenon treatment. Donors or recipients treated with xenon in combination with cyclosporin A had prolonged renal allograft survival. Xenon protects allografts against delayed graft function, attenuates acute immune rejection, and enhances graft survival after prolonged hypothermic storage. Furthermore, xenon works additively with cyclosporin A to preserve post-transplant renal function.

  4. Prospective evaluation of renal allograft dysfunction with 99mtechnetium-diethylenetriaminepentaacetic acid renal scans

    SciTech Connect

    McConnell, J.D.; Sagalowsky, A.I.; Lewis, S.E.; Gailiunas, P.; Helderman, J.H.; Dawidson, I.; Peters, P.C.

    1984-05-01

    A prospective, single-blinded study was done to determine the ability of serial 99mtechnetium-diethylenetriaminepentaacetic acid scans to diagnose renal allograft rejection. Among 28 transplant recipients 111 renal scans were obtained 1 day postoperatively and every 3 to 4 days thereafter for 3 weeks in all patients retaining an allograft. Computer-generated time-activity blood flow curves were analyzed semiquantitatively for the 1) interval between curve peaks of the allograft and iliac artery, 2) renal transit time and 3) renal washout of radionuclide. Excretory function was assessed by degree and interval to appearance of radionuclide in the calices and bladder. Deterioration of renal blood flow and excretion compared to the initial scan was considered rejection. Of 52 scans performed during clinical rejection 47 (90.4 per cent) were interpreted as showing rejection (sensitivity). Of 53 scans interpreted as showing rejection 47 (88.7 per cent) were positive for clinical rejection. The remaining 6 patients (initial false positive results) suffered clinical rejection within 24 to 72 hours. We conclude that 99mtechnetium-diethylenetriaminepentaacetic acid renal scans are useful in the differential diagnosis of renal allograft dysfunction.

  5. STAT4 gene polymorphism in patients after renal allograft transplantation

    PubMed Central

    Dąbrowska-Żamojcin, Ewa; Dziedziejko, Violetta; Safranow, Krzysztof; Domański, Leszek; Słuczanowska-Głabowska, Sylwia

    2016-01-01

    Introduction STAT4 (signal transducer and activator of transcription 4) is involved in the regulation of innate and adaptive immune responses. Some studies have suggested that STAT4 may be involved in the immune response after graft transplantation. Several polymorphisms in the STAT4 gene have been identified. The most commonly studied polymorphism in the STAT4 gene is rs7574865. In our study, we examined whether this polymorphism is associated with the early and late functions of renal allografts. Material and methods A total of 270 recipients of first renal transplants were included in the study. Single nucleotide polymorphisms (SNPs) within the STAT4 gene were genotyped using TaqMan genotyping assays. Results There were no statistically significant associations between the STAT4 gene rs7574865 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction, post-transplant diabetes mellitus, or creatinine serum concentrations after transplantation. Conclusions Our results suggest a lack of association between the STAT4 rs7574865 SNP and kidney allograft function in the Polish population. PMID:27833442

  6. Should the Ruptured Renal Allograft Be Removed?

    PubMed Central

    Dryburgh, Peter; Porter, Kendrick A.; Krom, Ruud A. F.; Uchida, Kazuharu; West, John C.; Weil, Richard; Starzl, Thomas E.

    2010-01-01

    During a 16-month period when 93 renal transplants were performed, eight kidney graft ruptures were detected within 18 days of transplantation, without evidence of venous obstruction. Six grafts were removed at the time of an exploratory operation for rupture and only one showed signs of probable irreversible rejection when examined by microscopy. Two graft ruptures were repaired and one of these grafts has had good long-term function 22 months later. These observations suggest that if bleeding at the site of graft rupture can be securely controlled and if the conditions of the patient and of the graft are favorable except for the rupture, it may be possible to save more than one of eight grafts. PMID:378181

  7. Should the ruptured renal allograft be removed?

    PubMed

    Dryburgh, P; Porter, K A; Krom, R A; Uchida, K; West, J C; Weil, R; Starzl, T E

    1979-07-01

    During a 16-month period when 93 renal transplants were performed, eight kidney graft ruptures were detected within 18 days of transplantation, without evidence of venous obstruction. Six grafts were removed at the time of an exploratory operation for rupture and only one showed signs of probable irreversible rejection when examined by microscopy. Two graft ruptures were repaired and one of these grafts has had good long-term function 22 months later. These observations suggest that if bleeding at the site of grafts has had good long-term function 22 months later. These observations suggest that if bleeding at the site of graft rupture can be securely controlled and if the conditions of the patient and of the graft are favorable except for the rupture, it may be possible to save more than one of eight grafts.

  8. Nephron-sparing surgery for renal tumor: a choice of treatment in an allograft kidney.

    PubMed

    Ribal, M J; Rodriguez, F; Musquera, M; Segarra, J; Guirado, L; Villavicencio, H; Alcaraz, A

    2006-06-01

    The incidence of de novo malignancies is an accepted complication of organ transplantation. Renal cell carcinoma (RCC) was 4.6% of cancers occurring de novo in organ allograft recipients compared with 3% in the general population. Less than 10% of these renal cancers affected the renal allograft. Among patients developing a renal tumor in the kidney allograft, transplant nephrectomy reduced the quality of life. For these patients for whom preservation of renal function is a relevant clinical consideration, partial nephrectomy may be considered the choice for treatment. Fifteen cases have been reported regarding conservative surgery on kidney transplant tumors. Herein we have reported three cases of renal masses in well-functioning kidney transplants that were successfully treated with nephon-sparing surgery. Our experience demonstrated that in selected patients, nephron-sparing surgery on a renal allograft represents a feasible approach for tumor removal with preservation of graft function.

  9. MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

    SciTech Connect

    Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao; Wu, William K.K.; Chan, Matthew T.V.; Zhang, Jie; Li, Haibin; Qin, Ke; Sun, Xuyong

    2015-04-10

    Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.

  10. Effect of a stable prostacyclin analogue on canine renal allograft rejection.

    PubMed Central

    Tobimatsu, M; Ueda, Y; Toyoda, K; Saito, S; Konomi, K

    1987-01-01

    The effect of OP-41483 (Ono Pharmaceutical Co., Osaka, Japan), a stable prostacyclin analogue, on canine renal allograft rejection was investigated. Administration for 4 days after transplantation significantly increased renal cortical blood flow and urine output when compared with untreated dogs with renal allografts. Serum creatinine levels remained relatively low during postoperative days 1-4. Mean animal survival time was prolonged. Vascular lesions and mononuclear cell infiltration were greatly diminished in biopsy specimens removed on day 4. This stable prostacyclin analogue provided a degree of protection against canine renal allograft rejection. Images Figs. 1A and B. PMID:3545109

  11. Scedosporium apiospermum causing brain abscess in a renal allograft recipient.

    PubMed

    Sharma, Amit; Singh, Divya

    2015-11-01

    Scedosporium apiospermum is the asexual form of a rare fungus Pseudallescheria boydii that is usually present in the soil, sewage and dirty water. In immunocompromised patients, it is a rare infection involving multiple organs. We present a case of renal allograft recipient who developed fever two weeks post renal transplant. He was initially found to have dengue fever. After five days, he became drowsy and developed right-sided hemiparesis. Magnetic resonance imaging of the brain revealed multiple irregular masses with associated edema consistent with fungal brain abscesses. Left parietal abscess was drained and he was started on voriconazole. His cyclosporine was stopped. Drained pus revealed fungal hyphae on potassium hydroxide stain and Scedosporium apiospermum on culture. Unfortunately, the patient died after five days. Scedosporium infections should be kept as a possibility in transplant recipients with disseminated infections, especially with a brain abscess. Despite antifungal therapy and surgical drainage, mortality rates are high.

  12. Renal allograft glomerulopathy and the value of immunohistochemistry.

    PubMed

    Freese, P M; Svalander, C T; Mölne, J; Nyberg, G

    2004-10-01

    Studies of late renal allograft biopsies focus on chronic damage investigated by light microscopy (LM). We evaluated the use of immunohistochemistry (IH) as applied in the routine study of transplant glomerulopathies. Among renal transplants in 1985 - 1997, 129 were identified where a graft biopsy had been obtained 6 months or more after transplantation, studied by LM and IH and the original renal disease was known. IH results were evaluated in relation to glomerular LM findings and the original diagnosis. The risk of graft loss in relation to recurrent and de novo glomerulopathy was evaluated. By LM, 69 biopsies (53%) showed glomerulopathy, mesangial sclerosis only in 26, proliferative changes in 15, membranous in 15 and combined membranous and proliferative in 13. By IH, 46 biopsies (36%) stained positive with IgM and/or complement only and 24 with immune complexes including IgA and/or IgG. Seven biopsies (5.4%) showed glomerular disease by IH in spite of normal LM. Recurrence was diagnosed in 22 grafts; 12 had IgA nephropathy, 3 had SLE, 6 other immune complex nephritides and 1 systemic vasculitis. Twenty-eight biopsies (22%) with proliferative and/or membranous glomerulopathy lacked clear connection to the original renal disorder. More than half of these had deposits of IgM and C3 only. The further graft survival was significantly reduced in the presence of de novo glomerulopathy by LM, relative risk 2.0 (confidence interval 1.1 - 3.8) in a Cox-proportional hazards analysis also including serum creatinine and Banff chronic allograft nephropathy (CAN) grade, p = 0.03. In conclusion, transplant glomerulopathy should be separated from recurrence. De novo glomerulopathy is frequent and ominous.

  13. Differential gene expression pattern in biopsies with renal allograft pyelonephritis and allograft rejection

    PubMed Central

    Oghumu, Steve; Nori, Uday; Bracewell, Anna; Zhang, Jianying; Bott, Cherri; Nadasdy, Gyongyi M.; Brodsky, Sergey V.; Pelletier, Ronald; Satoskar, Abhay R.; Nadasdy, Tibor; Satoskar, Anjali A.

    2016-01-01

    Differentiating acute pyelonephritis (APN) from acute rejection (AR) in renal allograft biopsies can sometimes be difficult because of overlapping clinical and histologic features, lack of positive urine cultures, and variable response to antibiotics. We wanted to study differential gene expression between AR and APN using biopsy tissue. Thirty-three biopsies were analyzed using NanoString multiplex platform and PCR (6 transplant baseline biopsies, 8 AR, 15 APN [8 culture positive, 7 culture negative], and 4 native pyelonephritis [NP]). Additional 22 biopsies were tested by PCR to validate the results. CXCL9, CXCL10, CXCL11, and IDO1 were the top differentially expressed genes, upregulated in AR. Lactoferrin (LTF) and CXCL1 were higher in APN and NP. No statistically significant difference in transcript levels was seen between culture-positive and culture-negative APN biopsies. Comparing the overall mRNA signature using Ingenuity pathway analysis, interferon-gamma emerged as the dominant upstream regulator in AR and allograft APN, but not in NP (which clustered separately). Our study suggests that chemokine pathways in graft APN may differ from NP and in fact resemble AR, due to a component of alloreactivity, resulting in variable response to antibiotic treatment. Therefore, cautious addition of steroids might help in resistant cases of graft APN. PMID:27352120

  14. Quantitative digital histochemistry with methenamine silver staining in renal allograft biopsies excluding pure chronic allograft nephropathy cases.

    PubMed

    Sarioglu, S; Sis, B; Celik, A; Tekis, D; Kavukcu, S; Bora, S; Camsari, T

    2006-03-01

    Deterioration of renal function is correlated with irreversible damage in chronic diseases. Recently we described a digital quantitative histochemistry method, relying on periodic acid methenamine silver (PAMS) staining to determine the chronic renal lesions. This index was strongly correlated with progressive deterioration of renal function in grafts with chronic allograft nephropathy (CAN). Herein the method has been applied to a cohort of renal allografts which were biopsied for various reasons, we sought to highlight its value to quantify chronic graft damage. Forty-four renal allograft biopsies from 37 patients with elevated serum creatinine values (SCr) underwent light microscopic image analysis (Mediscope, Dokuz Eylül University, Clinical Engineering Department, Izmir, Turkey) of the PAMS-stained area percentage (SAP). SCr was recorded at four intervals to overcome acute effects: the under SCr value before (SCr1) and after a biopsy within 3 months (SCr3), SCr at the time of the biopsy (SCr2), and the latest value (SCr4). The PAMS-SAP scores were strongly associated with increased interstitial fibrosis and tubular atrophy Banff scores (Kruskal-Wallis test, P = .006 and P = .003, respectively). There was a moderate positive correlation between PAMS and SCr3 (Pearson correlation test, P = .04, r = .312), and a strong positive correlation between time from transplantation to biopsy (Pearson correlation test, P < .000, r = .532). The present results show that PAMS-SAP seems to be of value to quantify renal scarring in allograft biopsies, reflecting four compartments. The strong correlation with time is noteworthy especially as a probable reflection of aging of the renal allograft.

  15. AA amyloidosis in the renal allograft: a report of two cases and review of the literature

    PubMed Central

    Rojas, Rebecca; Josephson, Michelle A.; Chang, Anthony; Meehan, Shane M.

    2012-01-01

    AA amyloidosis is a disorder characterized by the abnormal formation, accumulation and systemic deposition of fibrillary material that frequently involves the kidney. Recurrent AA amyloidosis in the renal allograft has been documented in patients with tuberculosis, familial Mediterranean fever, ankylosing spondylitis, chronic pyelonephritis and rheumatoid arthritis. De novo AA amyloidosis is rarely described. We report two cases of AA amyloidosis in the renal allograft. Our first case is a 47-year-old male with a history of ankylosing spondylitis who developed end-stage renal disease reportedly from tubulointerstitial nephritis from non-steroidal anti-inflammatory agent use. A biopsy was never performed. One year after transplantation, AA amyloidosis was identified in the femoral head and 8 years post-transplantation, AA amyloidosis was identified in the renal allograft. He was treated with colchicine and adalimumab and has stable renal function at 1 year-follow-up. Our second case is a 57-year-old male with a long history of intravenous drug use and hepatitis C infection who developed end-stage kidney disease due to AA amyloidosis. Our second patient's course was complicated by renal adenovirus, pulmonary aspergillosis and hepatitis C with AA amyloidosis subsequently being identified in the allograft 2.5 years post-transplantation. Renal allograft function remains stable 4-years post-transplantation. These reports describe clinical and pathologic features of two cases of AA amyloidosis presenting with proteinuria and focal involvement of the renal allograft. PMID:22833808

  16. Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

    PubMed Central

    Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

    2015-01-01

    Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

  17. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  18. Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis.

    PubMed

    Wei, Chengguo; Li, Li; Menon, Madhav C; Zhang, Weijia; Fu, Jia; Kidd, Brian; Keung, Karen L; Woytovich, Christopher; Greene, Ilana; Xiao, Wenzhen; Salem, Fadi; Yi, Zhengzi; He, John Cijiang; Dudley, Joel T; Murphy, Barbara

    2016-12-07

    Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an Src family tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently binds Hck with high selectivity. In vitro, Hck overexpression activated the TGF-β/Smad3 pathway, whereas HCK knockdown inhibited it. Treatment of tubular cells with dasatinib reduced the expression of Col1a1 Dasatinib also reduced proliferation and α-SMA expression in fibroblasts. In a murine model with unilateral ureteric obstruction, pretreatment with dasatinib significantly reduced the upregulation of profibrotic markers, phosphorylation of Smad3, and renal fibrosis observed in kidneys pretreated with vehicle alone. Dasatinib treatment also improved renal function, reduced albuminuria, and inhibited expression of profibrotic markers in animal models with lupus nephritis and folic acid nephropathy. These data suggest that Hck is a key mediator of renal fibrosis and dasatinib could be developed as an antifibrotic drug.

  19. Allograft and prostatic involvement in a renal transplant recipient with disseminated tuberculosis

    PubMed Central

    Sreejith, P.; Jha, V.; Kohli, H.S.; Rathi, M.; Gupta, K.L.; Sakhuja, V.

    2010-01-01

    Tuberculosis is a serious opportunistic infection in renal transplant recipients and is disseminated in nature in one-third of patients. Genito urinary tuberculosis is rare in renal transplant recipients. We report a patient presenting 5 years after renal transplantation with disseminated tuberculosis and allograft and prostatic involvement. PMID:20535270

  20. Allograft and prostatic involvement in a renal transplant recipient with disseminated tuberculosis.

    PubMed

    Sreejith, P; Jha, V; Kohli, H S; Rathi, M; Gupta, K L; Sakhuja, V

    2010-01-01

    Tuberculosis is a serious opportunistic infection in renal transplant recipients and is disseminated in nature in one-third of patients. Genito urinary tuberculosis is rare in renal transplant recipients. We report a patient presenting 5 years after renal transplantation with disseminated tuberculosis and allograft and prostatic involvement.

  1. Iatrogenic Arteriovenous Fistula in a Renal Allograft: The Result of a TAD Guidewire Injury

    SciTech Connect

    Lee-Elliott, Catherine; Khaw, Kok-Tee; Belli, Anna-Maria; Patel, Uday

    2000-07-15

    A case is presented of an iatrogenic arteriovenous fistula developing in a renal allograft following guidewire manipulation during transplant renal artery angioplasty. Hyperdynamic flow through the fistula was causing a shunt of blood away from the renal cortex as demonstrated on sonography and scintigraphy. Selective embolization was performed, correcting the maldistribution of flow to the peripheral renal cortex. The diagnosis and difficulty in management of asymptomatic renal arteriovenous fistulae is also discussed.

  2. Association between Reperfusion Renal Allograft Biopsy Findings and Transplant Outcomes.

    PubMed

    Mohan, Sumit; Campenot, Eric; Chiles, Mariana C; Santoriello, Dominick; Bland, Eric; Crew, R John; Rosenstiel, Paul; Dube, Geoffrey; Batal, Ibrahim; Radhakrishnan, Jai; Sandoval, P Rodrigo; Guarrera, James; Stokes, M Barry; D'Agati, Vivette; Cohen, David J; Ratner, Lloyd E; Markowitz, Glen

    2017-07-06

    Biopsy findings at the time of procurement of deceased donor kidneys remain the most common reason cited for kidney discard. To determine the value of renal allograft histology in predicting outcomes, we evaluated the significance of histologic findings, read by experienced renal pathologists, in 975 postreperfusion biopsy specimens collected from 2005 to 2009 after living donor (n=427) or deceased donor (n=548) renal transplant. We evaluated specimens for the degree of glomerulosclerosis, interstitial fibrosis and tubular atrophy, and vascular disease; specimens with a score of 0 or 1 (scale, 0-3) for each parameter were considered optimal. Overall, 66.3% of living donor kidneys and 50.7% of deceased donor kidneys received an optimal histology score (P<0.001). Irrespective of donor status, suboptimal kidneys came from older donors with a higher incidence of diabetes mellitus, hypertension, and obesity and a higher mean kidney donor risk index (all P<0.001). Death-censored outcomes after transplant differed significantly between optimal and suboptimal kidneys only in the deceased donor transplants (P=0.02). Regardless of histologic classification, outcomes with deceased donor kidneys were inferior to outcomes with living donor kidneys. However, 73.2% of deceased donor kidneys with suboptimal histology remained functional at 5 years. Our findings suggest that histologic findings on postreperfusion biopsy associate with outcomes after deceased donor but not living donor renal transplants, thus donor death and organ preservation-related factors may be of greater prognostic importance. Discarding donated kidneys on the basis of histologic factors may be inappropriate and merits further study. Copyright © 2017 by the American Society of Nephrology.

  3. Impact of Ramadan fasting on renal allograft function.

    PubMed

    Einollahi, B; Lessan-Pezeshki, M; Simforoosh, N; Nafar, M; Pour-Reza-Gholi, F; Firouzan, A; Khatami, M R; Nourbala, M H; Pourfarzini, V

    2005-09-01

    Fasting during the holy month of Ramadan is a religious duty for all healthy adult Muslims. They are only allowed to eat and drink between sunset and dawn. This study was designed to find the effect of Ramadan fasting on allograft function. We prospectively studied 19 kidney transplant recipients who voluntarily chose to fast during Ramadan versus 20 matched recipients, who had not fasted for 3 consecutive years. Data were recorded before, during, and after the fasting month. The mean posttransplant periods in the fasting and control groups were 52.6 +/- 30.3 and 56.6 +/- 30.0 months, respectively. A statistical analysis showed no significant changes in serum creatinine concentrations before and after Ramadan 1.07 +/- 0.24 versus 1.08 +/- 0.22 mg/dL (P > .05) and 1.00 +/- 0.24 versus 1.03 +/- 0.28 mg/dL (P > .05) in fasting and control groups, respectively. The results did not show any adverse effects of fasting in recipients with stable renal function. In conclusion, our study suggests that fasting during the month of Ramadan is safe and has no significant harmful effects on kidney transplant recipients with normal renal function.

  4. Renal cell carcinoma in kidney allografts: histologic types, including biphasic papillary carcinoma.

    PubMed

    Troxell, Megan L; Higgins, John P

    2016-11-01

    Kidney transplant recipients are at increased risk for malignancy, with about 5% incidence of cancer in native end-stage kidneys. Carcinoma in the renal allograft is far less common. Prior studies have demonstrated a propensity for renal cell carcinomas (RCCs) of papillary subtypes in end-stage kidneys, and perhaps in allograft kidneys, but most allograft studies lack detailed pathologic review and predate the current classification system. We reviewed our experience with renal carcinoma in kidney allografts at 2 academic centers applying the International Society of Urological Pathology classification, informed by immunohistochemistry. The incidence of renal allograft carcinoma was about 0.26% in our population. Of 12 allograft carcinomas, 6 were papillary (50%), 4 were clear cell (33%), 1 was clear cell (tubulo)papillary, and 1 chromophobe. Two of the papillary carcinomas had distinctive biphasic glomeruloid architecture matching the newly named "biphasic squamoid alveolar" pattern and were difficult to classify on core biopsies. The 2 cell types had different immunophenotypes in our hands (eosinophilic cells: RCC-/CK34betaE12+ weight keratin +/cyclin D1+; clear cells: RCC+/cytokeratin high molecular weight negative to weak/cyclin D1-). None of the patients experienced cancer recurrences or metastasis. Our study confirms the predilection for papillary RCCs in kidney allografts and highlights the occurrence of rare morphologic variants. Larger studies are needed with careful pathologic review, which has been lacking in the literature.

  5. Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles

    PubMed Central

    Huang, Shi-Ming; Zhao, Xia; Zhao, Xue-Mei; Wang, Xiao-Ying; Li, Shan-Shan; Zhu, Yu-Hui

    2014-01-01

    Objectives: Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. Methods: MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. Results: A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. Conclusions: We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may

  6. Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles.

    PubMed

    Huang, Shi-Ming; Zhao, Xia; Zhao, Xue-Mei; Wang, Xiao-Ying; Li, Shan-Shan; Zhu, Yu-Hui

    2014-01-01

    Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may be related to acute renal allograft

  7. Improved outcomes in cadaveric renal allografts with pulsatile preservation.

    PubMed

    Sellers, M T; Gallichio, M H; Hudson, S L; Young, C J; Bynon, J S; Eckhoff, D E; Deierhoi, M H; Diethelm, A G; Thompson, J A

    2000-12-01

    Early immunologic and non-immunologic injury of renal allografts adversely affects long-term graft survival. Some degree of preservation injury is inevitable in cadaveric renal transplantation, and, with the reduction in early acute rejection, this non-immunologic injury has assumed a greater relative importance. Optimal graft preservation will maximize the chances of early graft function and long-term graft survival, but the best method of preservation pulsatile perfusion (PP) versus cold storage (CS) is debated. Primary cadaveric kidney recipients from January 1990 through December 1995 were evaluated. The effects of implantation warm ischemic time (WIT) ( < or = 20 min, 21-40 min, or > 40 min) and total ischemic time (TIT) ( < or > or = 20 h) on death-censored graft survival were compared between kidneys preserved by PP versus those preserved by CS. The effect of preservation method on delayed graft function (DGF) was also examined. There were 568 PP kidneys and 268 CS kidneys. Overall death-censored graft survival was not significantly different between groups, despite worse donor and recipient characteristics in the PP group. CS kidneys with an implantation WIT > 40 min had worse graft survival than those with < 40 min (p = 0.0004). Survival of PP kidneys and those transplanted into 2 DR-matched recipients was not affected by longer implantation WIT. Longer TIT did not impact survival. DGF was more likely after CS preservation (20.2% versus 8.8%, p = 0.001). Preservation with PP improves early graft function and lessens the adverse effect of increased warm ischemia in cadaveric renal transplantation. This method is likely associated with less preservation injury and/or increases the threshold for injury from other sources and is superior to CS.

  8. [Neurologic complications induced by the treatment of the acute renal allograft rejection with the monoclonal antibody OKT3].

    PubMed

    Fernández, O; Romero, F; Bravo, M; Burgos, D; Cabello, M; González-Molina, M

    1993-10-01

    The treatment of the acute renal allograft rejection with the monoclonal antibody orthoclone OKT3 produces both systemic and neurologic alterations. In a series of 21 patients with an acute renal allograft rejection treated with this monoclonal antibody, 20 with a renal allograft transplantation and one with a renal and pancreatic allograft transplantation, 29% referred headache associated with fever and vomiting, and 14.2% presented severe neurological alterations induced by the treatment. We stress the need to know these secondary effects to differentiate them from other central nervous system disorders, particularly those of infectious origin.

  9. Immunosuppression after renal allograft failure: a survey of US practices.

    PubMed

    Bayliss, George P; Gohh, Reginald Y; Morrissey, Paul E; Rodrigue, James R; Mandelbrot, Didier A

    2013-01-01

    Little data exist to guide the management of immunosuppression after renal graft failure. More aggressive tapering of immunosuppressive medications may reduce the risk of infection, but may increase the risk of rejection and sensitization. To document current practices in the US, we emailed a questionnaire to medical and surgical transplant directors as identified by the United Network for Organ Sharing (UNOS). Emails were sent to 221 programs, of which 93 (42.1%) responded. About 24.7% of respondents reported adjusting immunosuppression according to a standard protocol; 75.3% said practices are physician dependent. The majority said that 80 or 100% of patients are off all immunosuppression one yr after returning to dialysis. The most important factors cited in deciding whether to stop immunosuppression were plans to retransplant (40.2%) and signs and symptoms of rejection (37.0%). When asked which immunosuppressive medications are continued indefinitely, 21.5% responded prednisone and 71.0% said none. Respondents most commonly said they performed graft nephrectomy only if there are signs and symptoms of rejection (47.3%) or if signs and symptoms of rejection fail to respond to steroids (34.4%). In the absence of good data to guide decisions on immunosuppression in patients with failed allografts, practices in the US vary greatly. More data are needed to determine which policies lead to the best outcomes. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Effect of blood transfusions on canine renal allograft survival

    SciTech Connect

    van der Linden, C.J.; Buurman, W.A.; Vegt, P.A.; Greep, J.M.; Jeekel, J.

    1982-04-01

    In this study significantly prolonged canine renal allograft survival has been demonstrated after transfusion of 100 ml of third-party whole blood given peroperatively. Peroperative transfusions of third-party leukocyte-free blood or pure lymphocyte cell suspensions did not influence graft survival. Furthermore, no improvement in graft survival has been found after a peroperative transfusion of irradiated whole blood (2500 rad). These data suggest that delayed graft rejection after blood transfusions can only be expected after the administration of whole blood. The role of competent lymphocytes in whole blood is questionable, since a transfusion or irradiated whole blood in combination with nonirradiated lymphocytes did not lead to prolonged graft survival. Immunosuppression of the recipient directly after transfusion seems to be essential to induce the beneficial effect of blood transfusions. This has been demonstrated for a transfusion of whole blood 14 days before transplantation. A single transfusion of 100 ml of whole blood 14 days before transplantation could effectively prolong graft survival if immunosuppression with azathioprine and prednisone was started on the day of transfusion. No improvement in graft survival has been found with such a transfusion if preoperative immunosuppression has been omitted.

  11. Effect of blood transfusions on canine renal allograft survival

    SciTech Connect

    Van Der Linden, C.J.; Buurman, W.A.; Vegt, P.A.; Greep, J.M.; Jeekel, J.

    1982-04-01

    In this study significantly prolonged canine renal allograft survival has been demonstrated after transfusion of 100 ml of third-party whole blood given peroperatively. Peroperative transfusions of third-party leukocyte-free blood or pure lymphocyte cell suspensions did not influence graft survival. Futhermore, no improvement in graft survival has been found after a peroperative transfuson of irradiated whole blood (2500 rad). These data suggest that delayed graft rejection after blood transfusions can only be expected after the administration of whole blood. The role of competent lymphocytes in whole blood is questionable, since a transfusion of irradiated whole blood in combination with nonirradiated lymphocytes did not lead to prolonged graft survival. Immunosuppression of the recipient directly after transfusion seems to be essential to induce the beneficial effect of blood transfusions. This has been demonstrated for a transfusion of whole blood 14 days before transplantation. A single transfusion of 100 ml of whole blood 14 days before transplantation could effectively prolong graft survival if immunosuppression with azathioprine and prednisone was started on the day of transfusion. No improvement in graft survival has been found with such a transfusion if preoperative immunosuppression has been omitted.

  12. Skin, subcutaneous tissue, and allograft infection with Mycobacterium fortuitum in a renal transplant recipient.

    PubMed

    Mushtaq, Raees F; Bappa, Adamu; Ahmad, Mustafa; AlShaebi, Fuad

    2014-11-01

    Different types of skin disorders are prevalent among kidney transplant recipients. The development of nodular skin lesions in these patients would usually raise a suspicion of Kaposi's sarcoma. We report a patient, who presented with nodular skin lesions one year post transplant, but the biopsy revealed a rare diagnosis - Mycobacterium fortuitum (M. fortuitum) infection of the skin, subcutaneous, and renal allograft. He was treated successfully with an initial two-week course of intravenous cefoxitin, followed by a six-month course of ciprofloxacin, clarithromycin, and co-trimoxazole. There are a few reported cases of M. fortuitum infection in renal transplant recipients in the literature - notably urinary tract infection, allograft infection, and psoas abscess, but to the best of our knowledge this is the first case demonstrating extensive infection involving the skin, subcutaneous tissue, and renal allograft. Physicians vested with the care of renal transplant patients should be aware of this rare infection in these patients.

  13. Nanoparticle Enhanced MRI Scanning to Detect Cellular Inflammation in Experimental Chronic Renal Allograft Rejection

    PubMed Central

    Alam, S. R.; Tse, G. H.; Stirrat, C.; MacGillivray, T. J.; Lennen, R. J.; Jansen, M. A.; Newby, D. E.; Marson, L.; Henriksen, P. A.

    2015-01-01

    Objectives. We investigated whether ultrasmall paramagnetic particles of iron oxide- (USPIO-) enhanced magnetic resonance imaging (MRI) can detect experimental chronic allograft damage in a murine renal allograft model. Materials and Methods. Two cohorts of mice underwent renal transplantation with either a syngeneic isograft or allograft kidney. MRI scanning was performed prior to and 48 hours after USPIO infusion using T2∗-weighted protocols. R2∗ values were calculated to indicate the degree of USPIO uptake. Native kidneys and skeletal muscle were imaged as reference tissues and renal explants analysed by histology and electron microscopy. Results. R2∗ values in the allograft group were higher compared to the isograft group when indexed to native kidney (median 1.24 (interquartile range: 1.12 to 1.36) versus 0.96 (0.92 to 1.04), P < 0.01). R2∗ values were also higher in the allograft transplant when indexed to skeletal muscle (6.24 (5.63 to 13.51)) compared to native kidney (2.91 (1.11 to 6.46) P < 0.05). Increased R2∗ signal in kidney allograft was associated with macrophage and iron staining on histology. USPIO were identified within tissue resident macrophages on electron microscopy. Conclusion. USPIO-enhanced MRI identifies macrophage. PMID:25954516

  14. [The clinical use of cryopreserved human skin allografts for transplantation].

    PubMed

    Martínez-Flores, Francisco; Chacón-Gómez, María; Madinaveitia-Villanueva, Juan Antonio; Barrera-Lopez, Araceli; Aguirre-Cruz, Lucinda; Querevalu-Murillo, Walter

    2015-01-01

    The biological recovery of human skin allografts is the gold standard for preservation in Skin Banks. However, there is no worldwide consensus about specific allocation criteria for preserved human skin allografts with living cells. A report is presented on the results of 5 years of experience of using human skin allografts in burned patient in the Skin and Tissue Bank at the "Instituto Nacional de Rehabilitacion" The human skin allografts were obtained from multi-organ donors. processed and preserved at -80 °C for 12 months. Allocation criteria were performed according to blood type match, clinical history, and burned body surface. Up to now, the Skin and Tissue Bank at 'Instituto Nacional de Rehabilitacion" has processed and recovered 125,000 cm(2) of human skin allografts. It has performed 34 surgical implants on 21 burned patients. The average of burn body surface was 59.2%. More than two-thirds (67.7%) of recipients of skin allografts were matched of the same to type blood of the donor, and 66.6% survived after 126 days hospital stay. It is proposed to consider recipient's blood group as allocation criteria to assign tissue; and use human skin allografts on patiens affected with burns over 30% of body surface (according the "rule of the 9"). Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  15. Renal Allograft Outcome After Simultaneous Heart and Kidney Transplantation.

    PubMed

    Grupper, Avishay; Grupper, Ayelet; Daly, Richard C; Pereira, Naveen L; Hathcock, Matthew A; Kremers, Walter K; Cosio, Fernando G; Edwards, Brooks S; Kushwaha, Sudhir S

    2017-08-01

    Chronic kidney disease frequently accompanies end-stage heart failure and may result in consideration of simultaneous heart and kidney transplantation (SHKT). In recent years, there has been a significant increase in SHKT. This single-center cohort consisted of 35 patients who underwent SHKT during 1996 to 2015. The aim of this study was to review factors that may predict better long-term outcome after SKHT. Thirteen patients (37%) had delayed graft function (DGF) after transplant (defined as the need for dialysis during the first 7 days after transplant), which was significantly associated with mechanical circulatory support device therapy and high right ventricular systolic pressure before transplant. Most of the recipients had glomerular filtration rate (GFR) ≥50 ml/min/1.73 m(2) at 1 and 3 years after transplant (21 of 26 [81%] and 20 of 21 [95%], respectively). Higher donor age was associated with reduced 1-year GFR (p = 0.017), and higher recipient pretransplant body mass index was associated with reduced 3-year GFR (p = 0.008). There was a significant association between DGF and reduced median GFR at 1 and 3 years after transplant (p <0.005). Patient survival rates at 6 months, 1, and 3 years after transplant were 97%, 91%, and 86% respectively. In conclusions, our data support good outcomes after SHKT. Mechanical circulatory support device therapy and pulmonary hypertension before transplant are associated with DGF, which is a risk factor for poor long-term renal allograft function. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Estimation of renal allograft half-life: fact or fiction?

    PubMed

    Azancot, M Antonieta; Cantarell, Carme; Perelló, Manel; Torres, Irina B; Serón, Daniel; Seron, Daniel; Moreso, Francesc; Arias, Manuel; Campistol, Josep M; Curto, Jordi; Hernandez, Domingo; Morales, José M; Sanchez-Fructuoso, Ana; Abraira, Victor

    2011-09-01

    Renal allograft half-life time (t½) is the most straightforward representation of long-term graft survival. Since some statistical models overestimate this parameter, we compare different approaches to evaluate t½. Patients with a 1-year functioning graft transplanted in Spain during 1990, 1994, 1998 and 2002 were included. Exponential, Weibull, gamma, lognormal and log-logistic models censoring the last year of follow-up were evaluated. The goodness of fit of these models was evaluated according to the Cox-Snell residuals and the Akaike's information criterion (AIC) was employed to compare these models. We included 4842 patients. Real t½ in 1990 was 14.2 years. Median t½ (95% confidence interval) in 1990 and 2002 was 15.8 (14.2-17.5) versus 52.6 (35.6-69.5) according to the exponential model (P < 0.001). No differences between 1990 and 2002 were observed when t½ was estimated with the other models. In 1990 and 2002, t½ was 14.0 (13.1-15.0) versus 18.0 (13.7-22.4) according to Weibull, 15.5 (13.9-17.1) versus 19.1 (15.6-22.6) according to gamma, 14.4 (13.3-15.6) versus 18.3 (14.2-22.3) according to the log-logistic and 15.2 (13.8-16.6) versus 18.8 (15.3-22.3) according to the lognormal models. The AIC confirmed that the exponential model had the lowest goodness of fit, while the other models yielded a similar result. The exponential model overestimates t½, especially in cohorts of patients with a short follow-up, while any of the other studied models allow a better estimation even in cohorts with short follow-up.

  17. Detection and measurement of tubulitis in renal allograft rejection

    NASA Astrophysics Data System (ADS)

    Hiller, John B.; Chen, Qi; Jin, Jesse S.; Wang, Yung; Yong, James L. C.

    1997-04-01

    Tubulitis is one of the most reliable signs of acute renal allograft rejection. It occurs when mononuclear cells are localized between the lining tubular epithelial cells with or without disruption of the tubular basement membrane. It has been found that tubulitis takes place predominantly in the regions of the distal convoluted tubules and the cortical collecting system. The image processing tasks are to find the tubule boundaries and to find the relative location of the lymphocytes and epithelial cells and tubule boundaries. The requirement for accuracy applies to determining the relative locations of the lymphocytes and the tubule boundaries. This paper will show how the different sizes and grey values of the lymphocytes and epithelial cells simplify their identification and location. Difficulties in finding the tubule boundaries image processing will be illustrated. It will be shown how proximate location of epithelial cells and the tubule boundary leads to distortion in determination of the calculated boundary. However, in tubulitis the lymphocytes and the tubule boundaries are proximate.In these cases the tubule boundary is adequately resolved and the image processing is satisfactory to determining relativity in location. An adaptive non-linear anisotropic diffusion process is presented for image filtering and segmentation. Multi-layer analysis is used to extract lymphocytes and tubulitis from images. This paper will discuss grading of tissue using the Banff system. The ability to use computer to use computer processing will be argued as obviating problems of reproducability of values for this classification. This paper will also feature discussion of alternative approaches to image processing and provide an assessment of their capability for improving the identification of the tubule boundaries.

  18. Acute Page kidney following renal allograft biopsy: a complication requiring early recognition and treatment.

    PubMed

    Chung, J; Caumartin, Y; Warren, J; Luke, P P W

    2008-06-01

    The acute Page kidney phenomenon occurs as a consequence of external compression of the renal parenchyma leading to renal ischemia and hypertension. Between January 2000 and September 2007, 550 kidney transplants and 518 ultrasound-guided kidney biopsies were performed. During that time, four recipients developed acute oligo-anuria following ultrasound-guided allograft biopsy. Emergent doppler-ultrasounds were performed demonstrating absence of diastolic flow as well as a sub-capsular hematoma of the kidney. Prompt surgical exploration with allograft capsulotomy was performed in all cases. Immediately after capsulotomy, intraoperative Doppler study demonstrated robust return of diastolic flow. Three patients maintained good graft function, and one kidney was lost due to acute antibody-mediated rejection. We conclude that postbiopsy anuria associated with a subcapsular hematoma and acute absence of diastolic flow on doppler ultrasound should be considered pathognomonic of APK. All renal transplant specialists should be able to recognize this complication, because immediate surgical decompression can salvage the allograft.

  19. Prevalence and risk factors for early chronic allograft nephropathy in a live related renal transplant program

    PubMed Central

    Khan, Hamid; Mubarak, Muhammed; Aziz, Tahir; Ahmed, Ejaz; Fazal Akhter, Syed; Kazi, Javed; AA Naqvi, Syed; AH Rizvi, Syed

    2014-01-01

    Background: Chronic allograft nephropathy (CAN) is a common cause of delayed allograft failure throughout the world. Its prevalence and risk factors vary depending on a number of factors. There is little information on the prevalence and risk factors for early CAN in live related renal transplant patients. Objectives: We aimed to determine the prevalence and the risk factors of early CAN in our setup. Patients and Methods: The study was conducted at Sindh Institute of Urology & Transplantation (SIUT), Karachi, from 2002 to 2005 on patients who had live related kidney transplantation and underwent at least one allograft biopsy within 18 months of transplantation. The biopsies were performed and prepared in accordance with established indications and guidelines. The Banff 97 classification and its updates were used to diagnose and categorize the biopsy pathology. Patients were divided into two groups depending on the presence or absence of CAN on biopsies. Following parameters were compared among the groups: age, sex, human leukocyte antigen (HLA) match, immunosuppression used, acute rejection (AR) episodes, urinary tract infections (UTIs), viral infections, cyclosporine levels, early and late graft function monitored by serum creatinine. Results: A total of 164 patients fulfilled the study inclusion criteria. The mean age of recipients and donors was relatively young. The majority of the donors were siblings. The overall prevalence of CAN was 25.6% (42/164), between 3 and 18 months post transplantation. The median time to the appearance of CAN was 9 months post-transplant. The prevalence of CAN increased as post-transplant duration increased. In 39 (92.8%) subjects, CAN was detected on the second or subsequent graft biopsy. Only 3 (7.2%) patients showed CAN on the first graft biopsy. The majority of cases belonged to moderate degree or grade II CAN. The mean serum creatinine values were higher in the CAN group at the time of discharge and all times post

  20. Calcium oxalate deposition in renal allografts: morphologic spectrum and clinical implications.

    PubMed

    Truong, Luan D; Yakupoglu, Ulkem; Feig, Daniel; Hicks, John; Cartwight, Joiner; Sheikh-Hamad, David; Suki, Wadi N

    2004-08-01

    Many aspects of calcium oxalate (CaOx) deposition in renal transplant biopsies are not known. Review of all renal transplant biopsies performed in a 7-year period showed that CaOx deposition could be classified into three groups. Group I: Seven biopsies within a month post-transplant displayed rare CaOx foci against a background of acute tubular necrosis or acute cell-mediated rejection. At follow-up, five grafts functioned well and two failed due to chronic allograft nephropathy. CaOx in this context was an incidental finding secondary to a sudden excretion of an end-stage renal disease-induced increased body burden of CaOx. Group II: Two biopsies performed 2 and 10 months post-transplant showed rare CaOx foci against a background of chronic allograft nephropathy, leading to graft loss. CaOx in this context reflected nonspecific parenchymal deposition due to chronic renal failure regardless of causes. Group III: One biopsy with recurrent PH1 characterized by marked CaOx deposition associated with severe tubulointerstitial injury and graft loss 6 months post-transplant. There were two previously reported cases in which CaOx deposition in the renal allografts was due the antihypertensive drug naftidrofuryl oxalate or increased intestinal absorption of CaOx. CaOx deposition in renal allografts can be classified in different categories with distinctive morphologic features and clinical implications.

  1. Cyclosporine-associated renal arteriopathy resulting in loss of allograft function

    SciTech Connect

    Sommer, B.G.; Innes, J.T.; Whitehurst, R.M.; Sharma, H.M.; Ferguson, R.M.

    1985-06-01

    Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

  2. Splicing alterations in human renal allografts: detection of a new splice variant of protein kinase Par1/Emk1 whose expression is associated with an increase of inflammation in protocol biopsies of transplanted patients.

    PubMed

    Hueso, Miguel; Beltran, Violeta; Moreso, Francesc; Ciriero, Eva; Fulladosa, Xavier; Grinyó, Josep Maria; Serón, Daniel; Navarro, Estanis

    2004-05-24

    Protein kinase Emk1/Par1 (GenBank accession no. X97630) has been identified as a regulator of the immune system homeostasis. Since immunological factors are critical for the development of chronic allograft nephropathy (CAN), we reasoned that expression of Par1/Emk1 could be altered in kidney allografts undergoing CAN. In this paper, we have analysed the association among renal allograft lesions and expression of Par1/Emk1, studied by RT-PCR on total RNA from 51 protocol biopsies of transplanted kidneys, five normal kidneys, and five dysfunctional allografts. The most significant result obtained has been the detection of alterations in the normal pattern of alternative splicing of the Par1/Emk1 transcript, alterations that included loss of expression of constitutively expressed isoforms, and the inclusion of a cryptic exon to generate a new Emk1 isoform (Emk1C). Expression of Emk1C was associated with an increase in the extension of the interstitial infiltrate (0.88+/-0.33 in Emk1C([+]) vs. 0.41+/-0.50 in Emk1C([-]); P<0.011), and with a trend to display higher interstitial scarring (0.66+/-0.70 vs. 0.29+/-0.52; P=0.09) in protocol biopsies when evaluated according to the Banff schema. Moreover, a higher mean arterial pressure (MAP) was also observed (110+/-11 vs. 99+/-11 mm Hg; P=0.012). From these results we propose that Par1/Emk1 could have a role in the development of CAN in kidney allografts.

  3. Association of high HLA-E expression during acute cellular rejection and numbers of HLA class I leader peptide mismatches with reduced renal allograft survival.

    PubMed

    Guberina, Hana; Rebmann, Vera; Wagner, Bettina; da Silva Nardi, Fabiola; Dziallas, Phillip; Dolff, Sebastian; Bienholz, Anja; Wohlschlaeger, Jeremias; Bankfalvi, Agnes; Heinemann, Falko M; Witzke, Oliver; Zoet, Yvonne M; Claas, Frans H J; Horn, Peter A; Kribben, Andreas; Doxiadis, Ilias I N

    2017-03-01

    Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n=12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p=0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p<0.0001 and p=0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p<0.008) and reduced allograft survival (p=0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses.

  4. Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection

    PubMed Central

    1987-01-01

    A sensitive radioimmunoassay was used for monitoring serum levels of endogenous cachectin/tumor necrosis factor alpha (TNF) in 10 renal transplant recipients. Acute allograft rejections were associated with marked elevations of circulating TNF. The peak levels of TNF (median 140 pg/ml) were in the same concentration range as previously reported in parasitic infections. The results show that the release of TNF into circulation is an early event in renal allograft rejection and that raised levels of TNF in man can also be induced by noninfectious stimuli. PMID:3309124

  5. Renal allograft recovery subsequent to apparent hyperacute rejection based on clinical, scintigraphic, and pathologic criteria

    SciTech Connect

    Sacks, G.A.; Sandler, M.P.; Partain, C.L.

    1983-02-01

    An unusual case is described in which in spite of clinical, scintigraphic and histologic findings strongly supportive of a diagnosis of hyperacute rejection, recovery of renal function occurred. These findings are in contrast to the current literature in which it is generally accepted that a renal allograft showing neither pertechnetate transit nor hippurate concentration warrants allograft nephrectomy irrespective of the etiology. Scintigraphic evaluation included both dynamic studies after a bolus administration of /sup 99m/Tc pertechnetate and serial renogram collections after the intravenous administration of /sup 131/I Hippuran.

  6. Current Safety of Renal Allograft Biopsy With Indication in Adult Recipients

    PubMed Central

    Tsai, Shang-Feng; Chen, Cheng-Hsu; Shu, Kuo-Hsiung; Cheng, Chi-Hung; Yu, Tung-Min; Chuang, Ya-Wen; Huang, Shih-Ting; Tsai, Jun-Li; Wu, Ming-Ju

    2016-01-01

    Abstract Renal biopsy remains the golden standard diagnosis of renal function deterioration. The safety in native kidney biopsy is well defined. However, it is a different story in allograft kidney biopsy. We conduct this retrospective study to clarify the safety of allograft kidney biopsy with indication. All variables were grouped by the year of biopsy and they were compared by Mann–Whitney U test (for continuous variables) or Chi-square test (for categorical variables). We collected possible factors associated with complications, including age, gender, body weight, renal function, cause of uremia, status of coagulation, hepatitis, size of needle, and immunosuppressants. We recruited all renal transplant recipients undergoing allograft biopsy between January of 2009 and December of 2014. This is the largest database for allograft kidney biopsy with indication. Of all the 269 biopsies, there was no difference in occurrence among the total 14 complications (5.2%) over these 6 years. There were only 3 cases of hematomas (1.11%), 6 gross hematuria (2.23%), 1 hydronephrosis (0.37%), and 2 hemoglobin decline (0.74%). The outcome of this cohort is the best compared to all other studies, and it is even better than the allograft protocol kidney biopsy. Among all possible factors, patients with pathological report containing “medullary tissue only” were susceptible to complications (P < 0.001, 1.8 of relative risk). In modern era, this study demonstrates the safety of allograft kidney biopsy with indication. Identifying the renal capsule before biopsy to avoid puncture into medulla is the most important element to prevent complications. PMID:26871853

  7. Current Safety of Renal Allograft Biopsy With Indication in Adult Recipients: An Observational Study.

    PubMed

    Tsai, Shang-Feng; Chen, Cheng-Hsu; Shu, Kuo-Hsiung; Cheng, Chi-Hung; Yu, Tung-Min; Chuang, Ya-Wen; Huang, Shih-Ting; Tsai, Jun-Li; Wu, Ming-Ju

    2016-02-01

    Renal biopsy remains the golden standard diagnosis of renal function deterioration. The safety in native kidney biopsy is well defined. However, it is a different story in allograft kidney biopsy. We conduct this retrospective study to clarify the safety of allograft kidney biopsy with indication.All variables were grouped by the year of biopsy and they were compared by Mann-Whitney U test (for continuous variables) or Chi-square test (for categorical variables). We collected possible factors associated with complications, including age, gender, body weight, renal function, cause of uremia, status of coagulation, hepatitis, size of needle, and immunosuppressants.We recruited all renal transplant recipients undergoing allograft biopsy between January of 2009 and December of 2014. This is the largest database for allograft kidney biopsy with indication. Of all the 269 biopsies, there was no difference in occurrence among the total 14 complications (5.2%) over these 6 years. There were only 3 cases of hematomas (1.11%), 6 gross hematuria (2.23%), 1 hydronephrosis (0.37%), and 2 hemoglobin decline (0.74%). The outcome of this cohort is the best compared to all other studies, and it is even better than the allograft protocol kidney biopsy. Among all possible factors, patients with pathological report containing "medullary tissue only" were susceptible to complications (P < 0.001, 1.8 of relative risk).In modern era, this study demonstrates the safety of allograft kidney biopsy with indication. Identifying the renal capsule before biopsy to avoid puncture into medulla is the most important element to prevent complications.

  8. Immunopathologic features of de novo membranous nephropathy in renal allografts.

    PubMed

    Ward, H J; Koyle, M A

    1988-03-01

    De novo membranous nephropathy (MN) is now one of the most common forms of posttransplant glomerular disease, second only to allograft glomerulopathy. We investigated several immunopathologic and physicochemical properties of the immune complex (IC) or IC components displayed in the sera of patients with de novo MN. The parameters studied included detection of small (9S) preformed IC by monoclonal rheumatoid factor, determination of IC isoelectric point by chromatofocusing, detection of cationic IgG spectrotypes (pI 8.0-9.2), and demonstration of brush border or tubular epithelial/interstitial antibodies in the sera by indirect immunofluorescence. Of 7 de novo MN sera, 5 demonstrated the presence of each of these four immunopathologic features, whereas normal transplant patients, transplant recipients with recurrent focal sclerosis (FSGN), and those with chronic rejection did not display such features. Sera of patients with untreated idiopathic MN revealed immunochemical properties of IC that were similar to those seen in circulating IC of de novo MN. These studies suggest that a strongly nephritogenic internal milieu exists in transplant recipients with de novo MN. Our data indicate that unique immunochemical properties of IC or their components may predispose to subepithelial immune deposit formation and should provide new insights into the pathogenesis of idiopathic human MN.

  9. Renal failure due to granulomatous interstitial nephritis in native and allograft renal biopsies: experience from a tertiary care hospital.

    PubMed

    Gupta, Pallav; Rana, D S; Bhalla, A K; Gupta, Ashwini; Malik, Manish; Gupta, Anurag; Bhargava, Vinant

    2014-10-01

    Granulomatous interstitial nephritis is a rare cause of renal failure in both native and allograft renal biopsies. Drugs and sarcoidosis are the commonest causes of granulomatous interstitial nephritis as reported in Western countries. Unlike the west, tuberculosis is the commonest cause of granulomatous interstitial nephritis in Indian subcontinent. The etiological factors, clinical course, glomerular and tubulointerstitial changes associated with granulomatous interstitial nephritis have been analyzed in the present study along with the outcome in patients with granulomatous interstitial nephritis.

  10. Laryngeal cryptococcus: a rare cause of hoarseness in renal allograft recipient

    PubMed Central

    Sandhu, Jashan; Sandhu, Jasvinder Singh; Kaur Puri, Harpreet; Munjal, Manish

    2017-01-01

    Cryptococcosis commonly involves central nervous system and lungs in organ transplant recipients. Isolated laryngeal infection is extremely rare. We report a rare case of cryptococcus in a renal allograft recipient that clinically presented with hoarseness of voice and mimicked laryngeal carcinoma on examination. PMID:28197527

  11. Treating chronic lower limb lymphedema with the Charles procedure in a renal allograft recipient.

    PubMed

    Wu, Hsiao-Su; Cheng, Hsu-Tang; Chen, Hung-Chi

    2012-01-01

    We report our experience in applying the Charles procedure to a female renal allograft recipient for her left lower leg lymphedema. This is a rare comorbidity in limb lymphedema victims, and the use of the Charles procedure has not been reported in such an immunocompromised patient. After surgery, infection was well controlled, and there was minimal scar in the affected limb.

  12. Enhanced resolution of interstitial fibrosis in pediatric renal allograft biopsies using image analysis of trichrome stain.

    PubMed

    Birk, Patricia E; Gill, John S; Blydt-Hansen, Tom D; Gibson, Ian W

    2010-11-01

    The Banff classification is ill suited to detect subtle histologic progression in renal allografts. We present image analysis methodology to precisely quantify IF in pediatric renal allograft biopsies routinely stained with MT. The mean area %IF was determined in 105 pediatric renal allograft biopsies. Associations between %IF or Banff ci scores and estimated GFR were determined using GEE modeling. Logistic regression was used to estimate IF progression. Percent IF (mean ± s.d.) was 6.83% ± 3.94, 10.39 ± 5.23%, and 20.53 ± 8.74 in patients with ci0, ci1, and ci2, respectively. The difference in %IF between biopsies with ci0, ci1, and ci2 was not proportionately incremental: compared to ci2, ci0 had 67% less IF (p < 0.0001), while ci1 had 48% less IF (p < 0.0001). AR had no impact on the precision of %IF measurements. Each 0.5% decrement in %IF was associated with a 1 mL/min per 1.73 m² increase in GFR (p < 0.004). Histologic progression was demonstrated by increasing %IF values (p < 0.0001) and could be estimated by IF = 2.61 × (months) + 6.43. This readily adaptable methodology may be used for the longitudinal assessment of IF in pediatric protocol renal allograft biopsies. © 2010 John Wiley & Sons A/S.

  13. An unusual case of a patient who lost his native kidneys and renal allograft from cholesterol crystal emboli.

    PubMed

    Ahmed, Wasim; Al Garni, Abdulkareem; Abdelgadir, Elbadri; Khamees, Khamess Obeid; Ellouly, Mohammed Ali Ahmed; Haleem, Abdul

    2015-09-01

    Cholesterol crystal emboli (CCE) syndrome involving native kidneys is an underdiagnosed condition. CCE is rare in renal allografts. It may present with acute kidney injury, but usually not acute graft loss. CCE should be considered in patients with a history of atherosclerosis and an invasive arterial procedure who present with acute or chronic renal allograft dysfunction. Therapy for CCE is mainly supportive and carries a high rate of mortality. To the best of our knowledge, this is the first reported case of a patient who lost his native kidneys and renal allograft due to CCE arising from his own vasculature.

  14. Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits complicated by immunoglobulin A nephropathy in the renal allograft.

    PubMed

    Sawada, Anri; Kawanishi, Kunio; Horita, Shigeru; Koike, Junki; Honda, Kazuho; Ochi, Ayami; Komoda, Mizuki; Tanaka, Yoichiro; Unagami, Kohei; Okumi, Masayoshi; Shimizu, Tomokazu; Ishida, Hideki; Tanabe, Kazunari; Nagashima, Yoji; Nitta, Kosaku

    2016-07-01

    Immunoglobulin (Ig) A nephropathy (IgAN) is a known autoimmune disease due to abnormal glycosylation of IgA1, and occasionally, IgG co-deposition occurs. The prognosis of IgG co-deposition with IgAN is adverse, as shown in the previous studies. However, in the clinical setting, monoclonality of IgG co-deposition with IgAN has not been observed. We describe a case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) combined with IgAN in a renal allograft. A-21-year-old man developed end-stage renal failure with unknown aetiology and underwent living-donor kidney transplantation from his mother 2 years after being diagnosed. One year after kidney transplantation, proteinuria 2+ and haematuria 2+ were detected; allograft biopsy revealed mesangial IgA and C3 deposits, indicating a diagnosis of IgAN. After tonsillectomy and steroid pulse therapy, proteinuria and haematuria resolved. However, 4 years after transplantation, pedal oedema, proteinuria (6.89 g/day) and allograft dysfunction (serum creatinine (sCr) 203.3 µmol/L) appeared. A second allograft biopsy showed mesangial expansion and focal segmental proliferative endocapillary lesions with IgA1λ and monoclonal IgG1κ depositions. Electron microscopic analysis revealed a massive amount of deposits, located in the mesangial and subendothelial lesions. A diagnosis of PGNMID complicated with IgAN was made, and rituximab and plasmapheresis were added to steroid pulse therapy. With this treatment, proteinuria was alleviated to 0.5 g/day, and the allograft dysfunction recovered to sCr 132.6 µmol/L. This case suggests a necessity for investigation of PGNMID and IgA nephropathy in renal allografts to detect monoclonal Ig deposition disease.

  15. Impaired Elastin Deposition in Fstl1−/− Lung Allograft under the Renal Capsule

    PubMed Central

    Dong, Yingying; Liu, Xue; Li, Xiao-He; Ning, Wen

    2013-01-01

    Lung alveolar development in late gestation is a process important to postnatal survival. Follistatin-like 1 (Fstl1) is a matricellular protein of the Bmp antagonist class, which is involved in the differentiation/maturation of alveolar epithelial cells during saccular stage of lung development. This study investigates the role of Fstl1 on elastin deposition in mesenchyme and subsequent secondary septation in the late gestation stage of terminal saccular formation. To this aim, we modified the renal capsule allograft model for lung organ culture by grafting diced E15.5 distal lung underneath the renal capsule of syngeneic host and cultured up to 7 days. The saccular development of the diced lung allografts, as indicated by the morphology, epithelial and vascular developments, occurred in a manner similar to that in utero. Fstl1 deficiency caused atelectatic phenotype companied by impaired epithelial differentiation in D3 Fstl1−/− lung allografts, which is similar to that of E18.5 Fstl1−/− lungs, supporting the role of Fstl1 during saccular stage. Inhibition of Bmp signaling by intraperitoneal injection of dorsomorphin in the host mice rescued the pulmonary atelectasis of D3 Fstl1−/− allografts. Furthermore, a marked reduction in elastin expression and deposition was observed in walls of air sacs of E18.5 Fstl1−/− lungs and at the tips of the developing alveolar septae of D7 Fstl1−/− allografts. Thus, in addition to its role on alveolar epithelium, Fstl1 is crucial for elastin expression and deposition in mesenchyme during lung alveologenesis. Our data demonstrates that the modified renal capsule allograft model for lung organ culture is a robust and efficient technique to increase our understanding of saccular stage of lung development. PMID:24282586

  16. Ex Situ Perfusion of Human Limb Allografts for 24 Hours.

    PubMed

    Werner, Nicole L; Alghanem, Fares; Rakestraw, Stephanie L; Sarver, Dylan C; Nicely, Bruce; Pietroski, Richard E; Lange, Paul; Rudich, Steven M; Mendias, Christopher L; Rojas-Pena, Alvaro; Magee, John C; Bartlett, Robert H; Ozer, Kagan

    2017-03-01

    Vascularized composite allografts, particularly hand and forearm, have limited ischemic tolerance after procurement. In bilateral hand transplantations, this demands a 2 team approach and expedited transfer of the allograft, limiting the recovery to a small geographic area. Ex situ perfusion may be an alternative allograft preservation method to extend allograft survival time. This is a short report of 5 human limbs maintained for 24 hours with ex situ perfusion. Upper limbs were procured from brain-dead organ donors. Following recovery, the brachial artery was cannulated and flushed with 10 000 U of heparin. The limb was then attached to a custom-made, near-normothermic (30-33°C) ex situ perfusion system composed of a pump, reservoir, and oxygenator. Perfusate was plasma-based with a hemoglobin concentration of 4 to 6 g/dL. Average warm ischemia time was 76 minutes. Perfusion was maintained at an average systolic pressure of 93 ± 2 mm Hg, flow 310 ± 20 mL/min, and vascular resistance 153 ± 16 mm Hg/L per minute. Average oxygen consumption was 1.1 ± 0.2 mL/kg per minute. Neuromuscular electrical stimulation continually displayed contraction until the end of perfusion, and histology showed no myocyte injury. Human limb allografts appeared viable after 24 hours of near-normothermic ex situ perfusion. Although these results are early and need validation with transplantation, this technology has promise for extending allograft storage times.

  17. Treatment of Focal Segmental Glomerulosclerosis Recurrence in the Renal Allograft: A Report of Two Cases

    PubMed Central

    Tran, Minh-Ha; Chan, Cynthia; Pasch, Whitney; Carpenter, Philip; Ichii, Hirohito; Foster, Clarence

    2016-01-01

    Focal segmental glomerulosclerosis (FSGS) causes glomerular lesions that can progress to end-stage renal disease. It is suspected to be caused by a circulating factor that is amenable to plasmapheresis removal and exhibits a risk for recurrence in the renal allograft. We present two patients with FSGS recurrence in their allograft kidneys diagnosed by biopsy after significant proteinuria developed in the posttransplant setting. Treatment with therapeutic plasma exchange induced long-term remission in both patients. Spot urine protein:creatinine ratios were monitored and treatment was continued until a target of <0.5 was achieved. In patient number two, a second peak in proteinuria and azotemia was ultimately attributable to ureteral stenosis and these values normalized following repair. In conclusion, therapeutic plasma exchange is an effective treatment for FSGS recurring following renal transplant. PMID:27099858

  18. Robotic trans-abdominal transplant nephrectomy for a failed renal allograft.

    PubMed

    Mulloy, M R; Tan, M; Wolf, J H; D'Annunzio, S H; Pollinger, H S

    2014-12-01

    Minimally invasive surgery for removal of a failed renal allograft has not previously been reported. Herein, we report the first robotic trans-abdominal transplant nephrectomy (TN). A 34-year-old male with Alport's syndrome lost function of his deceased donor allograft after 12 years and presented with fever, pain over his allograft and hematuria. The operation was performed intra-abdominally using the Da Vinci Robotic Surgical System with four trocars. The total operative time was 235 min and the estimated blood loss was less than 25 cm(3). There were no peri-operative complications observed and the patient was discharged to home less than 24 h postoperatively. The utilization of robotic technology facilitated the successful performance of a minimally invasive, trans-abdominal TN.

  19. Renal allograft granulomatous interstitial nephritis: observations of an uncommon injury pattern in 22 transplant recipients

    PubMed Central

    Ellis, Carla L.; Rogers, Thomas E.; James Chon, W.; Chang, Anthony; Meehan, Shane M.

    2017-01-01

    Abstract Background: Granulomatous interstitial nephritis (GIN) is uncommon in native kidneys, and descriptions in allografts are few. We report clinical and pathologic findings in 22 allograft recipients with GIN identified in renal allograft biopsies and nephrectomies. Methods: Renal allografts with GIN were retrieved from the pathology files of two academic medical centers. Available clinical and pathologic data were compiled retrospectively for a 23-year period. Results: GIN was present in 23 specimens from 22 patients (15 males and 7 females) with allograft dysfunction [serum creatinine averaged 3.3 mg/dL (range 1.4–7.8)], at a mean age of 48 years (range 22–77). GIN was identified in 0.3% of biopsies at a mean of 552 days post transplantation (range 10–5898). GIN was due to viral (5), bacterial (5) and fungal (2) infections in 12 (54.5%), and drug exposure was the likely cause in 5 cases (22.7%). One had recurrent granulomatosis with polyangiitis. In 4 cases, no firm etiology of GIN was established. Of 18 patients with follow up data, 33.3% had a complete response to therapy, 44.5% had a partial response and 22.2% developed graft loss due to fungal and E. coli infections. All responders had graft survival for more than 1 year after diagnosis of GIN. Conclusions: Allograft GIN is associated with a spectrum of etiologic agents and was identified in 0.3% of biopsies. Graft failure occurred in 22% of this series, due to fungal and bacterial GIN; however, most had complete or partial dysfunction reversal and long–term graft survival after appropriate therapy. PMID:28396741

  20. Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure

    PubMed Central

    Freedman, Barry I.; Julian, Bruce A.; Pastan, Stephen O.; Israni, Ajay K.; Schladt, David; Gautreaux, Michael D.; Hauptfeld, Vera; Bray, Robert A.; Gebel, Howard M.; Kirk, Allan D.; Gaston, Robert S.; Rogers, Jeffrey; Farney, Alan C.; Orlando, Giuseppe; Stratta, Robert J.; Mohan, Sumit; Ma, Lijun; Langefeld, Carl D.; Hicks, Pamela J.; Palmer, Nicholette D.; Adams, Patricia L.; Palanisamy, Amudha; Reeves-Daniel, Amber M.; Divers, Jasmin

    2016-01-01

    Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p=0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p=0.001) and African American recipient race/ethnicity (HR 1.60; p=0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes. PMID:25809272

  1. [Oleanolic acid synergizes with cyclosporine A to prolong renal allograft survival in rats].

    PubMed

    Qian, Kun; Liao, Wenting; Li, Jianjun; Jiang, Hongtao; Zhou, Hao; Long, Jianhua; Qin, Guoqing; Wang, Yi

    2014-06-01

    To investigate the synergistic effect of oleanolic acid (OA) and cyclosporine A (CsA) on the survival of renal allografts in rats. Renal allograft transplantation was performed using BN rats as donors and LEW rats as recipients. Forty male LEW rats were randomized into 4 equal groups for interventions with DMSO-PBS (control), OA, CsA, or CsA+OA, starting from 1 day before transplantation. Serum creatinine levels were regularly examined, and the survival of rats were recorded. On day 5 after transplantation, CD4(+) and CD8(+) T-cell infiltration in the renal grafts was analyzed by immunohistochemistry; the concentrations of the proinflammatory cytokines (IL-1β, IFN-γ, IL-2, IL-4, and IL-17), anti-inflammatory cytokine IL-10 and chemokines (IP-10, MCP-1, MIP, and Mig) were analyzed with Luminex; the T-cell phenotypes (IFN-γ, IL-10, IL-4, and IL-17) were analyzed using ELISpot. In OA+CsA group, renal allograft survival was markedly prolonged and CD4(+) and CD8(+) T cell infiltration in the graft significantly decreased as compared to other groups. A significant decrease in IL-2 was observed in OA group and OA+CsA group, especially the latter. Compared with the control group, all the 3 treated groups showed significantly decreased IL-1β, IP-10 and MCP-1, increased IL-10 levels, decreased percentages of T cells secreting IFN-γ, IL-4 and IL-17, and increased percentage of T cells secreting IL-10. The increments of serum IL-10 level and T cell percentage were more prominent in OA+CsA group than in the other two intervention groups. OA and CsA synergistically ameliorate renal graft rejection and inflammation and promote allograft survival and function in rats.

  2. Fetuin, Matrix-Gla Protein and Osteopontin in Calcification of Renal Allografts

    PubMed Central

    Lorenzen, Johan M.; Martino, Filippo; Scheffner, Irina; Bröcker, Verena; Leitolf, Holger; Haller, Hermann; Gwinner, Wilfried

    2012-01-01

    Background Calcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5∶1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification. Methods We analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined. Results Serum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression. Conclusion Anticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification. PMID:23284864

  3. Fetuin, matrix-Gla protein and osteopontin in calcification of renal allografts.

    PubMed

    Lorenzen, Johan M; Martino, Filippo; Scheffner, Irina; Bröcker, Verena; Leitolf, Holger; Haller, Hermann; Gwinner, Wilfried

    2012-01-01

    Calcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5∶1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification. We analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined. Serum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression. Anticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification.

  4. Thrombotic Microangiopathy and Peritubular Capillary C4d Expression in Renal Allograft Biopsies

    PubMed Central

    Kremer, Joseph; Ali, Farah N.; Curley, Jessica; Marino, Susana; Chang, Anthony; Kadambi, Pradeep V.

    2011-01-01

    Summary Background and objectives This study characterizes the pathologic and clinical relationships of thrombotic microangiopathy (TMA) to antibody-mediated rejection (AMR) in renal allograft biopsies. Design, setting, participants, & measurements Consecutive renal allograft biopsies, routinely stained for C4d over a period of 51 months (n = 1101), were reviewed. For comparative analysis of histology and clinical features, additional patients with TMA and peritubular capillary (PTC) C4d (n = 5) were combined with those identified in the 51-month period of review (n = 6). Results One hundred eighty-two of 1073 adequate biopsies from 563 allografts had PTC C4d in the study period. Six of 37 biopsies with TMA had PTC C4d (five at ≤90 days and one at 213 days). Early (≤90 days) C4d+ biopsies (n = 5) had more frequent TMA (11.9% C4d+ versus 3.4% C4d−; odds ratio, 3.84; P = 0.03). Graft loss was significantly greater in an early C4d+TMA+ group (n = 5 study + 2 archival patients) than in C4d+ controls without TMA (n = 21) (57% versus 9.5%; P = 0.02). Early TMA+C4d+ biopsies had more severe glomerulopathy and less severe arteriolopathy than TMA+C4d− and had more frequent neutrophilic capillaritis than TMA−C4d+ biopsies. Conclusions TMA was infrequent in this series of unselected, consecutive, renal allograft biopsies (3.4%). PTC C4d may be a significant risk factor for early TMA, and TMA is associated with glomerular thrombi and neutrophilic capillaritis. TMA in allografts with suspected AMR may portend a higher risk of graft loss. PMID:20966124

  5. Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes

    PubMed Central

    Naesens, Maarten; Khatri, Purvesh; Li, Li; Sigdel, Tara K.; Vitalone, Matthew J.; Chen, Rong; Butte, Atul J.; Salvatierra, Oscar; Sarwal, Minnie M.

    2015-01-01

    The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys. Hence, histologically unrecognized immunological injury at a molecular level sets the stage for the development of chronic tissue injury, while the same molecular response is accentuated during established and worsening chronic allograft damage. Irrespective of the hypothesized immune or nonimmune trigger for chronic allograft injury, a highly orchestrated regulation of innate and adaptive immune responses was found in the graft at the molecular level. This occurred months before histologic lesions appear, and quantitatively below the diagnostic threshold of classic T-cell or antibody-mediated rejection. Thus, measurement of specific immune gene expression in protocol biopsies may be warranted to predict the development of subsequent chronic injury in histologically quiescent grafts and as a means to titrate immunosuppressive therapy. PMID:21881554

  6. Radiofrequency Ablation of T1a Renal Cell Carcinomas within Renal Transplant Allografts: Oncologic Outcomes and Graft Viability.

    PubMed

    Cool, Derek W; Kachura, John R

    2017-09-13

    To evaluate oncologic outcomes and graft viability after percutaneous RF ablation of renal cell carcinoma (RCC) developing within renal transplant allografts. A single-institution, retrospective study reviewed all patients treated with RF ablation for RCC between February 2004 and May 2016. Ten patients were identified (age 49.6 y ± 12.6; 9 men, 1 woman) with 12 biopsy-confirmed RCC tumors within the allograft (all T1a, mean diameter 2.0 cm ± 0.7). Mean time from transplant to RCC diagnosis was 13.2 years ± 6.3. RF ablation was performed on an outpatient basis using conscious sedation. Procedural efficacy, complications, oncologic outcomes, and allograft function were evaluated. Statistical analysis with t tests and Pearson correlation compared allograft function before and after RF ablation and impact of proportional ablation size to allograft volume on function after ablation. Technical success rate and primary technique efficacy were 100% (12/12). No local or distant RCC progression was seen at mean follow-up of 54.3 months ± 38.7 (range, 9-136 months). Graft failure requiring hemodialysis or repeat transplantation occurred in 3 patients (26, 354, and 750 d after RF ablation), all of whom had glomerular filtration rate (GFR) < 30 mL/min/1.73 m(2) before ablation. For all patients, mean GFR 6 months after RF ablation (35.8 mL/min/1.73 m(2) ± 17.7) was not significantly different (P = .8) from preprocedure GFR (36.2 mL/min/1.73 m(2) ± 14.3). Proportional volume of allograft that was ablated did not correlate with immediate or long-term GFR changes. One patient died of unrelated comorbidities 52 months after ablation. No major complications occurred. RF ablation of renal allograft RCC provided effective oncologic control without adverse impact on graft viability. Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.

  7. Concentration of In-111-oxine-labeled autologous leukocytes in noninfected and nonrejecting renal allografts: concise communication

    SciTech Connect

    Collier, B.D.; Isitman, A.T.; Kaufman, H.M.; Rao, S.A.; Knobel, J.; Hellman, R.S.; Zielonka, J.S.; Pelc, L.

    1984-02-01

    Autologous leukocytes labeled with In-111 oxine (ILL) concentrated in the renal allografts of eight patients for whom transplant rejection, infection, or acute tubular necrosis (ATN) could be excluded. All patients had good-to-adequate renal function at the time of ILL scintigraphy, and none developed rejection or renal transplant failure during a 1-mo follow-up period. It is concluded that normally functioning renal allografts without evidence of rejection, infection, or ATN often will concentrate ILL. When a baseline study is not available for comparison, this phenomenon limits the value of ILL scintigraphy as a diagnostic test for transplant rejection or infection.

  8. Care of the patient after renal allograft failure: managing the present and planning for the future.

    PubMed

    Fuquay, Richard; Teitelbaum, Isaac

    2012-01-01

    The number of patients with end-stage renal disease undergoing kidney transplantation - both cadaveric and living-donor - continues to rise. With long-term graft survival relatively fixed, this trend means that increasing numbers of patients are returning to dialysis after graft loss. Most will never be retransplanted, which introduces a host of clinical questions regarding optimal management of this unique patient population. In this paper, we explore data that informs astute care of the patient requiring dialysis after graft loss. We address new data about the increased clinical risk and the optimal dialysis modality in renal allograft loss, explore new approaches to immunosuppression and transfusion management, and examine the risks and benefits of allograft nephrectomy and timing thereof. While there are no randomized clinical trials in this field, rapidly evolving data will aid the clinician whose practice includes patients who have been transplanted and are returning to dialysis. Copyright © 2012 S. Karger AG, Basel.

  9. Correction of base deficits in deceased organ donors: effects on immediate renal allograft function.

    PubMed

    Shen, G K; Recicar, J F; Hovsepian, R V; Salisbury, J A; Niles, P A

    2004-11-01

    Fluid status in the brain-dead donor is often difficult to assess. We hypothesized that using base deficit as a measure of tissue perfusion will facilitate fluid management in these donors, thereby improving renal allograft function. Consecutive donors over a 12-month period were prospectively studied. In Group I, resuscitation was based on maintaining normal blood pressure and urine output. In Group II, additional parameters of resuscitation included the correction of base deficit. Immediate renal allograft function was examined in the 48 recipients. Delayed graft function occurred in 48% of Group I, and in 19% of Group II recipients. Creatinine clearance on day 7, calculated by the Cockroft-Gault formula, was 29 +/- 6 mL/min in Group I versus 41 +/- 8 mL/min in Group II. We conclude that correcting base deficit is an extremely useful approach to expedite organ recovery and potentially improve function of transplanted kidneys.

  10. Serum hepcidin level correlates with hyperlipidemia status in patients following allograft renal transplantation.

    PubMed

    Xue, D; He, X; Zhou, C

    2014-01-01

    Hepcidin is synthesized and secreted by liver cells and has been reported as one of the hormone molecules that regulates iron homeostasis. To determine whether serum level of hepcidin can be used as a biomarker for the evaluation of chronic inflammatory status, iron level and renal function in patients following allograft renal transplantation, serum levels of hepcidin, interleukin (IL)-6, ferritin, serum iron, and renal functions were measured. Sixty patients were included in the current study and were further separated into groups with or without hyperlipidemia. We found that allogeneic kidney transplant recipients with hyperlipidemia have significantly increased serum levels of hepcidin, IL-6, and ferritin. The increased serum hepcidin is positively correlated with serum IL-6 and ferritin as analyzed by single-factor correlation analysis. Multivariant correlation analysis in all specimens further demonstrated that serum hepcidin negatively correlated with glomerular filtration rate, and positively correlated with serum total cholesterol, triglycerides, serum ferritin, and IL-6. Our study demonstrated that serum level of hepcidin after allogeneic kidney transplantation not only reflects the status of chronic inflammation but can also indicate changes in renal function. Thus, hepcidin has the potential to be used as a promising marker for the detection and monitoring of the status of chronic inflammation, hyperlipidemia, and renal function in patients following allograft renal transplantation.

  11. Antibodies directed against antigens on the endothelium of peritubular capillaries in patients with rejecting renal allografts.

    PubMed

    Paul, L C; van Es, L A; van Rood, J J; van Leeuwen, A; de la Rivière, G B; de Graeff, J

    1979-03-01

    This study was undertaken to examine the humoral immune response against endothelial antigens of the donor kidney in human renal allograft recipients. Sera from 61 transplant recipients who received 62 grafts were studied for the presence of circulating endothelial antibodies (CEAb) using an indirect immunofluorescence technique with a pretransplant biopsy of the graft as a substrate. IgG antibodies directed against the endothelium of peritubular capillaries were found in the sera of 6 of the 10 patients with graft rejection within 7 weeks after transplantation, whereas these antibodies were not found in the absence of rejection (P less than 0.001). Immunofluorescence studies of post-transplant biopsies showed IgG along the endothelium of peritubular capillaries only in the grafts of patients with CEAb. Eluates from these grafts contained IgG antibodies that bound to the endothelium of the donor as shown by the indirect immunofluorescence technique. Absorption of endothelial antibody (EAb)-positive sera with human platelets or Wistar strain rat erythrocytes showed that the EAb were not directed against serologically defined HLA antigens or against heterophile antigens on rat erythrocytes. We conclude from this study that the presence of antibodies directed against endothelial antigens is associated with poor graft prognosis and that these antibodies may be responsible for the rejection process.

  12. Effects of Aspirin Therapy on Ultrasound–Guided Renal Allograft Biopsy Bleeding Complications

    PubMed Central

    Baffour, Francis I.; Hickson, LaTonya J.; Stegall, Mark D.; Dean, Patrick G.; Gunderson, Tina M.; Atwell, Thomas D.; Kurup, A. Nicholas; Schmitz, John J.; Park, Walter D.; Schmit, Grant D.

    2017-01-01

    Purpose To determine if patient aspirin exposure and timing affect bleeding risk after renal allograft biopsy. Materials and Methods Review of 6,700 renal allograft biopsies (in 2,362 unique patients) was performed. Median patient age was 53.0 years [interquartile range 43.0, 62.0]; 56.2% of patients were male. Of biopsies, 4,706 (70.2%) were performed in patients with no aspirin exposure within 10 days of biopsy; 664 (9.9%), were performed within 8–10 days of aspirin exposure; 855 (12.8%), within 4–7 days; and 475 (7.1%), within 0–3 days. Follow-up to 3 months after the procedure was completed in all patients. Biopsies were categorized as protocol or indication; 19.7% were indication biopsies. Bleeding complications were graded based on SIR criteria. Logistic regression models examined the association between aspirin use and bleeding events. Results Rate [95% confidence interval] of major bleeding complications was 0.24% [0.14, 0.39], and rate of any bleeding complication was 0.66% [0.46, 0.90]. Bleeding events were significantly associated with patients undergoing indication biopsies compared with protocol biopsies (odds ratio [OR] 2.27, P = .012). Patient factors associated with major bleeding complications in multivariate models included estimated glomerular filtration rate (OR 0.61, P = .016) and platelet count (OR 0.64, P = .033). Aspirin use was not significantly associated with increased risk of bleeding complication except for use of 325 mg of aspirin within 3 days of biopsy (any complication OR 3.87 [1.12, 13.4], P = .032; major complication OR 6.30 [1.27, 31.3], P = .024). Conclusions Renal allograft biopsy bleeding complications are very rare, particularly for protocol biopsies. Use of 325 mg of aspirin within 3 days of renal allograft biopsy was associated with increased bleeding complications. PMID:27993506

  13. The Prevalence of Immunologic Injury in Renal Allograft Recipients with De Novo Proteinuria

    PubMed Central

    Sun, Qiquan; Jiang, Song; Li, Xue; Huang, Xianghua; Xie, Kenan; Cheng, Dongrui; Chen, Jinsong; Ji, Shuming; Wen, Jiqiu; Zhang, Mingchao; Zeng, Caihong; Liu, Zhihong

    2012-01-01

    Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term “chronic allograft nephropathy,” which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft. PMID:22586485

  14. Evaluation of oxidative stress markers for the early diagnosis of allograft rejection in feline renal allotransplant recipients with normal renal function

    PubMed Central

    2004-01-01

    Abstract The purpose of this study was to identify oxidative damage to renal allografts during graft rejection by evaluating changes in oxidative markers and plasma lactate levels in feline renal allotransplant recipients. Heterotopic renal allotransplantations were performed between 8 adult feline cross-matched donors. Following 14 d of immunosuppression, the drugs were discontinued to allow allograft rejection. Baseline and serial postoperative evaluations of serum creatinine, plasma lactate, plasma thiobarbituate reactive substances (TBARS), plasma creatol, urine creatol, and renal sonographic cross-sectional area were performed. When sonographic evaluation revealed the absence of blood flow to the allograft, the rejected kidney was nephrectomized and evaluated histopathologically. Allograft rejection occurred in all cats by day 26. A significant elevation in body temperature occurred during the rejection period. No significant change was observed between any of the time periods for plasma TBARS, creatol, or urine creatol. There was a significant decrease in plasma lactate levels throughout the study. Markers of oxidative stress from venous blood did not reflect renal allograft rejection in cats with a normally functioning native kidney. Renal allograft rejection may be associated with significant increases in body temperature and warrants further investigation. PMID:15532882

  15. Evaluation of oxidative stress markers for the early diagnosis of allograft rejection in feline renal allotransplant recipients with normal renal function.

    PubMed

    Halling, Krista B; Ellison, Gary W; Armstrong, Don; Aoyagi, Kasumi; Detrisac, Carol J; Graham, John P; Newell, Susan P; Martin, Frank G; Van Gilder, James M

    2004-10-01

    The purpose of this study was to identify oxidative damage to renal allografts during graft rejection by evaluating changes in oxidative markers and plasma lactate levels in feline renal allotransplant recipients. Heterotopic renal allotransplantations were performed between 8 adult feline cross-matched donors. Following 14 d of immunosuppression, the drugs were discontinued to allow allograft rejection. Baseline and serial postoperative evaluations of serum creatinine, plasma lactate, plasma thiobarbituate reactive substances (TBARS), plasma creatol, urine creatol, and renal sonographic cross-sectional area were performed. When sonographic evaluation revealed the absence of blood flow to the allograft, the rejected kidney was nephrectomized and evaluated histopathologically. Allograft rejection occurred in all cats by day 26. A significant elevation in body temperature occurred during the rejection period. No significant change was observed between any of the time periods for plasma TBARS, creatol, or urine creatol. There was a significant decrease in plasma lactate levels throughout the study. Markers of oxidative stress from venous blood did not reflect renal allograft rejection in cats with a normally functioning native kidney. Renal allograft rejection may be associated with significant increases in body temperature and warrants further investigation.

  16. Reliability of whole slide images as a diagnostic modality for renal allograft biopsies.

    PubMed

    Jen, Kuang-Yu; Olson, Jean L; Brodsky, Sergey; Zhou, Xin J; Nadasdy, Tibor; Laszik, Zoltan G

    2013-05-01

    The use of digital whole slide images (WSI) in the field of pathology has become feasible for routine diagnostic purposes and has become more prevalent in recent years. This type of technology offers many advantages but must show the same degree of diagnostic reliability as conventional glass slides. Several studies have examined this issue in various settings and indicate that WSI are a reliable method for diagnostic pathology. Since transplant pathology is a highly specialized field that requires not only accurate but rapid diagnostic evaluation of biopsy materials, this field may greatly benefit from the use of WSI. In this study, we assessed the reliability of using WSI compared to conventional glass slides in renal allograft biopsies. We examined morphologic features and diagnostic categories defined by the Banff 07 Classification of Renal Allograft Pathology as well as additional morphologic features not included in this classification scheme. We found that intraobserver scores, when comparing the use of glass slides versus WSI, showed substantial agreement for both morphologic features (κ = 0.68) and acute rejection diagnostic categories (κ = 0.74). Furthermore, interobserver reliability was comparable for morphologic features (κ = 0.44 [glass] vs 0.42 [WSI]) and acute rejection diagnostic categories (κ = 0.49 [glass] vs 0.51 [WSI]). These data indicate that WSI are as reliable as glass slides for the evaluation of renal allograft biopsies.

  17. Key role for CD4 T cells during mixed antibody mediated rejection of renal allografts

    PubMed Central

    Gaughan, A.; Wang, J.; Pelletier, R.P.; Nadasdy, T.; Brodsky, S.; Roy, S.; Lodder, M.; Bobek, D.; Mofatt-Bruce, S.; Fairchild, R.L.; Henry, M.L.; Hadley, G.A.

    2014-01-01

    We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated anti-donor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating anti-donor alloantibody responses. PMID:24410909

  18. Right renal vein extension with cryopreserved external iliac artery allografts in living-donor kidney transplantations.

    PubMed

    Puche-Sanz, Ignacio; Pascual-Geler, Manrique; Vázquez-Alonso, Fernando; Hernández-Vidaña, Adoración María; Flores-Martín, José Francisco; Espejo-Maldonado, Eduardo; Cózar-Olmo, José Manuel

    2013-12-01

    A short right renal vein remains a challenge for renal transplant surgery, especially in the living donor. Our objective was to report on a new technique to solve this problem. We describe our experience with the use of cryopreserved iliac artery grafts for right renal vein extension. Two renal grafts from living donors with a short right renal vein were subjected to an extension with a cryopreserved external iliac artery allograft. There were no perioperative or postoperative complications. There were also no changes in ischemia times. The renal implantation was performed easily and conveniently using our standard technique. For the first and second procedures, at 3 and 3.5 years after surgery, respectively, both vascular grafts maintain good patency, and the renal function of both recipients is optimal. Tissue-banked cryopreserved cadaveric vessels can be a useful tool in renal transplant surgery. The use of a cryopreserved iliac artery for renal vein extension is a simple and effective new technique that can be added to the pool of surgical solutions for a short renal vein in living-donor kidney transplantation. To our knowledge, this is the first time that the use of such grafts for this purpose has been described. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Compartment-specific quantitative gene expression analysis after laser microdissection from archival renal allograft biopsies.

    PubMed

    Serinsöz, E; Bock, O; Kirsch, T; Haller, H; Lehmann, U; Kreipe, H; Mengel, M

    2005-03-01

    Various immunological and non-immunological pathomechanisms are responsible for the cellular damage in renal allografts. Since the kidney is an anatomically complex organ with functional and morphological heterogeneous compartments (interstitium, tubuli, vessels, glomeruli), the local response to injury maybe variable, therefore, the identification of local pathomechanisms is important. To elucidate any discrepancies in quantitative mRNA expression profiles between a total specimen analysis and a cell-specific evaluation after laser microdissection. Real-time RT-PCR was performed for complement component C3 and heme oxygenase-1 (HO-1) genes compared to the housekeeping gene beta-actin using whole section RNA extracted from formalin-fixed and paraffin-embedded archival material of 16 explanted, rejected renal allografts. Ten non-transplant nephrectomies served as controls. For five cases from each group, five different compartments of the organs (interstitium, proximal tubuli, distal tubuli, vessels, glomeruli) were microdissected and quantitative analysis for C3 and HO-1 was performed identically. Whole section mRNA expression analysis: the data showed a constant expression of the housekeeping gene beta-actin, a 7-fold increased expression of C3 and a 3-fold decreased expression of HO-1 in the allograft group as compared to the control group. mRNA expression results from microdissected compartments: in the control group, C3 and HO-1 expression could only be detected in the proximal tubuli of all cases whereas all five compartments analyzed from the rejecting kidneys showed expression of the two genes. In the allografts, expression levels of the investigated genes varied considerably not only among the different compartments but between individual cases as well. Laser microdissection combined with real-time RT-PCR is a feasible approach for retrospective quantitative gene expression analysis in formalin-fixed and paraffin-embedded renal allograft specimens. As shown

  20. Deaths from occlusive arterial disease in renal allograft recipients.

    PubMed

    Ibels, L S; Stewart, J H; Mahony, J F; Sheil, A G

    1974-08-31

    In a series of 325 recipients of cadaveric renal transplants sudden occlusive arterial disease was found to be responsible for 12% of deaths. Acute myocardial infarction (9%) occurred 25 times more than expected in the normal population and cerebral thrombosis (3%) 300 times more. The greatest loss was in the initial three-month period after transplantation. Patients with renal failure due to essential hypertension were especially at risk, accounting for six of the 12 deaths.

  1. Extensive emphysematous pyelonephritis in a renal allograft treated conservatively: case report and review of the literature.

    PubMed

    Alexander, S; Varughese, S; David, V G; Kodgire, S V; Mukha, R P; Kekre, N S; Tamilarasi, V; Jacob, C K; John, G T

    2012-12-01

    Emphysematous pyelonephritis (EPN) is a rare occurrence in renal allografts. An aggressive approach resulting in transplant nephrectomy is viewed as the standard of care. Over the recent years, treatment with percutaneous drainage (PCD) of the renal and perinephric collections and appropriate antibiotics has been reported with good success in lesser grades of this infection. Only 4 cases of extensive EPN disease with Escherichia coli, treated with conservative management, are reported in the English-language literature. We present a case of severe EPN caused by Klebsiella pneumoniae, successfully managed with early PCD, and propose a step-up strategy aimed toward graft preservation.

  2. Immunoglobulin therapy for plasma cell-rich rejection in the renal allograft.

    PubMed

    Adrogue, Horacio E; Soltero, Liliana; Land, Geoffrey A; Ramanathan, Venkataraman; Truong, Luan D; Suki, Wadi N

    2006-08-27

    Plasma cell-rich acute rejection (PCAR) is associated with poor allograft outcome in renal transplantation. Previous studies report a graft half-life of six months after a single PCAR episode. However, the management of this condition is unclear. Intravenous immunoglobulin (IVIG) therapy, by virtue of its immunomodulating properties, and its influence on B-cell maturation into plasma cells, may be a good candidate for reversing this type of rejection. We report four episodes of PCAR in two patients who responded well to IVIG with improvement in renal function.

  3. Infectious anastomotic pseudoaneurysm complicating renal allograft: case report and review of literature

    PubMed Central

    Chung, Marvin MT; Chan, Yiu Che; Law, Yuk; Cheng, Stephen WK

    2017-01-01

    Infectious anastomotic pseudoaneurysm complicating renal transplant is rare, but probably under-reported with <30 cases worldwide. We report a 45-year-old man with hypertension, diabetes mellitus and end stage renal failure, who had a renal transplant anastomosed to the right external iliac artery and vein. Postoperatively, he made a slow recovery with malaise and persistent vague right iliac fossa discomfort. Ultrasound scan 1 month postoperatively showed perinephric collection, and fluid culture grew Enterococcus faecium and Pseudomonas aeruginosa. He was started on vancomycin, daptomycin and colistin. MAG-3 scan also showed suboptimal function in the renal allograft. His symptoms persisted with fever, and blood culture yielded P. aeruginosa. Repeated ultrasound scan, and subsequent computed tomography scan a few weeks later, showed perinephric collection and a large, 3.8×3.5 cm pseudoaneurysm posteromedial to the graft kidney. He underwent emergency graft excision, together with resection of the pseudoaneurysm with in situ reversed great saphenous vein interposition graft, and made a good recovery on hemodialysis. The aneurysm wall grew P. aeruginosa, and he was put on imipenem and cilastatin (tienam), colistin, ciprofloxacin and daptomycin. To our knowledge, this is one of very few cases in the world’s literature in which a P. aeruginosa infectious anastomotic pseudoaneurysm developed after a renal allograft. PMID:28260939

  4. Simultaneous pancreas and kidney transplantation with concurrent allograft nephrectomy for recipients with prior renal transplants lost to BK virus nephropathy: two case reports.

    PubMed

    Kubal, S; Powelson, J A; Taber, T E; Goble, M L; Fridell, J A

    2010-01-01

    Candidacy for retransplantation after allograft loss due to BK virus-associated nephropathy (BKVN) with or without allograft nephrectomy is controversial. This report describes 2 renal transplant recipients who lost their grafts to BKVN and subsequently underwent simultaneous kidney and pancreas transplantation with allograft nephrectomy.

  5. Comparison of nutritional status in hemodialysis patients with and without failed renal allografts.

    PubMed

    Yelken, B M; Gorgulu, N; Caliskan, Y; Yazici, H; Turkmen, A; Yildiz, A; Sever, M S

    2010-01-01

    The survival of patients returning to hemodialysis (HD) following kidney transplant failure is unfavorable. However, the factors responsible for this poor outcome are largely unknown; chronic inflammation due to failed allograft and malnutrition may contribute to morbidity and mortality. We aimed to compare the nutritional status and its relation with inflammation in patients on HD with and without previous kidney transplantation. Forty-three patients with failed renal allografts (27 males; mean age 36±9 yr) and 40 never transplanted HD patients (24 males; mean age 39±9 yr) were included in the study. Body weight, triceps (TSF), biceps (BSF), subscapular (SSSF), and suprailiac skinfold thicknesses (SISF); mid-arm, mid-arm muscle, hip and waist circumferences; as well as body mass indices (BMIs) were determined as anthropometric parameters. Moreover, biochemical markers of nutritional status, including serum cholesterol and albumin as well as high-sensitive C-reactive protein (hs-CRP), as a marker of inflammation, were measured. Associations among these variables were analyzed. There were no significant differences considering age, gender or duration of renal replacement therapy between the two groups. The TSF (p<0.0001), BSF (p=0.005), SSSF (p=0.001), SISF (p<0.0001) skinfold thicknesses; mid-arm (p=0.003) and mid-arm muscle circumferences (p=0.037) and BMIs (p=0.001) of the patients with failed renal allografts were significantly lower than those of the never transplanted HD patients. Waist circumference was significantly lower as well (p=0.028). Patients with failed transplants were characterized by lower serum albumin (p<0.0001) and higher hs-CRP levels (p=0.001) as compared with never transplanted HD patients. This study confirms the concept that retained failed allografts may induce chronic inflammation in chronic HD patients which may result in a worse nutritional status. © 2009 John Wiley & Sons A/S.

  6. Viable cells survive in fresh frozen human bone allografts.

    PubMed

    Simpson, David; Kakarala, Gopikrishna; Hampson, Karen; Steele, Niall; Ashton, Brian

    2007-02-01

    Fresh frozen bone allograft is available for human recipients after at least 6 months of quarantine at -80 degrees C. It is assumed that cryopreservation without cryoprotectant removes all viable donor cells. We studied the in vitro cell growth from samples of fresh frozen human femoral head allografts after they had been released for patient use, and compared it with cell growth from a control group of fresh cancellous bone specimens from excised femoral heads (8 samples in each group). Cell outgrowths were seen in all of the fresh cancellous bone specimens (100% of replicates, 48 replicates per specimen) but only in a small minority of replicates from 4 of the allograft samples (mean 3.1%). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) investigations revealed that cell outgrowths from both groups contained mRNA for transcription factors Runx2 and Osterix, and also for matrix proteins collagen type I, osteocalcin and bone sialoprotein. This is consistent with the cells being osteoblast-related. This study confirms that fresh frozen human bone allograft cells have the potential to grow in vitro, but the significance of this in recipients is currently unknown.

  7. Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates.

    PubMed

    Lo, D J; Farris, A B; Song, M; Leopardi, F; Anderson, D J; Strobert, E A; Ramakrishnan, S; Turgeon, N A; Mehta, A K; Turnbull, B; Maroni, B; Violette, S M; Kirk, A D

    2013-12-01

    The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation.

  8. Use of CTLA4Ig for Induction of Mixed Chimerism and Renal Allograft Tolerance in Nonhuman Primates

    PubMed Central

    Yamada, Yohei; Ochiai, Takanori; Boskovic, Svjetlan; Nadazdin, Ognjenka; Oura, Tetsu; Schoenfeld, David; Cappetta, Kate; Smith, Rex-Neal; Colvin, Robert B; Madsen, Joren C.; Sachs, David H.; Benichou, Gilles; Cosimi, A. Benedict; Kawai, Tatsuo

    2014-01-01

    We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates (NHP). In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4-Igs, Abatacept and Belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, ATG and a one month post-transplant course of cyclosporine (CyA)). Three recipients treated with the Abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the Belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the Belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with Belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance. PMID:25394378

  9. Utility of Iron Staining in Identifying the Cause of Renal Allograft Dysfunction in Patients with Sickle Cell Disease

    PubMed Central

    Wang, Yingchun; Khan, Salman; Li, Wei; Zhang, Ping L.

    2015-01-01

    Sickle cell nephropathy (SCN) is associated with iron/heme deposition in proximal renal tubules and related acute tubular injury (ATI). Here we report the utility of iron staining in differentiating causes of renal allograft dysfunction in patients with a history of sickle cell disease. Case 1: the patient developed acute allograft dysfunction two years after renal transplant. Her renal biopsy showed ATI, supported by patchy loss of brush border and positive staining of kidney injury molecule-1 in proximal tubular epithelial cells, where diffuse increase in iron staining (2+) was present. This indicated that ATI likely resulted from iron/heme toxicity to proximal tubules. Electron microscope confirmed aggregated sickle RBCs in glomeruli, indicating a recurrent SCN. Case 2: four years after renal transplant, the patient developed acute allograft dysfunction and became positive for serum donor-specific antibody. His renal biopsy revealed thrombotic microangiopathy (TMA) and diffuse positive C4d stain in peritubular capillaries. Iron staining was negative in the renal tubules, implying that TMA was likely associated with acute antibody-mediated rejection (AAMR, type 2) rather than recurrent SCN. These case reports imply that iron staining is an inexpensive but effective method in distinguishing SCN-associated renal injury in allograft kidney from other etiologies. PMID:26697257

  10. Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

    PubMed Central

    Moss, Jill; Moran, Linda; Brookes, Paul; Santos-Nunez, Eva; McLean, Adam G.; Cairns, Thomas; Taube, David; Cook, Terence H.; Roufosse, Candice

    2016-01-01

    The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy–free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor–specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation. PMID:26614383

  11. FTY720 in combination with cyclosporine--an analysis of skin allograft survival and renal function.

    PubMed

    Silva, Francieli Ruiz; Silva, Lea Bueno Lucas; Cury, Patricia Maluf; Burdmann, Emmanuel Almeida; Bueno, Valquiria

    2006-12-20

    Acute and chronic nephrotoxicity caused by CsA continuous administration impair kidney allograft survival. Several clinical and experimental protocols have shown benefits to the kidney after decreasing CsA dose, withdrawing the drug or delaying its introduction after transplantation. FTY720 is a new compound that has immunosuppressive characteristics and increase allograft survival in animal models without causing the side effects of calcineurin inhibitors (CNIs). FTY720 described mechanism of action that consists to alter the lymphocyte migration pattern without impairment of the immune system response against pathogens. In our mice model, FTY720 administered alone or in combination with CsA during 21 days increased skin allograft survival in a fully mismatched strain combination and did not cause significant changes in renal function. Moreover, renal structure was normal in all groups suggesting that at low doses (10 mg/kg/day) CsA can be associated during short-term period to other immunosuppressive drugs, i.e. FTY720 without affecting the kidney. Combination of immunosuppressive compounds with FTY720 and/or delayed introduction of low cyclosporine dose could prevent graft rejection and avoid nephrotoxicity.

  12. Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study

    PubMed Central

    Lerut, Evelyne; Emonds, Marie-Paule; Herelixka, Albert; Evenepoel, Pieter; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Meijers, Björn; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Kuypers, Dirk R.J.

    2016-01-01

    Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3–1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0–3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis. PMID:26152270

  13. Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study.

    PubMed

    Naesens, Maarten; Lerut, Evelyne; Emonds, Marie-Paule; Herelixka, Albert; Evenepoel, Pieter; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Meijers, Björn; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Kuypers, Dirk R J

    2016-01-01

    Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3-1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0-3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis. Copyright © 2016 by the American Society of Nephrology.

  14. Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction.

    PubMed

    Hu, Huaizhong; Aizenstein, Brian D; Puchalski, Alice; Burmania, Jeanine A; Hamawy, Majed M; Knechtle, Stuart J

    2004-03-01

    A noninvasive urinary test that diagnoses acute renal allograft dysfunction would benefit renal transplant patients. We aimed to develop a rapid urinary diagnostic test by detecting chemokines. Seventy-three patients with renal allograft dysfunction prompting biopsy and 26 patients with stable graft function were recruited. Urinary levels of CXCR3-binding chemokines, monokine induced by IFN-gamma (Mig/CXCL9), IFN-gamma-induced protein of 10 kDa (IP-10/CXCL10), and IFN-inducible T-cell chemoattractant (I-TAC/CXCL11), were determined by a particle-based triplex assay. IP-10, Mig and I-TAC were significantly elevated in renal graft recipients with acute rejection, acute tubular injury and BK virus nephritis. Using 100 pg/mL as the threshold level, both IP-10 and Mig had diagnostic value (sensitivity 86.4%; specificity 91.3%) in differentiating acute graft dysfunction from other clinical conditions. In terms of monitoring the response to antirejection therapy, this urinary test is more sensitive and predictive than serum creatinine. These results indicate that this rapid test is clinically useful.

  15. Is immunosuppression therapy in renal allograft recipients teratogenic? A single-center experience.

    PubMed

    Bar, Jacob; Stahl, Bracha; Hod, Moshe; Wittenberg, Clara; Pardo, Joseph; Merlob, Paul

    2003-01-01

    The aim of the study was to determine whether immunosuppressive agents used in renal allograft recipients are teratogenic or otherwise associated with pregnancy outcome. The study population consisted of 38 renal allograft recipients treated with combinations of prednisone, azathioprine, cyclosporin A, and tacrolimus attending our Hypertension in Pregnancy Clinic. The 48 live offspring of 73 pregnancies in this group were evaluated for major congenital malformations and mild errors of morphogenesis. Findings were compared with those in 48 offspring of 41 women with primary renal disease not treated with immunosuppressive drugs. Pregnancy outcome parameters were also compared between the study and control groups in the perinatal period and on a long-term basis (2-7 years after birth). Two major anomalies (4.2%), subcoronal hypospadias and rudimentary thumb, and 10 mild errors of morphogenesis (20.8%) were detected in the study group. These rates did not differ significantly from those in the control group (4.2% and 16.6%, respectively). Pregnancy outcome was worse in the renal transplant patients than in the women with primary renal disease in terms of prematurity (60% vs. 21%, P = 0.001), growth restriction (52% vs. 17%, P = 0.001), and hospitalization in a neonatal intensive care unit (35% vs. 6%, P = 0.01). In conclusion, the similar prevalence of major anomalies and mild errors of morphogenesis in offspring of the renal transplant patients and the women with primary renal disease suggests that immunosuppressive therapy is not a teratogenic factor. It may, however, be associated with worse pregnancy outcome. Copyright 2002 Wiley-Liss, Inc.

  16. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model.

    PubMed

    Wu, Douglas C; Hester, Joanna; Nadig, Satish N; Zhang, Wei; Trzonkowski, Piotr; Gray, Derek; Hughes, Stephen; Johnson, Paul; Wood, Kathryn J

    2013-10-27

    Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved. We engrafted human pancreatic islets of Langerhans into the renal subcapsular space of immunodeficient BALB/c.rag2(-/-).cγ(-/-) mice, previously rendered diabetic via injection of the β-cell toxin streptozocin. After the establishment of stable euglycemia, mice were reconstituted with allogeneic human peripheral blood mononuclear cells (PBMC) and the resultant alloreactive response studied. Ex vivo expanded CD25high CD4+ human Treg, which expressed FoxP3, CTLA-4, and CD62L and remained CD127low, were then cotransferred together with human PBMC and islet allografts and monitored for evidence of rejection. Human islets transplanted into diabetic immunodeficient mice reversed diabetes but were rejected rapidly after the mice were reconstituted with allogeneic human PBMC. Cotransfer of purified, ex vivo expanded human Treg prolonged islet allograft survival resulting in the accumulation of Treg in the peripheral lymphoid tissue and suppression of proliferation and interferon-γ production by T cells. In vitro, Treg suppressed activation of signal transducers and activators of transcription and inhibited the effector differentiation of responder T cells. Ex vivo expanded Treg retain regulatory activity in vivo, can protect a human islet allograft from rejection by suppressing signal transducers and activators of transcription activation and inhibiting T-cell differentiation, and have clinical potential as an adjunctive cellular therapy.

  17. Adenine phosphoribosyltransferase deficiency as a rare cause of renal allograft dysfunction.

    PubMed

    Kaartinen, Kati; Hemmilä, Ulla; Salmela, Kaija; Räisänen-Sokolowski, Anne; Kouri, Timo; Mäkelä, Satu

    2014-04-01

    Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive disorder manifesting as urolithiasis or crystalline nephropathy. It leads to the generation of large amounts of poorly soluble 2,8-dihydroxyadenine excreted in urine, yielding kidney injury and in some patients, kidney failure. Early recognition of the disease, institution of xanthine analog therapy to block the formation of 2,8-dihydroxyadenine, high fluid intake, and low purine diet prevent CKD. Because of symptom variability and lack of awareness, however, the diagnosis is sometimes extremely deferred. We describe a patient with adenine phosphoribosyltransferase deficiency who was diagnosed during evaluation of a poorly functioning second kidney allograft. This report highlights the risk of renal allograft loss in patients with undiagnosed adenine phosphoribosyltransferase deficiency and the need for improved early detection of this disease.

  18. Oral manifestations of allograft recipients before and after renal transplantation.

    PubMed

    Rezvani, Gita; Davarmanesh, Mehdy; Azar, Mohammad Reza; Salehipour, Mehdy; Sedaghat, Razieh; Karimi, Fatemeh; Pazhoohi, Neda; Ansari, Elham; Nazhvani, Ali Dehghani

    2014-03-01

    Renal transplantation is considered the best treatment option for patients with end-stage renal disease. In this study, the prevalence of oral lesions was studied in a cohort of renal transplant recipients before and after transplantation. Fifty-nine kidney transplant recipients were examined one week before and four months after transplantation. The information gathered included age, sex, smoking history, duration on dialysis, drugs and their doses. There were 41 males (69.5%) and 18 females (30.5%) with a mean age of 37 years. Before surgery, two patients had non-specific lesions and two other patients had leukoedema. Following transplantation, 24 patients (40.7%) did not have any specific lesion. In six patients, we observed non-specific erythematous lesions (10.2%). Other recorded observations are as follows: Gingival hyperplasia in five patients (8.5%), oral candidiasis of the erythematous type in five patients (8.5%), hairy leukoplakia in four patients (6.8%) and leukoedema in seven patients (11.9%). In our study patients, the prevalence of oral lesions increased after transplantation, although it was lower than that reported in other studies. This could be due to the differences in sample size, differences between Iranian race and other races and different pharmaceutical formulation of the drug produced in Iran.

  19. Peroxisome Proliferator-Activated Receptor (PPAR)γ Can Inhibit Chronic Renal Allograft Damage

    PubMed Central

    Kiss, Eva; Popovic, Zoran V.; Bedke, Jens; Adams, Judith; Bonrouhi, Mahnaz; Babelova, Andrea; Schmidt, Claudia; Edenhofer, Frank; Zschiedrich, Inka; Domhan, Sophie; Abdollahi, Amir; Schäfer, Liliana; Gretz, Norbert; Porubsky, Stefan; Gröne, Hermann-Josef

    2010-01-01

    Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ is a transcription factor known to have antidiabetogenic and immune effects, and PPARγ forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPARγ-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 ± 5.8 (controls) vs. 8.1 ± 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 ± 1.8 (controls) vs. 2.6 ± 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-β1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPARγ activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPARγ-dependent manner. The combination of PPARγ- and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPARγ activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/RXR-agonist. PMID:20363918

  20. Peroxisome proliferator-activated receptor (PPAR)gamma can inhibit chronic renal allograft damage.

    PubMed

    Kiss, Eva; Popovic, Zoran V; Bedke, Jens; Adams, Judith; Bonrouhi, Mahnaz; Babelova, Andrea; Schmidt, Claudia; Edenhofer, Frank; Zschiedrich, Inka; Domhan, Sophie; Abdollahi, Amir; Schäfer, Liliana; Gretz, Norbert; Porubsky, Stefan; Gröne, Hermann-Josef

    2010-05-01

    Chronic inflammation and fibrosis are the leading causes of chronic allograft failure. The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor known to have antidiabetogenic and immune effects, and PPARgamma forms obligate heterodimers with the retinoid X receptor (RXR). We have reported that a retinoic acid (RAR)/RXR-agonist can potently influence the course of renal chronic allograft dysfunction. In this study, in a Fischer to Lewis rat renal transplantation model, administration of the PPARgamma-agonist, rosiglitazone, independent of dose (3 or 30 mg/kgBW/day), lowered serum creatinine, albuminuria, and chronic allograft damage with a chronic vascular damage score as follows: 35.0 +/- 5.8 (controls) vs. 8.1 +/- 2.4 (low dose-Rosi; P < 0.05); chronic tubulointerstitial damage score: 13.6 +/- 1.8 (controls) vs. 2.6 +/- 0.4 (low dose-Rosi; P < 0.01). The deposition of extracellular matrix proteins (collagen, fibronectin, decorin) was strikingly lower. The expression of transforming growth factor-beta1 was inhibited, whereas that of bone morphogenic protein-7 (BMP-7) was increased. Intragraft mononuclear cells and activated fibroblast numbers were reduced by 50%. In addition, the migratory and proliferative activity of these cells was significantly inhibited in vitro. PPARgamma activation diminished the number of cells expressing the proinflammatory and fibrogenic proteoglycan biglycan. In macrophages its secretion was blocked by rosiglitazone in a predominantly PPARgamma-dependent manner. The combination of PPARgamma- and RAR/RXR-agonists resulted in additive effects in the inhibition of fibrosis. In summary, PPARgamma activation was potently immunosuppressive and antifibrotic in kidney allografts, and these effects were enhanced by a RAR/RXR-agonist.

  1. Transmission of infection with human allografts: essential considerations in donor screening.

    PubMed

    Fishman, Jay A; Greenwald, Melissa A; Grossi, Paolo A

    2012-09-01

    Transmission of infection via transplantation of allografts including solid organs, eyes, and tissues are uncommon but potentially life-threatening events. Donor-derived infections have been documented following organ, tissue, and ocular transplants. Each year, more than 70 000 organs, 100 000 corneas, and 2 million human tissue allografts are implanted worldwide. Single donors may provide allografts for >100 organ and tissue recipients; each allograft carries some, largely unquantifiable, risk of disease transmission. Protocols for screening of organ or tissue donors for infectious risk are nonuniform, varying with the type of allograft, national standards, and availability of screening assays. In the absence of routine, active surveillance, coupled with the common failure to recognize or report transmission events, few data are available on the incidence of allograft-associated disease transmission. Research is needed to define the optimal screening assays and the transmissibility of infection with allografts. Approaches are reviewed that may contribute to safety in allograft transplantation.

  2. Quantifying renal allograft loss following early antibody-mediated rejection.

    PubMed

    Orandi, B J; Chow, E H K; Hsu, A; Gupta, N; Van Arendonk, K J; Garonzik-Wang, J M; Montgomery, J R; Wickliffe, C; Lonze, B E; Bagnasco, S M; Alachkar, N; Kraus, E S; Jackson, A M; Montgomery, R A; Segev, D L

    2015-02-01

    Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19-3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73-4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37-8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57-14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10-5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55-67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81-10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.

  3. Fatal Apophysomyces elegans infection transmitted by deceased donor renal allografts.

    PubMed

    Alexander, B D; Schell, W A; Siston, A M; Rao, C Y; Bower, W A; Balajee, S A; Howell, D N; Moore, Z S; Noble-Wang, J; Rhyne, J A; Fleischauer, A T; Maillard, J M; Kuehnert, M; Vikraman, D; Collins, B H; Marroquin, C E; Park, B J

    2010-09-01

    Two patients developed renal mucormycosis following transplantation of kidneys from the same donor, a near-drowning victim in a motor vehicle crash. Genotypically, indistinguishable strains of Apophysomyces elegans were recovered from both recipients. We investigated the source of the infection including review of medical records, environmental sampling at possible locations of contamination and query for additional cases at other centers. Histopathology of the explanted kidneys revealed extensive vascular invasion by aseptate, fungal hyphae with relative sparing of the renal capsules suggesting a vascular route of contamination. Disseminated infection in the donor could not be definitively established. A. elegans was not recovered from the same lots of reagents used for organ recovery or environmental samples and no other organ transplant-related cases were identified. This investigation suggests either isolated contamination of the organs during recovery or undiagnosed disseminated donor infection following a near-drowning event. Although no changes to current organ recovery or transplant procedures are recommended, public health officials and transplant physicians should consider the possibility of mucormycosis transmitted via organs in the future, particularly for near-drowning events. Attention to aseptic technique during organ recovery and processing is re-emphasized. © 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

  4. A Case Report of Parvovirus B19 Infection in a Renal Allograft.

    PubMed

    Oramas, Diana M; Setty, Suman; Yeldandi, Vijay; Cabrera, Julio; Patel, Tushar

    2017-10-01

    Parvovirus B19 infection is undiagnosed in recipients undergoing solid organ transplantation. It is usually responsible for unexplained acute and chronic red blood cell aplasia that does not respond to erythropoietin therapy. Cases of parvovirus B19 infection associated with pancytopenia, solid organ dysfunction, and allograft rejection have been described in the literature. The deterioration of the immune system as a result of severe immunotherapy favors the reactivation of a previous infection or the acquisition of a new one. We present a case of a 32-year-old woman with a 1-year history of renal allograft transplant and previous cytomegalovirus (CMV) infection who presented with chest pain, polyarthritis, pancytopenia, and renal dysfunction. A serum sample using polymerase chain reaction showed a parvovirus titer of 13.8 trillion IU/mL and a CMV titer of 800 IU/mL. The renal biopsy revealed nucleomegaly with focal viral inclusions, along with changes associated with immunotherapy toxicity. Electron microscopy demonstrated capillary and tubular epithelial cells with "viral factories," thereby confirming the diagnosis. Thus, screening for parvovirus B19 is advised in high-risk patients who present with refractory anemia to avoid the complications of a chronic infection associated with the fatal rejection of the transplanted organ.

  5. Treatment of steroid-resistant acute renal allograft rejection with alemtuzumab.

    PubMed

    van den Hoogen, M W F; Hesselink, D A; van Son, W J; Weimar, W; Hilbrands, L B

    2013-01-01

    Steroid-resistant renal allograft rejections are commonly treated with rabbit antithymocyte globulin (RATG), but alemtuzumab could be an effective, safe and more convenient alternative. Adult patients with steroid-resistant renal allograft rejection treated with alemtuzumab (15-30 mg s.c. on 2 subsequent days) from 2008 to 2012 (n = 11) were compared to patients treated with RATG (2.5-4.0 mg/kg bodyweight i.v. for 10-14 days; n = 20). We assessed treatment-failure (graft loss, lack of improvement of graft function or need for additional anti-rejection treatment), infections during the first 3 months after treatment and infusion-related side effects. In both groups, the median time-interval between rejection and transplantation was 2 weeks, and approximately 75% of rejections were classified as Banff-IIA or higher. Three alemtuzumab-treated patients (27%) experienced treatment failure, compared to eight RATG treated patients (40%, p = 0.70). There was no difference in the incidence of infections. There were mild infusion-related side-effects in three alemtuzumab-treated patients (27%), and more severe infusion-related side effects in 17 RATG-treated patients (85%, p = 0.013). Drug related costs of alemtuzumab-treatment were lower than of RATG-treatment (€1050 vs. €2024; p < 0.01). Alemtuzumab might be an effective therapy for steroid-resistant renal allograft rejections. In contrast to RATG, alemtuzumab is nearly devoid of infusion-related side-effects. These data warrant a prospective trial. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  6. Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy.

    PubMed

    Elster, Eric A; Hale, Douglas A; Mannon, Roslyn B; Cendales, Linda C; Kleiner, David; Swanson, S John; Kirk, Allan D

    2005-04-01

    Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

  7. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature.

    PubMed

    Pham, Phuong-Thu T; Pham, Phuong-Chi T; Danovitch, Gabriel M; Gritsch, H Albin; Singer, Jennifer; Wallace, William D; Hayashi, Rick; Wilkinson, Alan H

    2005-10-01

    Scleroderma renal crisis (SRC) can lead to end-stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1-2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987-July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5-year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new-onset anemia and cardiac complications.

  8. The effect of cyclosporin A on peripheral blood T cell subpopulations in renal allografts.

    PubMed Central

    Sweny, P; Tidman, N

    1982-01-01

    Treatment with cyclosporin A (CyA) produces a reversal of the normal ratio of OKT4+ (inducer type) to OKT84 (suppressor-cytotoxic type) cells so that renal allograft recipients on CyA alone develop a four-fold increase in the absolute number of circulating OKT8 positive cells. Conventional immunosuppression with azathioprine and prednisolone reduces both populations of T cells without altering the ratio of OKT4+ to OKT8+ cells. This effect of CyA may help to explain its action as an immunosuppressive agent. PMID:6210475

  9. Nonfunctioning Renal Allograft Embolization as an Alternative to Graft Nephrectomy: Report on Seven Years' Experience

    SciTech Connect

    Atar, Eli; Belenky, Alexander; Neuman-Levin, Margalit; Yussim, A.; Bar-Nathan, Nathan; Bachar, Gil N.

    2003-02-15

    Purpose: Graft nephrectomy is the treatment of choice in patients with graft intolerance syndrome, but it is associated with high morbidity and mortality rates. Renal vascular embolization has been suggested as a possible alternative. The aim of this study was to evaluate the efficacy and safety of arterial embolization of these nonfunctioning transplanted kidneys. Methods: Twenty-six transplanted kidneys in 25 patients with irreversible renal graft rejection and graft intolerance who underwent arterial embolization at our center from August 1994 to April 2001 we reanalyzed for procedural success and long-term outcome. Embolization was performed with absolute alcohol or with polyvinyl alcohol (Ivalon) and coils. Results: Twenty-four of the 26 (92%) procedures were technically successful, but in one patient only partial occlusion of one of two renal arteries was achieved, and in another the renal artery was already completely occluded. There were two major complications: emphysematous pyelonephritis necessitating nephrectomy and groin abscess that was drained. Follow-up ranged from 8 to 84 months. Clinical success was achieved in 24 of the 26 procedures(92%), and only in one patient did embolization fail to relieve the symptoms, and nephrectomy was performed 3 months later. Conclusion: Renal vascular embolization is a simple, safe and effective technique for the treatment of nonfunctioning renal allografts associated with graft intolerance syndrome. We suggest that it be considered the treatment of choice.

  10. Focal segmental glomerulosclerosis in renal allografts: Is it possible to diagnose the etiology?

    PubMed Central

    Radha, S.; Afroz, T.; Prasad, Ch. R.; Sridhar, G.; Rajaram, K. G.; Reddy, S.

    2015-01-01

    Recurrence of FSGS in renal allo grafts is a major cause of graft loss. In this context, we tried to diagnose and classify FSGS in renal allografts. Indications for biopsy included graft dysfunction and/or proteinuria. Three hundred and sixty-three graft biopsies were studied over a period of 2 years. We classified FSGS into recurrent FSGS, new-onset primary FSGS and FSGS secondary to chronic humoral rejection, calcineurin inhibitor toxicity, and nephron loss and hyperfiltration injury. Twenty-four cases were diagnosed as FSGS, constituting 6.6%. Secondary FSGS was the most common FSGS in grafts in our study. Incidence of recurrent FSGS may not be accurate as pretransplant biopsy is available in very few cases. PMID:25838644

  11. Inferior allograft outcomes in adolescent recipients of renal transplants from ideal deceased donors.

    PubMed

    Levine, Matthew H; Reese, Peter P; Wood, Alexander; Baluarte, Jorge H; Huverserian, Ari; Naji, Ali; Abt, Peter L

    2012-03-01

    To measure the impact of the Share-35 policy on the allocation of ideal deceased donor kidneys and to examine the impact of age on outcomes after kidney transplantation using ideal donor kidneys. In the United States, through Share-35, transplant candidates aged 18 years or younger receive priority for the highest-quality deceased donor kidneys. Adolescent (15-18 years) kidney transplant recipients (KTRs), however, may be more susceptible to allograft loss due to elevated rates of acute rejection and a possible increased risk of primary renal disease recurrence. We used registry data to perform a retrospective cohort study of 39,136 KTRs from January 1, 1994, to December 31, 2008. Ideal donors were defined as 2 to 34 years old with creatinine <1.5 mg/dL and absence of hypertension, diabetes, and hepatitis C. After Share-35, the percentage of ideal donor kidneys allocated to pediatric recipients increased from 7% to 16%. In multivariable Cox regression, compared with adolescent KTRs, all age strata except recipients older than 70 years had a lower risk of allograft failure (P < 0.01 for each comparison); results were similar after excluding KTRs with diseases at high risk of recurrence. Adolescent recipients had higher mortality rates than KTRs younger than 14 years, similar mortality compared with that of KTRs older than 18 and younger than 40 years, and lower mortality than KTRs older than 40 years. The allocation of "ideal donors" to adolescent recipients may not maximize graft utility. Reevaluation of pediatric allocation priority may offer opportunities to optimize ideal renal allograft survival.

  12. Inferior allograft outcomes in adolescent recipients of renal transplants from ideal deceased donors

    PubMed Central

    Levine, Matthew H; Reese, Peter P; Wood, Alexander; Baluarte, H Jorge; Huverserian, Ari; Naji, Ali; Abt, Peter L

    2013-01-01

    Objective To measure the impact of the Share-35 policy on the allocation of ideal deceased donor kidneys, and to examine the impact of age on outcomes after kidney transplantation using ideal donor kidneys. Summary Background Data In the United States, through Share-35, transplant candidates <18 years of age receive priority for the highest-quality deceased donor kidneys. Adolescent (15 – 18 years) kidney transplant recipients (KTRs), however, may be more susceptible to allograft loss due to elevated rates of acute rejection and a possible increased risk of primary renal disease recurrence. Methods We used registry data to perform a retrospective cohort study of 39,136 KTRs from 1/1/1994 – 12/31/2008. Ideal donors were defined as 2 – 34 years old with creatinine <1.5mg/dL and absence of hypertension, diabetes and hepatitis C. Results After Share-35, the percentage of ideal donor kidneys allocated to pediatric recipients increased from 7 – 16%. In multivariable Cox regression, compared to adolescent KTRs, all age strata except recipients >70 years had a lower risk of allograft failure (p<0.01 for each comparison); results were similar after excluding KTRs with diseases at high risk of recurrence. Adolescent recipients had higher mortality rates than KTRs under 14 years, similar mortality compared to KTRs >18 and <40 years, and lower mortality than KTRs over 40 years. Conclusions The allocation of “ideal donors” to adolescent recipients may not maximize graft utility. Re-evaluation of pediatric allocation priority may offer opportunities to optimize ideal renal allograft survival. PMID:22330037

  13. Clinicopathological study of expression of lymphatic vessels in renal allograft biopsy after treatment for acute rejection.

    PubMed

    Oka, K; Namba, Y; Ichimaru, N; Moriyama, T; Kyo, M; Kokado, Y; Imai, E; Takahara, S

    2009-12-01

    Lymph vessel expression is related to inflammatory cell infiltration, around renal tubules in acute rejection episodes (ARE) of transplanted kidneys. However, there is little information on the lymph vessels after treatment of an ARE, particularly in relation to renal function and histological findings. We investigated 13 cases of ARE diagnosed by kidney transplant biopsy performed from 1997 to 2005 within 3 years of transplantation. Treatment of the ARE lead to an improved serum creatinine level in all cases. There was neither an ABO-incompatible nor an acute humoral rejection case. Lymphatic vessels in re-biopsies were examined using immunohistochemical staining with D2-40 antibody that detected lymphatic endothelium. Re-biopsy cases in which the baseline creatinine had increased by more than 20% despite treatment were considered the severe group; the others, as the stable group. The relation between lymphatic vessel density (LVD) and renal function was examined using Banff scores. LVD was significantly higher in the severe than the stable group. The expression of lymph vessels versus the Banff score showed a direct relation: greater Banff scores showed higher expressions of lymph vessels. The expression of lymph vessels in renal allograft specimens after treatment of an ARE was related to deterioration of renal function and inflammatory cell invasion. We plan a further examination of the relationship between the expression of lymph vessels and long-term prognosis.

  14. Outcome predictors in African-American deceased-donor renal allograft recipients.

    PubMed

    Brown, Kristian L; El-Amm, Jose M; Doshi, Mona D; Singh, Atul; Cincotta, Elizabeth; Morawski, Katherina; Losanoff, Julian E; West, Miguel S; Gruber, Scott A

    2009-01-01

    The relative importance of donor and recipient risk factors in predicting outcomes in African-American (AA) renal allograft recipients receiving contemporary immunosuppression, including early steroid withdrawal, has not been previously examined. We assessed the impact of 21 risk factors on five primary outcomes in 132 deceased-donor AA renal allograft recipients transplanted from July 2001 to August 2006 with follow-up 6-67 (mean 35 +/- 17) months by univariate and multivariate analysis. Thymoglobulin or basiliximab was given for induction, and mycophenolate mofetil with either tacrolimus or sirolimus (SRL) +/- prednisone for maintenance. Non-compliance accounted for 26% of graft loss (GL) and 19% of acute rejection (AR) episodes, and was more prevalent in patients who were HCV+ and those on prednisone. Delayed graft function remained a significant predictor of GL, but not via increased AR, and donor ethnicity emerged as an important predictor of patient death. De novo use of SRL resulted in increased AR, and only increased recipient age significantly predicted new-onset diabetes mellitus. Our preliminary results suggest the need for improvements in patient education, pre-transplant psychosocial assessment, and late post-transplant psychosocial support and can be utilized to help guide donor/recipient selection and tailor immunosuppressive management to optimize outcomes in this challenging group of patients.

  15. Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

    PubMed Central

    Li, Li; Greene, Ilana; Readhead, Benjamin; Menon, Madhav C.; Kidd, Brian A.; Uzilov, Andrew V.; Wei, Chengguo; Philippe, Nimrod; Schroppel, Bernd; He, John Cijiang; Chen, Rong; Dudley, Joel T.; Murphy, Barbara

    2017-01-01

    Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA. We experimentally validated the anti-fibrosis effects of kaempferol and esculetin using renal tubular cells in vitro and in vivo in a mouse Unilateral Ureteric Obstruction (UUO) model. Kaempferol significantly attenuated TGF-β1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/β-catenin pathway in vitro and in vivo. Histology confirmed significantly abrogated fibrosis by kaempferol and esculetin in vivo. We developed an integrative computational framework to identify kaempferol and esculetin as putatively novel therapies for IF/TA and provided experimental evidence for their therapeutic activities in vitro and in vivo using preclinical models. The findings suggest that both drugs might serve as therapeutic options for IF/TA. PMID:28051114

  16. Intragraft Toll-like receptor profiling in acute renal allograft rejection.

    PubMed

    Dessing, Mark C; Bemelman, Frederike J; Claessen, Nike; Ten Berge, Ineke J M; Florquin, Sandrine; Leemans, Jaklien C

    2010-12-01

    Experimental studies have shown potential for Toll-like receptor (TLR) profiling in renal allograft in predicting renal outcome after transplantation. Our goal was to determine if profiling of TLR1-10 and TLR-related genes could be used as a prognostic value for renal function and late clinical outcome after transplantation. TLR1-10, CD14, MD-2 and negative regulators Toll-interacting protein (TOLLIP) and single immunoglobulin domain IL-1R-related receptor were analysed in 36 biopsies from renal transplant recipients with acute rejection (AR) and in 14 biopsies from renal transplant recipients without rejection (NR). Analysis was performed by multiplex ligation-dependent probe amplification. TLR (-related) genes were correlated to Banff'07 classification, cellular influx, response to conventional anti-rejection therapy, renal function 12 and 24 months after rejection and graft loss. mRNA levels of most TLRs were significantly higher in acute rejection while TOLLIP mRNA level was decreased. mRNA levels of TLR1/2/4/7/8 were highly accurate in distinguishing AR from NR. TLR mRNA levels correlated to inflammatory parameters according to the Banff'07 classification and to cellular influx. Elevated mRNA level of TLR3 in acute rejection was independent from infiltrating leukocytes. TLR (-related) genes were not correlated with response to conventional anti-rejection therapy. Splice variant TLR4r3 was associated with poor renal function 24 months after transplantation, and TLR1 appeared to be associated with graft loss. The elevated mRNA levels of several TLRs in association with reduced mRNA levels of TOLLIP in renal transplant biopsies of patients with acute rejection indicate a pro-inflammatory state, which may contribute to uncontrolled inflammation.

  17. The use of mycophenolate mofetil suspension in pediatric renal allograft recipients.

    PubMed

    Bunchman, T; Navarro, M; Broyer, M; Sherbotie, J; Chavers, B; Tönshoff, B; Birk, P; Lerner, G; Lirenman, D; Greenbaum, L; Walker, R; Zimmerhackl, L B; Blowey, D; Clark, G; Ettenger, R; Arterburn, S; Klamerus, K; Fong, A; Tang, H; Thomas, S; Ramos, E

    2001-12-01

    Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

  18. Do the outcomes of living donor renal allograft recipients differ with peritoneal dialysis and hemodialysis as a bridge renal replacement therapy?

    PubMed

    Prasad, Narayan; Vardhan, Harsh; Baburaj, Vinod P; Bhadauria, Dharmendra; Gupta, Amit; Sharma, Raj K; Kaul, Anupama

    2014-11-01

    This study was undertaken to compare the outcomes of living donor renal transplant recipients using peritoneal dialysis (PD) and hemodialysis (HD) as a bridge modality for renal replacement therapy till renal transplantation. The demographic profiles of the recipients and donors, the patients' native kidney disease (diabetic versus non-diabetic), duration on dialysis, requirement of anti-hypertensive drugs, number of blood transfusions, human leukocyte antigen (HLA) mismatch status, pre- and post-transplant infectious complications, and post-transplant outcomes of patients were compared between the two groups. The demographic features of the study patients were similar in the two groups. The duration of dialysis prior to transplant was significantly longer in the PD group than in the HD group of patients. The anti-hypertensive drug requirement was lower and the hemoglobin level and residual urine volume at the time of transplant were relatively better in the PD patients compared to the HD patients. The number of acute rejection episodes, delayed graft function, surgical complications, glomerular filtration rate at one month and at the last follow-up, were also similar in both groups. The short-term and long-term graft survival was similar in both groups of patients. The one-, two-, five-, and eight-year death-censored graft survival rates of the PD patients were 98, 95, 85, and 73%, respectively, and in the HD group of patients, they were 100, 93, 84, and 79%, respectively. The one-, two-, five-, and eight-year patient survival rates in the PD group were 97, 92, 77, and 66%, respectively, and in the HD group, they were 97, 92, 79, and 69%, respectively. Our study suggests that the outcomes of the living donor renal allograft recipients did not differ between the groups of patients who used PD or HD as renal replacement therapy prior to renal transplantation.

  19. Histologic evaluation of socket augmentation with mineralized human allograft.

    PubMed

    Wang, Hom-Lay; Tsao, Yi-Pin

    2008-06-01

    Socket augmentation performed at the time of tooth extraction has been recommended by many authors, since successful socket augmentation may reduce or eliminate the need for future ridge grafts. An augmentation procedure is described here, along with histologic and histomorphometric findings. Five patients (three men, two women; mean age 56 years) were recruited for this pilot study, and seven sites were treated. Solvent-preserved mineralized cancellous allograft was used to fill each socket up to the bone crest (2 mm below soft tissue surface), and sites were covered with a bioabsorbable collagen wound dressing. Core biopsies were taken from the center of extraction sockets 5 to 6 months after augmentation. Histologic evaluation of the prepared biopsies showed formation and remodeling of trabecular bone in areas of mineralized cancellous allografts and no signs of inflammation. Histomorphometric analysis of the samples showed an average of 68.5% vital bone, 3.8% residual graft particles, and 27.7% of connective tissue/bone marrow. In addition, vital bone and connective tissues were seen in close contact with the remaining allograft. These data suggest that this combination of human mineralized bone and absorbable collagen wound dressing is a suitable technique for socket augmentation. Nevertheless, future controlled clinical trials with larger sample sizes are recommended to validate the findings of the current technique.

  20. Effect of hydrogen peroxide on human tendon allograft.

    PubMed

    Gardner, E M H; VonderHeide, N; Fisher, R; Brooker, G; Yates, P J

    2013-12-01

    Bacterial contamination of tendon allografts at the completion of processing has historically been about 2 %, with tendons that are found to be culture positive being discarded. Treatment of tendon allograft with hydrogen peroxide at the beginning of tissue processing may reduce bacterial contamination, however, the potential side effects of hydrogen peroxide treatment include hydrolysis of the collagen and this may alter the mechanical properties of the graft. Pairs of human tendons were used. One was washed in 3 % hydrogen peroxide for 5 min and the untreated tendon was used as a control. The ultimate tensile strength of the tendons was determined using a material testing machine. A freeze clamp technique was used to hold the tendons securely at the high loads required to cause tendon failure. There was no statistical difference in the ultimate tensile strength between the treated and untreated tendons. Mean strength ranged from Extensor Hallucis Longus at 588 Newtons to Tibialis Posterior at 2,366 Newtons. Hydrogen peroxide washing may reduce bacterial contamination of tendon allograft and does not affect the strength of the tendon.

  1. Quantitative podocyte parameters predict human native kidney and allograft half-lives

    PubMed Central

    Naik, Abhijit S.; Afshinnia, Farsad; Cibrik, Diane; Hodgin, Jeffrey B.; Zhang, Min; Kikuchi, Masao; Wickman, Larysa; Samaniego, Milagros; Bitzer, Markus; Wiggins, Jocelyn E.; Ojo, Akinlolu; Li, Yi; Wiggins, Roger C.

    2016-01-01

    BACKGROUND. Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives. METHODS. Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries. RESULTS. With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate. CONCLUSION. Native kidneys are designed to have a limited average life span of about 100–140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention. FUNDING: National Institutes of Health. PMID:27280173

  2. Preoperative preparation of high-risk, specifically hyperimmunized canine renal allograft recipients with total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Rapaport, F.T.; Meek, A.G.; Arnold, A.N.; Miura, S.; Hayashi, R.; Strober, S.

    1987-08-01

    Hyperimmunized subjects are a particularly high-risk and rapidly growing group in the patient population awaiting renal transplantation. In a search for methods designed to ameliorate the prognosis in such cases, dogs of defined DLA genotype were sensitized with DLA incompatible skin allografts and injections of buffy coat. Each recipient was challenged with a renal allograft bearing the same DLA incompatibilities. Five dogs received kidney transplants, without any other treatment, and rejected their transplants at 2.5, 4, 5, 6, and 6.5 days, respectively. Another four dogs were given a 9-11-week course (1760 +/- 35 cGy) of total-lymphoid irradiation (TLI), followed by rabbit antithymocyte globulin (ATG); these animals rejected their renal allografts at 7, 8, 14, and 17 days, respectively. Five other dogs were treated with TLI and received cyclosporine (CsA) and methylprednisolone (MPd) daily until graft rejection. Their renal allografts survived for 7.5, 8.5, 20, 62, and 227 days, respectively. Renal allografts placed in normal recipients under the same conditions of donor-recipient DLA incompatibility had a mean survival time of 12.4 days (range: 10-18 days). At the time of transplantation, the specific anti-DLA antibody titers in the recipients were 81 to 243 in the untreated dogs; 27 to 81 in the TLI-ATG-treated group, and 3 to 243 in the TLI-CsA/MPd-treated group. The titers fell within 24-48 hr after renal transplantation, to 3 to 81 in the untreated sensitized dogs; they were 3 to 9 in the TLI-ATG-treated group, and were 9 to 243 in the TLI-CsA/MPd treated group. The cytotoxic antibody titers reached postoperative peaks of 6500 to 200,000 in the untreated dogs; 729 to 6500 in the TLI-ATG-treated dogs, and 243 to 6500 in the TLI-CsA/MPd-treated recipients.

  3. Percutaneous renal artery embolisation of non-functioning allograft. Preliminary experience.

    PubMed

    Larini, Pietro; Marcato, Carla; Monaco, Delio; Bresciani, Paolo; Capocasale, Enzo; Mazzoni, Maria Patrizia; Dalla Valle, Raffaele; Busi, Nicola

    2005-01-01

    Percutaneous renal artery embolisation has been introduced as an alternative to nephrectomy in patients with non-functioning allograft and Graft Intolerance Syndrome (GIS). The symptoms resulting from GIS include fever, local pain, hypertension and haematuria. From April to October 2003, five patients were treated using this technique. The intraparenchymal renal arteries were embolized by injection of calibrated tris-acryl gelatin microspheres of increasing size (from 100-300 to 700-900 microns) and occlusion was completed by the insertion of 5mm to 8mm steel coils into the renal artery. The procedure was well tolerated in all cases and no major complications occurred. In 3 patients GIS-related symptoms disappeared immediately. One patient required a second embolisation due to collateral circulation arising from a lumbar artery with resolution of symptoms. In the last case, the patient underwent nephrectomy because of septic fever. On the basis of our preliminary experience we believe that, in selected patients, percutaneous renal artery embolisation is an effective, repeatable and minimally invasive alternative to nephrectomy with no significant serious complications.

  4. Association of calcium, phosphate and parathyroid hormone with renal allograft function: a retrospective cohort study.

    PubMed

    Hiemstra, Thomas F; Brown, Adam J D; Chaudhry, Afzal N; Walsh, Michael

    2013-01-01

    Significant variations in postoperative levels of parathyroid hormone (PTH), calcium and phosphate exist after renal transplantation, but whether they affect allograft function is unknown. We investigated the association between early post-transplant levels of PTH, calcium and phosphate and graft function. We performed a single-centre cohort study of renal transplant recipients from Addenbrooke's Hospital, Cambridge, between April 1997 and March 2007, evaluating the association between plasma calcium, phosphate and PTH 1 month after transplantation and change in epidermal growth factor receptor (eGFR) in the first 12 months after transplantation (estimated using the Modification of Diet in Renal Disease Study equation). Differences in eGFR between 26 and 52 weeks after transplantation were computed using mixed effects linear regression models for repeated measures of eGFR, while adjusting for sociodemographic and biochemical variables. Three hundred and forty-three patients were eligible for study. The mean age (standard deviation) at transplant was 43 years (13 years). Between 30 and 90 days after transplantation, the median (25th-75th percentile) eGFR was 33 (26-50) ml/min/1.73 m(2), the mean calcium level was 2.4 (0.17) mmol/l and the mean phosphate level was 0.78 (0.23) mmol/l. There was a significant interaction between calcium and phosphate levels (p = 0.006). In patients with low levels of phosphate, higher levels of calcium were associated with declining eGFR over time. However, in patients with a high phosphate level, higher calcium was associated with improved eGFR. Higher serum calcium in patients with low serum phosphate after transplantation is associated with a decline in graft function during the first year after transplantation. Disorders of mineral metabolism after transplant may represent an important therapeutic target to preserve allograft function. Copyright © 2013 S. Karger AG, Basel.

  5. CD256 can be found in antibody-mediated renal allograft rejection tissues.

    PubMed

    Xu, Haiyan; He, Xiaozhou; Zhao, Wei; Guo, Hui; Shi, Qianqian; Zhu, Yibei; Zhang, Xueguang

    2012-01-01

    CD256 and CD257 belong to the TNFSF (Tumor necrosis factor superfamily), share closest homology structure, and can form functional heterotrimers. They may be involved in the progression of SLE (Systemic lupus erythematosus), RA (Rheumatoid arthritis), and other autoimmune disorders. In this present study, CD256 and some related molecules were detected and were investigated regarding the potential role of the CD256 signal during the development of renal allograft rejection. In 2009, 46 cases of renal allografts were collected, excised for evaluation of dysfunction, and 10 renal protocol biopsies with normal renal function were controlled. Immunohistochemistry (IHC) staining was applied to detect CD256, CD257, C4d, CD138 and other related molecules. HistoQuest Analysis software and SPSS16.0 were used to read and analyse the results. Pathological diagnosis was made according to Banff 2005 guidelines: antibody-mediated rejection (ABMR) 15 cases, T-cell-mediated rejection (TCMR) 16 cases, and 15 unknown aetiology cases (UAC). IHC results showed that CD256, CD257, and receptors for B cell activating factor receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator calcium modulator, and cyclophilin ligand interactor (TACI) were expressed on the membrane/cytoplasm of renal tubular epithelial cells (RTEC) in the ABMR and TCMR group, while these molecules were not or weakly expressed in UAC and protocol biopsies. CD257 strong staining could be seen in ABMR, CD256 strong staining in both BCMR and TCMR, and there was statistical significance compared with other groups (p < 0.05). The receptors BAFF-R, BCMA, and TACI all strongly stained in ABMR, TACI also stained strongly in TCMR, and there was statistical significance compared with other groups (p < 0.05). The CD138+ molecule could be found in the renal interstitium and membrane/cytoplasm of RTEC, the CD138 mean expression in ABMR was statistically higher than other groups (p < 0.05). The correlation

  6. Metabolic control improves long-term renal allograft and patient survival in type 1 diabetes.

    PubMed

    Morath, Christian; Zeier, Martin; Döhler, Bernd; Schmidt, Jan; Nawroth, Peter P; Opelz, Gerhard

    2008-08-01

    It is a matter of debate whether pancreas allografts independently contribute to renal allograft and patient survival in individuals who have type 1 diabetes and receive a simultaneous pancreas and kidney transplant (SPK). Using data from the Collaborative Transplant Study, we studied patients who had type 1 diabetes and were recipients of deceased-donor kidneys (DDK), living-donor kidneys (LDK), or SPK. We analyzed graft and patient survival rates with a maximum of 18 yr of follow-up. DDK recipients had inferior graft and patient survival compared with LDK and SPK recipients. LDK recipients had superior graft and patient survival rates initially, but SPK recipients demonstrated equal survival rates toward the end of follow-up. Multivariate analysis, adjusting for pretransplantation cardiovascular risk, showed that patient survival of SPK recipients was superior to that of LDK recipients beyond the 10th year after transplantation (hazard ratio 0.55; P = 0.005). In summary, the early survival advantage of LDK over SPK is lost during long-term follow-up, probably as a result of improved glycemic control in SPK recipients.

  7. Properties of B cells and Thy-1-antigen-expressing cells infiltrating rat renal allografts

    SciTech Connect

    Leszczynski, D.; Halttunen, J.; Tiisala, S.; Ustinov, J.; Renkonen, R.; Haeyry, P. )

    1990-10-01

    We have examined (1) the frequency of B cells secreting antibodies against donor major histocompatibility complex (MHC) antigens and (2) the properties of Thy-1-antigen-expressing leukocytes in rats rejecting renal allografts. Our results show that B cells secreting antibodies are present in the inflammatory cell population at the frequency of 1:850. Among them only 1 out of 2-150 is engaged in production of antibodies directed to the graft MHC antigens, depending on the method of assay. This suggests that despite the observed significant production of nonspecific immunoglobulin in situ, only a minority of the B-cell population is specifically committed to the graft MHC antigens. This finding is concordant with the described previously low frequencies of the T cells specifically directed toward the graft MHC antigen. The role of the immunologically noncommitted cells in graft rejection is unknown. We have found that a substantial part (up to 60%) of inflammatory cells invading a rat kidney allograft express the Thy-1 antigen. This suggests that they might be immature (progenitor ) cells and, therefore, unable to respond to the graft antigens. Progenitor-like properties of these cells have been confirmed by their ability to reconstitute lethally irradiated syngeneic rat. Finally, these immature cells are of lymphoid, not of myeloid, linkage, because they do not proliferate in the presence of GM-CSF.

  8. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy.

    PubMed

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-02-23

    BACKGROUND To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). MATERIAL AND METHODS Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. RESULTS After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. CONCLUSIONS Hepcidin may be considered as a potential marker of impaired renal function.

  9. Association of Serum Fetuin-A Levels with Allograft Outcome in Renal Transplant Recipients.

    PubMed

    Mehrsai, Abdolrasoul; Pourmand, Gholamreza; Azhdari Tehrani, Hamed; Keyhan, Hossein; Rahmati, Mohamad Reza; Ahmadi, Ayat; Dehghani, Sanaz; Mashhadi, Rahil

    2015-07-01

    To determine serum fetuin-A pattern after renal transplantation and its association with graft outcome. In 41 renal transplant recipients, serum pretransplant fetuin-A levels and serum fetuin-A concentrations on days 7 and 30 after transplantation were measured using the enzyme-linked immunosorbent as­say (ELISA) method. Also, the association between serum fetuin-A levels with clinical and laboratory parameters was evaluated. A significant decrease in serum fetuin-A levels was noted in the first week after transplantation (P < .001). Subsequently, it started to increase and surpass pretransplant values during the first month (P < .001). Pretransplant fetuin-A levels did not differ among patients with different diethylenetriamine pentaacetic acid (DTPA) results. In addition, serum fetuin-A levels did not significantly correlate with metabolic parameters. In this prospective study there was no increase in serum fetuin-A levels during the first month and pretransplant fetuin-A levels are not predictive for allograft outcome in renal transplant recipients.

  10. Effect of poverty and other socioeconomic variables on renal allograft survival.

    PubMed

    Butkus, D E; Dottes, A L; Meydrech, E F; Barber, W H

    2001-07-27

    Socioeconomic variables including low income and noncompliance impact negatively upon long-term renal allograft survival, especially in African Americans. We sought to determine whether other socioeconomic variables contributed to noncompliance and allograft survival. A detailed history of socioeconomic variables was made at the time of renal transplant evaluation in 450 consecutive candidates, 128 of whom (89 African American, 39 Caucasian) have thus far undergone transplantation. Variables evaluated included household income, zip code income, insurance coverage, years of education, literacy, marital status, pretransplantation compliance, and history of substance abuse as well as the usual pre- and posttransplantation demographics. Immunologic graft loss occurred primarily in young African Americans with income below the federal poverty level, whereas nonimmunologic graft loss was distributed across racial, income, and other socioeconomic variables. Immunologic graft loss was also associated with a greater number of HLA mismatches, lower levels of education, and noncompliance with transplant medications and follow-up visits. Recipients with gross illiteracy, however, had excellent graft survival. Pretransplantation substance abuse, but not pretransplantation compliance, was predictive of posttransplantation noncompliance. By multivariate analysis, posttransplantation compliance emerged as the single most important factor predictive of graft survival. Immunologic graft loss in our population is related to noncompliance with transplant medications, which occurred primarily in recipients with a pretransplantation history of substance abuse and is not related to an inability to pay for medications at the time of graft loss. A change in criteria for acceptance of transplant candidates with a prior history of substance abuse might significantly improve graft survival in this patient population.

  11. Acute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long-term well-functioning renal allograft

    PubMed Central

    Wu, Chung-Kuan; Leu, Jyh-Gang; Wei, Cheng-Chun; Hsieh, Shih-Chung

    2016-01-01

    Abstract Background: Acute thrombosis of a transplanted renal artery is a serious vascular complication following renal allograft transplantation, which usually occurs within the first month after transplantation and often results in graft loss. It rarely occurs beyond the first month, except in a rejected kidney or in a kidney with high-grade transplant renal artery stenosis. Result: A 65-year-old male with a history of type 2 diabetes mellitus, hypertension, pulmonary tuberculosis, and end-stage renal disease was previously treated with hemodialysis (HD). He received a kidney transplant and had a well-functioning graft for 2 years. He presented to our emergency department with gastric ulcer bleeding and received treatment involving an endoscopic submucosal epinephrine injection, a proton pump inhibitor, and blood transfusions. Nine days later, he complained of sudden lower abdominal pain and had acute anuric kidney failure. Renal ultrasonography revealed an absence of blood flow to the allograft kidney. Renal artery angiogram demonstrated complete occlusion of the transplanted renal artery. After thrombectomy and percutaneous transluminal angioplasty (PTA) with stent placement, 60% stenosis of the proximal renal artery with distal perfusion was noted. However, his graft function did not improve, and he received HD again. Histopathology of the transplanted kidney revealed ischemic tubular nephropathy with focal infarction without rejection. Conclusion: This is the first case of acute thrombosis of the transplanted renal artery following gastric ulcer bleeding in a patient with a long-term well-functioning graft kidney. PMID:27472705

  12. Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.

    PubMed

    Suhre, Karsten; Schwartz, Joseph E; Sharma, Vijay K; Chen, Qiuying; Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana M; Ding, Ruchuang; Ikle, David N; Bridges, Nancy D; Williams, Nikki M; Kastenmüller, Gabi; Karoly, Edward D; Mohney, Robert P; Abecassis, Michael; Friedewald, John; Knechtle, Stuart J; Becker, Yolanda T; Samstein, Benjamin; Shaked, Abraham; Gross, Steven S; Suthanthiran, Manikkam

    2016-02-01

    Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy.

  13. Interobserver agreement for Polyomavirus nephropathy grading in renal allografts using the working proposal from the 10th Banff Conference on Allograft Pathology.

    PubMed

    Sar, Aylin; Worawichawong, Suchin; Benediktsson, Hallgrimur; Zhang, Jianguo; Yilmaz, Serdar; Trpkov, Kiril

    2011-12-01

    A classification schema for grading Polyomavirus nephropathy was proposed at the 2009 Banff allograft meeting. The schema included 3 stages of Polyomavirus nephropathy: early (stage A), florid (stage B), and late sclerosing (stage C). Grading categories for histologic viral load levels were also proposed. To examine the applicability and the interobserver agreement of the proposed Polyomavirus nephropathy grading schema, we evaluated 24 renal allograft biopsies with confirmed Polyomavirus nephropathy by histology and SV40. Four renal pathologists independently scored the Polyomavirus nephropathy stage (A, B, or C), without knowledge of the clinical history. Viral load was scored as a percent of tubules exhibiting viral replication, using either a 3-tier viral load score (1: ≤1%; 2: >1%-10%; 3: >10%) or a 4-tier score (1: ≤1%; 2: >1%-≤5%; 3: >5%-15%; 4: >15%). The κ score for the Polyomavirus nephropathy stage was 0.47 (95% confidence interval, 0.35-0.60; P < .001). There was a substantial agreement using both the 3-tier and the 4-tier scoring for the viral load (Kendall concordance coefficients, 0.72 and 0.76, respectively; P < .001 for both). A better complete agreement was found using the 3-tier viral load score. In this first attempt to evaluate the interobserver reproducibility of the proposed Polyomavirus nephropathy classifying schema, we demonstrated moderate κ agreement in assessing the Polyomavirus nephropathy stage and a substantial agreement in scoring the viral load level. The proposed grading schema can be applied in routine allograft biopsy practice for grading the Polyomavirus nephropathy stage and the viral load level.

  14. A single center comparison of long-term outcomes of renal allografts procured laparoscopically versus historic controls procured by the open approach.

    PubMed

    Nogueira, Joseph M; Jacobs, Stephen C; Haririan, Abdolreza; Phelan, Michael W; Weir, Matthew R; Seliger, Stephen L; Hurley, Heather A; Cooper, Matthew

    2008-09-01

    We have previously reported that renal allografts procured by the laparoscopic live donor nephrectomy (lapNx) demonstrate worse early renal outcomes but noninferior 1-year renal function as compared to those procured by the standard open nephrectomy (openNx). We undertook this study to examine whether the apparent early dysfunction will impair long-term renal allograft survival. We retrospectively updated the status of the first 132 consecutive adult left lapNx recipients at our center and the preceding 99 adult openNx recipients. With a mean follow-up of 5.8+/-2.0 years in lapNx and 8.7+/-3.3 years in openNx, we found that death-censored renal allograft survival was identical on univariate and multivariate analysis. Patient survival was worse (log rank P-value=0.048) in lapNx, but this finding did not persist in multivariate analysis. Combined graft-patient survival as well as 1-year mean serum creatinine levels were similar on univariate and multivariate analyses. We conclude that, despite having suffered early renal dysfunction, the lapNx cohort of renal allograft recipients enjoys similar long-term renal allograft survival as compared to openNx.

  15. Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients

    PubMed Central

    Tedesco-Silva, Helio; Peddi, V. Ram; Sánchez-Fructuoso, Ana; Marder, Brad A.; Russ, Graeme R.; Diekmann, Fritz; Flynn, Alison; Hahn, Carolyn M.; Li, Huihua; Tortorici, Michael A.; Schulman, Seth L.

    2016-01-01

    Background Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. Methods This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m2 or greater improvement in estimated glomerular filtration rate from randomization to month 24. Results The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). Conclusions Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus. PMID:27500260

  16. Bartonella henselae infection-associated vasculitis and crescentic glomerulonephritis leading to renal allograft loss.

    PubMed

    Chaudhry, A R; Chaudhry, M R; Papadimitriou, J C; Drachenberg, C B

    2015-06-01

    Bartonella henselae (BH) is the main cause of cat scratch disease (CSD), which more typically presents as a self-limited localized suppurative lymphadenopathy in immunocompetent individuals. In contrast, immunocompromised patients commonly have systemic disease with life-threatening complications. In addition to the angioproliferative lesions, such as bacillary angiomatosis, an increasing number of immune post-infectious complications are being recognized with BH infections, including glomerulonephritis, vasculitis, hemophagocytic syndrome, and neurological problems. We report the case of a renal transplant recipient who developed CSD in the second year post transplantation. In addition to prolonged fever and generalized lymphadenopathy and splenomegaly requiring differentiation from a post-transplant lymphoproliferative disorder, the course was complicated by the development of dermal leukocytoclastic vasculitis and pauci-immune necrotizing and crescentic glomerulonephritis, which led to failure of the renal graft. Glomerulonephritis as a complication of CSD has never been described in a kidney allograft, to our knowledge. Awareness of the diverse clinical symptoms associated with BH, including granulomatous/suppurative lesions and other less common complications can lead to more rapid and accurate diagnosis. Also, as recommended by the current guidelines, a thorough history of pet ownership should be part of the clinical evaluation before and after transplantation for all transplant recipients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Serum neopterin as an indicator of increased risk of renal allograft rejection.

    PubMed

    Carey, B Sean; Jain, Rashmi; Adams, Claire L; Wong, Kam Yim; Shaw, Steve; Tse, Wai Yee; Kaminski, Edward R

    2013-03-01

    Acute rejection remains associated with poor graft outcome. An early predictor of acute renal transplant rejection is the long sought after goal for transplant immunologists. In this study we measured levels of serum neopterin at day 5 post-transplant in a cohort of 216 consecutive renal allograft recipients, and compared this with serum creatinine and acute rejection episodes during the first year post transplant. We compared serum neopterin in recipients from living donors (LD), donors after brain death (DBD) and donors after cardiac death (DCD). In all cases higher neopterin levels were correlated with acute rejection in the first year post transplant, but this was only significant in recipients of DCD kidneys who suffered acute cellular or vascular rejection (p=0.04, odds ratio 1.08, 95% CI 1.003-1.012). The neopterin/creatinine ratio, which takes into account the effect of kidney function on circulating neopterin levels, was significantly higher for all recipients who suffered biopsy proven cellular or vascular rejection in the first year post transplant, compared to all other patients (p=0.001, for an increase of 0.1, odds ratio=1.64, 95% CI 1.21-2.20). The ability to use non-invasive biomarkers in the transplant recipient has the potential to increase transplant survival for these patients. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Effects of ureteral stents on risk of bacteriuria in renal allograft recipients.

    PubMed

    Chordia, P; Schain, D; Kayler, L

    2013-06-01

    Placement of ureteral stents at the time of renal transplantation is thought to decrease the incidence of postoperative complications, such as anastomotic leakage and stenosis. However, stents may also predispose to post-transplantation urinary tract infection, which can lead to increased risks of graft dysfunction, sepsis, and death. The aim of this study was to analyze the risk of post-transplantation bacteriuria with ureteral stent placement in renal allograft recipients. A retrospective single-center analysis was conducted to investigate the incidence of bacteriuria in all renal allograft recipients transplanted between January 2007 and March 2009. Recipients were categorized as in the nonstent group (NSTG) or the stent group (STG). Stent removal was performed per protocol at 6 weeks, and all patients were followed for at least 1 year post transplantation. In the NSTG, the incidence of bacteriuria was assessed at 0-6, 6-12, and 12 weeks to 1 year post transplantation. In the STG, bacteriuria was assessed prior to stent removal, 6 weeks after stent removal, and thereafter until 1 year post transplantation. A total of 395 renal allograft recipients, 183 in the NSTG and 212 in the STG groups, were studied. The overall incidence of bacteriuria within 1 year post transplantation was similar between NSTG and STG (28.0 vs. 24.0%, P = 0.38). No difference was found in the incidence of bacteriuria when NSTG and STG were compared at 0-6 weeks or prior to stent removal (9.7% vs. 9.1%, P = 0.81), at 6-12 weeks, or 6 weeks after stent removal (6.7% vs. 5.8%, P = 0.75), and thereafter for 1 year post transplantation (13.3% vs. 10.8%, P = 0.46). The incidence of graft failure at 1 year was similar in NSTG and STG (6.2% vs. 4.9%, P = 0.6). Urinary anastomotic leakage occurred in none of the NSTG and 2 of the STG recipients. On multivariate analysis, risk factors for bacteriuria were female recipient gender (odds ratio [OR] 2.5, 95% confidence interval [CI

  19. The epistemology of Ludwik Fleck and the thought community of Banff: reflections on the classification of the renal allograft pathology.

    PubMed

    Pena, G P

    2011-05-01

    Ludwik Fleck was a polish physician and bacteriologist with major interest in epistemology. In 1935, he published, in German, a monograph entitled 'Genesis and development of a scientific fact'. His concepts of 'thought collective', 'thought style' and 'active and passive associations' have been materialized in Banff classification of renal allograft pathology. The dynamics and evolution of the classification of renal allograft pathology, generated within Banff community, reflect perfectly Fleck's conceptions. In this essay, the Banff community of thought is characterized as a thought collective, according to Fleck's epistemology. Since its inception, the classification has been evolving in a continuum of active and passive connections, preserving its initial thought style, based on morphology. Whether the emergence of nonmorphological, molecular techniques will result in the end of morphological thought style is a question the community is presently facing.

  20. Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine

    PubMed Central

    Kamel, Mahmoud; Kadian, Manish; Srinivas, Titte; Taber, David; Posadas Salas, Maria Aurora

    2016-01-01

    AIM To compare the impact of tacrolimus (FK) and cyclosporine (CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors (CNIs). METHODS Retrospective review of 1835 patients who received a kidney transplant (KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group (P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejection rates [odds ratio (OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival (OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients. PMID:28058220

  1. Prediction of Long-term Renal Allograft Outcome By Early Urinary CXCL10 Chemokine Levels

    PubMed Central

    Hirt-Minkowski, Patricia; Ho, Julie; Gao, Ang; Amico, Patrizia; Koller, Michael T.; Hopfer, Helmut; Rush, David N.; Nickerson, Peter W.; Schaub, Stefan

    2015-01-01

    Background Predictive biomarkers for long-term renal allograft outcome could help to individualize follow-up strategies and therapeutic interventions. Methods We investigated the predictive value of urinary CXC chemokine ligand 10 (CXCL10) measured at different timepoints (ie, at 3 and 6 months, and mean of 3 and 6 months coined CXCL10-burden) for long-term allograft outcomes in 154 patients. The primary outcome was a composite graft endpoint of death-censored allograft loss and/or biopsy-proven rejection and/or decline of estimated glomerular filtration rate greater than 20% occurring beyond 6 months after transplantation. Results After a median follow-up of 6.6 years (interquartile range, 5.7-7.5 years) the endpoint was reached in 43/154 patients (28%). In a multivariable Cox-regression model independent predictors were 6-month CXCL10 levels, the CXCL10-burden, HLA-mismatches, donor age and delayed graft function while previous (sub)clinical rejection, estimated glomerular filtration rate and proteinuria at 6 months, as well as 3-month CXCL10 levels were not. Time-dependent receiver operating characteristic analysis revealed an area under the curve of 0.68 (6-month CXCL10) and 0.67 (CXCL10-burden). Grouped by optimal cutoff, low 6-month CXCL10 (<0.70 ng/mmol) was associated with a 95% endpoint-free 5-year survival compared to 78% with high 6-month CXCL10 (P = 0.0007). Only 2 of 62 patients (3%) with low 6-month CXCL10 levels (<0.70 ng/mmol) experienced late rejection or graft loss due to rejection compared to 15 of 92 patients (16%) with high 6-month CXCL10 levels (P = 0.008). Similar results were obtained when patients were grouped according to CXCL10-burden (cutoff, 1.06 ng/mmol). Conclusions Six-month urinary CXCL10 is an independent predictor for long-term graft outcome and thus might be a supplementary tool to tailor surveillance strategies and therapy. PMID:27500231

  2. In situ expression of cytokines in human heart allografts.

    PubMed

    Van Hoffen, E; Van Wichen, D; Stuij, I; De Jonge, N; Klöpping, C; Lahpor, J; Van Den Tweel, J; Gmelig-Meyling, F; De Weger, R

    1996-12-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process.

  3. Expression of pro- and antifibrotic genes in protocol biopsies from renal allografts with interstitial fibrosis and tubular atrophy.

    PubMed

    Mengel, M; Bock, O; Priess, M; Haller, H; Kreipe, H; Gwinner, W

    2008-06-01

    Better understanding of early onset of interstitial fibrosis and tubular atrophy (IF/TA), as the morphological surrogate of renal allograft deterioration might improve outcome after renal transplantation. We quantified mRNA expression of 3 profibrotic (transforming growth factor-beta (TGF-beta), tissue transglutaminase (tTG), tissue inhibitor of matrix metalloproteases (TIMP-1)) and 1 antifibrotic (matrix metalloprotease-2 (MMP-2)) molecule in protocol biopsies from renal allografts. From 107 transplants, two sequential protocol biopsies (6 weeks and 6 months) were analyzed. We evaluated a control group showing no IF/TA in both biopsies (n = 65) and a IF/TA group developing IF/TA at 6 months (n = 42). Expression data were correlated with clinical and histological risk factors for IF/TA and allograft function. The expression of the genes correlated strongly with each other, particularly the profibrotic genes and in patients who developed IF/TA. Analyzing protocol biopsies from stable grafts, not all patients in both groups showed increased gene expression. In patients with increased gene expression a significantly higher tTG expression (matrix stabilization) at 6 weeks and a significantly lower MMP-2 expression (failure in matrix degradation) at 6 months were observed in the IFTA group compared to controls. Multivariate logistic regression revealed donor age positively and TIMP-1 expression at 6 weeks inversely correlated with IF/TA at 6 months. We conclude that a disturbance in the equilibrium of pro- and antifibrotic pathways is decisive for early onset of IF/TA in renal allografts: insufficient degradation of exaggerated matrix production apparently changes the balance in the direction of IF/TA.

  4. Human skin allografts as a useful adjunct in the treatment of purpura fulminans.

    PubMed

    Gaucher, S; Stéphanazzi, J; Jarraya, M

    2010-08-01

    The aim of this report is to discuss the role of human skin allografts in surgical coverage procedures for patients with purpura fulminans. We describe cases of purpura fulminans in three adults and one infant treated at our burns unit between October 2006 and January 2008. The application of cryopreserved human skin allografts allowed us to obtain immediate wound closure after necrosis excision and enabled our team to subsequently perform autografts on favourable graft recipient sites. Recourse to human skin allografts must be considered a pertinent therapeutic option in patients with purpura fulminans.

  5. Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10

    PubMed Central

    Ho, Julie; Sharma, Atul; Mandal, Rupasri; Wishart, David S.; Wiebe, Chris; Storsley, Leroy; Karpinski, Martin; Gibson, Ian W.; Nickerson, Peter W.; Rush, David N.

    2016-01-01

    Background The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination. Methods Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed. Results PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen κ, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose. Conclusions Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal

  6. Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells

    PubMed Central

    Lee, Soyoung; Yamada, Yohei; Tonsho, Makoto; Boskovic, Svjetlan; Nadazdin, Ognjenka; Schoenfeld, David; Cappetta, Kate; Atif, Muhammad; Smith, Rex-Neal; Cosimi, A. Benedict; Benichou, Gilles; Kawai, Tatsuo

    2014-01-01

    Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow (DBM) transplantation. To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel conditioning regimen, the “delayed protocol” in which DBM is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8+ memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2highCD8+ effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2high cells including CD8+ TEM while sparing naïve CD8+ T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2high T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach. PMID:24165326

  7. The impact of steady-state cyclosporine concentrations on renal allograft outcome.

    PubMed

    Dunn, J; Grevel, J; Napoli, K; Lewis, R M; Van Buren, C T; Kahan, B D

    1990-01-01

    It has been reported that initial cyclosporine levels over 400 ng/ml posttransplantation result in an increased incidence of delayed graft function (DGF). Several studies have shown early graft function to be a major determinant for long-term graft survival. Continuous intravenous infusion (CIVI) has been employed to induce immunosuppression establishing therapeutic drug levels while minimizing toxicity in renal allograft recipients. This study examines the impact of the achieved serum CsA steady-state concentration (Css) levels upon transplant outcome in 228 patients given CsA by CIVI. In spite of administration of a specific drug dose, interindividual variation in elimination rates yields a broad range of Css levels. Six groups were stratified by CsA Css levels: group A 0-75 ng/ml, group B 76-100 ng/ml, group C 101-150 ng/ml, group D 151-200 ng/ml, group E 201-250 ng/ml, and group F greater than 250 ng/ml. Group A showed a significantly lower age and greater incidence of rejection at 0-10 days. Group F had significantly higher incidences of nephrotoxicity, hepatotoxicity, and delayed graft function. The findings suggest that the antirejection Css threshold for CsA may be at least 75 ng/ml, and the toxicity threshold above 250 ng/ml. Controversy exists about whether CsA influences the incidence of DGF, therefore risk factors for DGF were examined among the groups stratified by CsA Css levels. While cold ischemia time for all 228 patients as a group was highly correlated with DGF (P less than 0.001), neither cold ischemia time nor donor age was significantly different among the groups. There does appear to be a synergistic effect between CsA Css and CIT, since the incidence of DGF was significantly higher when the cold ischemia time was 21-24 hr and CsA Css greater than 200 ng/ml. Long-term graft function did not appear to be affected by early CsA Css levels. The Css of 100-250 ng/ml appears to achieve a satisfactory outcome with a 19.5% incidence of rejection

  8. The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients.

    PubMed

    Eng, H-S; Mohamed, Z; Calne, R; Lang, C C; Mohd, M A; Seet, W-T; Tan, S-Y

    2006-05-01

    Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.

  9. Genetic polymorphisms located in TGFB1, AGTR1, and VEGFA genes are associated to chronic renal allograft dysfunction.

    PubMed

    Jiménez-Sousa, María A; Fernández-Rodríguez, Amanda; Heredia, María; Tamayo, Eduardo; Guzmán-Fulgencio, María; Lajo, Carmen; López, Elisabeth; Gómez-Herreras, José I; Bustamante, Jesús; Bermejo-Martín, Jesús F; Resino, Salvador

    2012-06-01

    Persistent inflammation and fibrosis have been related to active progression of renal deterioration and reduced survival of kidney transplant. The aim of this study was to determine the impact of single-nucleotide polymorphisms (SNPs) located in regions related to inflammatory and immune processes on the development of chronic renal allograft dysfunction (CRAD). A retrospective study was carried out on 276 patients who received kidney transplant (KT). SNPs were genotyped via the SNPlex platform. Statistical analysis was performed with SNPstat and regression logistic analyses were adjusted by age and gender of recipients and donors, cold ischemia time and the number of human leukocyte antigen (HLA) mismatches. From 276 patients with KT, 118 were non-CRAD and 158 were CRAD. Three SNPs showed significant associations with CRAD development: rs1800471 in transforming growth factor beta 1 (TGFB1), rs5186 in angiotensin II receptor type 1 (AGTR1), and rs699947 in vascular endothelial growth factor A (VEGFA). GC genotype of rs1800471 was associated with increased odds of CRAD compared to GG genotype (OR=2.65 (95% confidence interval (CI)=1.09; 6.47), p=0.025), as well as AC and AA genotype of rs699947 assuming a dominant model (OR=1.80 (95% CI=1.02; 3.20), p=0.044). Besides, AC and CC genotypes of rs5186 were associated with reduced odds of CRAD assuming a dominant model (OR=0.56 (95% CI=0.33; 0.96), p=0.033). Our findings suggest that three genes related to immunity and inflammation (rs1800471, rs5186 and rs699947) are associated to susceptibility or protection to CRAD, and might have diagnostic utility in predicting the likelihood of developing CRAD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury.

    PubMed

    Sigdel, Tara K; Li, Li; Tran, Tim Q; Khatri, Purvesh; Naesens, Maarten; Sansanwal, Poonam; Dai, Hong; Hsieh, Szu-chuan; Sarwal, Minnie M

    2012-04-01

    Chronic allograft injury (CAI) results from a humoral response to mismatches in immunogenic epitopes between the donor and recipient. Although alloantibodies against HLA antigens contribute to the pathogenesis of CAI, alloantibodies against non-HLA antigens likely contribute as well. Here, we used high-density protein arrays to identify non-HLA antibodies in CAI and subsequently validated a subset in a cohort of 172 serum samples collected serially post-transplantation. There were 38 de novo non-HLA antibodies that significantly associated with the development of CAI (P<0.01) on protocol post-transplant biopsies, with enrichment of their corresponding antigens in the renal cortex. Baseline levels of preformed antibodies to MIG (also called CXCL9), ITAC (also called CXCL11), IFN-γ, and glial-derived neurotrophic factor positively correlated with histologic injury at 24 months. Measuring levels of these four antibodies could help clinicians predict the development of CAI with >80% sensitivity and 100% specificity. In conclusion, pretransplant serum levels of a defined panel of alloantibodies targeting non-HLA immunogenic antigens associate with histologic CAI in the post-transplant period. Validation in a larger, prospective transplant cohort may lead to a noninvasive method to predict and monitor for CAI.

  11. Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model.

    PubMed

    Villani, V; Yamada, K; Scalea, J R; Gillon, B C; Arn, J S; Sekijima, M; Tasaki, M; Cormack, T A; Moran, S G; Torabi, R; Shimizu, A; Sachs, D H

    2016-01-01

    Our recent studies in an inbred swine model demonstrated that both peripheral and intra-graft regulatory cells were required for the adoptive transfer of tolerance to a second, naïve donor-matched kidney. Here, we have asked whether both peripheral and intra-graft regulatory elements are required for adoptive transfer of tolerance when only a long-term tolerant (LTT) kidney is transplanted. Nine highly-inbred swine underwent a tolerance-inducing regimen to prepare LTT kidney grafts which were then transplanted to histocompatible recipients, with or without the peripheral cell populations required for adoptive transfer of tolerance to a naïve kidney. In contrast to our previous studies, tolerance of the LTT kidney transplants alone was achieved without transfer of additional peripheral cells and without strategies to increase the number/potency of regulatory T cells in the donor. This tolerance was systemic, since most subsequent, donor-matched challenge kidney grafts were accepted. These results confirm the presence of a potent tolerance-inducing and/or tolerance-maintaining cell population within LTT renal allografts. They suggest further that additional peripheral tolerance mechanisms, required for adoptive transfer of tolerance to a naïve donor-matched kidney, depend on peripheral cells that, if not transferred with the LTT kidney, require time to develop in the adoptive host.

  12. Deficiency of C4 from donor or recipient mouse fails to prevent renal allograft rejection.

    PubMed

    Lin, Tao; Zhou, Wuding; Farrar, Conrad A; Hargreaves, Roseanna E G; Sheerin, Neil S; Sacks, Steven H

    2006-04-01

    Complement effector products generated in the transplanted kidney are known to mediate transplant rejection, but which of the three main activation pathways of complement trigger this response is unclear. Here we assessed the role of the classical and lectin pathways by studying the common component C4 in mouse kidney transplant rejection. We transplanted wild-type or C4-null H-2(b) donor kidneys into H-2(k) or H-2(d) recipients, or vice-versa, to assess the roles of donor kidney and recipient expression of complement. Intragraft C4 gene expression rose substantially during rejection. However, we found no significant association between graft acceptance and the presence of C4 in either the donor kidney or recipient mouse. At the time of rejection, we found no significant differences in alloantibody response in the different groups. Tubular deposition of C3 to C9 occurred regardless of the absence or presence of C4 in either the donor or recipient mouse, indicating that C4 was dispensable for complement activation at this site. These data suggest that complement activation and renal allograft rejection are independent of the classical and lectin pathways in these models, implying that in the absence of these pathways the alternative pathway is the main trigger for complement-mediated rejection.

  13. [Antibody-mediated rejection of renal allograft and the update Banff classification 2013].

    PubMed

    Honsová, Eva

    2015-01-01

    The view on the role of donor-specific antibodies in organ transplantation has been changed during the last several decades. Today, it is considered that the majority of cases of the late renal allograft dysfunction and loss are caused by the presence of donor-specific antibodies to HLA antigens. The real breakthrough in the diagnosis of antibody-mediated rejection was represented by the discovery of C4d, which enabled the determination of the diagnostic criteria of acute and later chronic antibody-mediated rejection. Although detection of C4d has been the cornerstone in the diagnosis of antibody-mediated rejection for over 10 years, it has become clear that some cases with similar morphological and clinical features do not have detectable C4d. Outcomes of key studies concerning presence of donor specific antibodies and morphological features in the graft biopsy samples resulted in the modification of Banff classification of 2013, which includes integrating C4d negative antibody-mediated rejection and also that acute vascular rejection (v1, v2) can be a part of the antibody-mediated rejection.

  14. Effects of complement inhibition with soluble complement receptor-1 on vascular injury and inflammation during renal allograft rejection in the rat.

    PubMed

    Pratt, J R; Hibbs, M J; Laver, A J; Smith, R A; Sacks, S H

    1996-12-01

    Complement is both an effector of the humoral immune response and a stimulator of leukocyte activation. To examine the influence of complement on the allograft response, we inhibited complement using recombinant human soluble complement receptor-1 (sCR1; TP10), in an unsensitized model of rat renal allograft rejection. Lewis to DA renal transplant recipients were treated daily with 25 mg/kg sCR1 or saline and sacrificed on days 1 to 5 after transplant. Transplanted organs were examined histologically and immunohistochemically for leukocyte subset markers and for the third component of complement, C3, and membrane attack complex deposition. A second set of recipients was followed from day 5 to day 9 to assess graft survival. sCR1-treated recipients displayed > 90% inhibition of plasma complement activity and a marked reduction in tissue C3 and membrane attack complex deposition. Inactivation of complement reduced the vascular injury such that there was almost complete sparing of vascular damage in day 5 sCR1-treated rats. There was a significant reduction in infiltrating leukocytes by day 5 after transplant, and complement inhibition delayed the time to reach a histologically defined end point of graft survival from 5 days in controls to 9 days in the sCR1-treated group. These results imply that the vascular and cell-mediated injury arises, in part, from complement activation. The partial inhibition of these injuries by sCR1 may have functional implications for strategies to inhibit allograft rejection.

  15. Treatment of Acute Antibody-Mediated Renal Allograft Rejection With Cyclophosphamide.

    PubMed

    Waiser, Johannes; Duerr, Michael; Budde, Klemens; Rudolph, Birgit; Wu, Kaiyin; Bachmann, Friederike; Halleck, Fabian; Schönemann, Constanze; Lachmann, Nils

    2017-10-01

    Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR. Between March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6×), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity. Eleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7±0.4 mg/dL at 3 months before diagnosis to 3.7±2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 ± 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients. To our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR.

  16. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  17. Immature CD4⁺ dendritic cells conditioned with donor kidney antigen prolong renal allograft survival in rats.

    PubMed

    Wang, Tao; Xu, Lin; Li, Heng; Huang, Zheng-Yu; Zhang, Sheng-Ping; Miao, Bin; Na, Ning

    2012-07-01

    Allogeneic transplant rejection is currently a major problem encountered during organ transplantation. The dendritic cell (DC) is the most effective powerful known professional antigen-presenting cell, and recent studies have found that DCs can also induce immune tolerance, and avoid or reduce the degree of transplant rejection. The aim of this study was to evaluate the effect of transfused immature CD4(+) DCs on renal allografts in the rat model. In this study, we induced CD4(+) immature DCs from rat bone marrow cells by a cytokine cocktail. The immature CD4(+) DCs were identified by morphological analysis and then the suppressive activity of these cells conditioned with donor kidney antigen was evaluated in vitro and in vivo. Immature CD4(+) DCs conditioned with donor kidney antigen possessed immunosuppressive activity in vitro and they were able to prolong renal transplant survival in an allograft rat model in vivo. Our study provides new information on efficacious renal transplantation, which might be useful for understanding the function of immature CD4(+) DCs in modulating renal transplant rejection and improving clinical outcome in future studies.

  18. [A preliminary report of two cases of human hand allograft].

    PubMed

    Pei, G; Gu, L; Yu, L

    2000-06-01

    To study the feasibility of reconstruction of amputation by hand allograft in human being. Two male recipients with traumatic right wrist amputation for 2 years, were matched respectively to two ABO- and Rh-compatible, HLA- half mpatible brain-dead donors. Direct crossmatch was performed to confirm the absence of prior sensitization to alloantigens. After amputation the donor's arm was irrigated with UW organ preservation solution at 4 degrees, and transported in a box with ice. One of the two donor arms was randomly selected and irradiated by 8 gy x-ray before transplantation. The transplantation involved radial and ulnar bone fixation, anastomoses of radial and ulnar artery, sutures of median and ulnar and radial nerves, joining of tendons except flexors digitorum superficialis, and skin closure. After surgery the patients were given wide-spectrum antibiotics, anticoagulation and antispasm agents, and immunosuppressants, which included antithymocyte globins, FK506, mycophenolic acid, prednisone systematically and fluocinolone acetonide ointment locally. Clinical observations included vital signs and circulation of the hands. Immune state was monitored by assaying C-reactive protein, Igs and PRA in the blood. Skin biopsy was done to exclude the dermal rejection. After the surgery the patients received psychotherapy and hand rehabilitation. The circulation of the transplanted hands was similar to that of replanted ones. One of the patients developed hyperglycaemia, which required insulin administration. The skin healed naturally. The nerve regeneration were found more rapid by Tinel's sign. At 7 weeks erythema papulatum occurred on the skin, which was cured by withdrawing of fluocinolone acetonide ointment and application of calamine lotion. At 4 months the function of grafted hands recovered well, which could hold a drinking cup. The nerves had grown to the end of fingers and electromyograph showed regenerative action potentials of thenal muscles. Skin biopsy

  19. Evaluation of oxidant and antioxidant status in living donor renal allograft transplant recipients.

    PubMed

    Kumar, Sunil; Sharma, Ujjawal; Sharma, Ashish; Kenwar, Deepesh B; Singh, Sarbpreet; Prasad, Rajendra; Minz, Mukut

    2016-02-01

    The objective of this study was to evaluate the oxidant and antioxidant status in living donor renal allograft transplant recipients. Ninety-two renal transplant recipients with mean age of 34.75 ± 11.22 years were included in the present study. Venous samples of the recipients were drawn: before the transplant (baseline), 5 min after reperfusion, and 2 weeks after transplant. Samples were processed for the measurement of markers of oxidant and antioxidant status viz. malondialdehyde, catalase, glutathione peroxidase, reduced glutathione, ascorbic acid, and total antioxidant system. The mean baseline levels of reduced glutathione, ascorbic acid, and total antioxidant system were 1.61 ± 0.84 mg/g hemoglobin, 3.64 ± 1.49 mg/dL, and 1.42 ± 0.14 mmol/L which decreased at 5 min after reperfusion to 1.32 ± 0.72 (p = 0.010), 2.96 ± 1.25 (p = 0.002), and 1.36 ± 0.12 (p = 0.042), respectively. The malondialdehyde levels increased from a baseline value of 3.11 ± 1.02 µmol/mL to 3.32 ± 1.09 at 5 min after reperfusion (p = 0.344) and 4.01 ± 1.21 (p = 0.000) at 2 weeks. Glutathione peroxidase level decreased from 68.59 ± 32.79 units/g hemoglobin (baseline) to 63.65 ± 32.92 at 5 min after reperfusion (p = 0.530) and increased significantly at 2 weeks to 86.38 ± 37.18 (p = 0.00). There was no significant change in the catalase level. In living donor renal transplantation, oxidative stress starts after reperfusion and is reflected by fall in antioxidant factors and enzymes in the early period. Over the next 2 weeks, there is increased oxidative stress and simultaneous strengthening of antioxidant system which is implied by increase in malondialdehyde and improvement in the markers of antioxidant status.

  20. OKT3 therapy in addition to tacrolimus is associated with improved long-term function in patients with steroid refractory renal allograft rejection.

    PubMed

    Patschan, Daniel; Kribben, Andreas; Pietruck, Frank; Lutz, Jens; Binek, Matthias; Philipp, Thomas; Heemann, Uwe; Witzke, Oliver

    2006-01-01

    The aim of this study was to evaluate long-term allograft salvage rates of patients with steroid refractory allograft rejection after kidney transplantation and to identify factors indicating a successful outcome. Fifty patients with continuing rejection after high-dose steroids were included in the study. Baseline immunosuppression was switched from cyclosporine to tacrolimus in all patients. Twenty patients additionally received OKT3 as antirejection therapy. Patients having received a cadaveric renal transplant in 1995, excluding patients with steroid resistant rejection, were chosen as a control cohort. Patient survival rates were 96% (n = 48) and 90% (n = 45) and allograft survival rates were 66% (n = 33) and 62% (n = 31) after 5 and 7 years following steroid refractory renal allograft rejection. Graft survival within the control cohort was 73% after 5 years and 69% after 7 years. Creatinine clearance increased from 20 +/- 15 ml/min/1.73 m2 at the start of tacrolimus therapy to 37 +/- 29 ml/min/1.73 m2 and to 32 +/- 26 ml/min/1.73 m2 after 5 and 7 years. OKT3 treatment predicted successful rescue therapy (p = 0.005 and p = 0.04 after 5 and 7 years). Our data indicate a reasonable graft survival in steroid refractory renal allograft rejection using tacrolimus. OKT3 treatment in addition to tacrolimus therapy may be beneficial for long-term allograft survival. Copyright 2006 S. Karger AG, Basel

  1. MicroCRP: a highly sensitive CRP method applied in the monitoring of renal allograft recipients.

    PubMed

    Wergeland, R; Oyen, O; Bentdal, O; Stokke, O

    1999-10-01

    A new ultrasensitive fluoroimmunometric assay for C-reactive protein (CRP), called MicroCRP assay, has a lower detection limit of 0.05 mg/l, and a CV of 7.6% at concentration 0.25 mg/l. The microCRP levels in healthy adults show a skewed distribution, median 0.90 mg/l and mean 1.4 mg/l, with 2.5th and 97.5th percentiles of 0.17 and 4.7 mg/l, respectively, and no gender-related or age differences. Serial microCRP was applied in the monitoring of 37 renal allograft recipients. The operative trauma gave rise to an initial CRP peak, usually on day 2 after transplantation, with a return to preoperative value 1 week after surgery. There were significant CRP elevations (>25%) in all cases of rejections, indicating 100% sensitivity. The microCRP values started to increase about 3 days (range -1 to 9 days) before the rise in creatinine. The microCRP peak tended to be higher in rejection episodes with a vascular component, compared with episodes of cellular rejection (p=0.05). A rise in microCRP at days 7-12 after transplantation seems to predict the risk of rejections later on, and probably reflects the primary immune response to the graft. Recipients without this primary CRP response (only 6 of 37 patients) subsequently had uncomplicated courses. Tracking of values below the traditional lower limit is essential in order to recognize the different CRP peaks. Serial monitoring of microCRP is well suited for clinical use and provides clinical information previously unattainable with other assay systems.

  2. No change in complication rate using spring-loaded gun compared to traditional percutaneous renal allograft biopsy techniques.

    PubMed

    Kovalik, E C; Schwab, S J; Gunnells, J C; Bowie, D; Smith, S R

    1996-06-01

    The previous methods to biopsy renal allografts at our institution involved the use of the Franklin-Silverman or Tru-Cut needles. Unfortunately they had a significant rate of post biopsy bleeding secondary to deep penetration when excess force was used to penetrate a tough transplant capsule. Although spring loaded biopsy devices have been widely used for native kidney biopsies over the past three years, the complication rate for renal allograft biopsies has not been sufficiently evaluated. We describe our experience using a disposable spring loaded biopsy device on transplanted renal grafts. Fifty-four biopsies were performed with the device, all under ultrasound guidance. The ASAP automatic biopsy system by Medi-tech was used comprising of a spring loaded gun with a 15 cm long 15 GA needle echogenic tip and 17 mm specimen notch. All patients were ultrasounded immediately post biopsy to look for hematomas. Compared to 55 previous biopsies performed using Tru-Cut needles, we conclude that the ASAP automated biopsy system proved equally effective in obtaining adequate tissue for diagnosis with fewer post-biopsy hematomas compared to traditional biopsy methods.

  3. Correlation of whole kidney hypertrophy with glomerular over-filtration in live, gender-mismatched renal transplant allografts.

    PubMed

    Yanishi, Masaaki; Tsukaguchi, Hiroyasu; Huan, Nguyen Thanh; Koito, Yuya; Taniguchi, Hisanori; Yoshida, Kenji; Mishima, Takao; Sugi, Motohiko; Kinoshita, Hidefumi; Matsuda, Tadashi

    2016-08-30

    Optimizing nephron supply to recipient demand is a non-immunologic determinant of renal allograft outcome. Nephron reduction is usually caused by physical donor-recipient mismatch, but its pathologic relevance remains to be determined. Thirty-one recipients of living donor renal transplants were divided into three subgroups: those who received transplants from the same gender (n = 6, Group 1) and those who underwent male-to-female (n = 8, Group 2) and female-to-male (n = 17, Group 3) transplants. Renal mass was evaluated by three-dimensional computed tomography (3D-CT) volumetry before and one year after transplantation. Glomerular volume was determined from protocol biopsies obtained one hour and one year after transplantation. Histologically determined glomerular volume in biopsied tissues showed a significant linear correlation with allograft size on 3D-CT volumetry (p < 0.001, r = 0.625). Mismatches in body weight, glomerular volume and kidney volume ratios were significantly greater in female-to-male (Group 3) than in male-to-female (Group 2) transplants (p < 0.001 each). Despite the two groups having nearly equal graft filtration rates one year after transplantation, proteinuria rate was three-fold higher in Group 3 than in Group 2 (p < 0.001). These findings suggest that too small graft size, frequent in female-to-male transplants, could cause hypertrophy in both kidneys and glomeruli, thereby affecting allograft function and survival. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. Ultrasound Strain Relaxation Time Ratio: A Quantitative Marker for the Assessment of Cortical Inflammation/Edema in Renal Allografts.

    PubMed

    Gao, J; Hentel, K; Kazam, J; Min, R

    2016-10-01

    Purpose: To evaluate the ability of ultrasound strain relaxation time ratio to assess cortical inflammation/edema in renal allografts. Materials and Methods: We prospectively assessed renal allograft cortical inflammation/edema in 16 renal transplants using ultrasound elasticity imaging and correlated the findings with kidney biopsy. Strain relaxation times in the renal cortex and reference soft tissue were produced by free-hand compression with the ultrasound transducer and estimated with 2 D speckle tracking. Compression was performed in 3-second compression-relaxation cycles (push for 1 second, constant pressure for 1 second, and release for 1 second). We propose a strain relaxation time ratio (time of cortical strain to return to zero/time of the reference strain return to zero) to assess the relationship of compression-induced time-dependent strain relaxation in the cortex and reference tissue. 16 patients were divided into a group with ≤ 25 % (n = 8) and a group with > 26 % (n = 8) cortical inflammation/edema based on the Banff score. A t-test was used to examine the difference in the strain relaxation time ratio between the two groups. The diagnostic accuracy, inter-rater reliability, and reproducibility of this technique in discriminating between the groups were tested. Results: The strain relaxation time ratio of cortex/reference tissue was significantly higher in patients with > 26 % than in patients with ≤ 25 % cortical inflammation/edema (1.15 ± 0.10 vs. 0.91 ± 0.08, P = 0.0002). The strain relaxation time ratio has high reliability (Pearson correlation coefficient, R² = 0.93), reproducibility (intraclass correlation coefficient = 0.98, P = 0.000), and accuracy (area under curve = 1) in determining > 26 % renal cortical inflammation/edema. Conclusion: The strain relaxation time ratio of cortex/reference tissue can be used as a quantitative marker for the assessment of cortical

  5. Randomized controlled trial: lisinopril reduces proteinuria, ammonia, and renal polypeptide tubular catabolism in patients with chronic allograft nephropathy.

    PubMed

    Amara, Alieu B; Sharma, Asheesh; Alexander, John L; Alfirevic, Ana; Mohiuddin, Atif; Pirmohamed, Munir; Close, Graeme L; Grime, Steve; Maltby, Paul; Shawki, Howida; Heyworth, Sally; Shenkin, Alan; Smith, Linda; Sharma, Ajay K; Hammad, Abdel; Rustom, Rana

    2010-01-15

    Angiotensin-converting enzyme inhibitors in native nephropathies reduce proteinuria and delay progression to renal failure. Data in renal transplantation remain limited. A negative effect on glomerular filtration rate was concluded in a recent systematic review. In this novel randomized controlled trial, 47 patients with chronic allograft nephropathy, severe renal impairment, and more than or equal to 1 g/24 hr proteinuria were randomized to lisinopril (group A) or other hypotensives (group B) for 1 year. Sodium bicarbonate was given to all patients to treat metabolic acidosis prophylactically (acidosis increases significantly with lisinopril). The annual rate of decline of graft function was measured isotopically (primary outcome) and 24 hr proteinuria, genotyping, radiolabeled polypeptide aprotinin proximal tubular catabolic studies (in group A only) as secondary outcome measurements were undertaken. At baseline, groups were comparable except for greater proteinuria in group A. After 1 year, the rate of decline of graft function and graft survival were comparable in both groups. Proteinuria decreased significantly in group A patients only. Lisinopril also significantly reduced radiolabeled aprotinin uptake and metabolism, plasma aldosterone, and ammonia excretion. Plasma potassium, bicarbonate, and mean arterial pressures were comparable in both groups. Patients with more than or equal to 30% reduction in proteinuria had a significant association with rs699 polymorphism in the angiotensinogen gene. The rate of decline of renal graft function in patients with chronic allograft nephropathy was not adversely affected by lisinopril therapy given for 1 year. Lisinopril significantly reduced proteinuria, renal proximal tubular polypeptide catabolism, plasma aldosterone, and ammonia excretion suggesting relative preservation of graft function. Treating metabolic acidosis allowed safe and prolonged use of angiotensinogen-converting enzyme inhibitors.

  6. Racial Differences in Incident De Novo Donor-Specific Anti-HLA Antibody among Primary Renal Allograft Recipients.

    PubMed

    Everly, Matthew J; Briley, Kimberly P; Haisch, Carl E; Dieplinger, Georg; Bolin, Paul; Kendrick, Scott A; Morgan, Claire; Maldonado, Angela Q; Rebellato, Lorita M

    2017-02-17

    Controversy exists as to whether African American (AA) transplant recipients are at risk for developing de novo donor-specific anti-human leukocyte antigen (HLA) antibody (dnDSA). We studied 341 HLA-mismatched, primary renal allograft recipients who were consecutively transplanted between 3/1999 and 12/2010. Sera were collected sequentially pre- and post-transplant and tested for anti-HLA immunoglobulin G (IgG) via single antigen bead assay. Of the 341 transplant patients (225 AA and 116 non-AA), 107 developed dnDSA at a median of 9.2 months post-transplant. AA patients had a 5-year dnDSA incidence of 35%. This was significantly higher than the 5-year dnDSA incidence for non-AA patients (21%). DQ mismatch (risk) and receiving a living-related donor (LRD) transplant (protective) were transplant factors associated with dnDSA. Within the AA patient cohort, HLA-DQ mismatch, not-receiving a LRD transplant, non-adherence, and BK viremia were the most common factors associated with early dnDSA (occurring <24 months post-transplant). Non-adherence and pre-transplant diabetes history were the strong precursors to late dnDSA. Despite the higher rates of dnDSA in the AA cohort, post-dnDSA survival was the same in AA and non-AA patients. This study suggests that DQ matching, increasing LRD transplantation in AA patients, and minimizing under-immunosuppression will be key to preventing dnDSA. This article is protected by copyright. All rights reserved.

  7. Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell-Mediated Rejection.

    PubMed

    Matignon, M; Aissat, A; Canoui-Poitrine, F; Grondin, C; Pilon, C; Desvaux, D; Saadoun, D; Barathon, Q; Garrido, M; Audard, V; Rémy, P; Lang, P; Cohen, J; Grimbert, P

    2015-10-01

    Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell-mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell-mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il-17 and T-bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell-mediated rejection reversal (p = 0.03). The presence of IL-17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell-mediated rejection in recipients of expanded criteria allograft.

  8. Osteoinductive effect of bone bank allografts on human osteoblasts in culture.

    PubMed

    de la Piedra, Concepción; Vicario, Carlos; de Acuña, Lucrecia Rodríguez; García-Moreno, Carmen; Traba, Maria Luisa; Arlandis, Santiago; Marco, Fernando; López-Durán, Luis

    2008-02-01

    Incorporation of a human bone allograft requires osteoclast activity and growth of recipient osteoblasts. The aim of this work was to study the effects produced by autoclavated and -80 degrees C frozen bone allografts on osteoblast proliferation and synthesis of interleukin 6 (IL6), activator of bone resorption, aminoterminal propeptide of procollagen I (PINP), marker of bone matrix formation, and osteoprotegerin (OPG), inhibitor of osteoclast activity and differentiation. Allografts were obtained from human femoral heads. Human osteoblasts were cultured in the presence (problem group) or in the absence (control group) of allografts during 15 days. Allografts produced a decrease in osteoblast proliferation in the first week of the experiment, and an increase in IL6 mRNA, both at 3 h and 2 days, and an increase in the IL6 released to the culture medium the second day of the experiment. We found a decrease in OPG released to the culture on the 2nd and fourth days. These results suggest an increase in bone resorption and a decrease in bone formation in the first week of the experiment. In the second week, allografts produced an increase in osteoblast proliferation and PINP release to the culture medium, indicating an increase in bone formation; an increase in OPG released to the culture medium, which would indicate a decrease in bone resorption; and a decrease in IL6, indicating a decrease in bone resorption stimulation. These results demonstrate that autoclavated and -80 degrees C frozen bone allografts produce in bone environment changes that regulate their own incorporation to the recipient bone.

  9. Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction.

    PubMed

    Bombas, A; Stein-Oakley, A N; Baxter, K; Thomson, N M; Jablonski, P

    1999-01-01

    Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage.

  10. FK506 “RESCUE” FOR RESISTANT REJECTION OF RENAL ALLOGRAFTS UNDER PRIMARY CYCLOSPORINE IMMUNOSUPPRESSION1

    PubMed Central

    Jordan, Mark L.; Shapiro, Ron; Vivas, Carlos A.; Scantlebury, Velma P.; Rhandhawa, Parmjeet; Carrieri, Giuseppe; McCauley, Jerry; Demetris, A.J.; Tzakis, Andreas; Fung, John J.; Simmons, Richard L.; Hakala, Thomas R.; Starzl, Thomas E.

    2010-01-01

    Seventy-seven patients with ongoing acute rejection on initial CsA therapy were converted to FK506 to attempt graft salvage. Fifty-nine patients had undergone primary transplantation and 18 had been retransplanted; there were 52 cadaveric and 25 living-donor transplants. The indications for conversion to FK506 were ongoing, biopsy-confirmed rejection in all patients, including vascular rejection in 20. The median interval to rescue was 2 months (range 2 weeks to 36 months) after transplantation. Sixty-one of the 77 patients (79%) had already received one or more courses of an antilymphocyte preparation (OKT3: n=33; ALG or ATG: n=l; OKT3+ALG/ATG: n=27). Of the 77 patients, 57 (74%) have been successfully rescued and still have functioning grafts with a mean follow-up of 14 months, with a mean serum creatinine of 2.35±0.97 mg/dl. Eighteen patients were already dialysis-dependent at the time of conversion to FK506; of these, 9 (50%) were successfully salvaged and have a mean serum creatinine of 2.3 mg/dl. Of the 61 patients previously treated with antilymphocyte preparations, 48 (79%) were rescued. In those salvaged, prednisone doses have been lowered from 22.2±7.2 mg/day preconversion to 7.5±5.6 mg/day postconversion, and 12 patients are on FK506 monotherapy. In nondiabetics, mean serum glucose was 101.4±20.5 mg/dl preconversion and 93.2±22 postconversion (P=0.07), uric acid 7.3±2.3 and 7.1±1.5 mg/dl (P=0.53), and triglycerides 199.2±101.6 and 167.2±106.4 mg/dl (P=0.06). Cholesterol levels were significantly lower following FK conversion (207.7±46.5 mg/dl pre. vs. 188.3±39.7 post., P=0.007). FK506 is capable of salvaging renal allografts with ongoing acute rejection on CsA therapy, even when antilymphocyte preparations have been ineffective. PMID:7512293

  11. Ultrasound strain zero-crossing elasticity measurement in assessment of renal allograft cortical hardness: a preliminary observation.

    PubMed

    Gao, Jing; Rubin, Jonathan M

    2014-09-01

    To determine whether ultrasound strain zero-crossing elasticity measurement can be used to discriminate moderate cortical fibrosis or inflammation in renal allografts, we prospectively assessed cortical hardness with quasi-static ultrasound elastography in 38 renal transplant patients who underwent kidney biopsy from January 2013 to June 2013. With the Banff score criteria for renal cortical fibrosis as gold standard, 38 subjects were divided into two groups: group 1 (n = 18) with ≤25% cortical fibrosis and group 2 (n = 20) with >26% cortical fibrosis. We then divided this population again into group 3 (n = 20) with ≤ 25% inflammation and group 4 (n = 18) with >26% inflammation based on the Banff score for renal parenchyma inflammation. To estimate renal cortical hardness in both population divisions, we propose an ultrasound strain relative zero-crossing elasticity measurement (ZC) method. In this technique, the relative return to baseline, that is zero strain, of strain in the renal cortex is compared with that of strain in reference soft tissue (between the abdominal wall and pelvic muscles). Using the ZC point on the reference strain decompression slope as standard, we determined when cortical strain crossed zero during decompression. ZC was negative when cortical strain did not return or returned after the reference, whereas ZC was positive when cortical strain returned ahead of the reference. Fisher's exact test was used to examine the significance of differences in ZC between groups 1 and 2 and between groups 3 and 4. The accuracy of ZC in determining moderate cortical fibrosis and moderate inflammation was examined by receiver operating characteristic analysis. The intra-class correlation coefficient and analysis of variance were used to test inter-rater reliability and reproducibility. ZC had good inter-observer agreement (ICC = 0.912) and reproducibility (p = 0.979). ZCs were negative in 18 of 18 cases in group 1 and positive in 19 of 20 cases in

  12. The value of needle renal allograft biopsy. I. A retrospective study of biopsies performed during putative rejection episodes.

    PubMed Central

    Matas, A J; Sibley, R; Mauer, M; Sutherland, D E; Simmons, R L; Najarian, J S

    1983-01-01

    Following renal transplantation, immunosuppression is usually increased to treat presumed rejection episodes. However, a) many conditions mimic rejection in the post-transplant period, and b) many rejection episodes are irreversible. As increased immunosuppressive therapy is associated with an increased risk of infection, it would be ideal to limit antirejection therapy to only the rejection episodes that are reversible. The role of percutaneous allograft biopsy was studied as an aid to decide which patients to treat for rejection, to limit unnecessary immunosuppression and to predict allograft survival. One hundred thirty-five patients with suspected rejection underwent 206 allograft biopsies without complication. Two hundred four biopsies were available for study. Biopsies were coded on a 1-4 scale (minimal, mild, moderate, severe) for acute and chronic tubulointerstitial infiltrate and vascular rejection, as well as no rejection (e.g., recurrence of original disease). Treatment decisions were made on the basis of the biopsy combined with clinical data. All patients have been followed two years and outcome correlated with biopsy findings (death, nephrectomy, and return to dialysis defined as kidney loss). The results were the following: 1) biopsies represented changes within the kidney. Of 16 kidneys removed within one month of biopsy, no nephrectomy specimen showed less rejection than that seen on biopsy. 2) Eighty-one biopsies (39.7%) led to tapering or not increasing immunosuppression (either no rejection, minimal rejection, or irreversible changes). 3) Kidneys having either severe acute or chronic vascular rejection (less than 30% function at three months) had significantly (p less than 0.05) decreased survival three to 24 months postbiopsy than those with minimal or mild vascular rejection or tubulointerstitial infiltrate (83% function at three months). 4) Kidneys with moderate chronic vascular rejection and those with severe acute tubulointerstitial

  13. Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF.

    PubMed

    Gallon, L; Perico, N; Dimitrov, B D; Winoto, J; Remuzzi, G; Leventhal, J; Gaspari, F; Kaufman, D

    2006-07-01

    It is not known how different steroid-free immunosuppressive combinations affect renal graft survival and long-term kidney transplant function. Here we sought to compare the impact on graft survival and long-term graft function of two tacrolimus (Tac)-based, prednisone-free maintenance immunosuppressive protocols: Tac/Mycophenolate Mofetil (MMF) vs. Tac/Sirolimus (SRL). Renal transplant patients given induction therapy with IL2-RA and methylprednisolone on days 0, 1 and 2 post-transplant were prospectively randomized to two maintenance immunosuppressive regimens with Tac/MMF (n = 45) or Tac/SRL (n = 37). During the 3-year follow-up the following data were collected: patient survival, renal allograft survival, incidence of acute rejection and glomerular filtration rate (GFR) at different time-points post-transplant. Cumulative graft survival was significantly different in the two groups: one kidney loss in the Tac/MMF vs. six kidney losses in the Tac/SRL (log-rank test p = 0.04). GFR at different time-points post-transplant was consistently and statistically better in the Tac/MMF than in the Tac/SRL group. The slope of GFR decline per month was flatter in the Tac/MMF than in the Tac/SRL group. This study showed that renal graft survival and graft function were significantly lower in the combination of Tac/SRL than Tac/MMF.

  14. Suppression of Chronic Damage in Renal Allografts by Liver X Receptor (LXR) Activation

    PubMed Central

    Kiss, Eva; Popovic, Zoran; Bedke, Jens; Wang, Shijun; Bonrouhi, Mahnaz; Gretz, Norbert; Stettner, Paula; Teupser, Daniel; Thiery, Joachim; Porubsky, Stefan; Adams, Judith; Gröne, Hermann-Josef

    2011-01-01

    Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRα (mLXRα-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow–derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRα-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRα-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1– and mannose receptor C type 1–positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRα overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRα in allograft rejection and prevention of fibrosis. PMID:21703396

  15. Belatacept and Sirolimus Prolong Nonhuman Primate Renal Allograft Survival without a Requirement for Memory T Cell Depletion

    PubMed Central

    Lo, Denise J; Anderson, Douglas J; Weaver, Timothy A; Leopardi, Frank; Song, Mingqing; Farris, Alton B; Strobert, Elizabeth A; Jenkins, Joe; Turgeon, Nicole A; Mehta, Aneesh K; Larsen, Christian P; Kirk, Allan D

    2012-01-01

    Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, non-lymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, non-depleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation. PMID:23311611

  16. Ultimate tensile failure loads of a human dermal allograft rotator cuff augmentation.

    PubMed

    Barber, F Alan; Herbert, Morley A; Boothby, Michael H

    2008-01-01

    The purpose of this study was to examine the failure mode of supraspinatus tendon repairs with and without human dermal allograft augmentation. Ten matched pairs of human cadaveric supraspinatus muscles and tendons were detached from their greater tuberosity insertions and then reattached with four simple sutures in 2 suture anchors as a control group. One shoulder from each matched pair was augmented with human dermal allograft secured to the humerus and the supraspinatus tendon using the same sutures and suture anchors. Additional interrupted mattress sutures secured the edges of the dermal allograft to the supraspinatus tendon. Each construct was preloaded at 10 N and then cyclically loaded between 10 N and 100 N for 10 cycles at 20 N/s followed by destructive testing at 33 mm/s. Force and displacement were recorded. The mean failure strengths for the control and augmented constructs were 273 +/- 116 N and 325 +/- 74 N, respectively (P = .047). No significant displacement occurred during the cyclic phase, and no anchors failed. These constructs failed by 2 different mechanisms: tendon-suture interface failure (8/10 non-augmented repairs and 6/10 augmented repairs) and suture breakage (2/10 non-augmented repairs and 4/10 augmented repairs). This examination of the failure characteristics and ultimate failure load of supraspinatus tendon tears augmented with GraftJacket (Wright Medical Technology, Arlington, TN) supported the study hypothesis that a human dermal allograft significantly increases the strength of a repaired tendon. The human dermal allograft can be expected to significantly increase the initial strength of a rotator cuff repair.

  17. Relationship between European Mitochondrial Haplogroups and Chronic Renal Allograft Rejection in Patients with Kidney Transplant

    PubMed Central

    JIMÉNEZ-SOUSA, María Angeles; TAMAYO, Eduardo; GUZMÁN-FULGENCIO, María; FERNÁNDEZ-RODRÍGUEZ, Amanda; HEREDIA-RODRIGUEZ, María; GARCÍA-ÁLVAREZ, Mónica; BERMEJO-MARTIN, Jesús F; PINEDA-TENOR, Daniel; RUIZ-GRANADO, Patricia; ALVAREZ-FUENTE, Elisa; GÓMEZ-SANCHEZ, Esther; GÓMEZ-HERRERAS, José I; RESINO, Salvador

    2014-01-01

    Mitochondrial DNA variants may contribute to differences in mitochondrial function, leading to an altered immune system. The aim of this study was to analyze the relationship between mtDNA haplogroups and the development of chronic allograft dysfunction in patients with kidney transplant. A retrospective observational study was carried out on 261 patients who received kidney transplant (114 had stable transplant and 147 patients developed chronic allograft dysfunction). DNA samples were genotyped for 14 mtDNA polymorphisms by using Sequenom's MassARRAY platform (San Diego, CA, USA). Only European white patients within the N macro-cluster were included. Patients with haplogroups V (odds ratio (OR)=0.32; p=0.037) and J (OR=0.36; p=0.038) showed lower odds for developing CRAD than patients with haplogroup H. After adjusting for the most significant variables, haplogroups V and J tended to statistical significance (p=0.091 and p=0.067 respectively). This is a preliminary study in which mtDNA haplogroups seem to be implicated in susceptibility or protection for developing chronic allograft dysfunction. PMID:25170295

  18. Lymphocyte markers and prediction of long-term renal allograft acceptance.

    PubMed

    Babel, Nina; Reinke, Petra; Volk, Hans-Dieter

    2009-11-01

    Long-term allograft acceptance is the main goal of posttransplant care. Modern immunosuppression has reduced the incidence of acute rejection, the major risk factor for long-term allograft survival, and improved the 1-year results, despite increasing use of marginal donor organs. However, the long-term results are still unsatisfactory. Chronic allograft injury and side effects of chronic immunosuppression are the main causes. Therefore, preemptive reduced long-term immunosuppression is required. Present 'trial-and-error' strategies appear to be remarkably harmful for patients not suitable for partial drug weaning. In addition, preemptive interventions have been shown to be the only successful strategy for improving the long-term transplant outcome in animal models. These findings underline the importance of early identification of biomarkers in detecting the individual's risk. Recent technological advances have provided evidence of successful approaches to this goal. A set of parameters/tests are showing promise for guiding personalized immunosuppression, including different technology platforms such as antidonor responsiveness/nonresponsiveness, cellular parameters predicting risk of virus-associated complications, gene expression analysis etc. Although the data are very promising, multicentric, prospective, randomized clinical trials are crucial prerequisites for introducing immune monitoring into routine clinical use. International networks, such as RISET and ITN, can help to facilitate this process.

  19. Bilateral native kidney neoplasia detected by ultrasound in functionning renal allograft recipient.

    PubMed

    Noce, Annalisa; Iaria, Giuseppe; Durante, Olga; Sforza, Daniele; Canale, Maria Paola; Di Villahermosa, Simone Manca; Castagnola, Veronica; Tisone, Giuseppe; Di Daniele, Nicola

    2012-12-01

    We report the case of bilateral renal clear cell carcinoma in the native kidney, occurring fouryears after renal transplantation. Renal Doppler duplex sonography revealed large solid bilateral neoformation. Total-body computed tomography confirmed the presence of bilateral kidney lesions and also showed the presence of concomitant gross dyscariocinetic lesion of left hemotorax. The patient underwent bilateral native nephrectomy and the histological diagnosis was renal cell carcinoma. Subsequent left upper lobectomy revealed necrotic keratinizing squamous cell carcinoma. Then, the patients was switched tacrolimus to everolimus treatment and mycophenolate mofetil was reduced.

  20. Utility of human amniotic membrane allograft in re-epithelialization of the nasal tip

    PubMed Central

    Dennis, D'Antonio C.; Turnock, Adam R.; Sutton, Collin; Chastant, Bradley; Vanderlan, Wesley B.

    2016-01-01

    Variations in skin thickness and contours pose significant challenges to reconstruction of the lower third of the nose. Human amniotic membrane allograft offers a potential alternative to tissue transfer in reconstruction of the lower third of the nose. We reviewed the procedure and photographs of a healthy 56-year-old male with a 22 × 18 mm lower third nasal defect involving full thickness skin and subcutaneous tissue. Following preparation for grafting, dehydrated human amniotic membrane was fashioned to the dimensions of the defect and applied. No further surgical intervention was provided for 3 months. Complete re-epithelialization of the nasal and adjacent defects was achieved with minimal scar formation. Human amniotic membrane allograft provides an efficacious and cosmetically acceptable alternative to local and regional tissue transfer.

  1. Antibody response against perlecan and collagen types IV and VI in chronic renal allograft rejection in the rat.

    PubMed

    Joosten, Simone A; van Dixhoorn, Mieneke G A; Borrias, Maria C; Benediktsson, Hallgrimur; van Veelen, Peter A; van Kooten, Cees; Paul, Leendert C

    2002-04-01

    Chronic rejection is the leading cause of late renal transplant failure. Various structural lesions are observed in grafts undergoing chronic rejection including glomerular basement membrane (GBM) duplications. The well-established Fisher (F344) to Lewis (LEW) rat renal transplant model for chronic rejection was used to assess the presence and role of the humoral immune response against graft antigens during chronic rejection. LEW recipients of F344 allografts develop transplant glomerulopathy and produce IgG1 antibodies directed against F344 GBM preparations that are detectable 3 weeks after transplantation. Glomerular IgG1 deposition was observed that in vitro co-localized with a rabbit anti-rat GBM antiserum in rejecting F344 grafts; elution experiments of isolated glomeruli yielded IgG1 antibodies reactive in vitro with F344 GBM, but not LEW GBM. Prevention of acute rejection by transient treatment of the recipients with cyclosporin A completely abrogated the production of anti-GBM antibodies. Using proteomic techniques we identified the antigens recognized by the LEW posttransplant sera as being the heparan sulfate proteoglycan perlecan and the alpha1 chain of collagen type VI in association with the alpha5 chain of collagen type IV. In conclusion, LEW recipients of F344 kidney grafts produce IgG1 antibodies against donor type perlecan and alpha1(VI)/alpha5(IV) collagen and develop transplant glomerulopathy. These data implicate an important role for the humoral immune response in the development of glomerulopathy during chronic rejection.

  2. Excess risk of renal allograft loss and early mortality among elderly recipients is associated with poor exercise capacity.

    PubMed

    Yango, A F; Gohh, R Y; Monaco, A P; Reinert, S E; Gautam, A; Dworkin, L D; Morrissey, P E

    2006-06-01

    Successful renal transplantation in the elderly offers substantial benefits in quality and life expectancy. However, in this group of patients there is an early increased risk of death compared with those remaining on dialysis. Graft and patient outcomes in 64 older transplant recipients were compared with 338 patients aged 18 - 59 years. We identified potential risk factors that may predict clinical outcomes in older transplant recipients. A log-rank test and Cox regression analyses were performed to assess the impact of various patient characteristics on graft and patient survival. Among older patients, graft survival was 76.6% and 67% at 1 and 3 years, respectively. When graft survival was censored for death with functioning graft, the 1- and 3-year graft survival was 83% and 82%, respectively. Patient survival was 78% and 71% at 1 and 3 years, respectively. These survival rates were significantly lower than those of younger recipients. Pretransplant inactivity, delayed graft function, smoking history and longer waiting time predicted poor graft and patient survival. A history of chronic obstructive pulmonary disease, and peripheral vascular disease also predicted a higher mortality among older recipients. Older kidney transplant recipients are at high risk for allograft failure and early death. Poor functional capacity predicts a poor outcome for older patients undergoing renal transplantation. Therefore, careful patient selection is paramount, and every effort should be made to initiate timely interventions aimed at increasing physical activity in those with low fitness level.

  3. Innovative Applications of Robotic Surgery: Renal Allograft and Autologous Transplantation.

    PubMed

    Lee, Jason; Ordon, Michael

    2016-01-01

    Robotic surgery has enabled surgeons to offer more patients a minimally invasive surgical option in the management of their complex diseases. While renal transplantation is associated with significant improvements in quantity and quality of life for most end-stage renal disease (ESRD) patients, it is also not devoid of its surgical risks and potential morbidities. Robotic-assisted kidney transplantation is a recently described, innovative application of the robotic surgery platform, and early experiences suggest that it is associated with comparable graft function and lower rates of complications. Urinary tract obstruction, though less common than ESRD, can be a serious threat to renal function. Severe ureteric stricture disease can represent a clinically complex problem requiring major reconstructive surgery. Completely intra-corporeal robotic renal auto-transplantation is another innovative application of the robotic surgery platform and represents a significant advancement in urologic surgery. Initial reports of this procedure demonstrate safety, feasibility, and excellent renal function outcomes.

  4. A randomized, open-label study of sirolimus versus cyclosporine in primary de novo renal allograft recipients.

    PubMed

    Flechner, Stuart M; Gurkan, Alihan; Hartmann, Anders; Legendre, Christophe M; Russ, Graeme R; Campistol, Josep M; Schena, Francesco P; Hahn, Carolyn M; Li, Huihua; Korth-Bradley, Joan M; Tai, Sandi See; Schulman, Seth L

    2013-05-27

    Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, results in improved long-term renal function. This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm. Enrollment was stopped after ≈12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean±SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1±18.7 mL/min) and CsA (66.0±15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001). A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended.

  5. Association of peripheral NK cell counts with Helios(+) IFN-γ(-) Tregs in patients with good long-term renal allograft function.

    PubMed

    Trojan, K; Zhu, L; Aly, M; Weimer, R; Bulut, N; Morath, C; Opelz, G; Daniel, V

    2017-02-14

    Little is known about a possible interaction of natural killer (NK) cells with regulatory T cells (Treg ) in long-term stable kidney transplant recipients. Absolute counts of lymphocyte and Treg subsets were studied in whole blood samples of 136 long-term stable renal transplant recipients and 52 healthy controls using eight-colour fluorescence flow cytometry. Patients were 1946 ± 2201 days (153-10 268 days) post-transplant and showed a serum creatinine of 1·7 ± 0·7 mg/dl. Renal transplant recipients investigated > 1·5 years post-transplant showed higher total NK cell counts than recipients studied < 1·5 years after transplantation (P = 0·006). High NK cells were associated with high glomerular filtration rate (P = 0·002) and low serum creatinine (P = 0·005). Interestingly, high NK cells were associated with high CD4(+) CD25(+) CD127(-) forkhead box protein 3 (FoxP3(+) ) Treg that co-express the phenotype Helios(+) interferon (IFN)-γ(-) and appear to have stable FoxP3 expression and originate from the thymus. Furthermore, high total NK cells were associated with Treg that co-express the phenotypes interleukin (IL)-10(-) transforming growth factor (TGF)-β(+) (P = 0·013), CD183(+) CD62L(-) (P = 0·003), CD183(+) CD62(+) (P = 0·001), CD183(-) CD62L(+) (P = 0·002), CD252(-) CD152(+) (P < 0·001), CD28(+) human leucocyte antigen D-related (HLA-DR(-) ) (P = 0·002), CD28(+) HLA-DR(+) (P < 0·001), CD95(+) CD178(-) (P < 0·001) and CD279(-) CD152(+) (P < 0·001), suggesting that these activated Treg home in peripheral tissues and suppress effector cells via TGF-β and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). The higher numbers of NK and Treg cell counts in patients with long-term good allograft function and the statistical association of these two lymphocyte subsets with each other suggest a direct or indirect (via DC) interaction of these cell subpopulations that contributes to good

  6. Clinical Experience: Using Dehydrated Human Amnion/Chorion Membrane Allografts for Acute and Reconstructive Burn Care.

    PubMed

    Reilly, Debra Ann; Hickey, Sean; Glat, Paul; Lineaweaver, William C; Goverman, Jeremy

    2017-02-01

    Amniotic membrane is immunologically privileged and is a reservoir of growth factors and cytokines known to modulate inflammation and enhance the healing process, while also possessing antimicrobial, antifibrosis, and antiscarring properties. These properties establish a strong argument for using amniotic membrane derived products as a treatment for burns. The purpose of this article is to describe the use of commercially available dehydrated human amnion/chorion membrane allografts in patients with partial-thickness and full-thickness burns.

  7. High soluble CD30 levels and associated anti-HLA antibodies in patients with failed renal allografts.

    PubMed

    Karahan, Gonca E; Caliskan, Yasar; Ozdilli, Kursat; Kekik, Cigdem; Bakkaloglu, Huseyin; Caliskan, Bahar; Turkmen, Aydin; Sever, Mehmet S; Oguz, Fatma S

    2017-01-13

    Serum soluble CD30 (sCD30), a 120-kD glycoprotein that belongs to the tumor necrosis factor receptor family, has been suggested as a marker of rejection in kidney transplant patients. The aim of this study was to evaluate the relationship between sCD30 levels and anti-HLA antibodies, and to compare sCD30 levels in patients undergoing hemodialysis (HD) with and without failed renal allografts and transplant recipients with functioning grafts. 100 patients undergoing HD with failed grafts (group 1), 100 patients undergoing HD who had never undergone transplantation (group 2), and 100 kidney transplant recipients (group 3) were included in this study. Associations of serum sCD30 levels and anti-HLA antibody status were analyzed in these groups. The sCD30 levels of group 1 and group 2 (154 ± 71 U/mL and 103 ± 55 U/mL, respectively) were significantly higher than those of the transplant recipients (group 3) (39 ± 21 U/mL) (p<0.001 and p<0.001). The serum sCD30 levels in group 1 (154 ± 71 U/mL) were also significantly higher than group 2 (103 ± 55 U/mL) (p<0.001). Anti-HLA antibodies were detected in 81 (81%) and 5 (5%) of patients in groups 1 and 2, respectively (p<0.001). When multiple regression analysis was performed to predict sCD30 levels, the independent variables in group 1 were the presence of class I anti-HLA antibodies (β = 0.295; p = 0.003) and age (β = -0.272; p = 0.005), and serum creatinine (β = 0.218; p = 0.027) and presence of class II anti-HLA antibodies (standardized β = 0.194; p = 0.046) in group 3. Higher sCD30 levels and anti-HLA antibodies in patients undergoing HD with failed renal allografts may be related to higher inflammatory status in these patients.

  8. Non-mycotic anastomotic pseudoaneurysm of renal allograft artery. Case Report.

    PubMed

    Ardita, Vincenzo; Veroux, Massimiliano; Zerbo, Domenico; D'Arrigo, Giuseppe; Caglià, Pietro; Veroux, Pierfrancesco

    2016-06-20

    Le complicanze vascolari dopo il trapianto renale non sono comuni, e nella maggior parte dei casi si presentano nel periodo post-trapianto precoce. Gli pseudoaneurismi arteriosi coinvolgono l’anastomosi arteriosa del rene trapiantato e nella maggior parte dei casi riconoscono una eziologia micotica. Una donna di 62 anni, che è stata sottoposta otto mesi prima ad un trapianto renale, presentava un vago dolore in fossa iliaca destra. L’ecografia del rene trapiantato dimostrava la presenza di un’area ipoecogena in corrispondenza dell’ilo renale, che all’ecocolordoppler appariva riccamente vascolarizzata. La tomografia computerizzata confermava la diagnosi di pseudo-aneurisma anastomotico di 33 mm di diametro, coinvolgente l’arteria del rene trapiantato. La paziente è stata dunque sottoposta a intervento chirurgico di aneurismectomia, con successivo bypass fra arteria renale del rene trapiantato e arteria iliaca interna. La continuità arteriosa iliaca è stata dunque ristabilita attraverso un by-pass iliaco-esterno-femorale comune in vena safena invertita. L’ecocolordoppler intraoperatorio dimostrava la corretta perfusione del graft renale e la corretta pervietà del by-pass iliacofemorale. Il decorso post-operatorio è stato privo di complicanze significative, eccettuata una linforrea inguinale risolta spontaneamente in 22a giornata post-operatoria. Sei mesi dopo la procedura, la paziente è in ottime condizioni generali, con una funzionalità renale conservata e una corretta pervietà del by-pass iliacofemorale. Lo pseudo-aneurisma dell’arteria renale rappresenta una rara complicanza del trapianto renale. Nella maggior parte dei casi riconosce una eziologia micotica, spesso a causa di contaminazione diretta del graft durante le procedure di prelievo o conservazione dell’organo. Il trattamento è molto complesso, e in molti casi richiede l’espianto del graft. Tuttavia, in alcuni casi selezionati, è possibile eseguire il trattamento dell

  9. Cholecalciferol supplementation does not protect against renal allograft structural and functional deterioration: a retrospective study.

    PubMed

    Courbebaisse, Marie; Xu-Dubois, Yi-Chun; Thervet, Eric; Prié, Dominique; Zuber, Julien; Kreis, Henri; Legendre, Christophe; Rondeau, Eric; Pallet, Nicolas

    2011-01-27

    Apart from their important role in mediating calcium homeostasis, vitamin D derivatives regulate numerous vitamin D receptor-mediated renoprotective cellular functions including cell differentiation, negative regulation of inflammation, and fibrosis. Renal models of chronic kidney injury and clinical observational studies have suggested that vitamin D analogues may protect against the epithelial-to-mesenchymal transition (EMT), interstitial inflammation, and fibrosis. The aim of this retrospective study is to test whether oral supplementation with cholecalciferol (vitamin D3) between 3 and 12 months posttransplantation confers a structural and functional nephroprotection in a population of 64 renal transplant patients, using historical controls. We analyzed glomerular filtration rates using iohexol clearance, urinary procollagen III aminoterminal propeptide excretion, and epithelial phenotypic changes as markers of the EMT and Banff scores at 3 and 12 months after transplantation in 64 renal transplant recipients with or without cholecalciferol supplementation between months 3 and 12. Cholecalciferol supplementation in stable renal transplant recipients did not prevent EMT, interstitial fibrosis, tubular atrophy, or renal function deterioration. Our results challenge the experimental data, suggesting that vitamin D-analog supplementation confers nephroprotection. These findings should be confirmed by randomized prospective studies.

  10. Cultured Human Renal Cortical Cells

    NASA Technical Reports Server (NTRS)

    1998-01-01

    During the STS-90 shuttle flight in April 1998, cultured renal cortical cells revealed new information about genes. Timothy Hammond, an investigator in NASA's microgravity biotechnology program was interested in culturing kidney tissue to study the expression of proteins useful in the treatment of kidney diseases. Protein expression is linked to the level of differentiation of the kidney cells, and Hammond had difficulty maintaining differentiated cells in vitro. Intrigued by the improvement in cell differentiation that he observed in rat renal cells cultured in NASA's rotating wall vessel (a bioreactor that simulates some aspects of microgravity) and during an experiment performed on the Russian Space Station Mir, Hammond decided to sleuth out which genes were responsible for controlling differentiation of kidney cells. To do this, he compared the gene activity of human renal cells in a variety of gravitational environments, including the microgravity of the space shuttle and the high-gravity environment of a centrifuge. Hammond found that 1,632 genes out of 10,000 analyzed changed their activity level in microgravity, more than in any of the other environments. These results have important implications for kidney research as well as for understanding the basic mechanism for controlling cell differentiation.

  11. Cultured Human Renal Cortical Cells

    NASA Technical Reports Server (NTRS)

    1998-01-01

    During the STS-90 shuttle flight in April 1998, cultured renal cortical cells revealed new information about genes. Timothy Hammond, an investigator in NASA's microgravity biotechnology program was interested in culturing kidney tissue to study the expression of proteins useful in the treatment of kidney diseases. Protein expression is linked to the level of differentiation of the kidney cells, and Hammond had difficulty maintaining differentiated cells in vitro. Intrigued by the improvement in cell differentiation that he observed in rat renal cells cultured in NASA's rotating wall vessel (a bioreactor that simulates some aspects of microgravity) and during an experiment performed on the Russian Space Station Mir, Hammond decided to sleuth out which genes were responsible for controlling differentiation of kidney cells. To do this, he compared the gene activity of human renal cells in a variety of gravitational environments, including the microgravity of the space shuttle and the high-gravity environment of a centrifuge. Hammond found that 1,632 genes out of 10,000 analyzed changed their activity level in microgravity, more than in any of the other environments. These results have important implications for kidney research as well as for understanding the basic mechanism for controlling cell differentiation.

  12. The efficacy and safety of cyclosporine reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: results from an open-label comparative study.

    PubMed

    Mühlbacher, Ferdinand; Neumayer, Hans-Helmut; del Castillo, Domingo; Stefoni, Sergio; Zygmunt, Anthony J; Budde, Klemens

    2014-02-01

    This study evaluated the safety and efficacy of a sirolimus, corticosteroid, and cyclosporine reduction regimen in an open-label, 12-month trial of 420 de novo renal allograft recipients at 49 European transplant centers. One month post-transplantation, 357 patients were randomized to receive standard-dose cyclosporine (sCsA, n = 179) or reduced-dose cyclosporine (rCsA, n = 178). All patients also received sirolimus and corticosteroids. The primary end points were the rate of biopsy-confirmed acute rejection (BCAR) and renal function, as measured by serum creatinine. Baseline demographic and donor characteristics were similar between groups. BCAR rates at 12 months were not significantly different: 11.2% for rCsA patients and 16.2% for sCsA patients. Mean serum creatinine (±SEM) was significantly lower (1.75 ± 0.10 vs. 1.97 ± 0.07 mg/dl, P < 0.001), and creatinine clearance (±SEM; Nankivell method) was significantly higher (57.8 ± 1.78 vs. 49.5 ± 2.46 ml/min, P < 0.001) in patients receiving rCsA versus sCsA at 1 year, respectively. Patient and graft survival exceeded 98% in both groups. No significant differences in infection or malignancy were noted between groups. The rCsA with sirolimus and corticosteroid regimen resulted in excellent 12-month patient and graft survival, a low incidence of BCAR, and improved renal function in renal allograft recipients. Sirolimus administered with rCsA and corticosteroids provided adequate immunosuppression while reducing the potential for the nephrotoxic effects of cyclosporine. These findings may help to improve long-term renal allograft outcomes. © 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.

  13. Reduction of chronic rejection of renal allografts by anti-transforming growth factor-β antibody therapy in a rat model.

    PubMed

    Guan, Qiunong; Li, Shuyuan; Gao, Sihai; Chen, Huifang; Nguan, Christopher Y C; Du, Caigan

    2013-07-15

    There is no effective treatment for chronic rejection (CR) that largely limits long-term survival of kidney transplants. Transforming growth factor (TGF)-β is a fibrogenic factor for tissue fibrosis. This study was to test the efficacy of an anti-TGF-β antibody in preventing the CR of renal allografts in a preclinical model. Male Lewis rats (RT1¹) were orthotopically transplanted with donor kidneys from male Fischer 344 (RT11v1) rats and were treated with either anti-TGF-β or a control antibody. The CR of renal allografts was assessed by semiquantitative histological analyses, and intragraft cytokines and fibrosis-related genes ware examined by PCR arrays. Compared with the control antibody, anti-TGF-β antibody treatment significantly reduced recipients' proteinuria (P = 0.0002), and CR in renal transplants, which was indicated by the fewer injured renal tubules, glomeruli, and interlobular arterioles or arteries, and by less mononuclear cell infiltration and interstitial fibrosis in the anti-TGF-β antibody-treated group (P < 0.05), but not significantly attenuate the ratios of different infiltrating leukocytes. These pathological changes were associated with downregulation of TGF-β1, TGF-β2, and proinflammatory cytokines, or with upregulation of anti-fibrotic HGF, BMP5, and BMP7. The therapeutic effect of the anti-TGF-β antibody was further confirmed by its prevention of graft dysfunction, indicated by lower levels of serum creatinine and blood urea nitrogen or higher creatinine clearance in anti-TGF-β antibody-treated recipients compared with those in control recipients (P < 0.05). In conclusion, the anti-TGF-β antibody (1D11) treatment significantly reduces CR of renal allografts in rats, suggesting the therapeutic potential of this antibody therapy for treating CR of kidney transplants in patients.

  14. Implication of Ia-positive bone marrow interstitial stem cells in the induction of unresponsiveness to canine renal allografts

    SciTech Connect

    Rapaport, F.T.; Arnold, A.N.; Asari, H.; Sato, K.; Miura, S.; Chanana, A.; Cronkite, E.P.

    1987-02-01

    The removal from stored autologous host bone marrow of a monocytoid cell population by exposure to methylprednisolone is associated with successful introduction of unresponsiveness to renal allografts in irradiated recipients reconstituted with such treated marrow. The eliminated cells are a prominent component of the canine long bone marrow interstitium and share a number of important properties with dendritic cells (DC), including size and shape; poor or nonadherence to plastic or glass surfaces; negative staining for neutral esterase, acid phosphatase, or peroxidase; nonphagocytic; Ia positive, but negative for IgG or IgM; ability to act as accessory cells in augmenting the intensity of allogeneic mixed-lymphocyte reactions. Both cell types are of bone marrow origin and are susceptible to steroids in vitro. The results suggest that the bone marrow interstitial cells identified in the course of this study may be enriched with populations of canine dendritic cell precursors and dendritic cells at various stages of differentiation. The detection of a receptor site for Helix promatia on the surface of such cells may be of usefulness in their further characterization and in the analysis of their precise role in the modulation of allogeneic unresponsiveness.

  15. Improvement in late renal allograft survival between 1990 and 2002 in Spain: results from a multicentre case-control study.

    PubMed

    Moreso, Francesc; Alonso, Angel; Gentil, Miguel A; González-Molina, Miguel; Capdevila, Lluis; Marcén, Roberto; Pascual, Julio; Serón, Daniel

    2010-09-01

    Epidemiological studies have failed to show an improvement in graft survival beyond 1 year after kidney transplantation possibly because of an increased number of expanded donors and older recipients. Thus, we performed a case-control study matching patients transplanted in different eras by donor and recipient characteristics. We considered renal transplant recipients included in the database of the Spanish Chronic Allograft Dysfunction Study Group in 1990, 1994, 1998 and 2002 (n = 4842). We matched patients from these cohorts considering the following variables: donor and recipient age, cause of donor death, hepatitis C virus, panel reactive antibodies and re-transplantation. We identified a total of 896 patients distributed in four cohorts of 224 matched patients. Between 1990 and 2002, the use of cyclosporin decreased (96%, 94%, 80% and 23% respectively, P = 0.001), while the use of tacrolimus increased (0%, 1%, 15% and 63% respectively, P = 0.001) and the prevalence of acute rejection decreased (46%, 37.9%, 20.6% and 15.8% respectively, P < 0.001). One-year serum creatinine was 1.63 +/- 0.66, 1.64 +/- 0.70, 1.44 +/- 0.52 and 1.38 +/- 0.75 respectively, P = 0.001. Graft survival beyond the first year between 1990 and 2002 significantly improved while patient survival did not. Transplant outcome has improved between 1990 and 2002 when donors and recipients of similar characteristics are compared.

  16. Effect of donor pneumoperitoneum on early allograft perfusion following renal transplantation in pediatric patients: an intraoperative Doppler ultrasound study.

    PubMed

    Dave, S; Farhat, W; Pace, K; Navarro, O; Hebert, D; Khoury, A E

    2008-08-01

    Decreased perfusion and trauma during laparoscopic harvesting are proposed causative factors for DGF and rejection in children following renal transplantation with laparoscopic donor nephrectomy (LDN) allograft. We performed a retrospective review of 11 children who underwent LDN transplant and 11 preceding patients who underwent ODN transplant. Intraoperative DUS findings, creatinine values and clearance, time to nadir creatinine and AR episodes were compared. There were no significant differences in the BMI, vascular anatomy, side of nephrectomy, or warm ischemia time in the two groups. Mean follow-up duration was 11.4 and 30.4 months in LDN and ODN groups. DUS showed initial turbulent flow in five of the LDN and four of the ODN group with an average RI of 0.59 and 0.66 in the ODN and LDN groups, respectively (NS). Three patients in the ODN group had an abnormal RI compared to none in the LDN group (p = 0.034). The creatinine values, creatinine clearances (at 24 h, one, four wk and last follow-up) and AR episodes were similar in both groups. Pneumoperitoneum during LDN does not appear to have an adverse impact on early graft reperfusion.

  17. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Non-Human Primates

    PubMed Central

    Freitas, AM; Samy, KP; Farris, AB; Leopardi, FV; Song, M; Stempora, L; Strobert, EA; Jenkins, JA; Kirk, AD; Cendales, LC

    2016-01-01

    Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the non-lifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a non-human-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model. PMID:26139552

  18. Infection related renal impairment: a major cause of acute allograft dysfunction.

    PubMed

    Nampoory, Mangalathillam R N; Johny, Kaivilayil V; Costandy, Jamal N; Nair, Madhavan P; Said, Tarek; Homoud, Hani; Al-Muzairai, Ibrahim; Samhan, Mohmoud; Al-Moussawi, Mustafa

    2003-06-01

    We prospectively analyzed the impact of post-transplant infections on the renal function in 532 stable renal transplant recipients (M=340; F=192) over a period of 5 years. Their age ranged from 3-75 years (40+14 years). During the follow-up period, 52 patients expired and 64 lost on followup. We defined renal impairment (RI) as a persistent rise in serum creatinine above 20% from baseline value. 495 episodes of RI occurred in 269 recipients. This included 180-36% episodes of acute rejection, 53-10.7% Cyclosporine toxicity, 236-47.7% infection related renal impairment [IRRI] and 26-5.3% others. The severity of renal failure is less in IRRI (100+90.2) than that of acute rejection (166+127.1), but was more than that in cyclosporine toxicity (50+42.2). Sites of infection in IRRI were urinary (33%), respiratory (26.3%), septicemia (15.7%) and others (25.4%). Episode of IRRI occurred more frequently in LURD (159-67.4%) compared to LRD-RTR (50-21.2%). Occurrence of IRRI is more significantly higher in patients on triple drug immunosuppression (IS) (34.3%) than those on two drug IS (13.2%) (P=or<0.01). Ecoli (23.1%), Pseudomonas (11.1%), Salmonella (8.8%), Klebsiella (8.8%) and Staphylococai (8.3%) were the major organisms producing IRRI. IRRI is frequent (27.8%) during the first six months. Present study denotes that IRRI is a major cause of acute failure in RTR.

  19. Impact of Prophylactic Versus Preemptive Valganciclovir on Long-term Renal Allograft Outcomes

    PubMed Central

    Spinner, Michael L.; Saab, Georges; Casabar, Ed; Bowman, Lyndsey J.; Storch, Gregory A.; Brennan, Daniel C.

    2010-01-01

    Background Both prophylactic and preemptive oral valganciclovir therapy are effective for management of cytomegalovirus (CMV) post renal transplantation in the short-term. The long-term effect of either strategy is less well-defined. Methods We analyzed data on 115 adult recipients previously enrolled in a prospective randomized controlled trial of prophylaxis versus preemptive therapy for CMV. The primary outcome was a composite of freedom from acute rejection, graft loss, or death. Secondary outcomes included individual primary outcomes, post-transplant cardiovascular events, new-onset diabetes mellitus after transplant (NODAT), achievement of goal blood pressure, change in body mass index (BMI), interstitial fibrosis/tubular atrophy (IF/TA) and change in renal function. The analysis period was a 48-months post-transplant or date of death/graft loss, whichever was earlier. Results The primary outcome was similar between groups (83% prophylactic versus 81% preemptive, p = 0.754). The secondary outcomes showed similarities between the prophylactic and preemptive groups. Four patients in the prophylactic group (8%) compared to none in the preemptive group (0%) died with a functioning graft, p=0.043. Conclusions Within the limitations of sample size, our data suggest that either strategy for the management of CMV immediately post-transplantation appears effective for patient and graft survival in the long-term. CMV-management is one of many therapeutic strategies incorporated into a renal transplantation protocol which often differs among institutions, and the decision as to which approach to use remains center and resource specific. The increased incidence of death in the prophylactic group requires further investigation. PMID:20555305

  20. Gastric aspiration for diagnosis of pulmonary tubercolosis in adult renal allograft recipients.

    PubMed

    John, G T; Juneja, R; Mukundan, U; Date, A; Vincent, L; Jacob, C K; Shastry, J C

    1996-03-27

    Of 213 renal allgraft recipients suspected to have had pulmonary tuberculosis, 132 had sputum examinations and 14 showed acid-fast bacilli. Of the remaining 118 patients, 25 had gastric aspirations, 18 had bronchoalveolar lavage, and 75 did not require further investigation because of spontaneous improvement or confirmation of an alternative diagnosis. While 9 of the 25 patients' gastric aspirate examination was positive, all the 18 who had bronchoalveolar lavage were negative for acid-fast bacilli. Eighty-one patients without expectoration had gastric aspiration directly and 14 showed acid-fast bacilli. Of the remaining 67 patients only 17 had bronchoalveolar lavage, of which three were positive for AFB and the rest did not require further testing for tuberculosis. A total of 106 patients had gastric aspiration. Acid-fast bacillus positivity was significantly more (P<.01) in patients with abnormal chest radiographs as compared with patients with normal chest radiographs as compared with patients with normal chest radiograph results. We suggest gastric aspiration for AFB in all renal transplant recipients who have fever, scanty expectoration, and abnormal chest radiograph with clinical suspicion of pulmonary tuberculosis.

  1. Rituximab in Combination With Bortezomib, Plasmapheresis, and High-Dose IVIG to Treat Antibody-Mediated Renal Allograft Rejection

    PubMed Central

    Waiser, Johannes; Duerr, Michael; Schönemann, Constanze; Rudolph, Birgit; Wu, Kaiyin; Halleck, Fabian; Budde, Klemens; Lachmann, Nils

    2016-01-01

    Background Current treatment strategies for antibody-mediated renal allograft rejection (AMR) are not sufficiently effective. In most centers, “standard of care” treatment includes plasmapheresis (PPH) and IVIG preparations. Since several years, modern therapeutics targeting B cells and plasma cells have become available. We investigated, whether combined administration of rituximab and bortezomib in addition to PPH and high-dose IVIG is useful. Methods Between November 2011 and January 2013, we treated 10 consecutive patients with biopsy-proven AMR with rituximab (500 mg), bortezomib (4× 1.3 mg/m2), PPH (6×), and high-dose IVIG (1.5 g/kg) (group A). This group was compared with a group of 11 consecutive patients treated with an identical regimen without rituximab between July 2010 and November 2011 (group B). Results Median follow-up was 41(33-46) months in group A and 55(47-63) months in group B. At 40 months after treatment, graft survival was 60% in group A and 64% in group B, respectively (P = 0.87). Before and after treatment, serum creatinine, estimated glomerular filtration rate, and proteinuria were not different between groups. A significant reduction in donor-specific HLA antibody mean fluorescence intensity was observed in group A (25.2%, P = 0.046) and B (38.3%, P = 0.01) at 3 months posttreatment. In group A, more patients suffered from side effects compared with group B (infections: 70% vs 18%, P = 0.02). Conclusions The addition of rituximab to bortezomib, PPH, and high-dose IVIG did not further improve graft survival. Instead, we observed an increase of side effects. Therefore, combined administration of bortezomib and rituximab in addition to PPH and IVIG should be regarded with caution. PMID:27819032

  2. Lateral Ankle Stabilization Using Acellular Human Dermal Allograft Augmentation.

    PubMed

    Parks, Robert M; Parks, Stephanie M

    2015-05-01

    We describe a retrospective study that uses the Broström-type surgical procedure with modifications that augment deficient and torn ligaments with acellular human dermal grafts. At the onset of this study, the most prevalent dermal graft available to us was GraftJacket (Wright Medical Technology, Arlington, Tennessee). Greater than 50% of the study participants were grafted with this product, but more recently other equally effective human dermal grafts have been used with no apparent difference. Thirty-five lateral ankle stabilization procedures were performed in the past 6 years on 33 patients. Eight patients were considered athletes (mean age, 23 years). The balance of the study group consisted of sedentary patients (mean age, 41 years). The mean patient body mass index (calculated as the weight in kilograms divided by the square of the height in meters) was 31. All of the patients were satisfied with their results, with no recurrent instability. Two patients in this group went on to have contralateral ankle stabilization in a similar manner owing to their satisfaction. Complications included two soft-tissue infections. Lateral ankle stabilization using acellular human dermal graft augmentation is a useful tool in the surgical treatment of ankle instability. This procedure offers distinct advantages over traditional methods of ankle repair and can be performed with relatively limited surgical exposure. Ease of operation, consistent results, and limited patient morbidity should allow surgeons to use this procedure independently or adjunctively to improve surgical outcomes.

  3. Evaluation of OKT3 monoclonal antibody and anti-thymocyte globulin in the treatment of steroid-resistant acute allograft rejection in pediatric renal transplants.

    PubMed

    Mochon, M; Kaiser, B; Palmer, J A; Polinsky, M; Flynn, J T; Caputo, G C; Baluarte, H J

    1993-06-01

    We reviewed the effectiveness of Muromonab-CD3 (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P = NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P < 0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P = NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P = NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (> or = 1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.

  4. Cross-correlative 3D micro-structural investigation of human bone processed into bone allografts.

    PubMed

    Singh, Atul Kumar; Gajiwala, Astrid Lobo; Rai, Ratan Kumar; Khan, Mohd Parvez; Singh, Chandan; Barbhuyan, Tarun; Vijayalakshmi, S; Chattopadhyay, Naibedya; Sinha, Neeraj; Kumar, Ashutosh; Bellare, Jayesh R

    2016-05-01

    Bone allografts (BA) are a cost-effective and sustainable alternative in orthopedic practice as they provide a permanent solution for preserving skeletal architecture and function. Such BA however, must be processed to be disease free and immunologically safe as well as biologically and clinically useful. Here, we have demonstrated a processing protocol for bone allografts and investigated the micro-structural properties of bone collected from osteoporotic and normal human donor samples. In order to characterize BA at different microscopic levels, a combination of techniques such as Solid State Nuclear Magnetic Resonance (ssNMR), Scanning Electron Microscope (SEM), micro-computed tomography (μCT) and Thermal Gravimetric Analysis (TGA) were used for delineating the ultra-structural property of bone. ssNMR revealed the extent of water, collagen fine structure and crystalline order in the bone. These were greatly perturbed in the bone taken from osteoporotic bone donor. Among the processing methods analyzed, pasteurization at 60 °C and radiation treatment appeared to substantially alter the bone integrity. SEM study showed a reduction in Ca/P ratio and non-uniform distribution of elements in osteoporotic bones. μ-CT and MIMICS (Materialize Interactive Medical Image Control System) demonstrated that pasteurization and radiation treatment affects the BA morphology and cause a shift in the HU unit. However, the combination of all these processes restored all-important parameters that are critical for BA integrity and sustainability. Cross-correlation between the various probes we used quantitatively demonstrated differences in morphological and micro-structural properties between BA taken from normal and osteoporotic human donor. Such details could also be instrumental in designing an appropriate bone scaffold. For the best restoration of bone microstructure and to be used as a biomaterial allograft, a step-wise processing method is recommended that preserves all

  5. Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts.

    PubMed

    Walker, Natalie; Badri, Linda; Wettlaufer, Scott; Flint, Andrew; Sajjan, Uma; Krebsbach, Paul H; Keshamouni, Venkateshwar G; Peters-Golden, Marc; Lama, Vibha N

    2011-06-01

    Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft-derived MSCs uniquely express embryonic lung mesenchyme-associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stable in vivo fibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 by in situ hybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Cutaneous and bone marrow histoplasmosis after 18 years of renal allograft transplant.

    PubMed

    Ibrahim, K Y; Carvalho, N B; Mimicos, E V; Yeh-Li, H; Sotto, M N; França, F O S

    2014-10-01

    The frequency of histoplasmosis among solid organ transplant (SOT) recipients appears to be low where there are only a few case series, mostly among renal and liver transplant recipients. Herein we report a case of a 44-year-old woman who underwent a living-related renal transplant 18 years prior to evaluation, developed a nodule after followed by ulceration upon her posterior right leg and a second one upon her left leg 3 months and 2 months before her hospitalisation, respectively. The biopsy of lesion revealed the presence of Histoplasma spp. Bone marrow aspiration was performed and also revealed the same organism. She had initially received itraconazole without improvement of lesions, while a new lesion appeared on her left arm. Healing of all lesions could be observed after 40 days of liposomal amphotericin B when she was submitted to skin grafts on the legs and a surgical treatment on the arms, and the myelosuppression improved simultaneously. Histoplasmosis seems to be very uncommon among patients who underwent to organ solid transplantation. Most cases occur within 12-18 months after transplantation, although unusual cases have been presented many years post-transplant. There are cases reported in the literature, occurring from 84 days to 18 years after organ transplantation, but without cutaneous involvement. Our patient developed lesions on limbs and myelosuppression after 18 years of chronic immunosuppression medication. This case suggests that besides cutaneous histoplasmosis is an uncommon infection following iatrogenic immunosuppression and even rarer over a long period after the transplantation. Clinicians who care SOT recipient patients must bear in mind histoplasmosis infection as differential diagnosis in any case of cutaneous injury with prolonged fever and try to use as many tools as possible to make the diagnosis, once this disease presents a good prognosis if it is diagnosed and treated promptly.

  7. Improved renal allograft survival using the mixed lymphocyte culture for selection of nonidentical living related donors.

    PubMed

    Riggio, R R; Saal, S D; Katz, E B; Tapia, L; White, R; Chami, J; Sheigh, J S; Sullivan, J F; Stenzel, K H; Stubenbord, W T; Whitsell, J C; Rubin, A L

    1975-01-01

    Our results concur with earlier published work, by other groups, showing that LRD-recipient pairs with low MLC stimulation usually have better and more prolonged graft success than do those with higher stimulation. Specific HL-A compatibilities or incompatibilities did not seem to affect these results, nor did the presence of an increased number of common loci, short of increasing the apparent chromosome compatibility. The presence of pre-transplant cytotoxic antibodies, in patients with a high MI, however, may unfavorably affect the LRD transplant. The overall results of our LRD transplant experience is shown in Figure 1, and superimposed upon Figure 2, is the current extrapolation of data showing MLC stimulation and haplotype success. Thus, it appears that graft survival may be improved and more closely approach the levels seen in a full-house, diplotype match, by using the MLC results in considering patients for transplantation. Not all patients with a high MLC, however, (see table) reject their grafts and it is impossible to predict pre-transplant who will develop specific allograft enhancement. Before the MI becomes a specific criteria for transplant selection, additional studies of patient stimulation in MLC should be done. Suppression of stimulation by donor cells in autologous serum, as compared to the response to unrelated controls, might provide pre-transplant clues to the presence of enhancing factors. Such studies could provide an index that would be more meaningful than the MI in AB sera alone. Since overall results from both our series and from the Transplant Registry continue to indicate better long term graft survival for LRD than for cadaver transplants, and since the evidence suggests that a successful transplant offers a patient a better quality of life, as well as decreased morbidity and mortality compared to concomitant time spent on hemodialysis, continued LRD transplants with high MI is warranted in some circumstances with the patient

  8. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection

    PubMed Central

    Yamanaka, Kazuaki; Kakuta, Yoichi; Miyagawa, Shuji; Nakazawa, Shigeaki; Kato, Taigo; Abe, Toyofumi; Imamura, Ryoichi; Okumi, Masayoshi; Maeda, Akira; Okuyama, Hiroomi; Mizuno, Masashi; Nonomura, Norio

    2016-01-01

    Background The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. Methods We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. Results qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. Conclusions We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR. PMID:26928779

  9. The NOX2-mediated ROS producing capacity of recipient cells is associated with reduced T cell infiltrate in an experimental model of chronic renal allograft inflammation.

    PubMed

    Kraaij, Marina D; Koekkoek, Karin M; Gelderman, Kyra A; van Kooten, Cees

    2014-03-01

    We previously showed that anti-inflammatory Mph (Mph2) can both in vitro and in vivo induce regulatory T cells (Tregs) in a reactive oxygen species (ROS)-dependent fashion. As influx of Mph is an important characteristic of chronic inflammatory responses, we investigated the impact of NOX2-mediated ROS production by recipient cells in an experimental model of chronic allograft inflammation. We used a kidney transplantation (Tx) model with Lewis (Lew) rats as donor and congenic DA.Ncf1(DA/DA) (low ROS) and DA.Ncf1(E3/E3) (normal ROS) rats as recipients. At day 7 the contralateral kidney was removed, and the animals were sacrificed four weeks after Tx. Renal function and injury were monitored in serum and urine and the composition of the infiltrate was analyzed by immunohistochemistry. Four weeks after Tx, large leukocyte clusters were observed in the allograft, in which signs of ROS production could be demonstrated. These clusters showed no difference regarding composition of myeloid cells or the number of FoxP3 positive cells. However, T cell infiltrate was significantly reduced in the DA.Ncf1(E3/E3) recipients having normal ROS production. Therefore, this study suggests a regulatory effect of ROS on T cell infiltration, but no effect on other inflammatory cells in the allograft.

  10. Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts.

    PubMed

    Lin, Jiunn-Chang; Huang, Wei-Pang; Liu, Chien-Liang; Lee, Jie-Jen; Liu, Tsang-Pai; Ko, Wen-Chin; Huang, Yu-Chuen; Hsu, Ming-Ling; Wu, Chih-Hsiung; Chen, Yu-Jen

    2013-03-27

    Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection. Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay. We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo. This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells.

  11. Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome.

    PubMed

    Zuber, Julien; Shonts, Brittany; Lau, Sai-Ping; Obradovic, Aleksandar; Fu, Jianing; Yang, Suxiao; Lambert, Marion; Coley, Shana; Weiner, Joshua; Thome, Joseph; DeWolf, Susan; Farber, Donna L; Shen, Yufeng; Caillat-Zucman, Sophie; Bhagat, Govind; Griesemer, Adam; Martinez, Mercedes; Kato, Tomoaki; Sykes, Megan

    2016-10-01

    A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive "bystander" cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2D(Hi) CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.

  12. Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome

    PubMed Central

    Zuber, Julien; Obradovic, Aleksandar; Fu, Jianing; Yang, Suxiao; Lambert, Marion; Coley, Shana; Weiner, Joshua; Thome, Joseph; DeWolf, Susan; Farber, Donna L.; Shen, Yufeng; Caillat-Zucman, Sophie; Bhagat, Govind; Griesemer, Adam; Martinez, Mercedes; Kato, Tomoaki; Sykes, Megan

    2016-01-01

    A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive “bystander” cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2DHi CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population. PMID:28239678

  13. Effect of recipient's race on pediatric renal allograft survival: a single-center study.

    PubMed

    Schulman, S L; Palmer, J; Dunn, S; Kaiser, B A; Polinsky, M S; Baluarte, H J

    1992-06-01

    One hundred twenty-seven children (83 males, 44 females, 86 white, 41 nonwhite; mean age 12.1 years) who received 160 renal transplants between 1980 and 1989 were retrospectively studied. Variables such as age, sex, primary diagnosis, type, HLA-DR mismatching, and repeated transplants were compared between races and found not to be significant. However, HLA-A and -B cadaveric-graft mismatching, which was equivalent between whites and nonwhites prior to 1985 (pre-cyclosporine A era), has significantly favored whites (49% with 0 to 2 HLA-A and -B mismatch vs 16% in nonwhites) since 1985 (P less than .05), and a significantly higher proportion of nonwhite patients (59%) were receiving medical assistance (P less than .0001). Graft survival was evaluated with significantly poorer results in nonwhites as compared to whites (P less than .05). Although no difference was found between white and nonwhite cadaveric-graft survival before 1985, nonwhites had significantly worse graft survival since 1985 (72% vs 59% for 1 year and 61% vs 24% for 3 years in whites and nonwhites, respectively; P less than .05). Subpopulations such as nonwhite adolescents, nonwhite females, nonwhites with repeated transplants, and all low socioeconomic patients were identified as high-risk children with poor long-term survival. It is concluded that secondary to poorer matching since 1985 there has been decreased graft survival in nonwhites despite cyclosporine A. Attempts to improve matching and attention to high-risk groups are needed for equivalent survival.

  14. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists.

    PubMed

    King, G N; Fullinfaw, R; Higgins, T J; Walker, R G; Francis, D M; Wiesenfeld, D

    1993-04-01

    Although it is established that the immunosuppressant cyclosporin-A (CsA) and calcium antagonists [Nifedipine (Nif) and Diltiazem (Dz)] can independently induce gingival enlargement, little has been documented on the significance of the salivary CsA levels and the combined effect of CsA and a calcium antagonist upon gingival tissues. In the present cross-sectional investigation, clinical periodontal parameters and the pharmacologic profiles of CsA, Nif, and Dz were determined for 66 renal transplant recipients. Subjects were divided into the following groups: Group (Gp) 1: CsA [n = 18]; Gp 2: CsA + Nif [n = 15]; Gp 3: CsA + Dz [n = 12] and a negative Control Gp 4: azathioprine [n = 21]. A gingival enlargement score was assessed for each patient from study models using a hyperplastic index (HI). Pharmacologic profiles included CsA whole blood and whole saliva levels as measured by fluorescence polarization immunoassay. The HI scores between Gp 1, 2 and 3 were not significantly different. However, when compared with controls (Gp 4), there was a significant difference in HI and all individual groups (Gp 1, 2, 3) (p < 0.05). Gingival hyperplasia was only weakly related to plaque and calculus but was unrelated to CsA dose (mg/kg/day), duration of CsA therapy (months), CsA blood or saliva levels (ng/ml), or the concurrent administration of a Nif or Dz. Gingival enlargement was found to occur in 49% of subjects who were either on CsA or CsA and a calcium antagonist. It is concluded that CsA alone or in combination with a calcium antagonist caused a significant increase in gingival enlargement compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Mining the human urine proteome for monitoring renal transplant injury

    SciTech Connect

    Sigdel, Tara K.; Gao, Yuqian; He, Jintang; Wang, Anyou; Nicora, Carrie D.; Fillmore, Thomas L.; Shi, Tujin; Webb-Robertson, Bobbie-Jo; Smith, Richard D.; Qian, Wei-Jun; Salvatierra, Oscar; Camp, David G.; Sarwal, Minnie M.

    2016-06-01

    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 in 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.

  16. Re-emergence of hand-muscle representations in human motor cortex after hand allograft

    PubMed Central

    Vargas, Claudia D.; Aballéa, Antoine; Rodrigues, Érika C.; Reilly, Karen T.; Mercier, Catherine; Petruzzo, Palmina; Dubernard, Jean M.; Sirigu, Angela

    2009-01-01

    The human primary motor cortex (M1) undergoes considerable reorganization in response to traumatic upper limb amputation. The representations of the preserved arm muscles expand, invading portions of M1 previously dedicated to the hand, suggesting that former hand neurons are reassigned to the control of remaining proximal upper limb muscles. Hand allograft offers a unique opportunity to study the reversibility of such long-term cortical changes. We used transcranial magnetic stimulation in patient LB, who underwent bilateral hand transplantation 3 years after a traumatic amputation, to longitudinally track both the emergence of intrinsic (from the donor) hand muscles in M1 as well as changes in the representation of stump (upper arm and forearm) muscles. The same muscles were also mapped in patient CD, the first bilateral hand allograft recipient. Newly transplanted intrinsic muscles acquired a cortical representation in LB's M1 at 10 months postgraft for the left hand and at 26 months for the right hand. The appearance of a cortical representation of transplanted hand muscles in M1 coincided with the shrinkage of stump muscle representations for the left but not for the right side. In patient CD, transcranial magnetic stimulation performed at 51 months postgraft revealed a complete set of intrinsic hand-muscle representations for the left but not the right hand. Our findings show that newly transplanted muscles can be recognized and integrated into the patient's motor cortex. PMID:19366678

  17. Surgical repair of hip abductors. A new technique using Graft Jacket allograft acellular human dermal matrix.

    PubMed

    Rao, Biyyam M; Kamal, Tamer T; Vafaye, John; Taylor, Lee

    2012-10-01

    Avulsion of the abductors from the hip can be an infrequent but debilitating complication after total hip arthroplasty performed through a trans-gluteal approach. This can result in intractable pain, limp, Trendelenberg lurch and instability of the hip. There have been various methods described for repairing or reconstruction of this abductor muscle complex including direct trans-osseous repair, muscle transfers, muscle and tendon sling, bone tendon allograft reconstruction and endoscopic repair techniques. In a prospective study at our institution we evaluated the results of a surgical technique in 12 patients using a trans-osseous repair of gluteus medius and minimus insertions augmented by a Graft Jacket allograft acellular human dermal matrix (Graft Jacket; Wright Medical Technology, Arlington, TN) over the anterior and anterolateral aspects of the greater trochanter. Diagnosis of hip abductor avulsions was made by evaluation of the history of presenting complaint, clinical examination and confirmed by ultrasound or MRI scans. Evaluation of results included pain scoring, gait evaluation, Trendelenberg test, and the Harris hip score. There was a significant improvement in pain (VAS mean values 8.25 to 2.33; p value < 0.0001), limp and gait along with abductor strength. The Trendelenberg test became negative in all but one. At the mean follow up of 22 months Harris hip scores improved from 34.05 to 81.26 (p value <0.0001). Overall this procedure appears to be safe and associated with high patient satisfaction, without the morbidity of any tendon or muscle transfers.

  18. The effect of recombinant human osteogenic protein-1 (bone morphogenetic protein-7) impregnation on allografts in a canine intercalary bone defect.

    PubMed

    Cullinane, Dennis M; Lietman, Steven A; Inoue, Nozomu; Deitz, Luke W; Chao, Edmund Y S

    2002-11-01

    The utility of cortical allografts in repairing large bone defects is limited by their slow and incomplete incorporation into host bone. In order to determine the effects of recombinant human osteogenic protein-1 (rhOP-1) impregnation on allograft incorporation, we used a canine intercalary bone defect model. Bilateral resection of a 4 cm segment of the femoral diaphysis and reconstruction with structural bone allografts were performed. In one limb, the allograft was soaked in solution with rhOP-1 for 1 h before implantation. In the other limb, the allograft was soaked in the same solution without rhOP-1. Dynamic load-bearing, radiographic analysis, biomechanical testing, and histomorphometric analysis were conducted. Radiographic analysis showed significantly larger periosteal callus area in the rhOP-1 treated group at week 2. The rhOP-1 significantly increased allograft bone porosity and significantly increased the number of active osteons in the allografts. There were no significant differences between the rhOP-1 treated and non-treated allografts in load bearing and biomechanical analyses. These findings indicate that rhOP- I increases intercalary allograft remodeling without deleterious effects in mechanical and functional strength.

  19. Ratios of T lymphocyte subpopulations predict survival of cadaveric renal allografts in adult patients on low dose corticosteroid therapy.

    PubMed

    Van Es, A; Tanke, H J; Baldwin, W M; Oljans, P J; Ploem, J S; Vanes, L A

    1983-04-01

    Peripheral blood T lymphocyte subpopulations were monitored in 45 consecutive adult recipients of cadaveric renal allografts by using monoclonal antibodies and flow cytometrie. All patients were treated with low dose corticosteroids and azathioprine. In 37 patients pre-transplant OKT4/OKT8 ratios were available. Six of 26 patients (23%) with pre-transplant OKT4/OKT8 ratios greater than 1.6 and seven of 11 patients (64%) with pre-transplant OKT4/OKT8 ratio less than or equal to 1.6 lost their graft due to rejection within 6 months. The difference in transplant survival between patients with pre-transplant OKT4/OKT8 ratios greater than 1.6 and less than or equal to 1.6i is just significant (P = 0 . 049 Fishers test). No correlation was found between post-transplant values of individual lymphocyte subpopulations or OKT4/OKT8 ratios and the incidence of subsequent rejection episodes. Forty out of 45 patients suffered one or more rejection episodes which were treated by raising the dosage of prednisone. In 24 of these patients the rejection episode was reversed, leading to a transplant survival of at least 6 months. In these 24 patients the OKT4/OKT8 ratio was greater than 1.6 for at least 3 days before the institution of any rejection treatments. Sixteen patients lost their graft due to rejection within 6 months after transplantation. In 11 of these 16 patients OKT4/OKT8 ratios less than or equal to 1.6 preceded the institution of all rejection treatments for at least 3 days, while in three patients the OKT4/OKT8 ratio was greater than 1.6 before the first rejection episode but this ratio was less than or equal to 1.6 before subsequent rejection episodes. Thus, OKT4/OKT8 ratios greater than 1.i6 correlated with reversible rejection episodes and OKT4/OKT8 ratios less than or equal to 1.6 correlated with irreversible rejection (P less than 0 . 001).

  20. Ratios of T lymphocyte subpopulations predict survival of cadaveric renal allografts in adult patients on low dose corticosteroid therapy.

    PubMed Central

    Van Es, A; Tanke, H J; Baldwin, W M; Oljans, P J; Ploem, J S; Vanes, L A

    1983-01-01

    Peripheral blood T lymphocyte subpopulations were monitored in 45 consecutive adult recipients of cadaveric renal allografts by using monoclonal antibodies and flow cytometrie. All patients were treated with low dose corticosteroids and azathioprine. In 37 patients pre-transplant OKT4/OKT8 ratios were available. Six of 26 patients (23%) with pre-transplant OKT4/OKT8 ratios greater than 1.6 and seven of 11 patients (64%) with pre-transplant OKT4/OKT8 ratio less than or equal to 1.6 lost their graft due to rejection within 6 months. The difference in transplant survival between patients with pre-transplant OKT4/OKT8 ratios greater than 1.6 and less than or equal to 1.6i is just significant (P = 0 . 049 Fishers test). No correlation was found between post-transplant values of individual lymphocyte subpopulations or OKT4/OKT8 ratios and the incidence of subsequent rejection episodes. Forty out of 45 patients suffered one or more rejection episodes which were treated by raising the dosage of prednisone. In 24 of these patients the rejection episode was reversed, leading to a transplant survival of at least 6 months. In these 24 patients the OKT4/OKT8 ratio was greater than 1.6 for at least 3 days before the institution of any rejection treatments. Sixteen patients lost their graft due to rejection within 6 months after transplantation. In 11 of these 16 patients OKT4/OKT8 ratios less than or equal to 1.6 preceded the institution of all rejection treatments for at least 3 days, while in three patients the OKT4/OKT8 ratio was greater than 1.6 before the first rejection episode but this ratio was less than or equal to 1.6 before subsequent rejection episodes. Thus, OKT4/OKT8 ratios greater than 1.i6 correlated with reversible rejection episodes and OKT4/OKT8 ratios less than or equal to 1.6 correlated with irreversible rejection (P less than 0 . 001). PMID:6345032

  1. Enhanced cellular infiltration of human adipose-derived stem cells in allograft menisci using a needle-punch method.

    PubMed

    Nordberg, Rachel C; Charoenpanich, Adisri; Vaughn, Christopher E; Griffith, Emily H; Fisher, Matthew B; Cole, Jacqueline H; Spang, Jeffrey T; Loboa, Elizabeth G

    2016-10-28

    The meniscus plays a crucial role in knee joint stability, load transmission, and stress distribution. Meniscal tears are the most common reported knee injuries, and the current standard treatment for meniscal deficiency is meniscal allograft transplantation. A major limitation of this approach is that meniscal allografts do not have the capacity to remodel and maintain tissue homeostasis due to a lack of cellular infiltration. The purpose of this study was to provide a new method for enhanced cellular infiltration in meniscal allografts. Twenty medial menisci were collected from cadaveric human sources and split into five experimental groups: (1) control native menisci, (2) decellularized menisci, (3) decellularized menisci seeded with human adipose-derived stem cells (hASC), (4) decellularized needle-punched menisci, and (5) decellularized needle-punched menisci seeded with hASC. All experimental allografts were decellularized using a combined method with trypsin EDTA and peracetic acid. Needle punching (1-mm spacing, 28 G microneedle) was utilized to improve porosity of the allograft. Samples were recellularized with hASC at a density of 250 k/g of tissue. After 28 days of in vitro culture, menisci were analyzed for mechanical, biochemical, and histological characteristics. Menisci maintained structural integrity and material properties (compressive equilibrium and dynamic moduli) throughout preparations. Increased DNA content was observed in the needle-punched menisci but not in the samples without needle punching. Histology confirmed these results, showing enhanced cellular infiltration in needle-punched samples. The enhanced infiltration achieved in this study could help meniscal allografts better remodel post-surgery. The integration of autologous adipose-derived stem cells could improve long-term efficacy of meniscal transplantation procedures by helping to maintain the meniscus in vivo.

  2. Rat-derived processed nerve allografts support more axon regeneration in rat than human-derived processed nerve xenografts.

    PubMed

    Wood, Matthew D; Kemp, Stephen W P; Liu, Edward H; Szynkaruk, Mark; Gordon, Tessa; Borschel, Gregory H

    2014-04-01

    Processed nerve allografts are increasingly used as "off the shelf" nerve replacements for surgically bridging nerve gaps. Benchmarking the regenerative capacity of a commercially available human-derived nerve or xenograft in a rat nerve injury model would provide a convenient platform for future studies seeking to modify the processed nerve graft. Human and rat processed nerve grafts were used to bridge a 14 mm defect in a Sprague-Dawley rat sciatic nerve. Reversed autografts served as a positive control group. Twelve weeks following surgery, the distal nerve stumps were retrograde labeled and harvested for histology and histomorphometry. The cross-sectional areas of the human- and rat-derived processed nerve grafts were similar. Neuron counts and myelinated axon counts following use of the human-derived processed xenografts were decreased compared with those obtained from both the rat-derived processed nerve allografts and the autografts; the rat-derived processed nerve allografts were statistically equivalent to autografts. Measures of nerve fiber diameter and myelination revealed inferior axon regeneration maturity in both processed nerve grafts compared with autografts. Processed xenografts showed significantly reduced regeneration compared with autografts or processed allografts indicating that cross-species immunological reactions are important considerations in this rat model.

  3. A Higher Risk of Acute Rejection of Human Kidney Allografts Can Be Predicted from the Level of CD45RC Expressed by the Recipients’ CD8 T Cells

    PubMed Central

    Ordonez, Laurence; Bernard, Isabelle; Chabod, Marianne; Augusto, Jean-François; Lauwers-Cances, Valerie; Cristini, Christelle; Cuturi, Maria-Cristina; Subra, Jean-François; Saoudi, Abdelhadi

    2013-01-01

    Although transplantation is the common treatment for end-stage renal failure, allograft rejection and marked morbidity from the use of immunosuppressive drugs remain important limitations. A major challenge in the field is to identify easy, reliable and noninvasive biomarkers allowing the prediction of deleterious alloreactive immune responses and the tailoring of immunosuppressive therapy in individuals according to the rejection risk. In this study, we first established that the expression of the RC isoform of the CD45 molecule (CD45RC) on CD4 and CD8 T cells from healthy individuals identifies functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. We then investigated whether the frequency of the recipients CD45RC T cell subsets before transplantation would predict acute graft rejection in a cohort of 89 patients who had undergone their first kidney transplantation. We showed that patients exhibiting more than 54.7% of CD8 CD45RChigh T cells before transplantation had a 6 fold increased risk of acute kidney graft rejection. In contrast, the proportions of CD4 CD45RC T cells were not predictive. Thus, a higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients’ CD8 T cells. PMID:23894540

  4. Human Skin Allograft for Patients With Diabetic Foot Ulcers, Venous Leg Ulcers, or Surgical/Traumatic Wounds Retrospective, Descriptive Study.

    PubMed

    Desman, Eric; Bartow, William; Anderson, Louise H

    2015-07-01

    Chronic wounds such as diabetic foot ulcers (DFU) and venous leg ulcers (VLU) may take a long time to heal and increase the risk of complications. Previous studies have suggested human skin allograft may facilitate healing of these chronic wounds. A retrospective, descriptive study was conducted among outpatients with nonhealing DFU, VLU, surgical, or traumatic wounds managed with a meshed, partial-thickness, cryopreserved human skin allograft. Charts of all patients who received an allograft from 2011 to 2013 were abstracted if the wound was >1 cm2, had a duration>30 days, was adequately debrided, and was free of infection before the first allograft application. Primary outcome was percentage of wounds healed (ie, 100% epithelialized) at 12 and 20 weeks. Secondary outcome was the number of recorded adverse events. Wound measurements (area--calculated as width x length in cm2), wound type and duration, number of allograft applications, number of adverse events, and race, smoking status, and body mass index were abstracted. Of the 49 patients (average age 64.3 [SD 15.0]; 64% male) who met the inclusion criteria, 13 did not have medical follow-up through the primary outcomes at 12 and 20 weeks, leaving 36 patients (average age 65.1 [SD 15.4]; 67% male) available for analysis. The most common diagnoses were VLU (18 patients, 50%) and traumatic wounds (9 patients, 25%). Average wound size was 19.4 cm2 (SD 29.3, range 1.2-156, median 9.5), and average wound duration at initial treatment was 17.2 (SD 17.0, range 4-72, excluding outlier) weeks. Seventeen (17) wounds (47%) healed by 12 weeks, and 21 (58%) were healed by week 20 with an average of 3.3 (SD 2.0) allograft applications. No serious adverse events occurred. The results of this study are encouraging and add to the currently available literature on the use of allograft skin for chronic wounds, but the study design and sample size limit the ability to interpret the observations. Prospective, controlled clinical

  5. Complement Inhibition for Prevention and Treatment of Antibody-Mediated Rejection in Renal Allograft Recipients.

    PubMed

    Jordan, S C; Choi, J; Kahwaji, J; Vo, A

    2016-04-01

    Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo-controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development.

  6. Interdigitating reticulum cells in human renal grafts.

    PubMed

    Wakabayashi, T; Onoda, H

    1991-01-01

    Seventeen human renal graft biopsies taken 1 h to 50 days after transplantation and 3 human renal non-graft biopsies (2 minimal change and 1 non-tumour portion of angiomyolipoma) were investigated with immunoelectron microscopy in order to identify interdigitating reticulum cells (IDC) or dendritic cells (DC) in renal tissues. The antibodies used consisted of a rabbit polyclonal antibody of antihuman S100 beta protein, mouse monoclonal antibodies of antihuman HLA-DR, anti-CD3, and anti-CD1a. IDC or DC were identified in 11 renal grafts. They were found both in the glomerular and interstitial (peritubular) capillary lumens but not in the interstitium of 1 case: both were present in the interstitial capillary lumens and interstitium of another case, and in the interstitium only of 9 cases. In the remaining 6 grafts and 3 non-grafts they were not detected. These 6 grafts and 3 non-grafts did not show any pathological change except for foot process fusion of the glomerular epithelia in 2 cases of minimal change. These findings suggest that IDC or DC are not normally present in human renal tissues. The presence of the cell in the glomerular and peritubular capillary lumens of a biopsy taken after 1 h and their presence in the interstitial capillary lumens of another graft biopsy, suggest that the IDC or DC in human renal grafts are derived from recipients, not donors, and that they migrate from the circulating blood toward the interstitium.

  7. Human Split-Thickness Skin Allograft from Brain-Dead Donors

    PubMed Central

    Khodadadi, A.; Olang, O; Makhllough, A; Nozary Heshmati, B.; Azmoudeh Ardalan, F.; Tavakoli, S. A.

    2016-01-01

    Background: Looking for an appropriate skin substitute for temporary and permanent coverage of wounds remains one of the main obstacles of medical researchers. Objective: To investigate the rate of inflammation, symbiosis, and survival of grafted allograft skin from brain-dead donors (BDDs) in rabbits. Methods: After receiving negative serologic tests of BDDs, we prepared partial thickness skin grafts. They were then used in treating wounds of 5 rabbits in comparison with split-thickness skins taken from cardiac dead donors. Results: On histopathological examinations, we found no difference between the skins. All samples were separated from the baseline in 15–20 days. Conclusion: Gamma-irradiated freeze-dried human split-thickness skin taken from BDDs is safe and can be used for the treatment of deep skin burns. PMID:27721966

  8. Allograft immune response with sCR1 intervention.

    PubMed

    Pratt, J R; Hibbs, M J; Laver, A J; Smith, R A; Sacks, S H

    1996-03-01

    The deposition of complement (C) components on tissues of transplanted organs may induce many proinflammatory responses. The role of such C activation in allograft rejection is uncertain. We addressed this question by inhibiting C at the level of the C3 and C5 convertases, preventing C activation and progression of its cascade, using recombinant human soluble complement receptor 1 (sCR1) in an unsensitized rat renal allograft model. Fully MHC disparate Lewis to DA rat renal allograft recipients given 25 mg/kg sCR1 daily, with saline-treated allograft recipients as controls (n = 15 in each group), were sacrificed from day 1 to day 5 post-transplant, and examined histopathologically, and for the deposition of C3 and C5b-9 membrane attack complex (MAC), and for the presence of leucocyte antigen markers. Treated animals demonstrated a reduction in vascular injury and cellular infiltration, coincident with reduced C deposition. Flow cytometric analysis of leucocyte subpopulations in the spleen showed a reduction in activated (CD25 positive) B and T cells in treated animals, compared to saline treated controls. The results suggest that C inhibition with sCR1, in an unsensitized model of allograft rejection, was able to suppress the vascular and cell mediated components of tissue injury. The data support not only a role for C in antibody and possibly cell mediated cytotoxicity in the graft, but also suggest a role in the primary immune response leading to both T cell and B cell activation.

  9. Chondrocyte viability in fresh and frozen large human osteochondral allografts: effect of cryoprotective agents.

    PubMed

    Judas, F; Rosa, S; Teixeira, L; Lopes, C; Ferreira Mendes, A

    2007-10-01

    Chondrocyte survival is a major goal for the effective storage and clinical performance of human osteochondral allografts. The majority of animal and human cryopreservation studies conducted so far have been performed in small osteochondral cylinders. Using human tibial plateaus as a model for large osteochondral pieces, this work sought to evaluate the cryoprotective efficiency of glycerol and dimethylsulfoxide (DMSO), and to identify cryopreservation conditions suitable for use in tissue banks. Human tibial plateaus harvested from 7 cadaveric tissue donors were incubated in the presence or absence of cryoprotective agents (CPA): 10% or 15% glycerol and 10% DMSO in a Ham F-12 nutrient mixture. Chondrocyte viability was assessed immediately after thawing, using the MTT reduction assay and a fluorescence microscopic method. The tibial plateaus frozen in the absence of CPA showed a significant decrease in chondrocyte viability. The use of CPA significantly increased chondrocyte viability compared with cartilage frozen without CPA (nearly 50% versus 80% living chondrocytes with 10% glycerol versus 10% DMSO, respectively) relative to that in fresh cartilage. In this regard, 10% DMSO was slightly more effective than either 10% or 15% glycerol, eliciting the recovery of approximately 15% relative to the living chondrocyte content in fresh cartilage. In all conditions, fluorescence microscopic studies showed that surviving chondrocytes were restricted to the superficial cartilage layer. Human tibial plateaus seemed to be a good experimental model to establish cryopreservation methods applicable to large human osteochondral pieces in tissue banks.

  10. Decellularized extracellular matrix derived from human adipose tissue as a potential scaffold for allograft tissue engineering.

    PubMed

    Choi, Ji Suk; Kim, Beob Soo; Kim, Jun Young; Kim, Jae Dong; Choi, Young Chan; Yang, Hyun-Jin; Park, Kinam; Lee, Hee Young; Cho, Yong Woo

    2011-06-01

    Decellularized tissues composed of extracellular matrix (ECM) have been clinically used to support the regeneration of various human tissues and organs. Most decellularized tissues so far have been derived from animals or cadavers. Therefore, despite the many advantages of decellularized tissue, there are concerns about the potential for immunogenicity and the possible presence of infectious agents. Herein, we present a biomaterial composed of ECM derived from human adipose tissue, the most prevalent, expendable, and safely harvested tissue in the human body. The ECM was extracted by successive physical, chemical, and enzymatic treatments of human adipose tissue isolated by liposuction. Cellular components including nucleic acids were effectively removed without significant disruption of the morphology or structure of the ECM. Major ECM components were quantified, including acid/pepsin-soluble collagen, sulfated glycosaminoglycan (GAG), and soluble elastin. In an in vivo experiment using mice, the decellularized ECM graft exhibited good compatibility to surrounding tissues. Overall results suggest that the decellularized ECM containing biological and chemical cues of native human ECM could be an ideal scaffold material not only for autologous but also for allograft tissue engineering.

  11. The Use of Cryopreserved Human Skin Allograft for the Treatment of Wounds With Exposed Muscle, Tendon, and Bone.

    PubMed

    Wilson, Thomas C; Wilson, Jessica A; Crim, Brandon; Lowery, Nicholas J

    2016-04-01

    Wounds with exposed bone or tendon continue to be a challenge for wound care physicians, and there is little research pertaining to the treatment of these particular wounds with allograft skin. The purpose of this study was to evaluate the effectiveness and safety of a biologically active cryopreserved human skin allograft for treating wounds with exposed bone and/or tendon in the lower extremities. Fifteen patients with 15 wounds at a single hospital-based wound care center were included in the study. Eleven wounds had exposed bone, 1 wound had exposed ten- don, and 3 wounds had exposed bone and tendon. Standard treatment principles with adjunctive cadaveric allograft application were performed on all wounds in the study. In this study 14/15 (93.3%) of the wounds healed completely. The mean duration of days until coverage of the bone and/or tendon with granulation tissue was 36.14 (5.16 weeks) (range 5-117 days). Mean duration to complete healing of the wound was 133 days (19 weeks) (range 53-311 days). The mean number of grafts applied was 2. There were no adverse events directly related to the graft. Zero major amputations and 1 minor amputation occurred. This study found biologically active cryopreserved human skin allografts to be safe and effective in treating difficult wounds with exposed bone and/or tendon. To the authors' knowledge, this is the largest study to date focused on the utilization of allograft skin as an adjunct therapy for lower extremity wounds with exposed tendon and/or bone.

  12. Assessment of the biological properties of human split skin allografts disinfected with peracetic acid and preserved in glycerol.

    PubMed

    Lomas, R J; Cruse-Sawyer, J E; Simpson, C; Ingham, E; Bojar, R; Kearney, J N

    2003-09-01

    Skin allografts derived from cadaveric human donors are widely used in the treatment of serious burn injuries and other conditions, such as ulcers. In order to render these allografts safe for clinical use, and to enable them to be preserved and banked for long periods, effective methods of decontamination and preservation are required. These methods must not adversely affect graft properties essential for clinical performance. We have investigated the application of a peracetic acid (PAA) disinfection protocol, coupled with preservation in either glycerol or propylene glycol to achieve these goals. An effective decontamination procedure, comprising of a 3h exposure to 0.1% (v/v) PAA in phosphate buffered saline (PBS) at pH 7.0, was developed and had no significant detrimental effects on the structure of skin. Cadaveric skin allografts were then treated with this disinfection protocol and subsequently preserved in either 85% (v/v) glycerol or propylene glycol in PBS, and the biological properties of the allografts thought to be essential to successful clinical performance were assessed. The cytotoxicity of the grafts was assessed using both extract and contact assays; damage to the skin collagen was assessed using a collagenase susceptibility assay and the capacity of the grafts to elicit an inflammatory response in vitro was assessed by quantifying the production of the pro-inflammatory cytokine TNF-alpha by human peripheral blood mononuclear phagocytes. Neither the disinfection protocol nor either of the preservation techniques rendered the grafts cytotoxic or pro-inflammatory. The PAA disinfection and glycerol preservation protocol had no effects on collagenase susceptibility, whereas the disinfection protocol in combination with propylene glycol rendered some of the test samples significantly more susceptible to collagenase digestion. Therefore, this study has demonstrated that PAA disinfection combined with glycerol preservation is suitable for skin allografts

  13. Human microbiota characterization in the course of renal transplantation.

    PubMed

    Fricke, W F; Maddox, C; Song, Y; Bromberg, J S

    2014-02-01

    Recent studies demonstrate that the human microbiota, the collection of microorganisms growing on and in individuals, have numerous bidirectional interactions with the host, influencing immunity, resistance to infection, inflammation and metabolism. Little has been done to study the potential associations between microbiota composition and transplant outcome. Here, we investigated the longitudinal changes in the blood, urinary, oral and rectal microbiota of renal allograft recipients before and at 1 and 6 months after transplantation. The results showed major changes in microbiota composition as a result of the transplant episode and associated medications, and these changes persisted over time. The high interindividual variation as well as differences in response to transplantation suggested that it is unlikely that the same specific microbiota members can serve as universal diagnostic markers. Rather, longitudinal changes in each individual's microbiota have the potential to be indicative of health or disease. Use of sensitive nucleic acid-based testing showed that urine, irrespective of disease states, more often harbors a diverse microbiota than appreciated by conventional culture techniques. These results lay the groundwork to construct more comprehensive future investigations to identify microbiota characteristics that can serve as diagnostic markers for transplant health and to guide intervention strategies to improve transplant outcome.

  14. T-bet-positive mononuclear cell infiltration is associated with transplant glomerulopathy and interstitial fibrosis and tubular atrophy in renal allograft recipients.

    PubMed

    Yadav, Brijesh; Prasad, Narayan; Agrawal, Vinita; Jain, Manoj; Agarwal, Vikas; Jaiswal, Akhilesh; Bhadauria, Dharmendra; Sharma, R K; Gupta, Amit

    2015-04-01

    We aimed to study the role of T-bet-positive mononuclear cell infiltration in different compartments of kidney graft tissues in patients with chronic transplant glomerulopathy, interstitial fibrosis and tubular atrophy, and stable graft function. There were 80 living-related renal transplant recipients included (chronic transplant glomerulopathy, n = 28; interstitial fibrosis and tubular atrophy, n = 28; stable graft function, n = 24). Histologic characteristics and scoring for peritubular capillaritis, glomerulitis, interstitial fibrosis and tubular atrophy, and intimal arteritis were performed according to Banff 2007 classification and compared between the groups. Immunohistologic staining was performed for transcription factor T-bet, T-bet mononuclear cells were counted, and T-bet infiltration score was compared between groups. Patients in different groups had similar clinical profiles and human leukocyte antigen mismatches, except the groups differed in serum creatinine and proteinuria. The prevalence and scoring of peritubular capillaritis and glomerulitis were significantly higher in chronic transplant glomerulopathy than interstitial fibrosis and tubular atrophy (P = .001) and stable graft function (P < .001). Tubulitis was observed in 6 patients (21.4%) with chronic transplant glomerulopathy but no patients with interstitial fibrosis and tubular atrophy. The C4d/donor-specific antibody was positive in 100% patients with chronic transplant glomerulopathy, 0% patients with interstitial fibrosis and tubular atrophy, and 4.1 % patients with stable graft function. Interstitial fibrosis and tubular atrophy was seen in 100% patients who had interstitial fibrosis and tubular atrophy; in patients who had chronic transplant glomerulopathy, 24 patients (85.7%) had interstitial fibrosis and 78.5% patients had tubular atrophy. The degree and severity of T-bet-positive cell infiltration were significantly higher in chronic transplant glomerulopathy than interstitial

  15. Chronic allograft nephropathy.

    PubMed

    Vadivel, Nidyanandh; Tullius, Stefan G; Chandraker, Anil

    2007-07-01

    Chronic allograft nephropathy (CAN) remains the Achilles heel of renal transplantation. In spite of the significant strides achieved in one-year renal allograft survival with newer immunosuppressant strategies, the fate of long-term renal allograft survival remains unchanged. The number of renal transplant recipients returning to dialysis has doubled in the past decade. This is especially important since these patients pose a significantly increased likelihood of dying while on the waiting list for retransplantation, due to increasing disparity between donor organ availability versus demand and longer waiting time secondary to heightened immunologic sensitization from their prior transplants. In this review we analyze the latest literature in detail and discuss the definition, natural history, pathophysiology, alloantigen dependent and independent factors that play a crucial role in CAN and the potential newer therapeutic targets on the horizon. This article highlights the importance of early identification and careful management of all the potential contributing factors with particular emphasis on prevention rather than cure of CAN as the core management strategy.

  16. Conversion from tacrolimus/mycophenolic acid to tacrolimus/leflunomide to treat cutaneous warts in a series of four pediatric renal allograft recipients.

    PubMed

    Nguyen, Lieuko; McClellan, Robert B; Chaudhuri, Abanti; Alexander, Steven R; Chen, Sharon F; Concepcion, Waldo; Grimm, Paul

    2012-09-15

    The challenge of immunosuppression in pediatric renal transplantation is to balance preventing rejection while avoiding infectious complications. A dermatological complication of immunosuppression is viral warts, which cause significant disfigurement and increase the risk of skin malignancy. We present three pediatric and adolescent renal allograft recipients with multiple, recalcitrant verrucae vulgares lesions and one patient with molluscum contagiosum who were switched from mycophenolate mofetil to leflunomide. Teriflunomide metabolite levels were carefully maintained between 50,000 and 100,000 ng/mL to balance its immunosuppressive and antiviral properties. No adverse events requiring discontinuation of leflunomide were encountered. Switching from mycophenolate mofetil to leflunomide successfully cleared verrucae vulgares and molluscum lesions in all four renal transplant patients. The ability to minimize and even resolve warts can improve quality of life by reducing risk of skin malignancies and emotional distress in solid organ transplant patients. Leflunomide is a potential therapeutic option for posttransplantation patients with skin warts because it serves both as an adjunct to the immunosuppressive regimen and an antiviral agent.

  17. The impact of trimethoprim-sulfamethoxazole as Pneumocystis jiroveci pneumonia prophylaxis on the occurrence of asymptomatic bacteriuria and urinary tract infections among renal allograft recipients: a retrospective before-after study.

    PubMed

    Singh, Ramandeep; Bemelman, Frederike J; Hodiamont, Caspar J; Idu, Mirza M; Ten Berge, Ineke J M; Geerlings, Suzanne E

    2016-02-25

    The international guidelines recommend the administration of trimethoprim-sulfamethoxazole (TMP-SMX) as Pneumocystis jiroveci pneumonia (PJP) prophylaxis for six months after transplantation. The aim of this study is to evaluate the influence of TMP-SMX prophylaxis on the occurrence of asymptomatic bacteriuria (ASB) and urinary tract infections (UTIs) as cystitis and allograft pyelonephritis (AGPN) and its impact on the antimicrobial resistance pattern of causative microorganisms. We have conducted a retrospective before-after study in adult renal allograft recipients with one year follow-up after transplantation. We compared the ("after") group that received TMP-SMX as PJP prophylaxis to the ("before") group that did not receive it. In total, 343 renal allograft recipients were analysed, of whom 212 (61.8 %) received TMP-SMX as PJP prophylaxis. In this study, 63 (18.4 %) did only develop ASB without UTI, 26 (7.6 %) developed cystitis and 43 (12.5 %) developed AGPN. The remaining 211 (61.5 %) renal allograft recipients did not develop any bacteriuria at all. Multivariable Cox proportional regression analysis indicated that TMP-SMX as PJP prophylaxis was not associated with reduced prevalence of ASB (Hazard ratio (HR) = 1.52, 95 % CI = 0.79-2.94, p = 0.213), nor with reduced incidence of cystitis (HR = 2.21, 95 % CI = 0.76-6.39, p = 0.144), nor AGPN (HR = 1.12, 95 % CI = 0.57-2.21, p = 0.751). Among the group receiving TMP-SMX as PJP prophylaxis there was a trend was observed in increase of both amoxicillin (86 % versus 70 %) and TMP-SMX (89 % versus 48 %) resistance which already appeared within the first 30 days after TMP-SMX exposure. Among renal allograft recipients, administration of TMP-SMX as PJP prophylaxis does not prevent ASB nor UTI, however it is associated with tendency towards increased amoxicillin and TMP-SMX resistance.

  18. Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

    PubMed Central

    Walker, Natalie; Badri, Linda; Wettlaufer, Scott; Flint, Andrew; Sajjan, Uma; Krebsbach, Paul H.; Keshamouni, Venkateshwar G.; Peters-Golden, Marc; Lama, Vibha N.

    2011-01-01

    Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft–derived MSCs uniquely express embryonic lung mesenchyme–associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stable in vivo fibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 by in situ hybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs. PMID:21641374

  19. Suppression of chronic damage in renal allografts by Liver X receptor (LXR) activation relevant contribution of macrophage LXRα.

    PubMed

    Kiss, Eva; Popovic, Zoran; Bedke, Jens; Wang, Shijun; Bonrouhi, Mahnaz; Gretz, Norbert; Stettner, Paula; Teupser, Daniel; Thiery, Joachim; Porubsky, Stefan; Adams, Judith; Gröne, Hermann-Josef

    2011-07-01

    Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRα (mLXRα-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow-derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRα-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRα-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1- and mannose receptor C type 1-positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRα overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRα in allograft rejection and prevention of fibrosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  20. Renal hemodynamic effects of relaxin in humans.

    PubMed

    Smith, Marie; Davison, John; Conrad, Kirk; Danielson, Lee

    2005-05-01

    Rat studies have convincingly demonstrated the essential role of the ovarian hormone relaxin in mediating gestational renal hemodynamic and osmoregulatory changes in that species. We describe a model in nonpregnant volunteers using exogenous hCG to stimulate the production and release of ovarian relaxin in order to assess renal hemodynamic responses. Women (n = 10) were serially studied +/- hCG stimulation during menstrual cycles with measurement of inulin, PAH, and neutral dextran clearances (to determine glomerular filtration rate [GFR], renal plasma flow [RPF], and glomerular porosity, respectively). Controls were women without ovarian function (n = 6) and men (n = 10). GFR and RPF were increased in the luteal phase compared to the follicular phase (15.3% increase in GFR, P < 0.005; 17.8% increase in RPF, P < 0.05). In controls, GFR and RPF were not significantly different between study occasions. Although exogenous hCG did not stimulate relaxin secretion in women without ovarian function or in men, it did so in normal women, but not into the pregnancy range. In no group were renal hemodynamics augmented by administered hCG. In naturally occurring cycles, increased serum relaxin is associated with augmented renal hemodynamics. As luteal stimulation with hCG failed to yield pregnancy relaxin levels, the use of exogenous relaxin for human administration is needed to further elucidate the renal vasodilatory properties of relaxin.

  1. The influence of organ donor factors on early allograft function.

    PubMed

    Schwarz, Christoph; Oberbauer, Rainer

    2003-03-01

    Postischaemic acute renal allograft failure is among the main risk factors for reduced transplant survival. Although new immunosuppressive protocols have reduced the number of acute rejections, the incidence of acute renal failure remained unchanged. On the basis of histomorphology it is not possible to predict donor kidneys at risk of subsequent failure. Some factors are associated with failure, but even combinations of these risk factors can not precisely predict the development of acute renal failure. Studies have therefore evaluated the influence of demographic donor and recipient factors on acute renal failure. New biotechnology and data mining tools are currently being used to study and identify the molecular predictors of acute renal failure. Recent studies showed that donor factors contributed to approximately 40% of the variability in early allograft function. Deductive approaches identified some isolated molecular targets, such as adhesion molecules, as risk factors. Explorative analysis of the entire human genome, however, identified several predictive clusters of genes, which can be functionally grouped into categories such as cell death, stress response, cell adhesion, transcription factors, inflammatory response or cell cycle-related genes. Based on this information, preventative strategies using antisense oligonucleotides or antibodies were adopted. Clinical studies identified the use of catecholamines in the organ donor as beneficial. All these efforts aim to reduce renal tubular damage. A detailed analysis of the molecular events and pathways of renal gene expression in the donor and after reperfusion, together with sophisticated data analysis tools, will provide new insights into the pathophysiology of acute renal failure.

  2. Variability of the Estimated Glomerular Filtration Rate in the First Year after Kidney Transplantation Is an Independent Risk Factor for Poor Renal Allograft Outcomes: A Retrospective Cohort Study

    PubMed Central

    Choi, Hoon Young; Huh, Kyu Ha; Lee, Jae Geun; Song, Mi Kyung; Kim, Myoung Soo; Kim, Yu Seun; Kim, Beom Seok

    2016-01-01

    Renal function in the first year after kidney transplantation (KT) can predict long-term renal graft survival. This study investigated whether estimated glomerular filtration rate (eGFR) variability during the first year after KT is a risk factor for poor renal allograft outcomes. This retrospective cohort study included 3077 patients who underwent repeated eGFR measurements for 1 year after KT at Severance Hospital Transplantation Center between 1979 and 2012. The eGFR variability during the first year after KT was the predictor. The patients were divided into four quartile groups of eGFR variability according to the coefficient of variation for eGFR (eGFR-CV). We selected a cutoff of eGFR-CV for graft failure and performed the sensitivity analyses. The graft outcome was worse in the highest quartile group of eGFR variability than in the other groups among all patients (Q4: HR 1.631, 95% CI 1.278–2.081; p < 0.0001) and among patients without AR (Q4: HR 1.425, 95% CI 1.024–1.982; p = 0.0358) after adjusting for eGFR at 1 year after KT and other covariates. Additionally, all-cause mortality was higher in this highest quartile group than in the other groups among all patients but not among patients without AR. Higher eGFR-CVs than the cutoff were significantly associated with a high risk of graft failure among all patients (HR 1.670, 95% CI 1.395–2.000; p < 0.0001) and among patients without AR (HR 1.899, 95% CI 1.457–2.477; p < 0.0001) after fully adjusting for covariates. For all-cause mortality, a higher eGFR-CV was an independent risk factor among all patients but not among patients without AR after adjusting for covariates. eGFR variability in the first year after KT is an independent risk factor for poor renal allograft outcomes. PMID:27973553

  3. Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival.

    PubMed

    Koch, M; Lehnhardt, A; Hu, X; Brunswig-Spickenheier, B; Stolk, M; Bröcker, V; Noriega, M; Seifert, M; Lange, C

    2013-12-01

    Application of mesenchymal stromal cells (MSCs) has been proposed for solid organ transplantation based on their potent immuno-modulatory effects in vitro and in vivo. We investigated the potential of MSCs to improve acceptance of kidney transplants in an MHC-incompatible rat model including isogeneic kidney transplantation (RTx) as control. MSCs were administered i.v. or i.a. at time of transplantation. No immunosuppression was applied. Renal function was monitored by serum-creatinine, histopathology, immunochemistry for graft infiltrating cells and expressions of inflammatory genes. We demonstrated the short-term beneficial effects of MSC injection. In the long term, however, MSC-related life-threatening/shortening events (thrombotic microangiopathy, infarctions, infections) were evident despite decreased T- and B-cell infiltration, lower interstitial inflammation and downregulated inflammatory genes particularly after i.a. MSC injection. We conclude that i.a. MSC administration provides efficient immunomodulation after allogeneic RTx, although timing and co-treatment strategies need further fine-tuning to develop the full potential of powerful cell therapy in solid organ transplantation.

  4. Three-dimensional Reconstruction of the Microstructure of Human Acellular Nerve Allograft

    PubMed Central

    Zhu, Shuang; Zhu, Qingtang; Liu, Xiaolin; Yang, Weihong; Jian, Yutao; Zhou, Xiang; He, Bo; Gu, Liqiang; Yan, Liwei; Lin, Tao; Xiang, Jianping; Qi, Jian

    2016-01-01

    The exact inner 3D microstructure of the human peripheral nerve has been a mystery for decades. Therefore, it has been difficult to solve several problems regarding peripheral nerve injury and repair. We used high-resolution X-ray computed microtomography (microCT) to scan a freeze-dried human acellular nerve allograft (hANA). The microCT images were then used to reconstruct a 3D digital model, which was used to print a 3D resin model of the nerve graft. The 3D digital model of the hANA allowed visualization of all planes. The magnified 3D resin model clearly showed the nerve bundles and basement membrane tubes of the hANA. Scanning electron microscopy (SEM) was used to analyse the microstructure of the hANA. Compared to the SEM images, the microCT image clearly demonstrated the microstructure of the hANA cross section at a resolution of up to 1.2 μm. The 3D digital model of the hANA facilitates a clear and easy understanding of peripheral nerve microstructure. Furthermore, the enlarged 3D resin model duplicates the unique inner structure of each individual hANA. This is a crucial step towards achieving 3D printing of a hANA or nerve that can be used as a nerve graft. PMID:27476584

  5. Association of HLA-G promoter and 14-bp insertion-deletion variants with acute allograft rejection and end-stage renal disease.

    PubMed

    Misra, M K; Prakash, S; Kapoor, R; Pandey, S K; Sharma, R K; Agrawal, S

    2013-11-01

    The aim of this study was to investigate the HLA-G 14-bp insertion/deletion (I/D) polymorphism among end-stage renal disease (ESRD) patients. Cytomegalovirus (CMV) infection, acute allograft rejection (AR) and overall survival after renal transplantation was investigated in 300 ESRD patients and 302 age, sex and ethnicity-matched controls. Sequencing was performed to evaluate the impact of HLA-G promoter region single-nucleotide polymorphisms (SNPs) whereas semi-quantitative PCR method was used to determine the probable HLA-G expression pattern among ESRD and AR cases. Further, soluble human leukocyte antigen (HLA)-G (sHLA-G) expression levels were compared in AR vs non-AR cases in the light of HLA-G 14-bp I/D polymorphism. Increased risk was found for 14-bp D/D (deletion-DD) genotype and 14-bp D allele [DD: odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.03-2.06, P value = 0.0358; D: OR = 1.29, 95% CI = 1.03-1.62, P value = 0.0277], respectively for ESRD and CMV infection (DD: OR = 2.70, 95% CI = 1.45-5.05, P value = 0.0021; D: OR = 1.94, 95% CI = 1.22-3.08, P value = 0.0052). Nearly fourfold (OR = 3.62, 95%CI = 1.61-8.14, p = 0.0039) risk was observed for 14-bp I/I (insertion-II) genotype for AR. Survival analysis showed increased overall survival (OS) (AR or death) for 14-bp D/D genotype. HLA-G promoter region sequencing was carried out among 60 ESRD patients and 100 normal controls which showed increased risk for -964 G>A, -725 C>G/T and -486 A>C SNPs. -964 G>A and -725 C>G/T SNPs showed risk association for AR patients. High level of HLA-G transcripts was observed among non-AR patients. Further soluble HLA-G (sHLA-G) showed increased levels in ESRD patients (mean ± SEM; 62.16 ± 2.43 U/ml) as compared to controls (mean ± SEM; 21.06 ± 3.89 U/ml) (P = <0.0001). The 14-bp I/I, 14-bp I/D and 14-bp D/D genotypes showed significantly higher levels of sHLA-G among non-AR as

  6. Disinfection of human skin allografts in tissue banking: a systematic review report.

    PubMed

    Johnston, C; Callum, J; Mohr, J; Duong, A; Garibaldi, A; Simunovic, N; Ayeni, O R

    2016-12-01

    The use of skin allografts to temporarily replace lost or damaged skin is practiced worldwide. Naturally occurring contamination can be present on skin or can be introduced at recovery or during processing. This contamination can pose a threat to allograft recipients. Bacterial culture and disinfection of allografts are mandated, but the specific practices and methodologies are not dictated by standards. A systematic review of literature from three databases found 12 research articles that evaluated bioburden reduction processes of skin grafts. The use of broad spectrum antibiotics and antifungal agents was the most frequently identified disinfection method reported demonstrating reductions in contamination rates. It was determined that the greatest reduction in the skin allograft contamination rates utilized 0.1 % peracetic acid or 25 kGy of gamma irradiation at lower temperatures.

  7. SWOT analysis of Banff: strengths, weaknesses, opportunities and threats of the international Banff consensus process and classification system for renal allograft pathology.

    PubMed

    Mengel, M; Sis, B; Halloran, P F

    2007-10-01

    The Banff process defined the diagnostic histologic lesions for renal allograft rejection and created a standardized classification system where none had existed. By correcting this deficit the process had universal impact on clinical practice and clinical and basic research. All trials of new drugs since the early 1990s benefited, because the Banff classification of lesions permitted the end point of biopsy-proven rejection. The Banff process has strengths, weaknesses, opportunities and threats (SWOT). The strength is its self-organizing group structure to create consensus. Consensus does not mean correctness: defining consensus is essential if a widely held view is to be proved wrong. The weaknesses of the Banff process are the absence of an independent external standard to test the classification; and its almost exclusive reliance on histopathology, which has inherent limitations in intra- and interobserver reproducibility, particularly at the interface between borderline and rejection, is exactly where clinicians demand precision. The opportunity lies in the new technology such as transcriptomics, which can form an external standard and can be incorporated into a new classification combining the elegance of histopathology and the objectivity of transcriptomics. The threat is the degree to which the renal transplant community will participate in and support this process.

  8. Allograft inflammatory factor-1 stimulates chemokine production and induces chemotaxis in human peripheral blood mononuclear cells.

    PubMed

    Kadoya, Masatoshi; Yamamoto, Aihiro; Hamaguchi, Masahide; Obayashi, Hiroshi; Mizushima, Katsura; Ohta, Mitsuhiro; Seno, Takahiro; Oda, Ryo; Fujiwara, Hiroyoshi; Kohno, Masataka; Kawahito, Yutaka

    2014-06-06

    Allograft inflammatory factor-1 (AIF-1) is expressed by macrophages, fibroblasts, endothelial cells and smooth muscle cells in immune-inflammatory disorders such as systemic sclerosis, rheumatoid arthritis and several vasculopathies. However, its molecular function is not fully understood. In this study, we examined gene expression profiles and induction of chemokines in monocytes treated with recombinant human AIF (rhAIF-1). Using the high-density oligonucleotide microarray technique, we compared mRNA expression profiles of rhAIF-1-stimulated CD14(+) peripheral blood mononuclear cells (CD14(+) PBMCs) derived from healthy volunteers. We demonstrated upregulation of genes for several CC chemokines such as CCL1, CCL2, CCL3, CCL7, and CCL20. Next, using ELISAs, we confirmed that rhAIF-1 promoted the secretion of CCL3/MIP-1α and IL-6 by CD14(+) PBMCs, whereas only small amounts of CCL1, CCL2/MCP-1, CCL7/MCP-3 and CCL20/MIP-3α were secreted. Conditioned media from rhAIF-1stimulated CD14(+) PBMCs resulted in migration of PBMCs. These findings suggest that AIF-1, which induced chemokines and enhanced chemotaxis of monocytes, may represent a molecular target for the therapy of immune-inflammatory disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Pathway-Specific Engineered Mouse Allograft Models Functionally Recapitulate Human Serous Epithelial Ovarian Cancer

    PubMed Central

    Szabova, Ludmila; Bupp, Sujata; Kamal, Muhaymin; Householder, Deborah B.; Hernandez, Lidia; Schlomer, Jerome J.; Baran, Maureen L.; Yi, Ming; Stephens, Robert M.; Annunziata, Christina M.; Martin, Philip L.; Van Dyke, Terry A.

    2014-01-01

    The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53 and Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. Ovarian tumors deficient in Brca1 respond to treatment with cisplatin and olaparib, a PARP inhibitor, whereas Brca1-wild type tumors are non-responsive to treatment, recapitulating the relative sensitivities observed in patients. These mouse models provide the opportunity for evaluation of effective therapeutics, including prediction of differential responses in Brca1-wild type and Brca1–deficient tumors and development of relevant biomarkers. PMID:24748377

  10. The effect of glutathion S-transferase polymoprhisms and anti-GSTT1 antibodies on allograft functions in recipients of renal transplant.

    PubMed

    Akgul, S U; Oguz, F S; Çalişkan, Y; Kekik, C; Gürkan, H; Türkmen, A; Nane, I; Aydin, F

    2012-01-01

    The balance between oxidative stress and anti-oxidant defense systems after renal transplantation may explain the development and progression of allograft dysfunction. Glutathione S-transferase (GST) decreases the damage from oxidative stress. In contrast, recipient antibodies against GSTT1 expressed on the graft are believed to cause its dysfunction. The aim of our research was to study the probable relationship to rejection between GST gene polymorphisms and anti-GSTT1 antibodies. We included 122 patients transplantations from living donors and 51 healthy individuals as controls group in our study. The patient groups were comprised of 57 patients who did and 65 who did not experienced rejection episode. Polymerase chain reactions were used to detect GSTM1 and GSTT1 polymorphisms, whereas PCR-RFLP (restriction fragment length polymorphism), for GSTP1 polymorphism. An enzyme-linked immunosorbent assay method was used for anti-GSTT1 antibody scans. There was no significant difference between the groups for allele and genotype frequencies of GSTT1, GSTM1, GSTP1 polymorphisms of the recipients, donors, and controls. Within the rejection group the frequency of patients with the GSTM1 null genotype was higher among subjects prescribed cyclosporine A versus tacrolimus (P = .029). Among the entire patient group, 46 subjects with GSTT1 null genotype were scanned for anti-GSTT1 antibody which was detected in 5 of 8 patients with an acute rejection episode (P = .04). Anti-GSTT1 antibody was observed more frequently albeit not significantly, among the cyclosporine versus tacrolimus patient group (P = .16). This study suggested that GSTM1 genotype may be important for cyclosporine detoxification and for allograft outcomes due to drug nephrotoxicity. After transplantation, antigens distinct from the HLA system such as GSTT1 protein may also be targets for alloimmune responses.

  11. The effect of gamma irradiation on the osteoinductivity of demineralized human bone allograft.

    PubMed

    Arjmand, Babak; Aghayan, Hamid Reza; Larijani, Bagher; Sahebjam, Mehrnaz; Ghaderi, Firoozeh; Goodarzi, Parisa

    2014-01-01

    The gamma irradiation has been used for end sterilization of allograft bones and its effects with a 25 kGy dosage on the osteoinductive properties of demineralized bone allograft powder was studied. This work carried out using an experimental method in an animal model. In this study the demineralized bone allograft powder which had been sterilized and prepared with gamma irradiation in a 25 kGy dosage in 18 hours, was used as a study group and the demineralized bone allograft powder which had been prepared aseptically was used as the reference group. 30 mg of bone powder from each group were implanted into right and left paravertebral muscles of eighteen rats, separately. After four weeks, the implanted samples were harvested with a 0.5 cm border and then the osteoinductivity of implants in two groups were compared with histopathologic studies. In 94.4% of the reference samples a new bone formation was observed. In the study group, this difference was observed only in 27.7% of samples (P<0.002). It appears that using gamma irradiation may lead to a reduction in osteoinduction properties of demineralized bone allograft powder.

  12. Effects of a peracetic acid disinfection protocol on the biocompatibility and biomechanical properties of human patellar tendon allografts.

    PubMed

    Lomas, R J; Jennings, L M; Fisher, J; Kearney, J N

    2004-01-01

    Patellar tendon allografts, retrieved from cadaveric human donors, are widely used for replacement of damaged cruciate ligaments. In common with other tissue allografts originating from cadaveric donors, there are concerns regarding the potential for disease transmission from the donor to the recipient. Additionally, retrieval and subsequent processing protocols expose the graft to the risk of environmental contamination. For these reasons, disinfection or sterilisation protocols are necessary for these grafts before they are used clinically. A high-level disinfection protocol, utilising peracetic acid (PAA), has been developed and investigated for its effects on the biocompatibility and biomechanics of the patellar tendon allografts. PAA disinfection did not render the grafts either cytotoxic or liable to provoke an inflammatory response as assessed in vitro . However, the protocol was shown to increase the size of gaps between the tendon fibres in the matrix and render the grafts more susceptible to digestion with collagenase. Biomechanical studies of the tendons showed that PAA treatment had no effect on the ultimate tensile stress or Young's modulus of the tendons, and that ultimate strain was significantly higher in PAA treated tendons.

  13. A liquidus tracking approach to the cryopreservation of human cartilage allografts.

    PubMed

    Kay, A G; Hoyland, J A; Rooney, P; Kearney, J N; Pegg, D E

    2015-08-01

    In the "liquidus tracking" (LT) approach to cryopreservation both the temperature and the concentration of cryoprotectant (CPA) are controlled such that solution composition "tracks" the liquidus (melting point) line for that system. Ice crystal formation is prevented but the tissue is not exposed to CPA concentrations exceeding those experienced by cells during conventional cryopreservation. This approach is particularly appropriate for articular cartilage because chondrocytes in situ are exquisitely susceptible to damage by the crystallisation of ice. This project aimed to develop a suitable process for tissue to be used in the surgical repair of damaged human knee joints. A high proportion of the chondrocytes should be alive. Human articular cartilage was obtained from deceased donors and dimethyl sulphoxide (DMSO) was used as the CPA, cooling was at 0.14°C/min and warming at 0.42°C/min. The vehicle solution was CPTes2. A program of increasing DMSO concentration was developed for cooling and this gave satisfactory tissue concentrations but reduction of DMSO concentration during warming was inadequate, resulting in higher tissue concentrations than required. Biomechanical testing indicated a compressive modulus of 9.5±1.3 MPa in LT-processed cartilage, with control values of 11.6±0.8 MPa (p>0.05, Student's t-test). Measurement of GAG synthesis sometimes approached 65% or 85% of control, but the variability of replicate data prevented firm conclusions. Ideally allograft tissue should score 1A or above on the Noyes scale and the donor age should be less than 46 years but the cartilage used in this study did not meet these standards.

  14. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

    PubMed Central

    Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

    2016-01-01

    Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. PMID:26293822

  15. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.

    PubMed

    Lefaucheur, Carmen; Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

    2016-01-01

    Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. Copyright © 2016 by the American Society of Nephrology.

  16. Local anesthetics induce human renal cell apoptosis.

    PubMed

    Lee, H Thomas; Xu, Hua; Siegel, Cory D; Krichevsky, Igor E

    2003-01-01

    Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Local anesthetics induce apoptosis in neuronal and lymphocytic cell lines. We examined the effects of chronic (48 h) local anesthetic treatment (lidocaine, bupivacaine and tetracaine) on human proximal tubular (HK-2) cells. Apoptosis induction was assessed by detecting poly(ADP)-ribose polymerase fragmentation, caspase activation, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, DNA laddering and by cellular morphology. Cell death was quantified by measuring neutral red dye uptake and lactate dehydrogenase released into the cell culture medium. All 3 local anesthetics caused concentration-dependent cell death, induced HK-2 cell apoptosis and potentiated TNF-alpha induced apoptosis. Local anesthetics induced HK-2 cell apoptosis by activation of caspases 3, 6, 7, 8 and 9. ZVAD-fmk, a pan-caspase inhibitor, blocked the local anesthetic induced HK-2 cell apoptosis. Local anesthetics also inhibited the activities of anti-apoptotic kinases protein kinase B (Akt) and extracellular signal regulated mitrogen-activated protein kinase. Local anesthetic's pro-apoptotic effects are independent of sodium channel inhibition as tetrodotoxin, a selective voltage-gated sodium channel blocker, failed to mimic local anesthetic-mediated induction or potentiation of HK-2 cell apoptosis. We conclude that local anesthetics induce human renal cell apoptotic signaling by caspase activation and via inhibition of pro-survival signaling pathways.

  17. Treatment of Autonomous Hyperparathyroidism in Post Renal Transplant Recipients

    ClinicalTrials.gov

    2017-02-07

    Chronic Allograft Nephropathy; Chronic Kidney Disease; Chronic Renal Failure; Disordered Mineral Metabolism; End Stage Renal Disease; Hyperparathyroidism; Hypophosphatemia; Kidney Disease; Kidney Transplantation; Post Renal Transplantation

  18. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts

    PubMed Central

    Lama, Vibha N.; Smith, Lisa; Badri, Linda; Flint, Andrew; Andrei, Adin-Cristian; Murray, Susan; Wang, Zhuo; Liao, Hui; Toews, Galen B.; Krebsbach, Paul H.; Peters-Golden, Marc; Pinsky, David J.; Martinez, Fernando J.; Thannickal, Victor J.

    2007-01-01

    The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% ± 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ. PMID:17347686

  19. Site-specific rectocele repair with dermal graft augmentation: comparison of porcine dermal xenograft (Pelvicol) and human dermal allograft.

    PubMed

    Biehl, Roger C; Moore, Robert D; Miklos, John R; Kohli, Neeraj; Anand, Indu S; Mattox, T Fleming

    2008-01-01

    This study is a retrospective chart review comparing 195 women who underwent rectocele repair with either a porcine dermal xenograft or human allogenic cadaveric dermal graft augmentation over a two year period. A site-specific defect repair was completed prior to augmentation with the graft. Examinations were performed preoperatively and postoperatively using the pelvic organ prolapse quantification system. Questionnaires were used to assess constipation and dyspareunia. De novo dyspareunia and cure rates for constipation and dyspareunia were not statistically different between the two groups. Site-specific fascial rectocele repairs with xenograft or allograft augmentation were found to have similar complication rates as well as objective and subjective cure rates.

  20. Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India.

    PubMed

    Badwal, Sonia; Kumar, Arun; Hooda, A K; Varma, P P

    2015-11-01

    This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune-activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune-activation is associated with chronicity and may have implications on long-term graft survival.

  1. Successful Living-Related Renal Allograft in a Recipient With Factor V Leiden Deficiency: A Case Report.

    PubMed

    Florou, Evangelia; Koukoulaki, Maria; Theodoros, Theodoridis; Kalatzis, Vasileios; Vougas, Vasileios; Stamataki, Elissavet; Kokkinou, Vasiliki Christopoulou; Kostakis, Alkiviadis; Drakopoulos, Spiros

    2017-02-01

    Thrombophilia due to activated protein C resistance (Leiden mutation) is the most common inherited thrombophilic disorder with 5% incidence in whites. Renal transplant of these patients entails a risk of vascular thrombosis soon after the transplant; and acute rejection episodes and graft loss within the first year. We present a case of a successful living-related renal transplant in man with a recent history of repeat episodes of vascular access thrombosis attributed to inherited thrombophilia (heterozygosity for factor V mutation Q506 and homozygosity for mutation T677 for methylene-tetrahydrofolate reductase). Transplant recipient was administered anticoagulation therapy with low molecular weight heparin pre- and postoperatively. No thrombotic or hemorrhagic events occurred posttransplant. A high suspicion of thrombophilic disorders in patients with end-stage renal disease with vascular access thrombotic events should be screened further to prevent failure of a subsequent renal transplant. Inherited thrombophilic disorders may not exclude living-related kidney transplant provided that anticoagulation therapy is admin-istered perioperatively.

  2. Risk Factors for Urinary Tract Infections in Renal Allograft Recipients: Experience of a Tertiary Care Center in Hyderabad, South India.

    PubMed

    Mohan, M V N L R; Neeraja, M; Sudhaharan, S; Raju, S B; Gangadhar, T; Lakshmi, V

    2017-01-01

    Renal transplantation is an effective and commonly performed procedure for end-stage renal disease. Urinary tract infections are a major cause of morbidity and mortality in renal transplant patients. As data on postrenal transplant urinary tract infections from the Indian subcontinent are limited, the present study was conducted to estimate the burden of urinary tract infections in this vulnerable group of patients. This was a prospective study on patients undergoing renal transplantation in 2014 at our tertiary hospital in South India with a follow-up of 2 years to evaluate the risk factors for urinary tract infections. The prevalence of urinary tract infections was 41.9% with a male preponderance of 76.9%. Mean age of the 31 patients was 32.4 ± 10.2 years (range: 16-55 years). Gram-negative bacilli were the most common isolates with Escherichia coli being the predominant pathogen (53.3%). All the infections occurred within 1 year of transplantation with delayed graft function (P < 0.001; confidence interval [CI]: 29.0-96.3) and prolonged hospital stay (P = 0.0281; CI: 42.1-99.6) being the significant risk factors for acquiring urinary tract infections. Carbapenemase production was noted in 33.3% of isolates and all the Gram-negative organisms isolated in the 1(st) month of transplantation were carbapenem-resistant (CR) E. coli. The high rate of carbapenem-resistant organisms in the early posttransplant period is a point of concern, especially with cadaver transplants. Infection control practices and catheter care need to be strictly monitored to minimize the risk for UTI in the immediate posttransplant period.

  3. Varying expression of major histocompatibility complex antigens on human renal endothelium and epithelium.

    PubMed Central

    Evans, P. R.; Trickett, L. P.; Smith, J. L.; MacIver, A. G.; Tate, D.; Slapak, M.

    1985-01-01

    Pre-anastomosis wedge biopsies from 14 cadaveric donor kidneys were examined for the expression of class I (HLA-ABC) and class II (HLA-DR) antigens in renal tissue. Two monoclonal antibodies to class I antigens and four to class II antigens were used in an indirect immunoperoxidase technique. Consistent expression of both antigens was demonstrated on the surface of glomerular, peritubular capillary and venous endothelial cells. Renal arteries contained only class I antigens. Proximal tubules contained varying amounts of each antigen in their cytoplasm. Sixteen human lymphocytotoxic allo-antisera showed marked variation in their ability to detect HLA antigens on the kidney. The selection of donors for recipients of renal allografts involves the complement-dependent cytotoxicity test and the failure of some lymphocytotoxic antisera to bind to the kidney indicates that some suitable patients may be incorrectly excluded. The use of a binding assay using an immunoperoxidase technique should be included in cross-match techniques particularly for patients who have high levels of circulating cytotoxic antibodies. Images Fig. 1 Fig. 2 Fig. 3 PMID:3855644

  4. Disinfection of human musculoskeletal allografts in tissue banking: a systematic review.

    PubMed

    Mohr, J; Germain, M; Winters, M; Fraser, S; Duong, A; Garibaldi, A; Simunovic, N; Alsop, D; Dao, D; Bessemer, R; Ayeni, O R

    2016-12-01

    Musculoskeletal allografts are typically disinfected using antibiotics, irradiation or chemical methods but protocols vary significantly between tissue banks. It is likely that different disinfection protocols will not have the same level of microorganism kill; they may also have varying effects on the structural integrity of the tissue, which could lead to significant differences in terms of clinical outcome in recipients. Ideally, a disinfection protocol should achieve the greatest bioburden reduction with the lowest possible impact on tissue integrity. A systematic review of three databases found 68 laboratory and clinical studies that analyzed the microbial bioburden or contamination rates of musculoskeletal allografts. The use of peracetic acid-ethanol or ionizing radiation was found to be most effective for disinfection of tissues. The use of irradiation is the most frequently published method for the terminal sterilization of musculoskeletal allografts; it is widely used and its efficacy is well documented in the literature. However, effective disinfection results were still observed using the BioCleanse™ Tissue Sterilization process, pulsatile lavage with antibiotics, ethylene oxide, and chlorhexidine. The variety of effective methods to reduce contamination rate or bioburden, in conjunction with limited high quality evidence provides little support for the recommendation of a single bioburden reduction method.

  5. Effect of intraoperative transesophageal Doppler-guided fluid therapy versus central venous pressure-guided fluid therapy on renal allograft outcome in patients undergoing living donor renal transplant surgery: a comparative study.

    PubMed

    Srivastava, Divya; Sahu, Sandeep; Chandra, Abhilash; Tiwari, Tanmay; Kumar, Sanjay; Singh, P K

    2015-12-01

    Transesophageal Doppler (TED)-guided intraoperative fluid therapy has shown to noninvasively optimize intravascular volume and reduce postoperative morbidity. The aim of this study was to compare the effects of Doppler-guided intraoperative fluid administration and central venous pressure (CVP)-guided fluid therapy on renal allograft outcome and postoperative complications. A prospective nonrandomized active controlled study was conducted on end-stage renal disease patients scheduled for living donor renal transplant surgery. 110 patients received intraoperative fluid guided by corrected flow time (FTc) and variation in stroke volume values obtained by continuous TED monitoring. Data of 104 patients in whom intraoperative fluid administration was guided by CVP values were retrospectively obtained for a control. The amount of intraoperative fluid given in the study group (12.20 ± 4.24 ml/kg/h) was significantly lower than in the controls (22.21 ± 4.67 ml/kg/h). The amount of colloid used was also significantly less and fewer recipients were seen to require colloid (69 vs 85%). The mean arterial pressures were comparable throughout. CVP reached was 7.18 ± 3.17 mmHg in the study group. It was significantly higher in the controls (13.42 ± 3.12 mmHg). The postoperative graft function and rate of dysfunction were comparable. Side-effects like postoperative dyspnoea (4.8 vs 0%) and tissue edema (9.6 vs 2.7%) were higher in the controls. FTc-guided intraoperative fluid therapy achieved the same rate of immediate graft function as CVP-guided fluid therapy but used a significantly less amount of fluid. The incidence of postoperative complications related to fluid overload was also reduced. The use of TED may replace invasive central line insertions in the future.

  6. The use of a biostatic fascia lata thigh allograft as a scaffold for autologous human culture of fibroblasts--An in vitro study.

    PubMed

    Żurek, Jarek; Dominiak, Marzena; Botzenhart, Ute; Bednarz, Wojciech

    2015-05-01

    The method for covering gingival recession defects and augmenting keratinized gingiva involves the use of autogenuous connective tissue grafts obtained from palatal mucosa in combination with various techniques of flap repositioning or tunnel techniques. In the case of multiple gingival recession defects the amount of connective tissue available for grafting is insufficient. Therefore, the use of substitutes is necessary. The most widely used material in recent years has been the acellular dermal matrix allograft. The disadvantage of its application lies in the absence of cells and blood vessels, which increases incorporation time. Primary cultured human autologic fibroblasts are commonly used to optimize the healing process. The aim of this study was to examine the in vitro biocompatibility of human fascia lata allograft as a new scaffold for primary cultured human autologic fibroblasts. For that, a fibroblast culture obtained from a fragment of gingival tissue taken from the hard palate mucosa of a subject was used. After 14 days the colony cells were inoculated on a fragment of human fascia lata allograft. After a further 7 days of incubation the material was frozen, cut and prepared for histochemical examination. After two weeks of incubation, and 7 days after inoculation on a fragment of fascia lata allograft numerous accumulations of the cultured fibroblast were found that had a typical structure and produced collagen fibres. A human fascia lata allograft can be used as a scaffold for primary cultured human autologic fibroblasts. Further studies should confirm the clinical efficacy of this solution. Copyright © 2014 Elsevier GmbH. All rights reserved.

  7. Adenohypophysitis in rat pituitary allografts

    PubMed Central

    Rotondo, Fabio; Quintanar-Stephano, Andres; Asa, Sylvia L; Lombardero, Matilde; Berczi, Istvan; Scheithauer, Bernd W; Horvath, Eva; Kovacs, Kalman

    2010-01-01

    The histological, immunohistochemical and ultrastructural alterations in 81 pituitary allografts from Lewis rats transplanted beneath the renal capsule of Wistar rats were investigated. Intrasellar pituitaries of rats bearing allografts were also examined. Recipient rats were sacrificed at various time points after transplantation. Two days after transplantation, the central portion of the allografts demonstrated ischaemic necrosis. A week later, massive mononuclear cell infiltrates consisting primarily of lymphocytes and to a lesser extent, macrophages, plasma cells and granulocytes became prominent. At about three to four weeks after transplantation, the mononuclear cell infiltrate diminished; the surviving adenohypophysial cells, mainly prolactin (PRL) cells, increased in number and necrosis was replaced by connective tissue. No histological changes were noted in the intrasellar pituitaries of rats bearing allografts. Immunohistochemistry demonstrated that the surviving adenohypophysial cells were mainly PRL-producing cells. Electron microscopy revealed adenohypophysial cell destruction, a spectrum of inflammatory cells and, in late phase, accumulation of fibroblasts and collagen fibres. PRL cells were the prominent cell types; they increased in number. It appears that pituitary allografts are ‘foreign’ and evoke an immune response, suggesting that they may be used as an experimental animal model for morphological investigation of the development and progression of adenohypophysitis, a rare disease occurring mainly in young women often associated with pregnancy. PMID:20586813

  8. NOD-scid IL2rγnull (NSG) Mouse Model of Human Skin Transplantation and Allograft Rejection

    PubMed Central

    Racki, Waldemar J.; Covassin, Laurence; Brehm, Michael; Pino, Stephen; Ignotz, Ronald; Dunn, Raymond; Laning, Joseph; Graves, Susannah K.; Rossini, Aldo A.; Shultz, Leonard D.; Greiner, Dale L.

    2010-01-01

    Background Transplantation of human skin on immunodeficient mice that support engraftment with functional human immune systems would be an invaluable tool for investigating mechanisms involved in wound healing and transplantation. NOD-scid IL2rγnull (NSG) readily engraft with human immune systems but human skin graft integrity is poor. In contrast, human skin graft integrity is excellent on CB17-scid bg (SCID.bg) mice, but they engraft poorly with human immune systems. Methods Human skin grafts transplanted onto immunodeficient NSG, SCID.bg, and other immunodeficient strains were evaluated for graft integrity, preservation of graft endothelium and their ability to be rejected following engraftment of allogeneic peripheral blood mononuclear cells (PBMC). Results Human skin transplanted onto NSG mice develops an inflammatory infiltrate, consisting predominately of host Gr1+ cells, that is detrimental to the survival of human endothelium in the graft. Treatment of graft recipients with anti-Gr1 antibody reduces this cellular infiltrate, preserves graft endothelium, and promotes wound healing, tissue development and graft remodeling. Excellent graft integrity of the transplanted skin includes multilayered stratified human epidermis, well developed human vasculature, human fibroblasts and passenger leukocytes. Injection of unfractionated, CD4 or CD8 allogeneic human PBMC induces a rapid destruction of the transplanted skin graft. Conclusions NSG mice treated with anti-Gr1 antibody provide a model optimized for both human skin graft integrity and engraftment of a functional human immune system. This model provides the opportunity to investigate mechanisms orchestrating inflammation, wound healing, revascularization, tissue remodeling, and allograft rejection and can provide guidance for improving outcomes following clinical transplantation. PMID:20134397

  9. The value of serum neopterin, interferon-gamma levels and interleukin-12B polymorphisms in predicting acute renal allograft rejection

    PubMed Central

    Chin, G K; Adams, C L; Carey, B S; Shaw, S; Tse, W-Y; Kaminski, E R

    2008-01-01

    Acute rejection remains a poor predictor of graft outcome. In this study, we measured serum levels of interferon (IFN)-γ and neopterin by enzyme-linked immunosorbent assay and a single nucleotide polymorphism (SNP) within the 3′ untranslated region of the interleukin (IL)-12 B gene (1188 A/C) to determine whether either of these factors could predict acute rejection in renal transplantation. Significantly higher early post-transplant neopterin levels (days 5–7; 35·7 versus 19·9 nmol/l) were observed in recipients who subsequently rejected their grafts. Post-transplant neopterin levels showed a strong positive correlation with 1-month creatinine levels (Spearman's correlation 0·62, P < 0·001), suggesting macrophage activation early after transplantation. Pretransplant neopterin and IFN-γ levels and the IL-12B gene SNP did not predict acute rejection in this small retrospective study. The ability to predict acute rejection non-invasively early after transplantation could lead to individual tailoring of immunosuppressive regimens and perhaps lead eventually to longer graft survival. PMID:18341612

  10. Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients

    PubMed Central

    Bäckman, L; Kreis, H; Morales, J M; Wilczek, H; Taylor, R; Burke, J T

    2002-01-01

    Aims To determine whether bolus doses of methylprednisolone affect the steady-state trough concentrations of sirolimus. Methods Fourteen renal transplant recipients received concentration-controlled sirolimus therapy in combination with azathioprine and steroids (n = 8) or mycophenolate mofetil and steroids (n = 6). Bolus doses of methylprednisolone (mean total dose over 1–5 days, 1694 mg; range, 500–3000 mg) were given for the treatment of acute rejection. For each patient, the sirolimus dose (mean, 24.1 mg; range, 3.3–52.5 mg) was the same before and during methylprednisolone therapy. Results Mean sirolimus whole blood trough concentrations before and after treatment with methylprednisolone were 28.8 ng ml−1 (range, 13.9–45.3 ng ml−1), and 28.5 ng ml−1 (range, 13.0–47.9 ng ml−1), respectively (P = 0.85; 95% confidence interval on the difference −3.3, 4.0 ng ml−1). Conclusions Bolus methylprednisolone treatment does not affect steady-state sirolimus trough concentrations. PMID:12100227

  11. Extracellular Vesicles from MSC Modulate the Immune Response to Renal Allografts in a MHC Disparate Rat Model

    PubMed Central

    Koch, M.; Lemke, A.; Lange, C.

    2015-01-01

    Application of mesenchymal stromal cells (MSC) has been proposed for solid organ transplantation based on their potent immunomodulatory effects. Since side effects from the injection of large cells cannot be excluded, the hypothesis rises that extracellular vesicles (EV) may cause immunomodulatory effects comparable to MSC without additional side effects. We used MSC-derived EV in a rat renal transplant model for acute rejection. We analysed peripheral blood leukocytes (PBL), kidney function, graft infiltrating cells, cytokines in the graft, and alloantibody development in animals without (allo) and with EV application (allo EV). There was no difference in kidney function and in the PBL subpopulation including Tregs between allo and allo EV. In the grafts T- and B-cell numbers were significantly higher and NK-cells lower in the allo EV kidneys compared to allo. TNF-α transcription was lower in allo EV grafts compared to allo; there was no difference regarding IL-10 and in the development of alloantibodies. In conclusion, the different cell infiltrates and cytokine transcription suggest distinct immunomodulatory properties of EV in allotransplantation. While the increased T- and B-cells in the allo EV grafts may represent a missing or negative effect on the adaptive immune system, EV seem to influence the innate immune system in a contrary fashion. PMID:26351463

  12. CD16⁺ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction.

    PubMed

    Boersema, M; van den Born, J C; van Ark, J; Harms, G; Seelen, M A; van Dijk, M C R F; van Goor, H; Navis, G J; Popa, E R; Hillebrands, J L

    2015-05-01

    In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal α-SMA(+) smooth muscle-like cells are present in human renal allografts with CTD. Human PBMC contain myeloid cells capable of differentiating into α-SMA(+) cells in vitro; the phenotype of the ancestral subset is as yet unknown. This study aimed to investigate whether monocyte subsets contain cells with smooth muscle-like cell differentiation capacity and whether CTD in renal transplant recipients is associated with a shift in these monocyte subsets. To accomplish this goal, monocyte subsets from healthy controls were sorted based on CD14 and CD16 expression to investigate gene expression levels of mesenchymal markers α-SMA and SM22α. CD14(+)/CD16(++) monocytes displayed increased α-SMA and SM22α mRNA expression compared with CD14(++)/CD16(-) monocytes, suggesting increased differentiation potential toward smooth muscle-like cells. Flow cytometry revealed that in non-CTD transplant recipients the percentage of CD14(+)/CD16(++) monocytes was reduced, with an even further reduction in patients with CTD. To determine a potential correlation between CD14(+)/CD16(++) monocytes and α-SMA(+) cell outgrowth potential in vitro, PBMC of healthy controls and transplant recipients with and without CTD were cultured under fibrotic culture conditions, and indeed a significant correlation (p=0.0002, r=0.62) was observed. Finally, double staining for α-SMA and CD16 revealed presence of α-SMA(+)CD16(+) cells in kidney explants from CTD patients, albeit at very low numbers. Our data represent evidence that, compared to CD14(++)CD16(-) monocytes, CD14(+)CD16(++) monocytes have an increased expression of smooth muscle cell-associated genes. This monocyte subpopulation is reduced in renal transplant patients with CTD, possibly due to selective

  13. Renal handling of fleroxacin in rabbits, dogs, and humans.

    PubMed Central

    Shiba, K; Saito, A; Shimada, J; Hori, S; Kaji, M; Miyahara, T; Kusajima, H; Kaneko, S; Saito, S; Ooie, T

    1990-01-01

    The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular filtration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, minimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption. PMID:2109576

  14. Growth hormone and the kidney: the use of recombinant human growth hormone (rhGH) in growth-retarded children with chronic renal insufficiency.

    PubMed

    Fine, R N

    1991-04-01

    Hypothalamic production of growth hormone releasing hormone stimulates the anterior pituitary gland to release growth hormone (GH). The clinical manifestations of GH on tissues are either direct or are mediated by insulin-like growth factors (IGF). Both the somatic effects of GH and the renal manifestations of an increase in glomerular filtration rate and renal plasma flow are mediated by IGF. The increase in glomerular filtration rate/renal plasma flow that occurs with either exogenous or endogenous GH is not apparent in patients with chronic renal failure (CRF); therefore, it is unlikely that recombinant human growth hormone (rhGH) treatment of patients with CRF will result in glomerular hyperfiltration. Longitudinal studies are required to determine if the glomerulosclerosis and renal functional impairment occurring in GH and growth hormone releasing hormone transgenic mice occurs after rhGH treatment of growth-retarded uremic rats with GH resulted in an improvement in growth velocity. This led to preliminary studies in growth-retarded children with CRF by using rhGH. The acceleration of growth velocity was dramatic despite the fact that GH levels are elevated in uremia. The elevated IGF carrier proteins in uremic children may contribute to the growth retardation. Treatment with rhGH may be efficacious by stimulating a net increase in the free (unbound) IGF levels. Hyposecretion of GH may contribute to the failure to achieve optimal growth after successful renal transplantation. Treatment with rhGH may be efficacious in improving the growth velocity of renal allograft recipients.

  15. Quantitative assessment of human fetal renal blood flow.

    PubMed

    Veille, J C; Hanson, R A; Tatum, K; Kelley, K

    1993-12-01

    Our purpose was to longitudinally quantify human fetal renal blood flow. Twenty-two normal fetuses underwent a color-pulsed Doppler evaluation of the renal artery. The Doppler waveforms were digitized to assess the velocity-time integral. The size of the vessel was determined during systole with color high-resolution two-dimensional ultrasonography. Renal blood flow was estimated by multiplying the time-velocity integral (i.e., area under the curve) by the area of the renal artery. The combined cardiac output was calculated by adding right and left inflow Doppler-derived volumes. Renal artery size, peak flow velocity, time-velocity integral, and renal blood flow significantly increased with advancing gestational age. The resistivity indexes, such as the systolic/diastolic ratio or the Pourcelot index of the fetal renal artery, did not significantly change with advancing gestational age. The pulsatility index, however, was correlated with gestational age. The percentage of the combined cardiac output to the fetal kidney remained constant throughout gestation. Color pulsed Doppler can be used to visualize small and deep vascular structures in the human fetus. Renal blood flow increased with advancing gestational age. This increase seems to be related to the increase in the combined cardiac output.

  16. Heparin-based hydrogels induce human renal tubulogenesis in vitro.

    PubMed

    Weber, Heather M; Tsurkan, Mikhail V; Magno, Valentina; Freudenberg, Uwe; Werner, Carsten

    2017-07-15

    Dialysis or kidney transplantation is the only therapeutic option for end stage renal disease. Accordingly, there is a large unmet clinical need for new causative therapeutic treatments. Obtaining robust models that mimic the complex nature of the human kidney is a critical step in the development of new therapeutic strategies. Here we establish a synthetic in vitro human renal tubulogenesis model based on a tunable glycosaminoglycan-hydrogel platform. In this system, renal tubulogenesis can be modulated by the adjustment of hydrogel mechanics and degradability, growth factor signaling, and the presence of insoluble adhesion cues, potentially providing new insights for regenerative therapy. Different hydrogel properties were systematically investigated for their ability to regulate renal tubulogenesis. Hydrogels based on heparin and matrix metalloproteinase cleavable peptide linker units were found to induce the morphogenesis of single human proximal tubule epithelial cells into physiologically sized tubule structures. The generated tubules display polarization markers, extracellular matrix components, and organic anion transport functions of the in vivo renal proximal tubule and respond to nephrotoxins comparable to the human clinical response. The established hydrogel-based human renal tubulogenesis model is thus considered highly valuable for renal regenerative medicine and personalized nephrotoxicity studies. The only cure for end stage kidney disease is kidney transplantation. Hence, there is a huge need for reliable human kidney models to study renal regeneration and establish alternative treatments. Here we show the development and application of an in vitro human renal tubulogenesis model using heparin-based hydrogels. To the best of our knowledge, this is the first system where human renal tubulogenesis can be monitored from single cells to physiologically sized tubule structures in a tunable hydrogel system. To validate the efficacy of our model as a drug

  17. Transforming growth factor-β activated long non-coding RNA ATB plays an important role in acute rejection of renal allografts and may impacts the postoperative pharmaceutical immunosuppression therapy.

    PubMed

    Qiu, Jiang; Chen, Yehui; Huang, Gang; Zhang, Zhi; Chen, Lizhong; Na, Ning

    2017-10-01

    Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating the genome and proteome. The lncRNA activated by transforming growth factor β (TGF-β) (lncRNA-ATB) was discovered as a prognostic factor in hepatocellular carcinoma, gastric cancer, and colorectal cancer. However, little is known about the role of lncRNA-ATB in renal transplantation. This study aimed to assess lncRNA-ATB expression in renal transplant patients with acute kidney injury and explore its role in postoperative pharmaceutical immunosuppression therapy. We detected lncRNA-ATB expression in the kidney biopsies of a cohort of 72 patients with renal allograft rejection and 36 control transplant patients. lncRNA-ATB were overexpressed from lentiviral vectors in renal cells. We found that lncRNA-ATB was remarkably upregulated in patients with acute rejection compared with controls. Meanwhile, lncRNA-ATB could influence the kidney cell phenotypes and impact the nephrotoxicity of immunosuppressive drug. In conclusion, lncRNA-ATB are strongly altered in patients with acute rejection and may serve as a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function. © 2016 Asian Pacific Society of Nephrology.

  18. Disinfection of human cardiac valve allografts in tissue banking: systematic review report.

    PubMed

    Germain, M; Strong, D M; Dowling, G; Mohr, J; Duong, A; Garibaldi, A; Simunovic, N; Ayeni, O R

    2016-12-01

    Cardiovascular allografts are usually disinfected using antibiotics, but protocols vary significantly between tissue banks. It is likely that different disinfection protocols will not have the same level of efficacy; they may also have varying effects on the structural integrity of the tissue, which could lead to significant differences in terms of clinical outcome in recipients. Ideally, a disinfection protocol should achieve the greatest bioburden reduction with the lowest possible impact on tissue integrity. We conducted a systematic review of methods applied to disinfect cardiovascular tissues. The use of multiple broad spectrum antibiotics in conjunction with an antifungal agent resulted in the greatest reduction in bioburden. Antibiotic incubation periods were limited to less than 24 h, and most protocols incubated tissues at 4 °C, however one study demonstrated a greater reduction of microbial load at 37 °C. None of the reviewed studies looked at the impact of these disinfection protocols on the risk of infection or any other clinical outcome in recipients.

  19. Radionuclide surveillance of the allografted pancreas

    SciTech Connect

    George, E.A.; Salimi, Z.; Carney, K.; Castaneda, M.; Garvin, P.J.

    1988-04-01

    To determine the value of scintigraphy to detect posttransplantation complications of the allografted pancreas, we retrospectively reviewed 209 scintigrams obtained with /sup 99m/Tc-sulfur colloid (/sup 99m/Tc-SC) and /sup 99m/Tc-glucoheptonate (/sup 99m/Tc-GH). The scintigraphic studies were performed in 37 recipients of simultaneous renal and pancreatic allografts harvested from the same donor. /sup 99m/Tc-SC was used as an indicator of thrombotic vasculitis; pancreatic perfusion and blood-pool parameters were monitored with /sup 99m/Tc-GH. In 11 of the 37 recipients, scintigraphic abnormalities suggested posttransplantation infarction. Recurrent episodes of acute rejection of the pancreatic allograft, which always coincided with acute rejection of the renal allograft, were monitored in 24 recipients. Rejection-induced ischemic pancreatitis was suggested in 12 of the 24 recipients and persisted in 10 recipients for several weeks after improvement of renal allograft rejection. Pancreatic atrophy was suggested scintigraphically in 16 of the 24 recipients with recurrent episodes of rejection. Spontaneous pancreatic-duct obstruction and obstructive pancreatitis were associated with a scintigraphic pattern similar to that of rejection-induced ischemic pancreatitis. We concluded that the specific radionuclides used in this series are useful for the surveillance and assessment of posttransplantation pancreatic infarction, acute rejection, pancreatitis, and atrophy

  20. Cathepsin B from human renal cortex.

    PubMed Central

    Gounaris, A D; Slater, E E

    1982-01-01

    Cysteine-proteinase activity was observed in homogenates of human-cadaver renal cortex. This activity co-purified with renin enzymic activity until separation by aminohexyl-Sepharose--pepstatin affinity chromatography. The cysteine proteinase was purified 1780-fold after the following successive chromatographic procedures: Sephadex G-75, DEAE-cellulose DE-52, and an organomercurial affinity resin. The proteinase activity was dependent upon activation by thiol-containing compounds such as dithiothreitol, as well as by EDTA, and was inhibited by the thiol-group-specific alkylating reagents iodoacetic acid and N-ethylmaleimide. DE-52 cellulose chromatography resolved the cysteine proteinase into two components. On the basis of molecular size (26 000 daltons), activity as a function of pH, stability as a function of pH, substrate specificity and thermal lability, the major component (95%) has been identified as cathepsin B. The DE-52 cellulose elution pattern of the minor component (5%) is suggestive of cathepsin H [Schwartz & Barrett (1980) Biochem. J. 191, 487-497] Enzymic activity was determined with synthetic substrates, in particular alpha-N-benzoyl-DL-arginine 2-naphthylamide (Bz-Arg-NNap), thus precluding the detection of cathepsin L [Kirschke, Langner, Wiederanders, Ansorge, Bohley & Broghammer (1976) Acta Biol. Med. Germ. 35, 285-299]. Inhibition by dimethyl sulphoxide was observed in the determination of Km = 7.0 +/- 0.4 mM for the substrate Bz-Arg-NNap, and care must therefore be taken in the preparation of substrate solutions. Images Fig. 4. PMID:7138503

  1. A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate.

    PubMed

    Baskin, David S; Ryan, Patrick; Sonntag, Volker; Westmark, Richard; Widmayer, Marsha A

    2003-06-15

    A prospective, randomized, pilot clinical trial compared recombinant human bone morphogenetic protein-2 (rhBMP-2) with iliac crest autograft bone for the treatment of human cervical disc disease. To examine the safety and effectiveness of using INFUSE Bone Graft (rhBMP-2 applied to an absorbable collagen sponge), as compared with an autogenous iliac crest bone graft placed inside the CORNERSTONE-SR fibular allograft, in anterior cervical discectomy and interbody fusion. Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that induces a reliable fusion in the lumbar spine, but it has not been studied in patients with degenerative cervical disc disease. For this study, 33 patients with degenerative cervical disc disease were randomly assigned to investigational or control groups. The investigational group received a fibular allograft (CORNERSTONE-SR Allograft Ring) with an rhBMP-2-laden collagen carrier inside the graft along with an ATLANTIS anterior cervical plate. The control group received a fibular allograft with cancellous iliac crest autograft placed inside it, along with an ATLANTIS anterior cervical plate. The patients underwent plain radiographs at 6 weeks, then at 3, 6, 12, and 24 months, and CT scans at 3 and 6 months after surgery. They also completed general health profiles and self-evaluation scales. Adverse events were evaluated for severity, duration, association with the implant, and the need for a second surgical procedure. All the patients evaluated had solid fusions 6, 12, and 24 months after surgery. There were no device-related adverse events. At 24 months, the investigational group had mean improvement superior to that of the control group in neck disability and arm pain scores (P < 0.03 each). This pilot study demonstrates the feasibility of using rhBMP-2 safely and effectively in the cervical spine.

  2. Transport of circulating serum cholesterol by human renal cell carcinoma

    SciTech Connect

    Clayman, R.V.; Figenshau, R.S.; Prigge, W.F.; Forstrom, L.; Gebhard, R.L.

    1987-06-01

    Clear cell renal cancer contains a large quantity of cholesterol ester (300-mg./gm. protein). To determine whether abnormalities in cholesterol transport could account for this sterol accumulation, the uptake, release, and imaging capabilities of intravenously injected /sup 131/I-6-iodomethyl-29-norcholesterol, a cholesterol analogue, were studied preoperatively in five patients with clear cell renal cancer. At surgery, samples of the liver, tumor, adrenal, and non-tumor kidney were obtained for analysis. /sup 131/I-sterol uptake by the tumor, when normalized for cholesterol content, was less than for adrenal, liver or kidney. In contrast, release of preloaded /sup 131/I-sterol from the human tumors was consistently slower than for normal kidney. The reduced release of free cholesterol from renal cancer cells may, in part, be responsible for the accumulation of cholesterol in human renal cancer.

  3. Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection.

    PubMed Central

    Zhao, X M; Frist, W H; Yeoh, T K; Miller, G G

    1994-01-01

    Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV. Images PMID:7521891

  4. Adenovirus Interstitial Nephritis and Rejection in an Allograft

    PubMed Central

    Storsley, Leroy

    2011-01-01

    Viral infections are an important complication of solid organ transplantation. Although polyoma is the virus that most commonly infects the renal allograft, adenoviral infections are also reported. We describe the clinical and pathologic findings in a patient with adenoviral infection associated with acute rejection of the renal allograft. The pathologic findings of adenovirus infection usually include a granulomatous interstitial nephritis, which is helpful in distinguishing from acute rejection. We discuss the differential diagnosis and pathophysiology of allograft viral infections and concomitant rejection. PMID:21436288

  5. Development of bioartificial renal tubule devices with lifespan-extended human renal proximal tubular epithelial cells.

    PubMed

    Sanechika, Noriyuki; Sawada, Kaichiro; Usui, Yukio; Hanai, Kazuya; Kakuta, Takatoshi; Suzuki, Hajime; Kanai, Genta; Fujimura, Satoshi; Yokoyama, Tun Aung; Fukagawa, Masafumi; Terachi, Toshiro; Saito, Akira

    2011-09-01

    The bioartificial renal tubule device is a cell therapy system for renal failure. The major obstacle in the development of the bioartificial renal tubule device is the obtainment of a large number of viable renal tubule cells to seed on the inner surface of hollow fibers. Although our previous studies had used a transformed cell line, they may be dangerous for clinical uses. Therefore, different approaches to amplify renal proximal tubular epithelial cells (RPTEC) in culture without oncogenes, vectors and carcinogens have been required. The limitation of the replicative lifespan of human RPTEC, which is ∼12 population doublings (PDs), was extended by invalidating messenger RNA of cell cycle-related genes with antisense oligonucleotide or small interfering RNA (siRNA). Periodic transfection of siRNA to a tumor suppressor p53 or a cyclin-dependent kinase inhibitor p16(INK4a) extended the lifespan by 33 and 63 PDs, respectively, in 3 months of culture. The siRNA-mediated lifespan extension was controllable because cell division ceased within 2 weeks after the transfection was discontinued. Expressions of γ-glutamyltransferase 1 and glucose transporter 1 were recovered in siRNA-transfected RPTEC cultured on porous membranes. Bioartificial renal tubule devices (0.8 m(2)) constructed with these cells showed reabsorption of water (122.3 ± 4.2 mL/30 min), sodium (18.1 ± 0.7 mEq/30 min) and glucose (121.7 ± 4.4 mg/30 min) after 1 week of circulation. Furthermore, β2-microglobulin and pentosidine were metabolized by RPTEC in mini-devices (65 cm(2)) within 48 h of circulation. These approaches enabled us to yield a high enough number of RPTEC for construction of bioartificial renal tubule devices repeatedly. Lifespan-extended RPTEC could recover their specific characteristics by culturing on porous membranes, and bioartificial renal tubule devices constructed with these cells showed good performances of reabsorption and metabolism. A large number of human renal tubular

  6. Reducing allograft contamination and disease transmission: intraosseous temperatures of femoral head allografts during autoclaving

    PubMed Central

    Ang, Chay-You; Yew, Andy Khye-Soon; Tay, Darren Keng-Jin; Chia, Shi-Lu; Yeo, Seng-Jin; Lo, Ngai-Nung; Chin, Pak-Lin

    2014-01-01

    INTRODUCTION The Singapore General Hospital Bone Bank, which exclusively stores femoral head allografts, relies on flash sterilisation to prevent allograft-related disease transmission and wound infection. However, intraosseous temperatures during autoclaving may be lower than required to eliminate human immunodeficiency virus, and hepatitis B and C viruses. The aim of this study is to determine the intraosseous temperatures of femoral head allografts during autoclaving and to assess the adequacy of autoclaving in preventing disease transmission. METHODS Six femoral heads were acquired from patients who underwent hip arthroplasty. The specimens were divided into two groups. The first group underwent flash sterilisation with a sterilisation time of 4 min, while a longer sterilisation time of 22 min was used for the second group. RESULTS The highest core temperature in the first group was 130°C, while the core temperatures in the second group plateaued at 133°C for all allografts. In the first group, only smaller allografts maintained temperatures sufficient for the inactivation of the clinically relevant viral pathogens. In contrast, all allografts in the second group were terminally sterilised. CONCLUSION There is an inverse correlation between the size of allografts and intraosseous temperatures achieved during autoclaving. Therefore, we recommend dividing large allografts into smaller pieces, in order to achieve intraosseous temperatures adequate for the elimination of transmissible pathogens during flash sterilisation. Allografts should not be terminally sterilised, as the resulting allografts will become unusable. Despite modern processing techniques, stringent donor selection remains vital in the effort to prevent allograft-related infections. Autoclaving is an economical and efficacious method of preventing allograft-related disease transmission. PMID:25631893

  7. Reducing allograft contamination and disease transmission: intraosseous temperatures of femoral head allografts during autoclaving.

    PubMed

    Ang, Chay-You; Yew, Andy Khye-Soon; Tay, Darren Keng-Jin; Chia, Shi-Lu; Yeo, Seng-Jin; Lo, Ngai-Nung; Chin, Pak-Lin

    2014-10-01

    The Singapore General Hospital Bone Bank, which exclusively stores femoral head allografts, relies on flash sterilisation to prevent allograft-related disease transmission and wound infection. However, intraosseous temperatures during autoclaving may be lower than required to eliminate human immunodeficiency virus, and hepatitis B and C viruses. The aim of this study is to determine the intraosseous temperatures of femoral head allografts during autoclaving and to assess the adequacy of autoclaving in preventing disease transmission. Six femoral heads were acquired from patients who underwent hip arthroplasty. The specimens were divided into two groups. The first group underwent flash sterilisation with a sterilisation time of 4 min, while a longer sterilisation time of 22 min was used for the second group. The highest core temperature in the first group was 130°C, while the core temperatures in the second group plateaued at 133°C for all allografts. In the first group, only smaller allografts maintained temperatures sufficient for the inactivation of the clinically relevant viral pathogens. In contrast, all allografts in the second group were terminally sterilised. There is an inverse correlation between the size of allografts and intraosseous temperatures achieved during autoclaving. Therefore, we recommend dividing large allografts into smaller pieces, in order to achieve intraosseous temperatures adequate for the elimination of transmissible pathogens during flash sterilisation. Allografts should not be terminally sterilised, as the resulting allografts will become unusable. Despite modern processing techniques, stringent donor selection remains vital in the effort to prevent allograft-related infections. Autoclaving is an economical and efficacious method of preventing allograft-related disease transmission.

  8. The human renal lymphatics under normal and pathological conditions.

    PubMed

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-09-01

    The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics.

  9. Gremlin: a novel mediator of epithelial mesenchymal transition and fibrosis in chronic allograft nephropathy.

    PubMed

    Carvajal, G; Droguett, A; Burgos, M E; Aros, C; Ardiles, L; Flores, C; Carpio, D; Ruiz-Ortega, M; Egido, J; Mezzano, S

    2008-04-01

    Chronic allograft nephropathy (CAN) is the most frequent cause of chronic dysfunction and late loss of renal allografts. Epithelial mesenchymal transition (EMT) has been identified as responsible for the presence of activated interstitial fibroblasts (myofibroblasts) and transforming growth factor beta (TGF-beta)/Smad is the key signaling mediator. It has been proposed that the bone morphogenetic protein 7 (BMP-7) antagonist, Gremlin, could participate in EMT, as a downstream mediator of TGF-beta. We evaluated 33 renal allograft biopsies, 16 of which showed CAN, versus 17 controls. By in situ hybridization we studied the expression of TGF-beta and Gremlin mRNA. Gremlin, BMP-7, E-cadherin, and alpha-smooth muscle actin (alpha-SMA) proteins were evaluated by immunohistochemistry and Smad3 activation by Southwestern. In cultured human tubuloepithelial cells (HK2 cell line), Gremlin induction by TGF-beta was studied by confocal microscopy. Among renal biopsies of transplanted patients with CAN, we detected up-regulation of TGF-beta in colocalization with Gremlin (RNA and protein), mainly in areas of tubulointerstitial fibrosis. In the same tubules, we observed decreased expression of E-cadherin and induction of vimentin and alpha-SMA. BMP-7 was significantly decreased in the CAN biopsies. In addition, HK2 stimulated with TGF-beta (1 ng/mL) induced Gremlin production at 72 hours. We postulated that Gremlin is a downstream mediator of TGF-beta, suggesting a role for Gremlin in EMT observed in CAN.

  10. Renal

    MedlinePlus

    ... term "renal" refers to the kidney. For example, renal failure means kidney failure. Related topics: Kidney disease Kidney disease - diet Kidney failure Kidney function tests Renal scan Kidney transplant

  11. Assessment of strategies to increase chondrocyte viability in cryopreserved human osteochondral allografts: evaluation of the glycosylated hydroquinone, arbutin.

    PubMed

    Rosa, S C; Gonçalves, J; Judas, F; Lopes, C; Mendes, A F

    2009-12-01

    Allogeneic cartilage is used to repair damaged areas of articular cartilage, requiring the presence of living chondrocytes. So far, no preservation method can effectively meet that purpose. Identification of more effective cryoprotective agents (CPAs) can contribute to this goal. The aim of this study was to determine whether the glycosylated hydroquinone, arbutin, alone or in combination with low concentrations of other CPAs, has cryoprotective properties towards human articular cartilage. Human tibial plateaus were procured from multi-organ donors, with the approval of the Ethics Committee of the University Hospital of Coimbra. The tibial plateaus were treated with or without arbutin (50 or 100mM), alone or in combination with various concentrations of dimethyl sulfoxide (DMSO) and glycerol, for 0.5-1.5h/37 degrees C, then frozen at -20 degrees C and 24h later transferred to a biofreezer at -80 degrees C. Two to 3 months later, thawing was achieved by immersion in cell culture medium at 37 degrees C/1h. Chondrocyte viability was assessed before and after freeze-thawing using a colorimetric assay based on the cell's metabolic activity and fluorescent dyes to evaluate cell membrane integrity. Before freezing, chondrocyte metabolic activity was identical in all the conditions tested. After freeze-thawing, the highest activity, corresponding to 34.2+/-2.1% of that in the Fresh Control, was achieved in tibial plateaus incubated in 50mM arbutin for 1h whereas in those left untreated it was 11.1+/-4.7. Addition of DMSO and glycerol to arbutin did not increase chondrocyte viability any further. Fluorescence microscopy confirmed these results and showed that living chondrocytes were mainly restricted to the superficial cartilage layers. Arbutin seems to be an effective cryoprotective agent for osteochondral allografts with potential benefits over DMSO and glycerol.

  12. Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

    PubMed

    Afzali, B; Chapman, E; Racapé, M; Adam, B; Bruneval, P; Gil, F; Kim, D; Hidalgo, L; Campbell, P; Sis, B; Duong Van Huyen, J P; Mengel, M

    2017-02-01

    Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

  13. The human renal lymphatics under normal and pathological conditions

    PubMed Central

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-01-01

    Ishikawa Y, Akasaka Y, Kiguchi H, Akishima-Fukasawa Y, Hasegawa T, Ito K, Kimura-Matsumoto M, Ishiguro S, Morita H, Sato S, Soh S & Ishii T (2006) Histopathology 49, 265–273 The human renal lymphatics under normal and pathological conditions Aims The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Methods and results Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Conclusions Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics. PMID:16918973

  14. Recruitment of renal transplant patients into patrolling police roles using orthotic shields

    PubMed Central

    Levene, Sara; Levene, Charlotte Amy; Makanjuola, David; Rajakariar, Ravi

    2014-01-01

    Renal allografts are transplanted to an anatomically unnatural site where they are exposed to trauma, and may fail if damaged. Individuals with renal allografts have been excluded from patrolling police roles as these often necessitate confrontation. We describe two patients with renal allografts who have been recruited by the Metropolitan Police Service, using bespoke orthotic shields to protect the grafts. PMID:24879727

  15. Replicative senescence in kidney aging, renal disease, and renal transplantation.

    PubMed

    Naesens, Maarten

    2011-01-01

    Cellular or replicative senescence is classically seen as the key element of aging. In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age. In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the available literature on aging of native kidneys, kidney diseases, and outcome of renal allografts. Recent data illustrate the complex biology of senescence in vivo, and disprove the concept that senescence is an intrinsic injury process with immanent deleterious consequences. Senescence acts as a homeostatic mechanism that can even limit renal fibrosis, at least in animal studies. In a human setting, it remains to be investigated whether cellular senescence plays an active or a bystander role in fibrogenesis and atrophy of renal tissue.

  16. Radiation sterilization of tissue allografts: A review

    PubMed Central

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-01-01

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

  17. Radiation sterilization of tissue allografts: A review.

    PubMed

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-04-28

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts.

  18. B Lymphocytes Differentially Influence Acute and Chronic Allograft Rejection in Mice1

    PubMed Central

    DiLillo, David J.; Griffiths, Robert; Seshan, Surya V.; Magro, Cynthia M.; Ruiz, Phillip; Coffman, Thomas M.; Tedder, Thomas F.

    2013-01-01

    The relative contributions of B lymphocytes and plasma cells during allograft rejection remain unclear. Therefore, the effects of B cell depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Strikingly, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloantigen-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Moreover, CD19 mAb may represent a new approach for depleting both B cells and plasma cells to concomitantly impair T cell activation, inhibit the generation of new allograft-specific Abs, or reduce preexisting allograft-specific Ab levels in transplant patients. PMID:21248259

  19. Renal Vasoconstriction Occurs Early During Shockwave Lithotripsy in Humans.

    PubMed

    Lee, Franklin C; Hsi, Ryan S; Sorensen, Mathew D; Paun, Marla; Dunmire, Barbrina; Liu, Ziyue; Bailey, Michael; Harper, Jonathan D

    2015-12-01

    In animal models, pretreatment with low-energy shock waves and a pause decreased renal injury from shockwave lithotripsy (SWL). This is associated with an increase in perioperative renal resistive index (RI). A perioperative rise is not seen without the protective protocol, which suggests that renal vasoconstriction during SWL plays a role in protecting the kidney from injury. The purpose of our study was to investigate whether there is an increase in renal RI during SWL in humans. Subjects were prospectively recruited from two hospitals. All subjects received an initial 250 shocks at low setting, followed by a 2-minute pause. Treatment power was then increased. Measurements of the renal RI were taken before start of procedure, at 250, after 750, after 1500 shocks, and at the end of the procedure. A linear mixed-effects model was used to compare RIs at the different time points. Fifteen patients were enrolled. Average treatment time was 46 ± 8 minutes. Average RI at pretreatment, after 250, after 750, after 1500 shocks, and post-treatment was 0.67 ± 0.06, 0.69 ± 0.08, 0.71 ± 0.07, 0.73 ± 0.07, and 0.74 ± 0.06, respectively. In adjusted analyses, RI was significantly increased after 750 shocks compared with pretreatment (p = 0.05). Renal RI increases early during SWL in humans with the protective protocol. Monitoring for a rise in RI during SWL is feasible and may provide real-time feedback as to when the kidney is protected.

  20. Renal Vasoconstriction Occurs Early During Shockwave Lithotripsy in Humans

    PubMed Central

    Hsi, Ryan S.; Sorensen, Mathew D.; Paun, Marla; Dunmire, Barbrina; Liu, Ziyue; Bailey, Michael; Harper, Jonathan D.

    2015-01-01

    Abstract Introduction: In animal models, pretreatment with low-energy shock waves and a pause decreased renal injury from shockwave lithotripsy (SWL). This is associated with an increase in perioperative renal resistive index (RI). A perioperative rise is not seen without the protective protocol, which suggests that renal vasoconstriction during SWL plays a role in protecting the kidney from injury. The purpose of our study was to investigate whether there is an increase in renal RI during SWL in humans. Materials and Methods: Subjects were prospectively recruited from two hospitals. All subjects received an initial 250 shocks at low setting, followed by a 2-minute pause. Treatment power was then increased. Measurements of the renal RI were taken before start of procedure, at 250, after 750, after 1500 shocks, and at the end of the procedure. A linear mixed-effects model was used to compare RIs at the different time points. Results: Fifteen patients were enrolled. Average treatment time was 46 ± 8 minutes. Average RI at pretreatment, after 250, after 750, after 1500 shocks, and post-treatment was 0.67 ± 0.06, 0.69 ± 0.08, 0.71 ± 0.07, 0.73 ± 0.07, and 0.74 ± 0.06, respectively. In adjusted analyses, RI was significantly increased after 750 shocks compared with pretreatment (p = 0.05). Conclusion: Renal RI increases early during SWL in humans with the protective protocol. Monitoring for a rise in RI during SWL is feasible and may provide real-time feedback as to when the kidney is protected. PMID:26239232

  1. The natural history of chronic allograft nephropathy.

    PubMed

    Nankivell, Brian J; Borrows, Richard J; Fung, Caroline L-S; O'Connell, Philip J; Allen, Richard D M; Chapman, Jeremy R

    2003-12-11

    declining renal function and graft failure. Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes. Copyright 2003 Massachusetts Medical Society

  2. Clinical evaluation of demineralized bone allograft for sinus lifts in humans: a clinical and histologic study.

    PubMed

    Won, Young-Hoon; Kim, Su-Gwan; Oh, Ji-Su; Lim, Sung-Chul

    2011-12-01

    Severe alveolar bony resorption in the edentulous posterior maxilla and pneumatization of the maxillary sinus wall make traditional implant placement impossible in the posterior maxilla. To reconstruct the severely resorbed maxilla for dental implant placement, 1 successful technique is to elevate the maxillary sinus floor using demineralized bone matrix (DBM) grafts. The purpose of this study was to evaluate a histologic and histomorphometric evaluation of DBM grafts in the human maxilla. Nine months after grafting, at the time of dental implantation, biopsy samples were taken from the grafted areas of 8 patients and were analyzed histologically. All the sinus lifts were successful in the clinical study conducted after implantation. Resorption of the graft materials and new bone formation were observed, and there was direct deposition of bone on the surface of the graft particles. The results of this study indicate that limited maxillary sinus lift with DBM graft material is a clinically reliable preimplant procedure.

  3. Renal Aplasia in Humans Is Associated with RET Mutations

    PubMed Central

    Skinner, Michael A.; Safford, Shawn D.; Reeves, Justin G.; Jackson, Margaret E.; Freemerman, Alex J.

    2008-01-01

    In animal models, kidney formation is known to be controlled by the proteins RET, GDNF, and GFRA1; however, no human studies to date have shown an association between abnormal kidney development and mutation of these genes. We hypothesized that stillborn fetuses with congenital renal agenesis or severe dysplasia would possess mutations in RET, GDNF, or GFRA1. We assayed for mutations in these genes in 33 stillborn fetuses that had bilateral or unilateral renal agenesis (29 subjects) or severe congenital renal dysplasia (4 subjects). Mutations in RET were found in 7 of 19 fetuses with bilateral renal agenesis (37%) and 2 of 10 fetuses (20%) with unilateral agenesis. In two fetuses, there were two different RET mutations found, and a total of ten different sequence variations were identified. We also investigated whether these mutations affected RET activation; in each case, RET phosphorylation was either absent or constitutively activated. A GNDF mutation was identified in only one fetus with unilateral agenesis; this subject also had two RET mutations. No GFRA1 mutations were seen in any fetuses. These data suggest that in humans, mutations in RET and GDNF may contribute significantly to abnormal kidney development. PMID:18252215

  4. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers

    PubMed Central

    Zelen, Charles M; Serena, Thomas E; Snyder, Robert J

    2014-01-01

    The aim of this study is to determine if weekly application of dehydrated human amnion/chorion membrane allograft reduce time to heal more effectively than biweekly application for treatment of diabetic foot ulcers. This was an institutional review board-approved, registered, prospective, randomised, comparative, non-blinded, single-centre clinical trial. Patients with non-infected ulcers of ≥ 4 weeks duration were included for the study. They were randomised to receive weekly or biweekly application of allograft in addition to a non-adherent, moist dressing with compressive wrapping. All wounds were offloaded. The primary study outcome was mean time to healing. Overall, during the 12-week study period, 92·5% (37/40) ulcers completely healed. Mean time to complete healing was 4·1 ± 2·9 versus 2·4 ± 1·8 weeks (P = 0·039) in the biweekly versus weekly groups, respectively. Complete healing occurred in 50% versus 90% by 4 weeks in the biweekly and weekly groups, respectively (P = 0·014). Number of grafts applied to healed wounds was similar at 2·4 ± 1·5 and 2·3 ± 1·8 for biweekly versus weekly groups, respectively (P = 0·841). These results validate previous studies showing that the allograft is an effective treatment for diabetic ulcers and show that wounds treated with weekly application heal more rapidly than with biweekly application. More rapid healing may decrease clinical operational costs and prevent long-term medical complications. PMID:24618401

  5. Regulation of human aortic endothelial cell-derived mesenchymal growth factors by allogeneic lymphocytes in vitro. A potential mechanism for cardiac allograft vasculopathy.

    PubMed Central

    Wagner, C R; Morris, T E; Shipley, G D; Hosenpud, J D

    1993-01-01

    Cardiac allograft vasculopathy is thought to be triggered by an alloreactive response to the donor coronary vasculature, resulting in smooth muscle cell proliferation and ultimate occlusion of the donor coronary arteries. To determine whether allogeneic lymphocytes are capable of regulating endothelial-derived smooth muscle cell (SMC) growth factors, human aortic endothelial cells (HAECs) were exposed to allogeneic lymphocytes. The HAEC-lymphocyte co-cultures were assessed for (a) lymphocyte proliferation in response to the allogeneic HAECs; (b) release of soluble factors that stimulate human aortic SMC proliferation; and (c) alteration of HAEC mRNA levels for a panel of known SMC growth factors. Co-culture conditioned medium increased SMC proliferation, compared to medium conditioned by HAECs alone. HAECs exposed to allogeneic lymphocytes increased their expression of mRNA for basic fibroblast growth factor, transforming growth factors alpha and beta, and platelet derived growth factor A and B chains. These results demonstrate that allogeneic lymphocytes are capable of inducing HAECs to increase mRNA levels for several mesenchymal growth factors and to release bioactive products capable of stimulating SMC cell proliferation in vitro. Additionally, the data support the hypothesis that alloreactive lymphocytes can stimulate allogeneic donor endothelial cells to produce growth factors that may contribute to the intimal thickening seen in cardiac allograft vasculopathy. Images PMID:8376585

  6. Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

    PubMed

    Zhao, Hailin; Luo, Xianghong; Zhou, Zhaowei; Liu, Juying; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

    2014-01-01

    Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.

  7. Renal Differentiation of Mesenchymal Stem Cells Seeded on Nanofibrous Scaffolds Improved by Human Renal Tubular Cell Lines-Conditioned Medium.

    PubMed

    Ardeshirylajimi, Abdolreza; Vakilian, Saeid; Salehi, Mohammad; Mossahebi-Mohammadi, Majid

    Kidney injuries and renal dysfunctions are one of the most important clinical problems, and tissue engineering could be a valuable method for solving it. The objective of this study was to investigate the synergistic effect of renal cell line-conditioned medium and Polycaprolactone (PCL) nanofibers on renal differentiation of human mesenchymal stem cells (MSCs). In the current study, after stem cells isolation and characterization, PCL nanofibrous scaffold was fabricated using electrospinning methods and characterized morphologically, mechanically, and for biocompatibility. The renal differentiation of seeded MSCs on the surface of PCL nanofibers with and without human renal tubular cell lines-conditioned medium was investigated by evaluation of eight important renal-related genes expression by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. Fabricated nanofibrous scaffolds were good in all characterized items. Almost highest expression of all genes was detected in stem cells seeded on PCL under conditioned media in comparison with the stem cells seeded on PCL, tissue culture polystyrene (TCPS) under renal induction medium, and TCPS under conditioned medium. According to the results, PCL nanofibers in contribution with conditioned medium can provide the optimal conditions for renal differentiation of MSCs and could be a promising candidate for renal tissue engineering application.

  8. Methenamine silver staining quantitative digital histochemistry in chronic allograft nephropathy.

    PubMed

    Sarioglu, S; Celik, A; Sakar, M; Sonmez, D; Tekis, D

    2004-12-01

    Renal function and final outcome of renal allografts have been correlated with irreversible damage. This study describes a quantitative histochemical method relying on periodic acid methenamine silver (PAMS) staining of all renal compartments. Among 60 renal allograft biopsies from 43 patients, 15 biopsies showing pure chronic allograft nephropathy were selected to determine PAMS-stained area percentage (SAP), using image analysis with quantitative histochemistry. Of the 15 cases, 9 (60%) were grade I and 6 (40%) were grade II chronic allograft nephropathy (CAN). The mean serum creatinine (sCr) value was 1.86 +/- 0.47 for allograft biopsies. The mean (+/-SD) SAP for the implantation biopsies was 10.58 +/- 1.87%, and for allograft biopsies 25.26 +/- 9.67 (P <.000). The serum creatinine (sCr) values for grade I versus II CAN were 1.63 +/- 0.24 versus 2.20 +/- 0.54 mg/dL, respectively (P=.019), and SAP values were 18.97 +/- 0.24 versus 34.7 +/- 5.89 (P=.003). There was a strong positive correlation between sCr values and SAP (P=.005; r=0.64). These findings show the PAMS approach to be a useful alternative method for reflecting damage in more than one compartment of the renal tissue. Also, the method can discriminated implantation and allograft biopsies as well as grade I and II CAN cases. The series is small for a multivariate analysis of the value of SAP measurements in PAMS-stained sections as a prognosticator, but the data support its use.

  9. Non-inferiority of creatinine excretion rate to urinary L-FABP and NGAL as predictors of early renal allograft function

    PubMed Central

    2014-01-01

    Background We evaluated accuracy of urinary liver type fatty acid-binding protein (L-FABP) for prediction of early allograft function and compared it to neutrophil gelatinase associated lipocalin (NGAL), diuresis and urinary creatinine excretion rate (UCr). Methods Urine samples from 71 consecutive patients were taken 4, 10, 24 and 48 h after transplantation. We classified recipients into two groups: immediate graft function (IGF), with more than 70% reduction of serum Cr at 7th day post-transplant, and delayed graft function (DGF)/slow graft function (SGF) group (DGF - the need for hemodialysis procedure in the first week, SGF - less than 70% reduction of serum Cr in the first week). Results Thirty-one recipients had IGF and 40 had DGF/SGF. L-FABP was only useful 48 h post-transplant with ROC AUC of 0.85 (95% C.I. 0.74-0.92); NGAL 24 h post-transplant had ROC AUC of 0.82 (0.7-0.91). Sensitivity, specificity, PPV and NPV for prediction of DGF/SGF with L-FABP > 9.5 mg/mmol Cr and NGAL > 33.1 μg/mmol Cr were: 86, 80, 83 and 83% (L-FABP), and 68, 93, 91, and 73% (NGAL). The difference in urine output between the groups was largest 4 h post-transplant (p = 0.001), later on the difference diminished. There were no significant differences in ROC AUC between L-FABP at 48 h, NGAL at 24 h, urine output at 4 h and UCr excretion rate at 10 h post-transplant. UCr < 0.56 mmol/h 10 h post-transplant predicted DGF/SGF with 94% sensitivity, 84% specificity, 89% PPV and 91% NPV, ROC AUC was 0.9. Classification tree with urine output 4 h and UCr 10 h post-transplant accurately predicted 89% of outcomes. When L-FABP or NGAL were added, the prediction was accurate in 92 or 90%, respectively. Conclusions L-FABP is comparable to NGAL for prediction of first week allograft function, however UCr and diuresis were non-inferior. PMID:25027586

  10. Cadmium concentrations in human renal cortex tissue (necropsies)

    SciTech Connect

    Lopez-Artiguez, M.; Repetto, M.; Camean, A.; Gonzalez, G.

    1995-06-01

    Cadmium is toxic to most living organisms. It occurs as part of different types of rocks, sedimentation sludges, coals and mineral oils; in minerals, cadmium (Cd) is frequently associated with zinc. Its world wide presence and considerable industrial use has given rise to an increase in its content in trophic food chains, which contribute mainly to human exposure. Oral absorption is relatively low and is influenced by the solubility of the compound, type of diet, and individual nutritional state. Interest in Cd contamination began after the outbreak of itai-itai disease in Japan. Evaluation of Cd contamination has been carried out in all the countries of the European Economic Community, and it has been estimated that in Spain emissions to the atmosphere and water are respectively 6.89 and 3.79% of total emissions in the European Communities. After exposure, the kidney is the organ which contains the highest concentrations of the Cd and retains it longest. When critical body concentration is reached, renal malfunction and damage are produced. Moreover, studies on humans not occupationally exposed to Cd show 50% of the body burden is found in the kidneys. Cd in the renal cortex increases with age, reaching a maximum between 40-60 years. Differences found among populations have been associated with daily intake in the diet and smoking habits. Taking into consideration the lack of studies on factors influencing the Cd burden in renal cortex in our country, the aim of the present paper was to find out the levels of Cd in renal cortex samples obtained from necropsies of inhabitants of Andalusia, Spain, and compare them with levels in other populations not occupationally exposed to the element; also to investigate the influence of individual factors, such as sex, age and drug addition on said Cd levels. 21 refs., 1 fig., 2 tabs.

  11. Skin donors and human skin allografts: evaluation of an 11-year practice and discard in a referral tissue bank.

    PubMed

    Gaucher, Sonia; Khaznadar, Zena; Gourevitch, Jean-Claude; Jarraya, Mohamed

    2016-03-01

    The Saint Louis hospital tissue bank provides skin allografts to pediatric and adult burn units in the Paris area. The aim of this study was to analyze our activity during the last 11 years focusing on the reasons for skin discard. Skin is procured solely from the back of the body, which is divided into 10 zones that are harvested and processed separately. This retrospective study included all skin donors harvested between June 2002 and June 2013, representing a total of 336 donors and 2770 zones. The donors were multiorgan heart-beating donors in 91 % of cases (n = 307). The main reason for discarding harvested skin was microbial contamination, detected in 99 donors (29 %). Most contaminants were of low pathogenicity. Other reasons for discard included positive serologic tests for 2 donors [17 zones (0.61 %)], unsuitable physical skin characteristics for 3 zones (0.11 %), the donor's medical history for 53 zones (1.91 %), and technical issues with processing or distribution for 61 zones (2.2 %). In our experience, microbial contamination continues to be the main reason for discarding potential skin allografts. However, discards are limited by separate harvesting and processing of multiple zones in each donor.

  12. High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function.

    PubMed

    Nickel, Peter; Bold, Gantuja; Presber, Franziska; Biti, Didier; Babel, Nina; Kreutzer, Stephanie; Pratschke, Johann; Schönemann, Constanze; Kern, Florian; Volk, Hans-Dieter; Reinke, Petra

    2009-03-01

    Cytomegalovirus (CMV) infection has been associated with allograft rejection in solid organ transplantation. However, the immunologic mechanisms behind this observation have not been elucidated. One proposed mechanism is direct cross-reactivity of antiviral T-cells with allogeneic MHC/peptide complexes, a process termed heterologous immunity. Another model favours indirect stimulation of alloimmunity by CMV-induced proinflammatory cytokines and upregulation of MHC class II and adhesion molecules. Recently, we found that protection from CMV disease was correlated with high levels of CMV-immediate early-1 (IE-1) specific IFN-gamma-producing T-cell responses in heart and lung transplant recipients. The aim of this study was to define the relation of CMV-specific T-cell responses to acute rejection, donor-reactive memory T cells, and allograft function after kidney transplantation. To address this issue, IFN-gamma-producing T-cell responses following ex-vivo stimulation with pools of overlapping peptides representing the CMV pp65 and IE-1 proteins, as well as donor-reactive IFN-gamma-producing T-cells were determined at multiple time points before (pre-Tx) and during the first 6 months posttransplant (post-Tx) in 36 kidney transplant recipients using an enzyme linked immunoabsorbent spot assay (ELISPOT). CMV-specific T cells were not exclusively detectable in CMV seropositive patients, as 3/12 seronegative patients had significant pre- and post-Tx pp65/IE-1-specific T-cell responses. In patients with detectable anti-CMV antibody or T-cell responses, no difference in CMV-specific T-cell frequencies was found between patients with versus without acute rejection. However, early (week 1, r=0.457, p=0.037) and average IE-1-specific T-cell responses (r=-0.415, p=0.032) during 6 months post-Tx showed a significant inverse correlation with average post-Tx donor-reactive T-cell responses. Furthermore, average post-Tx IE-1-specific T-cell responses correlated significantly with

  13. Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models.

    PubMed

    Van der Hauwaert, Cynthia; Savary, Grégoire; Buob, David; Leroy, Xavier; Aubert, Sébastien; Flamand, Vincent; Hennino, Marie-Flore; Perrais, Michaël; Lo-Guidice, Jean-Marc; Broly, Franck; Cauffiez, Christelle; Glowacki, François

    2014-09-15

    Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies.

  14. Biochemical characterization of human renal tumors by in vitro nuclear magnetic resonance

    NASA Astrophysics Data System (ADS)

    Tosi, M. R.; Tugnoli, V.; Bottura, G.; Lucchi, P.; Battaglia, A.; Giorgianni, P.

    2001-05-01

    This study reports an in vitro magnetic resonance spectroscopy characterization of healthy renal parenchyma, renal cell carcinomas and oncocytomas. In vitro 1H NMR measurements allow in-depth biochemical characterization of human healthy and neoplastic renal tissues. Some metabolites with an osmotic activity are considered markers of physiological renal function. Moreover, the HPLC technique was applied to investigate the amino acidic profile of these tissues: some amino acids appear to have statistic significance.

  15. Multifocal Primary Neoplasms in Kidney Allografts: Evaluation of Two Cases

    PubMed Central

    Ellis, Robert J.; Ng, Keng Lim; Samaratunga, Hemamali; Del Vecchio, Sharon J.; Wood, Simon T.

    2016-01-01

    Renal cell carcinoma (RCC) is the fifth most common malignancy in kidney transplant recipients, with increased risk arising due to immunosuppression. De novo RCC occurrence in kidney allografts is much less common when compared with the native kidneys. Multifocal RCC in allograft kidneys is rarely described. In this report, we discuss two cases of de novo multifocal renal neoplasms in allograft kidneys. Case 1 had three distinct neoplastic lesions of >5 mm, and case 2 had four. Using the World Health Organization 2016 classification of adult renal tumours, case 1 had one clear-cell (cc) RCC (grade 3) and two papillary adenomas; all confined to the kidney. Case 2 had a nodular lesion classified as ccRCC (grade 4) with focal rhabdoid differentiation and some infiltration of renal sinus fat; a cc tubulopapillary RCC; a multilocular cystic renal neoplasm of low malignant potential; and a mucinous tubular and spindle cell carcinoma; the last three all confined to the kidney. This is the first report of mucinous tubular and spindle cell carcinoma in a kidney allograft. When considering multifocal RCC with discordant histology, it is likely that these represent independent tumourigenic events. PMID:28326280

  16. Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models

    SciTech Connect

    Van der Hauwaert, Cynthia; Savary, Grégoire; Buob, David; Leroy, Xavier; Aubert, Sébastien; Flamand, Vincent; Hennino, Marie-Flore; Perrais, Michaël; and others

    2014-09-15

    Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies. - Highlights: • Renal proximal tubular (PT) cells are highly sensitive to xenobiotics. • Expression of genes involved in xenobiotic disposition was measured. • PT cells exhibited the highest similarities with renal tissue.

  17. Human Kidney-Derived Cells Ameliorate Acute Kidney Injury Without Engrafting into Renal Tissue.

    PubMed

    Santeramo, Ilaria; Herrera Perez, Zeneida; Illera, Ana; Taylor, Arthur; Kenny, Simon; Murray, Patricia; Wilm, Bettina; Gretz, Norbert

    2017-04-04

    Previous studies have suggested that CD133(+) cells isolated from human kidney biopsies have the potential to ameliorate injury following intravenous (IV) administration in rodent models of kidney disease by integrating into damaged renal tissue and generating specialized renal cells. However, whether renal engraftment of CD133(+) cells is a prerequisite for ameliorating injury has not yet been unequivocally resolved. Here, we have established a cisplatin-induced nephropathy model in immunodeficient rats to assess the efficacy of CD133(+) human kidney cells in restoring renal health, and to determine the fate of these cells after systemic administration. Specifically, following IV administration, we evaluated the impact of the CD133(+) cells on renal function by undertaking longitudinal measurements of the glomerular filtration rate using a novel transcutaneous device. Using histological assays, we assessed whether the human kidney cells could promote renal regeneration, and if this was related to their ability to integrate into the damaged kidneys. Our results show that both CD133(+) and CD133(-) cells improve renal function and promote renal regeneration to a similar degree. However, this was not associated with engraftment of the cells into the kidneys. Instead, after IV administration, both cell types were exclusively located in the lungs, and had disappeared by 24 hours. Our data therefore indicate that renal repair is not mediated by CD133(+) cells homing to the kidneys and generating specialized renal cells. Instead, renal repair is likely to be mediated by paracrine or endocrine factors. © Stem Cells Translational Medicine 2017.

  18. Renal Primary Cilia Lengthen after Acute Tubular Necrosis

    PubMed Central

    Verghese, Elizabeth; Ricardo, Sharon D.; Weidenfeld, Raphael; Zhuang, Junli; Hill, Prudence A.; Langham, Robyn G.

    2009-01-01

    Renal primary cilia are sensory antennas required for the maintenance of normal epithelial differentiation and proliferation in the kidney, but they also have a potential role in epithelial differentiation during renal injury and repair. In mice, tubular damage causes an increase in the length of renal cilia, which may modify their sensory sensitivity during repair. Here, we investigated whether the alteration of renal cilium length during renal injury is clinically relevant. Using biopsies of human renal transplants that suffered acute tubular necrosis during transplantation, we compared the length of renal primary cilia with renal function. Serial biopsies showed that acute tubular necrosis resulted in more than a doubling of cilium length throughout the nephron and collecting duct approximately 1 wk after injury. Allografts displayed a trend toward normalization of cilium length in later biopsies, and this correlated with functional recovery. A mouse model of renal ischemia-reperfusion confirmed the increase and subsequent regression of cilium length during renal repair, displaying complete normalization of cilium length within 6 wk of injury. These findings demonstrate that the length of renal cilia is a clinically relevant indicator of renal injury and repair. PMID:19608704

  19. Optimization and Implementation of Long Nerve Allografts

    DTIC Science & Technology

    2013-03-01

    mimics the production of the human nerve allograft product used clinically. This includes detergent decellularization , treatment with...is  on  schedule.     The  early  Milestone  to  obtain  ACURO  approval  for   animal  use  was  accomplished...months  1-­‐6):       Task  1a.    Collect,  process  ( decellularize )  and  prepare  7  cm  acellular  allografts

  20. Alpha-1-antitrypsin for the improvement of autoimmunity and allograft rejection in beta cell transplantation.

    PubMed

    Ye, Jian; Liao, Yu-Ting; Jian, You-Qiang; Zhang, Xiao-Dan; Wei, Pei; Qi, Hui; Deng, Chun-Yan; Li, Fu-Rong

    2013-02-01

    Islet transplantation offers hope for patients with type 1 diabetes, which is an autoimmune disease. However, islet transplant recipients must overcome two obstacles in both allograft rejection and autoimmune reaction. Alpha-1-antitrypsin (a1-proteinase inhibitor, AAT) possesses anti-inflammatory properties, reduces cytokine-mediated islet damage, and induces specific immune tolerance. In this study, an insulinoma cell line, NIT-1, was transfected with human AAT (hAAT), named NIT-hAAT, and was transplanted to the left renal subcapsular spaces of 7-week-old female non-obese diabetic (NOD) mice (n=22). Cyclophosphamide(CY) was administered to synchronize and accelerate the development of diabetes. Thus, the immunosuppressive and cytoprotective activity of hAAT in β-cell transplantation was investigated. NIT-hAAT has immunomodulatory properties, which delay the onset of autoimmune diabetes, reduce diabetes incidence, inhibit insulitis and β-cell apoptosis, and dampen transplant site inflammation. We propose that NIT-hAAT has a dual function by improving islet autoimmunity and protecting transplanted β-cells from allograft rejection. However, the low expression of hAAT in vivo results in the inability of NIT-hAAT to induce long-term specific immune tolerance and to completely block allograft rejection.

  1. Radiation sterilization of skin allograft

    NASA Astrophysics Data System (ADS)

    Kairiyama, E.; Horak, C.; Spinosa, M.; Pachado, J.; Schwint, O.

    2009-07-01

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10 -6. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm 2. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  2. Human embryonic stem cells differentiate into functional renal proximal tubular-like cells.

    PubMed

    Narayanan, Karthikeyan; Schumacher, Karl M; Tasnim, Farah; Kandasamy, Karthikeyan; Schumacher, Annegret; Ni, Ming; Gao, Shujun; Gopalan, Began; Zink, Daniele; Ying, Jackie Y

    2013-04-01

    Renal cells are used in basic research, disease models, tissue engineering, drug screening, and in vitro toxicology. In order to provide a reliable source of human renal cells, we developed a protocol for the differentiation of human embryonic stem cells into renal epithelial cells. The differentiated stem cells expressed markers characteristic of renal proximal tubular cells and their precursors, whereas markers of other renal cell types were not expressed or expressed at low levels. Marker expression patterns of these differentiated stem cells and in vitro cultivated primary human renal proximal tubular cells were comparable. The differentiated stem cells showed morphological and functional characteristics of renal proximal tubular cells, and generated tubular structures in vitro and in vivo. In addition, the differentiated stem cells contributed in organ cultures for the formation of simple epithelia in the kidney cortex. Bioreactor experiments showed that these cells retained their functional characteristics under conditions as applied in bioartificial kidneys. Thus, our results show that human embryonic stem cells can differentiate into renal proximal tubular-like cells. Our approach would provide a source for human renal proximal tubular cells that are not affected by problems associated with immortalized cell lines or primary cells.

  3. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a...

  4. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a...

  5. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a...

  6. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a...

  7. Urinary proteomic analysis of chronic allograft nephropathy

    PubMed Central

    O’Riordan, Edmond; Orlova, Tatyana N.; Mendelev, Natalia; Patschan, Daniel; Kemp, Rowena; Chander, Praveen N.; Hu, Rena; Hao, Gang; Gross, Steven S.; Iozzo, Renato V.; Delaney, Veronica; Goligorsky, Michael S.

    2015-01-01

    The pathogenesis of progressive renal allograft injury, which is termed chronic allograft nephropathy (CAN), remains obscure and is currently defined by histology. Prospective protocolbiopsy trials have demonstrated that clinical and standard laboratory tests are insufficiently sensitive indicators of the development and progression of CAN. The study aim was to determine if CAN could be characterized by urinary proteomic data and identify the proteins associated with disease. The urinary proteome of 75 renal transplant recipients and 20 healthy volunteers was analyzed using surface enhanced laser desorption and ionization MS. Patients could be classified into subgroups with normal histology and Banff CAN grades 2-3 with a sensitivity of 86% and a specificity of 92% by applying the classification algorithm Adaboost to urinary proteomic data. Several urinary proteins associated with advanced CAN were identified including α1-micro-globulin, β2-micro-globulin, prealbumin, and endorepellin, the antiangiogenic C-terminal fragment of perlecan. Increased urinary endorepellin was confirmed by ELISA and increased tissue expression of the endorepellin/perlecan ratio by immunofluoresence analysis of renal biopsies. In conclusion, analysis of urinary proteomic data has further characterized the more severe CAN grades and identified urinary endorepellin, as a potential biomarker of advanced CAN. PMID:21136903

  8. Complement C5 Inhibition Reduces T Cell-Mediated Allograft Vasculopathy Caused by Both Alloantibody and Ischemia Reperfusion Injury in Humanized Mice

    PubMed Central

    Qin, Lingfeng; Li, Guangxin; Kirkiles-Smith, Nancy; Clark, Pamela; Fang, Caodi; Wang, Yi; Yu, Zhao-Xue; Devore, Denise; Tellides, George; Pober, Jordan S; Jane-wit, Dan

    2016-01-01

    Allograft vasculopathy (AV) is characterized by diffuse stenoses in the vasculature of solid organ transplants. Previously, we developed two humanized models showing that alloantibody and ischemia reperfusion injury (IRI) exacerbated T cell-mediated AV in human arterial xenografts in vivo. Here we examined a causal role for terminal complement activation in both settings. IRI, in contrast to alloantibody, elicited widespread membrane attack complex (MAC) assembly throughout the vessel wall. Both alloantibody and IRI caused early (24 h) and robust endothelial cell (EC) activation localized to regions of intimal MAC deposition, indicated by increases in NF-κB inducing kinase, a MAC-dependent activator of non-canonical NF-kB, VCAM-1 expression, and Gr-1+ neutrophil infiltration. Endothelial cell activation by alloantibody was inhibited by anti- mouse C5 mAb, but not by anti-C5a mAb or by control mAb, implicating MAC as the primary target of anti-C5 mAb. Anti-mouse C5 mAb significantly reduced alloantibody- and IRI-enhanced T cell infiltration and AV-like changes including neointimal hyperplasia as well as intraluminal thrombosis in a subset of IRI-treated arterial grafts. These results indicate that increased AV lesion formation in response to either alloantibody or IRI are dependent on complement C5 activation and accordingly inhibition of this pathway may attenuate AV. PMID:27104811

  9. Kidney allograft survival in dogs treated with total lymphoid irradiation

    SciTech Connect

    Howard, R.J.; Sutherland, D.E.R.; Lum, C.T.; Lewis, W.I.; Kim, T.H.; Slavin, S.; Najarian, J.S.

    1981-02-01

    Total lymphoid irradiation (TLI) is immunosuppressive and, in rodents, can induce a state where transplantation of allogenic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950 to 3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned for a mean +- (SE) of 4.7 +- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15 to 76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemaglutinin and in mixed lymphocyte culture was suppressed for at least one month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.

  10. Effects of Renal Denervation on Renal Artery Function in Humans: Preliminary Study

    PubMed Central

    Doltra, Adelina; Hartmann, Arthur; Stawowy, Philipp; Goubergrits, Leonid; Kuehne, Titus; Wellnhofer, Ernst; Gebker, Rolf; Schneeweis, Christopher; Schnackenburg, Bernhard; Esler, Murray; Fleck, Eckart; Kelle, Sebastian

    2016-01-01

    Aim To study the effects of RD on renal artery wall function non-invasively using magnetic resonance. Methods and Results 32 patients undergoing RD were included. A 3.0 Tesla magnetic resonance of the renal arteries was performed before RD and after 6-month. We quantified the vessel sharpness of both renal arteries using a quantitative analysis tool (Soap-Bubble®). In 17 patients we assessed the maximal and minimal cross-sectional area of both arteries, peak velocity, mean flow, and renal artery distensibility. In a subset of patients wall shear stress was assessed with computational flow dynamics. Neither renal artery sharpness nor renal artery distensibility differed significantly. A significant increase in minimal and maximal areas (by 25.3%, p = 0.008, and 24.6%, p = 0.007, respectively), peak velocity (by 16.9%, p = 0.021), and mean flow (by 22.4%, p = 0.007) was observed after RD. Wall shear stress significantly decreased (by 25%, p = 0.029). These effects were observed in blood pressure responders and non-responders. Conclusions RD is not associated with adverse effects at renal artery level, and leads to an increase in cross-sectional areas, velocity and flow and a decrease in wall shear stress. PMID:27003912

  11. Isolation, growth, and characterization of human renal epithelial cells using traditional and 3D methods.

    PubMed

    Gildea, John J; McGrath, Helen E; Van Sciver, Robert E; Wang, Dora Bigler; Felder, Robin A

    2013-01-01

    The kidney is a highly heterogeneous organ that is responsible for fluid and electrolyte balance. Much interest is focused on determining the function of specific renal epithelial cells in humans, which can only be accomplished through the isolation and growth of nephron segment-specific epithelial cells. However, human renal epithelial cells are notoriously difficult to maintain in culture. This chapter describes the isolation, growth, immortalization, and characterization of the human renal proximal tubule cell. In addition, we describe new paradigms in 3D cell culture which allow the cells to maintain more in vivo-like morphology and function.

  12. Recruitment of renal transplant patients into patrolling police roles using orthotic shields.

    PubMed

    Levene, Sara; Levene, Charlotte Amy; Makanjuola, David; Rajakariar, Ravi

    2014-05-30

    Renal allografts are transplanted to an anatomically unnatural site where they are exposed to trauma, and may fail if damaged. Individuals with renal allografts have been excluded from patrolling police roles as these often necessitate confrontation. We describe two patients with renal allografts who have been recruited by the Metropolitan Police Service, using bespoke orthotic shields to protect the grafts. 2014 BMJ Publishing Group Ltd.

  13. Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin.

    PubMed

    Franz, Marcus; Doll, Fabia; Grün, Katja; Richter, Petra; Köse, Nilay; Ziffels, Barbara; Schubert, Harald; Figulla, Hans R; Jung, Christian; Gummert, Jan; Renner, André; Neri, Dario; Berndt, Alexander

    2015-09-15

    Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8-IL10) in the process of chronic rejection development. A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal). In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (α-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups. All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. A Bioartificial Renal Tubule Device Embedding Human Renal Stem/Progenitor Cells

    PubMed Central

    Sciancalepore, Anna Giovanna; Sallustio, Fabio; Girardo, Salvatore; Gioia Passione, Laura; Camposeo, Andrea; Mele, Elisa; Di Lorenzo, Mirella; Costantino, Vincenzo; Schena, Francesco Paolo; Pisignano, Dario

    2014-01-01

    We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs) was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na+K+ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5)% and (13±5)%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative “lab-on-a-chip” platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses. PMID:24498117

  15. A bioartificial renal tubule device embedding human renal stem/progenitor cells.

    PubMed

    Sciancalepore, Anna Giovanna; Sallustio, Fabio; Girardo, Salvatore; Gioia Passione, Laura; Camposeo, Andrea; Mele, Elisa; Di Lorenzo, Mirella; Costantino, Vincenzo; Schena, Francesco Paolo; Pisignano, Dario

    2014-01-01

    We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs) was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na(+)K(+)ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5)% and (13±5)%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative "lab-on-a-chip" platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses.

  16. Antigenic composition of human renal vascular endothelium assessed by kidney perfusion.

    PubMed

    Baldwin, W M; Claas, F H; van Rood, J J; van Es, L A

    1984-05-01

    Intravascular perfusion of healthy, viable human kidneys either with human sera or with monoclonal antibodies specific for individual HLA-A, B, DR or E-M antigens demonstrated that all of these antigens are exposed to circulating antibodies and thus can serve as stimuli or targets for immunologic mediators of renal transplant rejection. In addition, these antibodies could be recovered from the renal vessels by brief treatment with acid buffer.

  17. Facial tissue allograft transplantation.

    PubMed

    Siemionow, M Z; Demir, Y; Sari, A; Klimczak, A

    2005-01-01

    A hemifacial allograft transplant model was used to investigate the rationale for development of functional tolerance across an MHC barrier. Thirty hemiface transplantations were performed in five groups of six Lewis (RT1(1)) rat recipients each. Isografts were performed in group 1. Transplants were obtained from semiallogenic LBN(RT1(1+n)) in group 2 and from fully allogenic ACI(RT1(a)) in group 3 donors, which served as allograft rejection controls. Group 4 grafts using LBN donors and group 5 using ACI donors in addition received CsA monotherapy (16 mg/kg/d for 1 week) and maintained at 2 mg/kg/d. Signs of graft rejection were sought daily. Isograft controls survived indefinitely. All nontreated allografts were rejected within 5 to 8 days posttransplant. Eighty-three percent of face-transplant recipients from LBN donors and 67% from ACI donors did not show any signs of rejection up to 270 days and 200 days, respectively. Flow cytometry at day 63 in LBN recipients showed the presence of donor-specific chimerism for MHC class I RT1(n) antigens, namely 3.39% CD4/RT1(n); 1.01% CD8/RT1(n) T-lymphocytes; and 3.54% CD45RA/RT1(n) B-lymphocytes. In ACI recipients the chimerism test revealed 10.55% CD4/RT1(a) and 4.59% of CD8/RT1(a) T-lymphocytes. MLR assay at day 160 posttransplant revealed suppressed responses against LBN donor antigens in group 4, but moderate reactivity to ACI donor antigens in group 5. Functional tolerance toward hemifacial allograft transplants induced across MHC barrier using a CsA monotherapy protocol was associated with the presence of donor-specific chimerism in T- and B-cell subpopulations.

  18. T-cell alloimmunity and chronic allograft dysfunction.

    PubMed

    Safinia, Niloufar; Afzali, Behdad; Atalar, Kerem; Lombardi, Giovanna; Lechler, Robert I

    2010-12-01

    Solid organ transplantation is the standard treatment to improve both the quality of life and survival in patients with various end-stage organ diseases. The primary barrier against successful transplantation is recipient alloimmunity and the need to be maintained on immunosuppressive therapies with associated side effects. Despite such treatments in renal transplantation, after death with a functioning graft, chronic allograft dysfunction (CAD) is the most common cause of late allograft loss. Recipient recognition of donor histocompatibility antigens, via direct, indirect, and semidirect pathways, is critically dependent on the antigen-presenting cell (APC) and elicits effector responses dominated by recipient T cells. In allograft rejection, the engagement of recipient and donor cells results in recruitment of T-helper (Th) cells of the Th1 and Th17 lineage to the graft. In cases in which the alloresponse is dominated by regulatory T cells (Tregs), rejection can be prevented and the allograft tolerated with minimum or no immunosuppression. Here, we review the pathways of allorecognition that underlie CAD and the T-cell effector phenotypes elicited as part of the alloresponse. Future therapies including depletion of donor-reactive lymphocytes, costimulation blockade, negative vaccination using dendritic cell subtypes, and Treg therapy are inferred from an understanding of these mechanisms of allograft rejection.

  19. Is Duplex-Ultrasound a useful tool in defining rejection episodes in composite tissue allograft transplants?

    PubMed

    Loizides, Alexander; Kronberger, Irmgard-Elisabeth; Plaikner, Michaela; Gruber, Hannes

    2015-12-01

    Immunologic reactions in transplanted organs are in more or less all allograft patients detectable: clear parameters exist as e.g. in renal transplants where the clearance power reduces by rejection. On the contrary, in composite tissue allografts clear and objective indicators stating a rejection episode lack. We present the case of a hand-transplanted subject with signs of acute transplant rejection diagnosed by means of Duplex Ultrasound and confirmed by biopsy.

  20. Expression of cytokine genes in human cardiac allografts: correlation of IL-6 and transforming growth factor-beta (TGF-beta) with histological rejection.

    PubMed Central

    Zhao, X M; Frist, W H; Yeoh, T K; Miller, G G

    1993-01-01

    Cytokines may play critical roles in allograft rejection. Currently, a clear pattern of cytokine production that correlates with rejection has not emerged. Our preliminary studies suggested a trend toward increased IL-6 and TGF-beta gene expression in cardiac allografts during rejection. We have extended these studies using reverse transcriptase/polymerase chain reaction (RT/PCR) to detect the expression of IL-6, TGF-beta, and T cell receptor beta chain constant region (TCR-beta) genes in 21 additional consecutive myocardial biopsies obtained from six heart transplant patients and from five pre-transplant donor hearts. Cytokine gene expression was compared with histological diagnosis of rejection. There was strong correlation between IL-6 as well as TGF-beta gene expression, and histological rejection (6/8 biopsies with versus 0/7 without rejection (P = 0.006) and 7/9 biopsies with versus 0/7 without rejection (P = 0.003) respectively). Neither IL-6 nor TGF-beta transcripts were detected in any pre-transplant donor heart. TCR-beta chain mRNA was found in all allograft biopsies regardless of the presence of rejection, but was absent in pre-transplant donor hearts. Our results indicate that expression of IL-6 and TGF-beta is highly correlated with allograft rejection and thus may play an important role in regulation of cardiac allograft rejection. T cell infiltration of allografted myocardium is invariably detected by PCR regardless of histological rejection. The long-term functional significance of these cells in transplanted hearts needs further investigation. Images Fig. 1 PMID:8370174

  1. Metabolomic Profiling in Individuals with a Failing Kidney Allograft

    PubMed Central

    Biancone, Luigi; Bussolino, Stefania; Merugumala, Sai; Tezza, Sara; D’Addio, Francesca; Ben Nasr, Moufida; Valderrama-Vasquez, Alessandro; Usuelli, Vera; De Zan, Valentina; El Essawy, Basset; Venturini, Massimo; Secchi, Antonio; De Cobelli, Francesco; Lin, Alexander; Chandraker, Anil; Fiorina, Paolo

    2017-01-01

    Background Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease. Methods To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls. Results LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels. Conclusions We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function. PMID:28052095

  2. Oxalosis presenting as early renal allograft failure.

    PubMed

    Alsuwaida, Abdulkareem; Hayat, Ashik; Alwakeel, Jamal S

    2007-06-01

    Hyperoxaluria can result in the deposition of oxalate in bones, arteries, eyes, heart, nerves, kidneys and other structures when there is a reduction in glomerular filtration rate. Liver and kidney transplantation is curative for patients with Type I primary hyperoxaluria. Here we report a case of recurrent oxalosis in a post-transplant kidney with early graft failure in an adult male.

  3. Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft

    PubMed Central

    Koyama, I.; Nadazdin, O.; Boskovic, S.; Ochiai, T.; Smith, R. N.; Sykes, M.; Sogawa, H.; Murakami, T.; Strom, T. B.; Colvin, R. B.; Sachs, D. H.; Benichou, G.; Cosimi, A. B.; Kawai, T.

    2013-01-01

    Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti- CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide ‘proof of principle’ that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled. PMID:17286617

  4. Impact of Tacrolimus Compared With Cyclosporin on the Incidence of Acute Allograft Rejection in Human Immunodeficiency Virus-Positive Kidney Transplant Recipients.

    PubMed

    Gathogo, Esther; Harber, Mark; Bhagani, Sanjay; Levy, Jeremy; Jones, Rachael; Hilton, Rachel; Davies, Graham; Post, Frank A

    2016-04-01

    Kidney transplantation (KT) of human immunodeficiency virus (HIV)-positive patients has transformed the management of end-stage kidney disease in this population. Although favourable outcomes have been reported, patients experience high rates of acute allograft rejection (AR). We examined factors associated with AR in the first year after KT, with particular emphasis on the choice of calcineurin inhibitor (CNI) immunosuppressive therapy. We conducted a national observational cohort study of HIV/KT in the United Kingdom. Patients were included if HIV positive at KT, transplanted in the United Kingdom between January 2005 and December 2013, and did not experience primary graft failure. Kaplan-Meier methods were used to estimate host/graft survival and cumulative incidence of biopsy proven AR. Logrank tests were used to compare survival, and Cox proportional hazard models to examine factors associated with AR. Our study analyzed the incidence of AR in the first year after KT in 78 HIV-positive patients of whom 31 initiated cyclosporin (CsA) and 47 tacrolimus (Tac) based immunosuppression. AR was observed in 28 patients (36%) after a median of 2.6 (interquartile range, 0.5-5.9) months. The cumulative incidence of AR at 1 year was 58% and 21% among patients on CsA and Tac, respectively (P =0.003). Choice of CNI was the only factor significantly associated with AR (hazard ratio for Tac vs CsA 0.25 [95% confidence interval, 0.11-0.57], P = 0.001). Subtherapeutic CNI concentrations were common in the first 12 weeks after KT. Our data suggest that Tac may be the preferred CNI for use in KT in people living with HIV.

  5. De novo expression of fetal ED-A(+) fibronectin and B (+) tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection.

    PubMed

    Franz, Marcus; Matusiak-Brückner, Monika; Richter, Petra; Grün, Katja; Ziffels, Barbara; Neri, Dario; Maschek, Hansjörg; Schulz, Uwe; Pfeil, Alexander; Jung, Christian; Figulla, Hans R; Gummert, Jan; Berndt, Alexander; Renner, André

    2014-10-01

    Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re-expression could be demonstrated for ED-A(+) Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A(+) Fn, B(+) Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A(+) Fn (r = 0.442, p = 0.000) and B(+) Tn-C (r = 0.408, p = 0.001) as well as between both proteins (r = 0.663, p = 0.000). A spatial association of ED-A(+) Fn and B(+) Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C following human heart transplantation could be demonstrated with spatial association to

  6. Effect of cyclosporine, dexamethasone, and human CTLA4-Ig on production of cytokines in lymphocytes of clinically normal cats and cats undergoing renal transplantation.

    PubMed

    Aronson, Lillian R; Stumhofer, Jason S; Drobatz, Kenneth J; Hunter, Christopher A

    2011-04-01

    To evaluate effects of cyclosporine, dexamethasone, and the immunosuppressive agent human CTLA4-Ig on cytokine production by feline lymphocytes in vitro and to assess patterns of cytokine production for 5 immunosuppressed renal transplant recipient cats. 21 clinically normal cats and 5 immunosupressed renal transplant recipient cats. Peripheral blood mononuclear cells were isolated from clinically normal cats and stimulated with concanavalin A (Con A; 10 μg/mL) alone or Con A with cyclosporine (0.05 μg/mL), dexamethasone (1 × 10(-7)M), a combination of cyclosporine-dexamethasone, or human CTLA4-Ig (10 g/mL). Cells from transplant recipients were stimulated with Con A alone. An ELISA was performed to measure production of interferon (IFN)-γ, granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-2, IL-4, and IL-10. Proliferation of CD4+ and CD8+T cells from immunosuppressed cats were also evaluated. Pairwise comparisons were performed via a Wilcoxon signed rank test or Wilcoxon rank sum test. Cyclosporine, dexamethasone, cyclosporine-dexamethasone combination, and CTLA4-Ig caused a significant decrease in IL-2, IFN-γ, and GM-CSF production. Cyclosporine and cyclosporine-dexamethasone, but not human CTLA4-Ig, caused a significant decrease in IL-10 production. High basal concentrations of IL-2 and IL-10 were identified in transplant recipients, and IL-10 was significantly increased in stimulated cultures. In immunosuppressed cats, there was a decrease in frequency of responders and proliferative capacity of CD4+ and CD8+T cells. CTLA4-Ig successfully inhibited proinflammatory cytokines while sparing cytokines critical for allograft tolerance. These data may be useful for developing better strategies to prevent rejection while sparing other immune functions.

  7. Ameliorative Effect of Recombinant Human Erythropoietin and Ischemic Preconditioning on Renal Ischemia Reperfusion Injury in Rats

    PubMed Central

    Elshiekh, Mohammed; Kadkhodaee, Mehri; Seifi, Behjat; Ranjbaran, Mina; Ahghari, Parisa

    2015-01-01

    Background: Ischemia-reperfusion (IR) injury is one of the most common causes of renal dysfunction. There is increasing evidence about the role of the reactive oxygen species (ROS) in these injuries and endogenous antioxidants seem to have an important role in decreasing the renal tissue injury. Objectives: The aim of this study was to compare the effect of recombinant human erythropoietin (EPO) and ischemic preconditioning (IPC) on renal IR injury. Materials and Methods: Twenty four male Wistar rats were allocated into four experimental groups: sham-operated, IR, EPO + IR, and IPC + IR. Rats were underwent 50 minutes bilateral ischemia followed by 24 hours reperfusion. Erythropoietin (5000 IU/kg, i.p) was administered 30 minutes before onset of ischemia. Ischemic preconditioning was performed by three cycles of 3 minutes ischemia followed by 3 minutes reperfusion. Plasma concentrations of urea and creatinine were measured. Kidney samples were taken for reactive oxidative species (ROS) measurement including superoxide dismutase (SOD) activity, glutathione (GSH) contents, and malondialdehyde (MDA) levels. Results: Compared to the sham group, IR led to renal dysfunction as evidenced by significantly higher plasma urea and creatinine. Treatment with EPO or IPC decreased urea, creatinine, and renal MDA levels and increased SOD activity and GSH contents in the kidney. Conclusions: Pretreatment with EPO and application of IPC significantly ameliorated the renal injury induced by bilateral renal IR. However, both treatments attenuated renal dysfunction and oxidative stress in kidney tissues. There were no significant differences between pretreatment with EPO or application of IPC. PMID:26866008

  8. Zika Virus Infection of the Human Glomerular Cells: Implications for Viral Reservoirs and Renal Pathogenesis.

    PubMed

    Alcendor, Donald J

    2017-07-15

    Zika virus (ZIKV) infection in the human renal compartment has not been reported. Several clinical reports have describe high-level persistent viral shedding in the urine of infected patients, but the associated mechanisms have not been explored until now. The current study examined cellular components of the glomerulus of the human kidney for ZIKV infectivity. I infected primary human podocytes, renal glomerular endothelial cells (GECs), and mesangial cells with ZIKV. Viral infectivity was analyzed by means of microscopy, immunofluorescence, real-time reverse-transcription polymerase chain reaction (RT-PCR), and quantitative RT-PCR (qRT-PCR), and the proinflammatory cytokines interleukin 1β, interferon β, and RANTES (regulated on activation of normal T cells expressed and secreted) were assessed using qRT-PCR. I show that glomerular podocytes, renal GECs, and mesangial cells are permissive for ZIKV infection. ZIKV infectivity was confirmed in all 3 cell types by means of immunofluorescence staining, RT-PCR, and qRT-PCR, and qRT-PCR analysis revealed increased transcriptional induction of interleukin 1β, interferon β, and RANTES in ZIKV-infected podocytes at 72 hours, compared with renal GECs and mesangial cells. The findings of this study support the notion that the glomerulus may serve as an amplification reservoir for ZIKV in the renal compartment. The impact of ZIKV infection in the human renal compartment is unknown and will require further study.

  9. A Case Report of Human Infection with Dioctophyma Renale from Iran.

    PubMed

    Norouzi, Roghayeh; Manochehri, Arman; Hanifi, Mustafa

    2017-03-16

    A 75-year-old man from Kurdistan province, western part of Iran was diagnosed with a mass in the right kidney by ultrasound and computed tomography. In operation, a parasitic helminth, 30 cm long and 1.2 cm in diameter consistent with D. renale was found in the right kidney. Microscopic examination revealed that the male Dioctophyma renale. Following removal of worm, the symptoms completely resolved within a few hours. Generally, parasitism by D. renale in human is a necropsy finding, nevertheless imaging techniques as ultrasound and computed tomography have been proven to be important tool to achieve diagnosis.

  10. Haematogenous dissemination of cells from human renal adenocarcinomas.

    PubMed Central

    Glaves, D.; Huben, R. P.; Weiss, L.

    1988-01-01

    Estimates were made of the rates at which cancer cells were released directly into the renal vein in patients undergoing radical nephrectomy for primary renal cancer. Cancer cells were counted in blood samples taken from the renal vein using a density gradient centrifugation procedure, and identified using immunocytochemical techniques, on the basis of their cytoskeletal intermediate filament proteins. Cancer cells were released as single cells and multicell emboli in 8/10 patients, in numbers varying widely between 14-7509 emboli ml-1 of blood. Despite a calculated median input into the metastatic process of 3.7 x 10(7) cancer cells per day for at least 180 days, only 3/10 patients had extraperitoneal metastases prior to surgery and only 1 of the remaining disease-free patients subsequently developed distant metastases over a maximum 35 month period. These results are discussed in terms of primary tumour kinetics and metastatic inefficiency. Images Figure 1 PMID:3279993

  11. Differential CMV-Specific CD8+ Effector T Cell Responses in the Lung Allograft Predominate over the Blood during Human Primary Infection1

    PubMed Central

    Pipeling, Matthew R.; West, Erin E.; Osborne, Christine M.; Whitlock, Amanda B.; Dropulic, Lesia K.; Willett, Matthew H.; Forman, Michael; Valsamakis, Alexandra; Orens, Jonathan B.; Moller, David R.; Lechtzin, Noah; Migueles, Stephen A.; Connors, Mark; McDyer, John F.

    2009-01-01

    Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor+/recipient− (D+R−) individuals. In 15 D+R− LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8+ T cells into the lung airways/allograft was observed, with inversion of the CD4+:CD8+ T cell ratio. De novo CMV-specific CD8+ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4+ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8+ T cells in the lung airways following primary infection. CMV-tetramer+CD8+ T cells from PBMC were CD45RA− during viremia and transitioned to CD45RA+ following resolution. In contrast, CMV-specific CD8+ effectors in the lung airways/allograft maintained a CD45RA− phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8+ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection. PMID:18566421

  12. Allograft vasculopathy after allogeneic vascularized knee transplantation.

    PubMed

    Diefenbeck, Michael; Nerlich, Andreas; Schneeberger, Stefan; Wagner, Frithjof; Hofmann, Gunther O

    2011-01-01

    Composite tissue allotransplantation represents a new discipline in reconstructive surgery. Over the past 10 years, we have performed six human vascularized allogeneic knee transplantations. All of these grafts have been lost within the first 56 months. A histomorphologic assessment of the latest case resulted in the detection of diffuse concentric fibrous intimal thickening and occlusion of graft vessels. Findings are comparable with cardiac allograft vasculopathy. The lack of adequate tools for monitoring graft rejection might have allowed multiple untreated episodes of acute rejection, triggering myointimal proliferation and occlusion of graft vessels. Graft vasculopathy represents an obstacle to long-term vascularized bone and joint allograft survival, and adequate tools for monitoring need to be developed.

  13. Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study.

    PubMed

    Atherton, Daniel S; Deep, Nicholas L; Mendelsohn, Farrell O

    2012-07-01

    Hypertension remains an epidemic uncontrolled with pharmacologic therapies. A novel catheter inserted into the renal artery has been shown to lower blood pressure by ablating the renal sympathetic nerves with radiofrequency energy delivered through the arterial wall. We report a histologic study describing the anatomic substrate for this technique, specifically the renal sympathetic nervous system. Histological sections from proximal, middle, and distal renal artery segments from nine renal arteries (five human autopsies) were analyzed. Nerves were manually counted and their distance from the lumen-intima interface was measured using a micrometer. The nerves were then categorized by location into 0.5-mm-wide "rings" that were arranged circumferentially around the renal artery lumen. Of all nerves detected, 1.0% was in the 0-0.5 mm ring, 48.3% were in the 0.5-1.0 mm ring, 25.6% were in the 1.0-1.5 mm ring, 15.5% were in the 1.5-2.0 mm ring, and 9.5% were in the 2.0-2.5 mm ring. Beyond 0.5 mm, the proportion of nerves tended to decrease as the distance from the lumen increased. Totally, 90.5% of all nerves in this study existed within 2.0 mm of the renal artery lumen. Additionally, the number of nerves tended to increase along the length of the artery from proximal to distal segments (proximal = 216; middle = 323; distal = 417). In conclusion, our analysis indicates that a great proportion of renal sympathetic nerves have close proximity to the lumen-intima interface and should thus be accessible via renal artery interventional approaches such as catheter ablation. This data provides important anatomic information for the development of ablation and other type devices for renal sympathetic denervation. © 2011 Wiley Periodicals, Inc.

  14. Microcirculation of human pancreatic islets transplanted under the renal capsule of nude mice.

    PubMed

    Jansson, L; Tyrberg, B; Carlsson, P O; Nordin, A; Andersson, A; Källskog O

    2001-08-27

    The aim was to measure the capillary blood pressure in transplanted human islets. Human islets were isolated at the Central Unit of the beta-cell Transplant in Brussels, Belgium. After transport to our laboratory, the islets were implanted under the renal capsule of normoglycemic nude mice. Two weeks later the capillary and venous blood pressures in the islet graft and adjacent renal parenchyma were measured with a micropuncture technique. Capillary blood pressure was approximately 5-8 mmHg in both graft and renal capillaries: twice as high as in native islets. Venous blood pressures were similar (4-5 mmHg) in the veins draining the graft and in the renal interlobular veins. All veins leading from the graft emptied into the renal parenchyma, that is, into interlobular veins. The capillary hypertension seen in transplanted human islets is probably necessary to secure adequate drainage through the renal veins. Whether this contributes to the poor results of long-term islet graft survival is unknown.

  15. Human anion exchanger1 mutations and distal renal tubular acidosis.

    PubMed

    Yenchitsomanus, Pa-thai

    2003-09-01

    The human anion exchanger 1 (AE1 or SLC4A1) gene encodes anion exchanger 1 (or band 3) protein in erythrocytes and in alpha-intercalated cells of the kidney. Thus, AE1 mutations show pleiotrophic effects resulting in two distinct and seemingly unrelated defects, an erythrocyte abnormality and distal renal tubular acidosis (dRTA). Southeast Asian ovalocytosis (SAO), a well-known red blood cell (RBC) defect, which is widespread in Southeast Asian regions, is caused by AE1 mutation due to a deletion of 27 base pairs in codons 400-408 (delta400-408) leading to an in-frame 9 amino-acid loss in the protein. Co-existence of SAO and dRTA is usually not seen in the same individual. However, the two conditions can co-exist as the result of compound heterozygosities between delta400-408 and other mutations. The reported genotypes include delta400-408/G701D, delta400-408/R602H, delta400-408/deltaV850, and delta400-408/A858D. The presence of dRTA, with or without RBC abnormalities, may occur from homozygous or compound heterozygous conditions of recessive AE1 mutations (eg G701D/G701D, V488M/V488M, deltaV850/deltaV850, deltaV850/A858D, G701D/S773P) or heterozygous dominant AE1 mutations (eg R598H, R589C, R589S, S613F, R901X). Codon 589 of this gene seems to be a 'mutational hot-spot' since repeated mutations at this codon occurring in different ethnic groups and at least two de novo (R589H and R589C) mutations have been observed. Therefore, AE1 mutations can result in both recessive and dominant dRTA, possibly depending on the position of the amino acid change in the protein. As several mutant AE1 proteins still maintain a significant anion transport function but are defective in targeting to the cell surface, impaired intracellular trafficking of the mutant AE1 is an important molecular mechanism involved in the pathogenesis of dRTA associated with AE1 mutations.

  16. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells.

    PubMed

    Mazzinghi, Benedetta; Ronconi, Elisa; Lazzeri, Elena; Sagrinati, Costanza; Ballerini, Lara; Angelotti, Maria Lucia; Parente, Eliana; Mancina, Rosa; Netti, Giuseppe Stefano; Becherucci, Francesca; Gacci, Mauro; Carini, Marco; Gesualdo, Loreto; Rotondi, Mario; Maggi, Enrico; Lasagni, Laura; Serio, Mario; Romagnani, Sergio; Romagnani, Paola

    2008-02-18

    Recently, we have identified a population of renal progenitor cells in human kidneys showing regenerative potential for injured renal tissue of SCID mice. We demonstrate here that among all known chemokine receptors, human renal progenitor cells exhibit high expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7. In SCID mice with acute renal failure (ARF), SDF-1 was strongly up-regulated in resident cells surrounding necrotic areas. In the same mice, intravenously injected renal stem/progenitor cells engrafted into injured renal tissue decreased the severity of ARF and prevented renal fibrosis. These beneficial effects were abolished by blocking either CXCR4 or CXCR7, which dramatically reduced the number of engrafting renal progenitor cells. However, although SDF-1-induced migration of renal progenitor cells was only abolished by an anti-CXCR4 antibody, transendothelial migration required the activity of both CXCR4 and CXCR7, with CXCR7 being essential for renal progenitor cell adhesion to endothelial cells. Moreover, CXCR7 but not CXCR4 was responsible for the SDF-1-induced renal progenitor cell survival. Collectively, these findings suggest that CXCR4 and CXCR7 play an essential, but differential, role in the therapeutic homing of human renal progenitor cells in ARF, with important implications for the development of stem cell-based therapies.

  17. Platonin improves survival of skin allografts.

    PubMed

    Cheng, Shih-Ping; Lee, Jie-Jen; Chi, Chin-Wen; Chang, Kuo-Ming; Chen, Yu-Jen

    2010-11-01

    Platonin is an immunomodulator with NF-κB inhibitory activity. It not only inhibits interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production in sepsis, but also attenuates heatstroke reactions. In addition, platonin redirects differentiation of dendritic cells toward an intermediate stage of maturation. The study was designed to examine whether platonin can reduce acute graft rejection. A C57BL/6 to BALB/c mice skin transplantation model was used. Platonin was given intraperitoneally to transplant recipients at various doses. Skin grafts were submitted to histologic analysis. NF-κB DNA binding activity and inducible nitric oxide synthase (iNOS) expression were determined in harvested draining lymph nodes. Leukocyte count, hepatic and renal functions were serially assessed. An array of serum cytokines was evaluated on d 1, 3, 5, and 7 after skin transplantation. Platonin resulted in significantly prolonged skin allograft survival in a dose- and time-dependent manner. Histologic changes in the skin allografts paralleled the gross appearance of rejection. Serum cytokine analysis shows that platonin significantly suppressed the production of the proinflammatory cytokines IL-6 and TNF-α. However, no significant changes occurred in the serum levels of Th1-type and Th2-type cytokines. NF-κB activity and iNOS expression were remarkably suppressed in draining lymph nodes. In terms of toxicity, there were no significant differences in body weight, leukocyte count, plasma alanine aminotransferase, or creatinine between the platonin-treated and control groups. Platonin effectively prolongs skin allograft survival without major toxicity. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Renal denervation and hypertension - The need to investigate unintended effects and neural control of the human kidney.

    PubMed

    Grisk, Olaf

    2017-05-01

    Increased renal sympathetic nerve activity (RSNA) is present in human and experimental forms of arterial hypertension. Experimental denervation studies showed that renal nerves contribute to the development of hypertension. Clinical trials provided equivocal results on the antihypertensive efficacy of renal denervation in patients spurring discussions on technical aspects of renal denervation and further research on the role of renal nerves for the regulation of kidney function as well as the pathophysiology of hypertension. This review summarizes recent findings on adrenoceptor expression and function in the human kidney, adrenoceptor-dependent regulation of sodium chloride transport in the distal nephron, experimental data on chronic RSNA and the development of high arterial pressure and consequences of renal denervation that may limit its antihypertensive efficacy. Future research needs to reduce the gap between our knowledge on neural control of renal function in animals vs. humans to facilitate translation of experimental animal data to humans. More experimental studies on the temporal relationship between RSNA and arterial pressure in the chronic setting are needed to better define the pathogenetic role of heightened RSNA in different forms of arterial hypertension in order to improve the rational basis for renal denervation in antihypertensive therapy. Finally, research on unintended consequences of renal denervation including but not limited to reinnervation and denervation supersensitivity needs to be intensified to further assess the potential of renal denervation to slow the progression of renal disease and hypertension.

  19. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    PubMed

    Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony; Lechler, Robert; Lombardi, Giovanna

    2014-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  20. Ex Vivo Expanded Human Regulatory T Cells Delay Islet Allograft Rejection via Inhibiting Islet-Derived Monocyte Chemoattractant Protein-1 Production in CD34+ Stem Cells-Reconstituted NOD-scid IL2rγnull Mice

    PubMed Central

    Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony

    2014-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo. PMID:24594640

  1. Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury

    PubMed Central

    Aggarwal, Shikhar; Grange, Cristina; Iampietro, Corinne; Camussi, Giovanni; Bussolati, Benedetta

    2016-01-01

    Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133+ renal progenitor cells on maladaptive repair and fibrosis following AKI in a model of glycerol-induced rhabdomyolysis. In parallel, we evaluated the effect of CD133+ cells on erythropoietin production. Administration of CD133+ cells promoted the restoration of the renal tissue, limiting the presence of markers of injury and pro-inflammatory molecules. In addition, it promoted angiogenesis and protected against fibrosis up to day 60. No effect of dermal fibroblasts was observed. Treatment with CD133+ cells, but not with PBS or fibroblasts, limited anemia and increased erythropoietin levels both in renal tissue and in circulation. Finally, CD133+ cells contributed to the local production of erythropoietin, as observed by detection of circulating human erythropoietin. CD133+ cells appear therefore an effective source for cell repair, able to restore renal functions, including erythropoietin release, and to limit long term maldifferentiation and fibrosis. PMID:27853265

  2. SORCS1 contributes to the development of renal disease in rats and humans

    PubMed Central

    Lazar, Jozef; O'Meara, Caitlin C.; Sarkis, Allison B.; Prisco, Sasha Z.; Xu, Haiyan; Fox, Caroline S.; Chen, Ming-Huei; Broeckel, Ulrich; Arnett, Donna K.; Moreno, Carol; Provoost, Abraham P.

    2013-01-01

    Many lines of evidence demonstrate that genetic variability contributes to chronic kidney disease susceptibility in humans as well as rodent models. Little progress has been made in discovering causal kidney disease genes in humans mainly due to genetic complexity. Here, we use a minimal congenic mapping strategy in the FHH (fawn hooded hypertensive) rat to identify Sorcs1 as a novel renal disease candidate gene. We investigated the hypothesis that genetic variation in Sorcs1 influences renal disease susceptibility in both rat and human. Sorcs1 is expressed in the kidney, and knocking out this gene in a rat strain with a sensitized genome background produced increased proteinuria. In vitro knockdown of Sorcs1 in proximal tubule cells impaired protein trafficking, suggesting a mechanism for the observed proteinuria in the FHH rat. Since Sorcs1 influences renal function in the rat, we went on to test this gene in humans. We identified associations between single nucleotide polymorphisms in SORCS1 and renal function in large cohorts of European and African ancestry. The experimental data from the rat combined with association results from different ethnic groups indicates a role for SORCS1 in maintaining proper renal function. PMID:23780848

  3. Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35

    SciTech Connect

    Kos, C.H.; Tenenhouse, H.S. ); Tihy, F.; Lemieux, N. ); Econs, M.J. ); Murer, H. )

    1994-01-01

    Several Mendelian disorders of renal phosphate reabsorption, associated with hypophosphatemia and bone disease, have been described. These include X-linked hypophosphatemia (XLH), hereditary hypophosphatemic rickets with hypercalciuria, hypophosphatemic bone disease, and autosomal dominant and autosomal recessive hypophosphatemic rickets. The underlying mechanisms for renal phosphate wasting in these disorders remain unknown. The proximal tubule is the major site of renal phosphate reabsorption. Thus, mutations in genes that participate in the transepithelial transport of phosphate in this segment of the nephron may be responsible for these disorders. Recently, a cDNA encoding a renal proximal tubular, brush-border membrane Na[sup +]-phosphate cotransporter (NaP[sub i]-3) was cloned from human kidney cortex. As a first step in establishing whether mutations in the NaP[sub i]-3 gene are the cause of inherited disorders in phosphate homeostasis, the authors sought to determine its chromosomal localization. 9 refs., 1 fig.

  4. Natural Scaffolds for Renal Differentiation of Human Embryonic Stem Cells for Kidney Tissue Engineering.

    PubMed

    Batchelder, Cynthia A; Martinez, Michele L; Tarantal, Alice F

    2015-01-01

    Despite the enthusiasm for bioengineering of functional renal tissues for transplantation, many obstacles remain before the potential of this technology can be realized in a clinical setting. Viable tissue engineering strategies for the kidney require identification of the necessary cell populations, efficient scaffolds, and the 3D culture conditions to develop and support the unique architecture and physiological function of this vital organ. Our studies have previously demonstrated that decellularized sections of rhesus monkey kidneys of all age groups provide a natural extracellular matrix (ECM) with sufficient structural properties with spatial and organizational influences on human embryonic stem cell (hESC) migration and differentiation. To further explore the use of decellularized natural kidney scaffolds for renal tissue engineering, pluripotent hESC were seeded in whole- or on sections of kidney ECM and cell migration and phenotype compared with the established differentiation assays for hESC. Results of qPCR and immunohistochemical analyses demonstrated upregulation of renal lineage markers when hESC were cultured in decellularized scaffolds without cytokine or growth factor stimulation, suggesting a role for the ECM in directing renal lineage differentiation. hESC were also differentiated with growth factors and compared when seeded on renal ECM or a new biologically inert polysaccharide scaffold for further maturation. Renal lineage markers were progressively upregulated over time on both scaffolds and hESC were shown to express signature genes of renal progenitor, proximal tubule, endothelial, and collecting duct populations. These findings suggest that natural scaffolds enhance expression of renal lineage markers particularly when compared to embryoid body culture. The results of these studies show the capabilities of a novel polysaccharide scaffold to aid in defining a protocol for renal progenitor differentiation from hESC, and advance the promise

  5. Validation of cold chain shipping environment for transport of allografts as part of a human tissue bank returns policy.

    PubMed

    Rooney, P; Eagle, M J; Kearney, J N

    2015-12-01

    Human tissue is shipped to surgeons in the UK in either a freeze-dried or frozen state. To ensure quality and safety of the tissue, frozen tissue must be shipped in insulated containers such that tissue is maintained at an appropriate temperature. UK Blood Transfusion Service regulations state "Transportation systems must be validated to show maintenance of the required storage temperature" and also state that frozen, non-cryopreserved tissue "must be transported… at -20 °C or lower" (Guidelines for the Blood Transfusion Services in the United Kingdom, 8th Edn. 2013). To maintain an expiry date for frozen tissue longer than 6 months, the tissue must be maintained at a temperature of -40 °C or below. The objective of this study was to evaluate and validate the capability of a commercially available insulated polystyrene carton (XPL10), packed with dry ice, to maintain tissue temperature below -40 °C. Tissue temperature of a single frozen femoral head or a single frozen Achilles tendon, was recorded over a 4-day period at 37 °C, inside a XPL10 carton with dry ice as refrigerant. The data demonstrate that at 37 °C, the XPL10 carton with 9.5 kg of dry ice maintained femoral head and tendon tissue temperature below -55 °C for at least 48 h; tissue temperature did not rise above -40 °C until at least 70 h. Data also indicated that at a storage temperature lower than 37 °C, tissue temperature was maintained for longer periods.

  6. Ascorbic acid against reperfusion injury in human renal transplantation.

    PubMed

    Norio, Karri; Wikström, Mårten; Salmela, Kaija; Kyllönen, Lauri; Lindgren, Leena

    2003-08-01

    The cadaveric renal graft is exposed to ischaemic injury during preservation and to oxidative damage during reperfusion. Both these mechanisms are known to cause cell damage, which may impair graft function. Reperfusion injury (RPI) is mediated by reactive oxygen species (ROS). Ascorbic acid (AA) is a potent physiological extracellular scavenger of ROS. We perfused 31 renal grafts immediately before implantation with a solution of Euro-Collins containing 0.5 mg/ml of AA to diminish RPI. From every donor, the contralateral kidney served as a control. The control grafts were perfused with the same perfusion as those of the AA group, only without the AA substitution. We assessed the effect of AA by recording serum creatinine, creatinine clearance, initial graft function and early rejections. The incidence of delayed graft function (DGF) was 32% in the AA group, and 29% in the control group. Other parameters were also similar in both groups, except for the length of DGF, which showed a trend towards a shorter duration in the AA group. The pre-operative systemic AA concentration was significantly ( P=0.01) lower in the haemodialysis patients than in those on peritoneal dialysis. In conclusion, this clinical study could not demonstrate significant benefits of AA in renal transplantation.

  7. Sequestration of human cytomegalovirus by human renal and mammary epithelial cells

    SciTech Connect

    Twite, Nicolas; Andrei, Graciela; Kummert, Caroline; Donner, Catherine; Perez-Morga, David; De Vos, Rita; Snoeck, Robert; Marchant, Arnaud

    2014-07-15

    Urine and breast milk represent the main routes of human cytomegalovirus (HCMV) transmission but the contribution of renal and mammary epithelial cells to viral excretion remains unclear. We observed that kidney and mammary epithelial cells were permissive to HCMV infection and expressed immediate early, early and late antigens within 72 h of infection. During the first 24 h after infection, high titers of infectious virus were measured associated to the cells and in culture supernatants, independently of de novo synthesis of virus progeny. This phenomenon was not observed in HCMV-infected fibroblasts and suggested the sequestration and the release of HCMV by epithelial cells. This hypothesis was supported by confocal and electron microscopy analyses. The sequestration and progressive release of HCMV by kidney and mammary epithelial cells may play an important role in the excretion of the virus in urine and breast milk and may thereby contribute to HCMV transmission. - Highlights: • Primary renal and mammary epithelial cells are permissive to HCMV infection. • HCMV is sequestered by epithelial cells and this phenomenon does not require viral replication. • HCMV sequestration by epithelial cells is reduced by antibodies and IFN-γ.

  8. A Lifetime of Allograft Function with Kidneys from Older Donors.

    PubMed

    Rose, Caren; Schaeffner, Elke; Frei, Ulrich; Gill, Jagbir; Gill, John S

    2015-10-01

    Strategies to increase expanded criteria donor (ECD) transplantation are needed. We quantified the extent to which ECD kidneys provide recipients with a lifetime of allograft function by determining the difference between patient survival and death-censored allograft survival (graft survival). Initial analyses compared 5-year outcomes in the Eurotransplant Senior Program (European) and the United States Renal Data System. Among European recipients ≥65 years, patient survival exceeded graft survival, and ECD recipients returned to dialysis for an average of 5.2 months after transplant failure. Among United States recipients ≥60 years, graft survival exceeded patient survival. Although patient survival in elderly recipients in the United States was low (49% at 5 years), the average difference in patient survival at 10 years in elderly recipients in the United States with an ECD versus non-ECD transplant was only 7 months. The probability of patient survival with a functioning allograft at 5 years was higher with ECD transplantation within 1 year after activation to the waiting list than with delayed non-ECD transplantation ≥3 years after activation to the waiting list. Subsequent analyses demonstrated that ECD transplants do not provide a lifetime of allograft function in recipients <50 years in the United States. These findings should encourage ECD transplantation in patients ≥60 years, demonstrate that rapid ECD transplantation is superior to delayed non-ECD transplantation, and challenge the policy in the United States of allowing patients <50 years to receive an ECD transplant.

  9. Bacterial contamination of allografts.

    PubMed

    Barrios, R H; Leyes, M; Amillo, S; Oteiza, C

    1994-01-01

    The risk of bacterial infection through allogenic bone transplantation is one of the major problems facing tissue banks. The purpose of this study is to report the contamination rate in 987 grafts obtained under strictly aseptic conditions, between 1989 and 1992. The grafts were stored at -80 degrees C (cortical bone and tendons) and -40 degrees C (cancellous bone). The overall contamination rate was 6.6%, with Gram-positive bacteria responsible for 80% of the positive cultures. We discuss the sources of contamination, the most frequently isolated bacteria and the steps in the donation and transplantation procedures that help to reduce the risk of contamination. We conclude that the methods of acquisition, processing and storage of tissues are effective in making sterile allografts available.

  10. Bacterial contamination of allografts.

    PubMed

    Barrios, R H; Leyes, M; Amillo, S; Oteiza, C

    1994-01-01

    The risk of bacterial infection through allogeneic bone transplantation is one of the problems facing tissue banks. The purpose of this study is to report the contamination rate in 987 grafts obtained under strictly aseptic conditions, between 1989 and 1992. The grafts were stored at -80 degrees C (cortical bone and tendons) and -40 degrees C (cancellous bone). The overall contamination rate was 6.6%, with Gram-positive bacteria responsible for 80% of the positive cultures. We discuss the sources of contamination, the most frequently isolated bacteria and the steps in the donation and transplantation procedures that help to reduce the risk of contamination. We conclude that the methods of procurement, processing and storage of tissues are effective in making sterile allografts available.

  11. Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

    PubMed Central

    Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C.; Khadayate, Sanjay; Mas, Valeria R.; Nitsch, Dorothea D.; Wang, Zhen; Norman, Jill T.; Wilcox, Christopher S.; Wheeler, David C.; Leiper, James

    2015-01-01

    Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule–specific Ddah1 knockout (Ddah1PT−/−) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT−/− mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. PMID:25855779

  12. High-Throughput Proteomic Approaches to the Elucidation of Potential Biomarkers of Chronic Allograft Injury (CAI)

    PubMed Central

    Cassidy, Hilary; Slyne, Jennifer; Frain, Helena; Slattery, Craig; Ryan, Michael P.; McMorrow, Tara

    2013-01-01

    This review focuses on the role of OMICs technologies, concentrating in particular on proteomics, in biomarker discovery in chronic allograft injury (CAI). CAI is the second most prevalent cause of allograft dysfunction and loss in the first decade post-transplantation, after death with functioning graft (DWFG). The term CAI, sometimes referred to as chronic allograft nephropathy (CAN), describes the deterioration of renal allograft function and structure as a result of immunological processes (chronic antibody-mediated rejection), and other non-immunological factors such as calcineurin inhibitor (CNI) induced nephrotoxicity, hypertension and infection. Current methods for assessing allograft function are costly, insensitive and invasive; traditional kidney function measurements such as serum creatinine and glomerular filtration rate (GFR) display poor predictive abilities, while the current “gold-standard” involving histological diagnosis with a renal biopsy presents its own inherent risks to the overall health of the allograft. As early as two years post-transplantation, protocol biopsies have shown more than 50% of allograft recipients have mild CAN; ten years post-transplantation more than 50% of the allograft recipients have progressed to severe CAN which is associated with diminishing graft function. Thus, there is a growing medical requirement for minimally invasive biomarkers capable of identifying the early stages of the disease which would allow for timely intervention. Proteomics involves the study of the expression, localization, function and interaction of the proteome. Proteomic technologies may be powerful tools used to identify novel biomarkers which would predict CAI in susceptible individuals. In this paper we will review the use of proteomics in the elucidation of novel predictive biomarkers of CAI in clinical, animal and in vitro studies. PMID:28250402

  13. A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

    PubMed Central

    Blish, Kimberly Rose; Wang, Wei; Willingham, Mark C.; Du, Wei; Birse, Charles E.; Krishnan, Surekha R.; Brown, Julie C.; Hawkins, Gregory A.; Garvin, A. Julian; D'Agostino, Ralph B.; Torti, Frank M.

    2008-01-01

    We analyzed expression of candidate genes encoding cell surface or secreted proteins in normal kidney and kidney cancer. This screen identified a bone morphogenetic protein (BMP) antagonist, SOSTDC1 (sclerostin domain–containing-1) as down-regulated in kidney tumors. To confirm screening results, we probed cDNA dot blots with SOSTDC1. The SOSTDC1 message was decreased in 20/20 kidney tumors compared with normal kidney tissue. Immunohistochemistry confirmed significant decrease of SOSTDC1 protein in clear cell renal carcinomas relative to normal proximal renal tubule cells (p < 0.001). Expression of SOSTDC1 was not decreased in papillary and chromophobe kidney tumors. SOSTDC1 was abundantly expressed in podocytes, distal tubules, and transitional epithelia of the normal kidney. Transfection experiments demonstrated that SOSTDC1 is secreted and binds to neighboring cells and/or the extracellular matrix. SOSTDC1 suppresses both BMP-7–induced phosphorylation of R-Smads-1, -5, and -8 and Wnt-3a signaling. Restoration of SOSTDC1 in renal clear carcinoma cells profoundly suppresses proliferation. Collectively, these results demonstrate that SOSTDC1 is expressed in the human kidney and decreased in renal clear cell carcinoma. Because SOSTDC1 suppresses proliferation of renal carcinoma cells, restoration of SOSTDC1 signaling may represent a novel target in treatment of renal clear cell carcinoma. PMID:18032587

  14. Magnetic resonance spectroscopy and chromatographic methods identify altered lipid composition in human renal neoplasms.

    PubMed

    Tosi, M R; Rodriguez-Estrada, M T; Lercker, G; Poerio, A; Trinchero, A; Reggiani, A; Tugnoli, V

    2004-07-01

    We report on the characterization of the lipid obtained from cortical and medullary normal human kidney tissue, benign renal neoplasms (oncocytoma) and 2 different types of malignant renal neoplasms (chromophobic cell carcinoma and clear cell carcinoma). The total lipid fractions were analyzed by 13C magnetic resonance spectroscopy and thin-layer chromatography, whereas the composition of the total fatty acids and the content of total cholesterol were determined by gas chromatography. alpha-Tocopherol was detected and quantified by high-performance liquid chromatography. The spectroscopic and chromatographic analysis revealed significant differences in the renal tissues examined. It was confirmed that cholesteryl esters (mainly oleate) are typical of clear cell renal carcinomas. Their potential role as prognostic and diagnostic factors is discussed, with particular emphasis on its capability to indicate the tumor diffusion in healthy renal parenchyma. alpha-Tocopherol is prevalent in clear cell carcinoma and it is present in nearly the same low amounts in cortex, medulla and chromophobic cell renal carcinoma. Q10 coenzyme and dolichols were detected by thin-layer chromatography and they are present in significant amounts in the cortex and the benign oncocytoma. Great variations were found in the distribution of saturated and unsaturated fatty acids, especially in the docosapentaenoic, docosahexaenoic and arachidonic acids and the corresponding omega-6/omega-3 fatty acids ratio.

  15. The role of HIF-1 in up-regulating MICA expression on human renal proximal tubular epithelial cells during hypoxia/reoxygenation

    PubMed Central

    2010-01-01

    Background Human major histocompatibility complex class I-related chain A (MICA) plays a dual role in adaptive and innate immune responses. Increasing evidence demonstrates that MICA is closely correlated with acute and chronic kidney allograft rejection. Therefore, understanding the activation mechanisms of MICA is important in kidney transplantation. We previously demonstrated that ischemia/reperfusion injury (IRI) could up-regulate MICA expression on mouse kidney allografts. Since hypoxia-inducible factor-1 (HIF-1) is the master regulator of cellular adaptive responses to hypoxia during IRI, here we investigate whether HIF-1 could up-regulate MICA expression and its influence on NK cell cytotoxicity. Results We find that HIF-1alpha plays an important role in up-regulating MICA expression, inducing IFNgamma secretion and NK cell cytotoxicity during hypoxia/reoxygenation. First, we generated a HIF-1alphaDELTAODD-expressing adenovirus to stably and functionally express HIF-1alpha in human renal proximal tubular epithelial (HK-2) cells under normoxia conditions. HIF-1alpha over-expression in HK-2 cells induces MICA expression and enhances NK cell cytotoxic activity towards cells that express HIF-1alpha. Second, we used a hypoxia/reoxygenation cell model to simulate IRI in vitro and found that the suppression of HIF-1alpha by RNAi induces down-regulation of MICA expression and inhibits NK cytotoxicity. In antibody blocking experiments, an anti-MICA mAb was able to down-regulate NK cell cytotoxic activity towards HK-2 cells that over-expressed HIF-1alpha. Moreover, when NK cells were co-cultured with the HK-2 cells expressing MICA, which was up-regulated by over-expression of HIF-1alpha, there was a significant increase in the secretion of IFNgamma. In the presence of the blocking MICA mAb, IFNgamma secretion was significantly decreased. Conclusions These results demonstrate that hypoxia/reoxygenation-promoted MICA expression on HK-2 cells is through a HIF-1 pathway

  16. Expression of a functional asialoglycoprotein receptor in human renal proximal tubular epithelial cells.

    PubMed

    Seow, Ying-ying T; Tan, Michelle G K; Woo, Keng Thye

    2002-07-01

    The asialoglycoprotein receptor (ASGPR) is a C lectin which binds and endocytoses serum glycoproteins. In humans, the ASGPR is shown mainly to occur in hepatocytes, but does occur extrahepatically in thyroid, in small and large intestines, and in the testis. In the kidney, there has been evidence both for and against its existence in mesangial cells. Standard light microscopy examination of renal tissue stained with an antibody against the ASGPR was performed. The mRNA expression for the ASGPR H1 and H2 subunits in primary human renal proximal tubular epithelial cells (RPTEC), in the human proximal tubular epithelial cell line HK2, and in human renal cortex was investigated using reverse-transcribed nested polymerase chain reaction. ASGPR protein expression as well as ligand binding and uptake were also examined using confocal microscopy and flow cytometry (fluorescence-activated cell sorting). Light microscopy of paraffin renal biopsy sections stained with a polyclonal antibody against the ASGPR showed proximal tubular epithelial cell staining of the cytoplasm and particularly in the basolateral region. Renal cortex and RPTEC specifically have mRNA for both H1 and H2 subunits of the ASGPR, but HK2 only expresses mRNA for H1. Using a monoclonal antibody, the presence of the ASGPR in RPTEC was shown by fluorescence-activated cell sorting and immunofluorescent staining. Specific binding and uptake of fluorescein isothiocyanate labelled asialofetuin which is a specific ASGPR ligand was also demonstrated in RPTEC. Primary renal proximal tubular epithelial cells have a functional ASGPR, consisting of the H1 and H2 subunits, that is capable of specific ligand binding and uptake. Copyright 2002 S. Karger AG, Basel

  17. A simple and accurate grading system for orthoiodohippurate renal scans in the assessment of post-transplant renal function

    SciTech Connect

    Zaki, S.K.; Bretan, P.N.; Go, R.T.; Rehm, P.K.; Streem, S.B.; Novick, A.C. )

    1990-06-01

    Orthoiodohippurate renal scanning has proved to be a reliable, noninvasive method for the evaluation and followup of renal allograft function. However, a standardized system for grading renal function with this test is not available. We propose a simple grading system to distinguish the different functional phases of hippurate scanning in renal transplant recipients. This grading system was studied in 138 patients who were evaluated 1 week after renal transplantation. There was a significant correlation between the isotope renographic functional grade and clinical correlates of allograft function such as the serum creatinine level (p = 0.0001), blood urea nitrogen level (p = 0.0001), urine output (p = 0.005) and need for hemodialysis (p = 0.007). We recommend this grading system as a simple and accurate method to interpret orthoiodohippurate renal scans in the evaluation and followup of renal allograft recipients.

  18. Effect of CTLA-4 gene polymorphisms on long-term kidney allograft function in Han Chinese recipients

    PubMed Central

    Guo, Fang

    2016-01-01

    Single nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte associated antigen-4 gene (CTLA-4) have been associated with graft rejection and long-term clinical outcome after organ transplantation. Our aim was to examine the association between CTLA-4 SNPs (rs733618, rs4553808, rs5742909, rs231775, rs3087243) and long-term allograft function in Chinese renal transplant recipients. Genotyping of CTLA-4 SNPs was performed in 292 renal transplantation recipients. To assess long-term allograft function, the estimated glomerular filtration rate (eGFR) was determined 1, 3, 6, 12, 24, 36, 48 and 60 months after renal transplantation. CTLA-4 rs733618 and rs3087243 alleles and genotypes as well as the rs5742909 and rs231775 genotypes were significantly associated with long-term allograft function after transplantation (P<0.05). Patients with favorable genotypes had higher allograft function during the 60 months after transplantation. The TACGG, CACAG and CGTAA haplotypes were also associated with long-term kidney function after renal transplantation (P<0.05 or P<0.01). In sum, the favorable CTLA-4 rs5742909TT genotype, CTLA-4 rs733618C and rs3087243A alleles, and CACAG and CGTAA haplotypes, as well as the unfavorable rs733618TT, rs3087243GG and rs231775GG genotypes and TACGG haplotype could potentially serve as effective indicators of long-term allograft function in Chinese renal transplantation recipients. PMID:27081086

  19. Reassortment of lymphocytes in lymph from normal and allografted sheep.

    PubMed Central

    Miller, H. R.; Adams, E. P.

    1977-01-01

    The distribution and nature of surface immunoglobulin-bearing (SIg) cells were studied in various sources of lymph from normal sheep and from sheep bearing renal autografts and renal allografts. In normal sheep, 12.2% +/- 1.5 of all mononuclear cells in peripheral lymph SIg and, of these, more than 50% were monocytes and macrophages. Less than 6% of the lymphocytes in peripheral lymph carried SIg. In contrast, 24.7% +/- 1.3 of the mononuclear cells in central lymph had SIg, and all of the labeled cells were lymphocytes. The frequencies of SIg cells in peripheral lymph issuing from renal autografts and from renal allografts were 6.7% +/- 1.3 and 6.9% +/- 0.8, respectively, and the labeled cells were predominantly lymphocytes. The proportion of SIg cells in central lymph from graft-bearing sheep was similar to that from normal sheep. The differences between central lymph and peripheral lymph from both normal and graft-bearing sheep are thought to reflect a restriction on the passage of SIg cells through capillary endothelium in nonlymphoid tissues. Images Figure 3 Figure 4 Figure 5 Figure 6 Figure 1 Figure 2 PMID:322506

  20. Assessment of renal function by the stable oxygen and hydrogen isotopes in human blood plasma.

    PubMed

    Kuo, Tai-Chih; Wang, Chung-Ho; Lin, Hsiu-Chen; Lin, Yuan-Hau; Lin, Matthew; Lin, Chun-Mao; Kuo, Hsien-Shou

    2012-01-01

    Water (H(2)O) is the most abundant and important molecule of life. Natural water contains small amount of heavy isotopes. Previously, few animal model studies have shown that the isotopic composition of body water could play important roles in physiology and pathophysiology. Here we study the stable isotopic ratios of hydrogen (δ(2)H) and oxygen (δ(18)O) in human blood plasma. The stable isotopic ratio is defined and determined by δ(sample) = [(R(sample)/R(STD))-1] * 1000, where R is the molar ratio of rare to abundant, for example, (18)O/(16)O. We observe that the δ(2)H and the δ(18)O in human blood plasma are associated with the human renal functions. The water isotope ratios of the δ(2)H and δ(18)O in human blood plasma of the control subjects are comparable to those of the diabetes subjects (with healthy kidney), but are statistically higher than those of the end stage renal disease subjects (p<0.001 for both ANOVA and Student's t-test). In addition, our data indicate the existence of the biological homeostasis of water isotopes in all subjects, except the end stage renal disease subjects under the haemodialysis treatment. Furthermore, the unexpected water contents (δ(2)H and δ(18)O) in blood plasma of body water may shed light on a novel assessment of renal functions.

  1. Assessment of Renal Function by the Stable Oxygen and Hydrogen Isotopes in Human Blood Plasma

    PubMed Central

    Kuo, Tai-Chih; Wang, Chung-Ho; Lin, Hsiu-Chen; Lin, Yuan-Hau; Lin, Matthew; Lin, Chun-Mao; Kuo, Hsien-Shou

    2012-01-01

    Water (H2O) is the most abundant and important molecule of life. Natural water contains small amount of heavy isotopes. Previously, few animal model studies have shown that the isotopic composition of body water could play important roles in physiology and pathophysiology. Here we study the stable isotopic ratios of hydrogen (δ2H) and oxygen (δ18O) in human blood plasma. The stable isotopic ratio is defined and determined by δsample = [(Rsample/RSTD)−1] * 1000, where R is the molar ratio of rare to abundant, for example, 18O/16O. We observe that the δ2H and the δ18O in human blood plasma are associated with the human renal functions. The water isotope ratios of the δ2H and δ18O in human blood plasma of the control subjects are comparable to those of the diabetes subjects (with healthy kidney), but are statistically higher than those of the end stage renal disease subjects (p<0.001 for both ANOVA and Student's t-test). In addition, our data indicate the existence of the biological homeostasis of water isotopes in all subjects, except the end stage renal disease subjects under the haemodialysis treatment. Furthermore, the unexpected water contents (δ2H and δ18O) in blood plasma of body water may shed light on a novel assessment of renal functions. PMID:22348150

  2. [Growth retardation in children with chronic renal disease].

    PubMed

    2014-01-01

    Despite recent advances in the management of children with chronic renal disease (CRD), growth retardation remains its most visible comorbid condition. Growth retardation has adverse impact on morbidity and mortality rates, quality of life and education, and in adult patients on job family life, and independent leaving accomodation. Pathophysiology of impaired growth in CRD is complex and still not fully understood. The following complications are: anorexia, malnutrition, inflammation, decreased residual renal function, dialysis frequency and adequacy, renal anemia, metabolic acidosis, fluid/electrolyte imbalance, renal osteodistrophy, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) resistance. Malnutrition is most frequent and most important factor contributing to the degree of growth retardation in infancy. The degree of renal dysfunction is the major determinant of variability in growth from third year of age until puberty onset, while in puberty hypergonadotropic hypogonadism has negative effect. The main factors that influence growth after renal transplantation are the age of the recipient and glucocorticoid drugs dosage with negative effect and allograft function with positive effect. In order to improve growth in children with CRD it is necessary to include: diet with optimal caloric intake, correction of fluid/ electrolyte imbalance, correction of acidosis, renal osteodistrophy and anemia. If growth velocity is insufficient to normalize growth, it is necessary to start recombinant human GH (rhGH) therapy at 0.05 mg/kg per day (0.35 mg/kg per week or 28 IU/m2 per week) administered by subcutaneous injection.

  3. Serum and urine biomarkers for human renal cell carcinoma.

    PubMed

    Pastore, A L; Palleschi, G; Silvestri, L; Moschese, D; Ricci, S; Petrozza, V; Carbone, A; Di Carlo, A

    2015-01-01

    Renal cell carcinoma (RCC) diagnosis is mostly achieved incidentally by imaging provided for unrelated clinical reasons. The surgical management of localized tumors has reported excellent results. The therapy of advanced RCC has evolved considerably over recent years with the widespread use of the so-called "targeted therapies." The identification of molecular markers in body fluids (e.g., sera and urine), which can be used for screening, diagnosis, follow-up, and monitoring of drug-based therapy in RCC patients, is one of the most ambitious challenges in oncologic research. Although there are some promising reports about potential biomarkers in sera, there is limited available data regarding urine markers for RCC. The following review reports some of the most promising biomarkers identified in the biological fluids of RCC patients.

  4. Formation of bobierrite (magnesium phosphate) crystal aggregates by bacteria from human urine and renal calculi.

    PubMed

    del Moral, A; Rivadeneyra, M A; Roldán, E; Perez-García, I; Ramos-Cormenzana, A; García-Cervigón, A

    1989-01-01

    The formation of extracellular crystal aggregates of bobierrite [Mg3(PO4)2.8H2O] by bacteria isolated from renal calculi and urine of urolithiasic patients is found with the use of B-17 and B-43 media. The crystal aggregates were observed in the colonies as deposits of brown-yellow coloration, and were identified by X-ray powder diffraction, chemical analysis and scanning electron microscopy. The production of bobierrite by bacteria from human urine and renal calculi implies further versatility of crystal formation by microorganisms, and it may be interesting to investigate the possible relationships between calculi precipitation and urinary infection.

  5. Sarcomatoid renal cell carcinoma with osteogenic differentiation and paraneoplastic hepatopathy in a dog, possibly related to human Stauffer's syndrome.

    PubMed

    Zini, E; Bovero, A; Nigrisoli, E; Ratto, A; Rampazzo, A; Zatelli, A

    2003-11-01

    Sarcomatoid renal cell carcinoma is an uncommon tumour in human beings, and osteogenic differentiation is a rare feature. This report describes such a case in a male dog aged 8 years. The tumour, which showed extensive osseous metaplasia and a few necrotic areas, protruded into the renal pelvis, disrupting the renal capsule. Light microscopical and immunohistochemical examination revealed the epithelial nature of the tumour. Abnormal liver biochemistry, mild hepatocyte degeneration and the absence of histological evidence of metastasis suggested a paraneoplastic hepatopathy.

  6. The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

    PubMed Central

    Eisner, Gilbert M.; Armando, Ines; Browning, Shaunagh; Pezzullo, John C.; Rhee, Lauren; Dajani, Mustafa; Carey, Robert M.; Jose, Pedro A.

    2016-01-01

    The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na+/day) and high (300 mmol Na+/day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D1-like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D1-like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions. PMID:25977313

  7. Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans.

    PubMed

    Drew, Rachel C; Blaha, Cheryl A; Herr, Michael D; Cui, Ruda; Sinoway, Lawrence I

    2017-06-01

    Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR - 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV - 0% trial = Δ -3.8 ± 1.1 cm/s, 70% trial = Δ -2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans. Copyright © 2017 the American Physiological Society.

  8. Tubular Overexpression of Gremlin Induces Renal Damage Susceptibility in Mice

    PubMed Central

    Droguett, Alejandra; Krall, Paola; Burgos, M. Eugenia; Valderrama, Graciela; Carpio, Daniel; Ardiles, Leopoldo; Rodriguez-Diez, Raquel; Kerr, Bredford; Walz, Katherina; Ruiz-Ortega, Marta; Egido, Jesus; Mezzano, Sergio

    2014-01-01

    A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This

  9. Tubular overexpression of gremlin induces renal damage susceptibility in mice.

    PubMed

    Droguett, Alejandra; Krall, Paola; Burgos, M Eugenia; Valderrama, Graciela; Carpio, Daniel; Ardiles, Leopoldo; Rodriguez-Diez, Raquel; Kerr, Bredford; Walz, Katherina; Ruiz-Ortega, Marta; Egido, Jesus; Mezzano, Sergio

    2014-01-01

    A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This

  10. Brown adipogenic potential of brown adipocytes and peri-renal adipocytes from human embryo

    PubMed Central

    Wu, Nan-Nan; Zhang, Chuan-Hai; Lee, Hyuek-Jong; Ma, Yan; Wang, Xin; Ma, Xiao-Juan; Ma, Wei; Zhao, Dong; Feng, Ying-Mei

    2016-01-01

    Both brown adipocytes (BAC) and beige cells hold therapeutic potential for the treatment of metabolic disorders. Unfortunately, the amount and activity of these cells are limited in adults. Although BAC marker expression has been shown in peri-renal adipose tissues in children and adults, functional assessment is lacking. Furthermore, it is entirely unknown whether adipose progenitors are present in human embryo and able to give rise to BAC in situ during evolution. Therefore, adipose tissues in the interscapular and peri-renal regions were dissected from human embryo and subcutaneous white adipose tissues (sWAT) were obtained from an adult. After subjected to differentiation in vitro, adipocyte progenitors were detected present in all these adipose tissues. When stimulated for adipogenesis, differentiated adipocytes in the intercapular and peri-renal regions showed similar features: (1) induced BAC and beige cell marker expression including UCP1 and PRDM16 and comparable mitochondrion copy number; (2) similar gene expression patterns by RNA-Seq analysis; and (3) similar maximal oxygen consumption rates examined by respirometry. Nevertheless, stimulation of adipocyte progenitors in sWAT induces neither BAC and beige cell marker expression nor any change of oxygen consumption. In conclusion, peri-renal adipocyte progenitors in human embryo hold browning potential for BAC production. PMID:27982067

  11. The human Bosniak model applied to a cat with renal cystadenoma. A classification to differentiate benign and malignant cystic renal masses via computed tomography and ultrasound.

    PubMed

    Baloi, P; Del Chicca, F; Ruetten, M; Gerber, B

    2015-01-01

    A 13-year-old domestic shorthair cat was presented with weight loss and azotemia. Abdominal ultrasound revealed a large cystic space- occupying lesion with multiple septae in the left kidney. A core needle biopsy yielded a renal cystadenoma originating from the epithelial cells. This report describes the clinical, ultrasonographic and computed tomographic features and the growth progression of a renal cystadenoma. We describe the first attempt to apply the human Bosniak classification to a cat with renal cystic neoplasia to differentiate between benign and malignant lesions. Cystadenoma should be a differential diagnosis in cases of renal cystic space-occupying lesions. Other differentials, imaging features to differentiate benign and malignant lesions and the risk of malignant transformation will be discussed.

  12. Osteochondral Allograft of the Talus

    PubMed Central

    Bisicchia, Salvatore; Rosso, Federica; Amendola, Annunziato

    2014-01-01

    Osteochondral lesions of the talus are being recognized as an increasingly common injury. They are most commonly located postero-medially or antero-laterally, while centrally located lesions are uncommon. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation (or similar methods) or osteochondral allograft transplantation. Allograft procedures have become popular due to inherent advantages over other resurfacing techniques. Cartilage viability is one of the most important factors for successful clinical outcomes after transplantation of osteochondral allografts and is related to storage length and intra-operative factors. While there is abundant literature about osteochondral allograft transplantation in the knee, there are few papers about this procedure in the talus. Failure of non-operative management, initial debridement, curettage or microfractures are an indication for resurfacing. Patients should have a functional ankle motion, closed growth plates, absence of cartilage lesions on the tibial side. This paper reviews the published literature about osteochondral allograft transplantation of the talus focusing on indications, pre-operative planning, surgical approaches, postoperative management, results and complications of this procedure. PMID:25328456

  13. IVIg Treatment Reduces Catalytic Antibody Titers of Renal Transplanted Patients

    PubMed Central

    Mahendra, Ankit; Peyron, Ivan; Dollinger, Cécile; Gilardin, Laurent; Sharma, Meenu; Wootla, Bharath; Padiolleau-Lefevre, Séverine; Friboulet, Alain; Boquet, Didier; Legendre, Christophe; Kaveri, Srinivas V.

    2013-01-01

    Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy. PMID:23967092

  14. Ochratoxin A induced premature senescence in human renal proximal tubular cells.

    PubMed

    Yang, Xuan; Liu, Sheng; Huang, Chuchu; Wang, Haomiao; Luo, Yunbo; Xu, Wentao; Huang, Kunlun

    2017-05-01

    Ochratoxin A (OTA) has many nephrotoxic effects and is a promising compound for the study of nephrotoxicity. Human renal proximal tubular cells (HKC) are an important model for the study of renal reabsorption, renal physiology and pathology. Since the induction of OTA in renal senescence is largely unknown, whether OTA can induce renal senescence, especially at a sublethal dose, and the mechanism of OTA toxicity remain unclear. In our study, a sublethal dose of OTA led to an enhanced senescent phenotype, β-galactosidase staining and senescence associated secretory phenotype (SASP). Cell cycle arrest and cell shape alternations also confirmed senescence. In addition, telomere analysis by RT-qPCR allowed us to classify OTA-induced senescence as a premature senescence. Western blot assays showed that the p53-p21 and the p16-pRB pathways and the ezrin-associated cell spreading changes were activated during the OTA-induced senescence of HKC. In conclusion, our results demonstrate that OTA promotes the senescence of HKC through the p53-p21 and p16-pRB pathways. The understanding of the mechanisms of OTA-induced senescence is critical in determining the role of OTA in cytotoxicity and its potential carcinogenicity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. 1H-NMR and 13C-NMR lipid profiles of human renal tissues.

    PubMed

    Tugnoli, V; Bottura, G; Fini, G; Reggiani, A; Tinti, A; Trinchero, A; Tosi, M R

    2003-01-01

    Lipids from human renal tissues are studied by means of (1)H- and (13)C-NMR spectroscopy. The total lipid fractions obtained from healthy kidneys, malignant renal cell carcinomas, and benign oncocytomas are characterized and analyzed to elucidate the main differences between the functional and neoplastic tissues. In all cases the lipid components are well identified. The healthy kidney is characterized by high amounts of triglycerides and the presence of cholesterol in its free form. On the contrary, renal cell carcinomas contain high amounts of cholesterol that are almost completely esterified as oleate, suggesting an intracellular localization of the cholesteryl esters synthesis. Cholesteryl esters are considered markers of renal cell carcinomas, thus supporting recent theories that these compounds play a leading role in cell proliferation. Oncocytomas are particularly rich in phosphatidylcholine and, analogous to the healthy kidney, are completely lacking in cholesteryl esters. Healthy kidneys and oncocytomas appear to have other similarities if compared with renal cell carcinomas: a very high fatty acyl/cholesterol ratio, the presence of dolichols, and a higher grade of unsaturation. The (13)C data suggest a new method for the direct evaluation of the saturated/unsaturated fatty acyl ratio.

  16. Renal involvement in antiphospholipid syndrome.

    PubMed

    Pons-Estel, Guillermo J; Cervera, Ricard

    2014-02-01

    Renal involvement can be a serious problem for patients with antiphospholipid syndrome (APS). However, this complication has been poorly recognized and studied. It can be present in patients who have either primary or systemic lupus erythematosus-associated APS. Clinical and laboratory features of renal involvement in APS include hypertension, hematuria, acute renal failure, and progressive chronic renal insufficiency with mild levels of proteinuria that can progress to nephrotic-range proteinuria. The main lesions are renal artery stenosis, venous renal thrombosis, and glomerular lesions (APS nephropathy) that may be acute (thrombotic microangiopathy) and/or chronic (arteriosclerosis, arterial fibrous intimal hyperplasia, tubular thyroidization, arteriolar occlusions, and focal cortical atrophy). APS can also cause end-stage renal disease and allograft vascular thrombosis. This article reviews the range of renal abnormalities associated with APS, and their diagnosis and treatment options.

  17. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders.

    PubMed

    Lazzeri, Elena; Ronconi, Elisa; Angelotti, Maria Lucia; Peired, Anna; Mazzinghi, Benedetta; Becherucci, Francesca; Conti, Sara; Sansavini, Giulia; Sisti, Alessandro; Ravaglia, Fiammetta; Lombardi, Duccio; Provenzano, Aldesia; Manonelles, Anna; Cruzado, Josep M; Giglio, Sabrina; Roperto, Rosa Maria; Materassi, Marco; Lasagni, Laura; Romagnani, Paola

    2015-08-01

    The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders.