Association between transplant glomerulopathy and graft outcomes following kidney transplantation: A meta-analysis.
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ABSTRACT:
SUBMITTER: Kovacs G
PROVIDER: S-EPMC7188300 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Association between transplant glomerulopathy and graft outcomes following kidney transplantation: A meta-analysis.
Kovács Gábor G Devercelli Giovanna G Zelei Tamás T Hirji Ishan I Vokó Zoltán Z Keown Paul A PA
PloS one 20200428 4
Transplant glomerulopathy (TG), a morphological lesion associated with confluent mechanisms of endothelial injury of renal allografts, may provide a viable predictor of graft failure. This systematic literature review and meta-analysis were performed according to the PRISMA statement to examine evidence describing the association between TG and graft loss or failure and time to these events. The literature review was conducted using the Scopus, EBSCO, and Cochrane Library search engines. Hazard ...[more]
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Project description:BACKGROUND:Serum uric acid (UA) level has been reported to be associated with chronic allograft nephropathy and graft failure in patients who undergo kidney transplantation (KT). However, the role of serum UA level in renal graft survival remains controversial. OBJECTIVE:This study aimed to investigate the effect of mean serum UA level during two different post-KT periods on long-term renal graft outcomes in a large population cohort in which living donor KT prevails. MATERIAL AND METHODS:A retrospective cohort study was performed using KT data prospectively collected at a single institution. Patients (n = 2,993) were divided into low-, normal-, and high-UA groups according to the mean serum UA level within the first year (1-YR) and 1-5 years (5-YR) after transplantation. RESULTS:In the 1-YR Cox proportional hazards analysis, the low- and high-UA groups had a significantly decreased and increased risk, respectively, for overall graft failure (OGF), death-censored graft failure (DCGF), and composite event (return to dialysis, retransplantation, death from graft dysfunction, and 40% decline in estimated glomerular filtration rate) compared with the normal-UA group. Similarly, in the 5-YR analysis, the low-UA group had a significantly reduced risk of DCGF compared with the normal-UA group, whereas the high-UA group had a significantly increased risk of all three graft outcomes. In a marginal structural model, hyperuricemia had a significant causal effect on worsening graft outcomes, with consideration of all confounding variables (OGF: hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.33-3.78; DCGF: HR 2.38, 95% CI 1.09-4.9; composite event: HR 3.05, 95% CI 1.64-5.49). CONCLUSIONS:A low-to-normal serum UA level within the first year and 1-5 years after KT is an independent factor for better renal allograft outcomes in the long-term follow-up period rather than high serum UA level.
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Project description:Transplant glomerulopathy develops through multiple mechanisms, including donor-specific antibodies, T cells and innate immunity. This study investigates circulating small RNA profiles in serum samples of kidney transplant recipients with biopsy-proven transplant glomerulopathy. Among total small RNA population, miRNAs were the most abundant species in the serum of kidney transplant patients. In addition, fragments arising from mature tRNA and rRNA were detected. Most of the tRNA fragments were generated from 5' ends of mature tRNA and mainly from two parental tRNAs: tRNA-Gly and tRNA-Glu. Moreover, transplant patients with transplant glomerulopathy displayed a novel tRNA fragments signature. Gene expression analysis from allograft tissues demonstrated changes in canonical pathways related to immune activation such as iCos-iCosL signaling pathway in T helper cells, Th1 and Th2 activation pathway, and dendritic cell maturation. mRNA targets of down-regulated miRNAs such as miR-1224-5p, miR-4508, miR-320, miR-378a from serum were globally upregulated in tissue. Integration of serum miRNA profiles with tissue gene expression showed that changes in serum miRNAs support the role of T-cell mediated mechanisms in ongoing allograft injury.
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Project description:Interleukin-10 (IL-10) is an important immunomodulatory cytokine. Several studies focused the association between IL-10 promoter gene polymorphisms and graft rejection risk in kidney transplantation recipients. However, the results of these studies remain inconclusive. The aim of this study was to conduct a meta-analysis to further assess the associations.The PubMed, Embase, and Ovid Medline databases were searched. Two independent authors extracted data, and the effects were estimated from an odds ratio (OR) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses identified sources of heterogeneity.A total of 16 studies including 595 rejection patients and 1239 stable graft patients were included in order to study the IL-10 -1082 (rs1800896 G/A), -819 (rs1800871 C/T), -592 (rs1800872 C/A) and IL-10 (-1082,-819,-592) polymorphisms. The -1082 G/A polymorphism was not associated with an increased graft rejection risk (OR = 1.03; 95%CI, 0.85-1.25, P = 0.74 for GA+AA vs. GG model). Moreover, all of the -819 C/T (OR = 1.06, 95%CI, 0.79-1.42, P = 0.70 for TA+TT vs. CC model), -592 C/A (OR = 1.10, 95% CI, 0.85-1.42, P = 0.47 for AC+AA vs. CC model) and IL-10 (-1082,-819,-592) polymorphisms (OR = 1.00, 95%CI, 0.79-1.27, P = 0.98 for I+L vs. H model) did not increase the graft rejection risk. In addition, we also performed subgroup analysis by ethnic group (mainly in Europeans or Asians) and rejection type (acute or chronic). There was also lack of evidence of a significant association between the IL-10 gene polymorphism and graft rejection risk. The present meta-analysis indicated that the IL-10 gene polymorphism was not associated with graft rejection risk in kidney transplantation recipients.This meta-analysis found evidence that the IL-10 polymorphism does not increase the risk of graft rejection in kidney transplantation recipients. Further chronic rejection and other ethnic population studies are needed to confirm our results.
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Project description:IntroductionIt is critical to identify kidney transplant recipients (KTRs) at higher risk for adverse outcomes, to focus on monitoring and interventions to improve outcomes. We examined the associations between graft function variability and long-term outcomes in KTRs in an observational study.MethodsWe identified 2919 KTRs in the Wisconsin Allograft Recipient Database (WisARD) who had a functioning allograft 2 years posttransplantation and at least 3 outpatient measurements of estimated glomerular filtration rate (eGFR) from 1 to 2 years posttransplantation. Graft function slope was calculated from a linear regression of eGFR, and variability was defined as the coefficient of variation around this regression line. Associations of eGFR variability and slope with death, graft failure, cardiovascular events, and acute rejection were estimated.ResultsCompared to the lowest quartile, the highest quartile of eGFR variability was associated with a higher risk of death (adjusted hazard ratio [HR] = 1.85; 95% CI = 1.23-2.76), but not with a higher risk of graft failure (subhazard ratio = 1.16; 95% CI = 0.85-1.58), independent of eGFR and slope of eGFR. Greater eGFR variability was associated with higher risk of cardiovascular- and infection-related death and cardiovascular events but not malignancy-related death or allograft rejection. Including variability of eGFR significantly improved prediction of mortality but not prediction of graft failure.ConclusionVariability of eGFR is independently associated with risk of death, especially cardiovascular disease-related death and cardiovascular events, but not graft failure. Variability of eGFR may help identify KTRs at higher risk for death and cardiovascular events.
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Project description:Ischemia-reperfusion injury (IRI) leading to delayed graft function (DGF), defined by the United Network for Organ Sharing as dialysis in the first week (UNOS-DGF), associates with poor kidney transplant outcomes. Controversies remain, however, about dialysis initiation thresholds and the utility for other criteria to denote less severe IRI, or slow graft function (SGF).Multicenter, prospective study of deceased-donor kidney recipients to compare UNOS-DGF to a definition that combines impaired creatinine reduction in the first 48 hours or greater than 1 dialysis session for predicting 12-month estimated glomerular filtration rate (eGFR). We also assessed 10 creatinine and urine output-based SGF definitions relative to 12-month eGFR.In 560 recipients, 215 (38%) had UNOS-DGF, 330 (59%) met the combined definition, 14 (3%) died, and 23 (4%) had death-censored graft failure by 12 months. Both DGF definitions were associated with lower adjusted 12-month eGFR (95% confidence interval)-by 7.3 (3.6-10.9) and 7.4 (3.8-11.0) mL/min per 1.73 m, respectively. Adjusted relative risks for 12-month eGFR less than 30 mL/min per 1.73 m were 1.9 (1.2-3.1) and 2.1 (1.1-3.7), with unadjusted areas under the curve of 0.618 and 0.627, respectively. For SGF definitions, postoperative day (POD) 7 creatinine had the strongest association with 12-month eGFR, and POD5 creatinine and creatinine reduction between POD1 and POD2 demonstrated modest separations in 12-month eGFR.Although UNOS-DGF does not adequately predict 12-month function on its own, our findings do not support changing the definition. Postoperative day 7 creatinine is correlated with 12-month eGFR, but large translational studies are needed to understand the biological link between IRI severity at transplant and longer-term outcomes.
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Project description:Uromodulin and microRNAs (miRNAs) have recently been investigated as potential biomarkers for kidney graft associated pathology and outcome, with a special focus on biomarkers indicating specific disease processes and kidney graft survival. The study's aim was to determine whether expression of serum uromodulin concentration and selected miRNAs might be related to renal function in kidney transplant recipients (KTRs). The uromodulin concentration and expression of six selected miRNAs (miR-29c, miR-126, miR-146a, miR-150, miR-155, and miR-223) were determined in the serum of 100 KTRs with stable graft function and chronic kidney disease of all five stages. Kidney graft function was estimated with routine parameters (creatinine, urea, cystatin C, and Chronic Kidney Disease Epidemiology Collaboration study equations) and precisely measured using chromium-51 labelled ethylenediaminetetraacetic-acid clearance. The selected miRNAs were shown to be independent of kidney graft function, indicating their potential as biomarkers of associated kidney graft disease processes. In contrast, the serum uromodulin level depended entirely on kidney graft function and thus reflected functioning tubules rather than any specific kidney graft injury. However, decreased concentrations of serum uromodulin can be observed in the early course of tubulointerstitial injury, thereby suggesting its useful role as an accurate, noninvasive biomarker of early (subclinical) kidney graft injury.
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Project description:BackgroundPost-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic nephropathy (DN) occurrence in transplanted kidneys is poorly investigated. Current knowledge describes DN recurrence in graft 5.9?years from kidney transplantation however there is little data about PTDM and DN. Here, we report a clinical case peculiar for an early appearance of advanced glomerular diabetic lesions, after kidney transplantation.Case presentationA 45-year-old Caucasian male affected by autosomal polycystic kidney disease was transplanted with a cadaveric-kidney-donor from 58-year-old male. Induction immunosuppressive therapy included basiliximab and steroids while the maintenance treatment included, tacrolimus, mofetil micophenolate and methylprednisolone. One month after transplantation the patient developed diabetes requiring treatment with repaglinide quickly replaced with insulin to obtain an acceptable glycemic control (HbA1c 52?mmol/mol). Glycosuria was detected persistently during the first six months after transplantation. To achieve further improvement in glycemic control, a shift from tacrolimus to cyclosporine (CyA) was made and steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors toxicity, which was revealed in the 1-year-protocol-biopsy, everolimus was introduced thereby lowering CyA through levels. Moderate hypertension was well controlled with doxazosin. Thirty months after transplantation a second graft biopsy was performed owing to renal function decline and microalbuminuria appearance. Histological analysis surprisingly showed mesangiolysis and microaneurysms; glomerular sclero-hyalinosis and basal membrane thickness and typical nodular glomerulosclerosis. C4d staining was negative and no evidence of immune deposits were detected. Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative. Retrospective analysis on donor history didn't show diabetes or insulin resistance and no diabetic lesions were found in kidney pre-implant biopsy.ConclusionsIn our knowledge, this is the first report describing a very early onset of advanced diabetic glomerular lesions in a graft biopsy after PTDM. We hypothesize that additional factors such as everolimus and hypertension, may have contribute to kidney damage.
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Project description:Background:Calcineurin inhibitors (CNI; cyclosporine, tacrolimus) are critical for kidney transplant immunosuppression, but have multiple potential drug interactions, such as with macrolide antibiotics. Macrolide antibiotics (clarithromycin, erythromycin, and azithromycin) are often used to treat atypical infections. Clarithromycin and erythromycin inhibit CNI metabolism and increase the risk of CNI nephrotoxicity, while azithromycin does not. Objective:To determine the frequency of CNI-macrolide co-prescriptions, the proportion who receive post-prescription monitoring, and the risk of adverse drug events in kidney transplant recipients. Design:Retrospective cohort study. Setting:We used linked health care databases in Alberta, Canada. Patients:We included 293 adult kidney transplant recipients from 2008-2015 who were co-prescribed a CNI and macrolide. Measurements:The primary outcome was a composite of all-cause hospitalization, acute kidney injury (creatinine increase ?0.3 mg/dL or 1.5 times baseline), or death within 30 days of the macrolide prescription. Methods:We identified CNI-macrolide co-prescriptions and compared outcomes in those who received clarithromycin/erythromycin versus azithromycin. We used a linear mixed-effects model to examine the mean change in serum creatinine and estimated glomerular filtration rate (eGFR). Results:Of the 293 recipients who were co-prescribed a CNI and a macrolide, 38% (n = 112) were prescribed clarithromycin/erythromycin while 62% (n = 181) were prescribed azithromycin. Compared with azithromycin users, clarithromycin/erythromycin users were less likely to have outpatient serum creatinine monitoring post-prescription (56% vs 69%, P = .03). There was no significant difference in the primary outcome between the 2 groups (17% vs 11%, P = .11); however, the risk of all-cause hospitalization was higher in the clarithromycin/erythromycin group (10% vs 3%, P = .02). The mean decrement in eGFR was significantly greater in the clarithromycin/erythromycin versus azithromycin group (-5.4 vs -1.9 mL/min/1.73 m2, P < .05). Limitations:We did not have CNI levels to correlate with the timing of CNI-macrolide co-prescriptions. We also did not have information regarding the indications for macrolide prescriptions. Conclusion:Clarithromycin and erythromycin were frequently co-prescribed in kidney transplant recipients on CNIs despite known drug interactions. Clarithromycin/erythromycin use was associated with a higher risk of hospitalization compared with azithromycin users. Safer prescribing practices in kidney transplant recipients are warranted.
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Project description:ImportanceIn the United States, substantial disparities in access to kidney transplant exist for wait-listed candidates with end-stage renal disease. The implications of transplant centers' willingness to accept kidney offers for access to transplant and mortality outcomes are unknown.ObjectiveTo determine the outcomes for wait-listed kidney transplant candidates after the transplant center's refusal of a deceased donor kidney offer.Design, setting, and participantsThis cohort study obtained data from the United Network for Organ Sharing Potential Transplant Recipient data set on all deceased donor kidney offers in the United States made between January 1, 2008, and December 31, 2015. The final study cohort included adult patients who were wait-listed for kidney transplant and received at least 1 allograft offer during the study period (N?=?280?041). Data analysis was conducted from June 1, 2018, to March 30, 2019.ExposureCandidate state of residence.Main outcomes and measuresWaiting list outcome event groups included received deceased donor allograft, received living donor allograft, died while on the waiting list, removed from the waiting list without a transplant, or still on the waiting list at the end of follow-up.ResultsAmong the 280?041 kidney transplant candidates included in the study, the mean (SD) age at wait-listing was 51.1 (13.1) years, and male patients were predominant (171 517 [61.2%]). In this cohort, 81 750 candidates (29.2%) received a deceased donor kidney allograft, 30 870 (11.0%) received a living donor allograft, 25 967 (9.3%) died while on the waiting list, and 59 359 (21.2%) were removed from the waiting list. Overall, 10 candidates with at least 1 previous allograft offer died each day during the study period. Time to first offer was similar for candidates who received deceased donor kidney allograft compared with those who died while waiting (median [interquartile range {IQR}] time, 79 [16-426] days vs 78 [17-401] days, respectively). Deceased donor allograft recipients had a median of 17 offers (IQR, 6-44) over 422 days (IQR, 106-909 days), whereas candidates who died while waiting received a median of 16 offers (IQR, 6-41) over 651 days (IQR, 304-1117 days). Most kidneys (84%) were declined on behalf of at least 1 candidate before being accepted for transplant. As reported by centers, organ or donor quality concerns accounted for 8 416 474 (92.6%) of all declined offers, whereas offers were infrequently refused because of patient-related factors (232 193 [2.6%]), logistical limitations (49 492 [0.5%]), or other concerns. The odds of death after an offer and the median number of offers received prior to death varied considerably by state.Conclusions and relevanceThis study found that transplant candidates appeared to receive a large number of viable deceased donor kidney offers that were refused on their behalf by transplant centers, potentially exacerbating the detrimental consequences of the organ shortage; increased transparency in organ allocation process and decisions may improve patient-centered care and access to kidney transplant.
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Project description:INTRODUCTION:Certain ABO blood types have been linked to cardiovascular disease, infection and cancers. The effect of recipient ABO blood group on patient and graft survival has not been studied in ABO-matched kidney transplantation. This study aims to determine the association between kidney transplant recipient ABO blood groups with patient and graft survival in Australian and New Zealand. METHODS:All Australian and New Zealand transplant recipients who received ABO-compatible primary kidney transplants between 1995-2016 were analysed using a de-identified dataset from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Primary analysis was undertaken of recipient ABO blood group O versus non-O blood groups. The primary outcome was patient survival post kidney transplantation and the secondary outcome was death censored graft survival. Recipient age at first transplant, gender, ethnicity, body mass index, smoking status, vascular disease, presence of diabetes mellitus, chronic lung disease, primary kidney disease, donor source, donor age and gender, and era of transplants were included in the multivariate model as confounders. RESULTS AND CONCLUSIONS:On analysis of 15,523 kidney transplant recipients, blood group O was not associated with patient survival (hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.89-1.04) nor death censored graft survival (HR 0.97, 95% CI 0.89-1.05) compared to non-blood group O recipients. Competing risks analyses showed an increased risk of cancer-related mortality in blood group O recipients on univariate analyses (HR 1.18, 95% CI 1.01-1.37) however, this became insignificant on multivariate analyses. On secondary analyses, recipient blood group AB (4.11% participants) was associated with inferior death censored graft survival compared to those with blood group O (HR 1.24, 95% CI 1.02-1.50). Although recipient ABO blood groups were not associated with patient nor graft survival, differences in cause-specific mortality between individual blood groups cannot be excluded based on current analyses.
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