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Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Alport syndrome is an inherited renal disease characterized by hematuria, renal failure, hearing loss and a lamellated glomerular basement membrane. Patients with Alport syndrome who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases., Methods: In this national case series, based in Beaumont Hospital Dublin, we studied the cohort of patients who underwent renal transplantation over the past 33 years, recorded prospectively in the Irish Renal Transplant Registry, and categorized them according to the presence or absence of Alport syndrome. The main outcomes assessed were patient and renal allograft survival., Results: Fifty-one patients diagnosed with Alport syndrome in Beaumont Hospital received 62 transplants between 1982 and 2014. The comparison group of non-Alport patients comprised 3430 patients for 3865 transplants. Twenty-year Alport patient survival rate was 70.2%, compared to 44.8% for patients with other renal diseases (p = .01). Factors associated with patient survival included younger age at transplantation as well as differences in recipient sex, donor age, cold ischemia time, and episodes of acute rejection. Twenty-year graft survival was 46.8% for patients with Alport syndrome compared to 30.2% for those with non-Alport disease (p = .11)., Conclusions: Adjusting for baseline differences between the groups, patients with end-stage kidney disease (ESKD) due to Alport syndrome have similar patient and graft survival to those with other causes of ESKD. This indicates that early diagnosis and management can lead to favorable outcomes for this patient cohort.

Aims: The purpose of this study is to investigate tacrolimus trough-level variability from 3 to 12 months following transplantation and its association with allograft survival in renal transplant recipients., Materials and Methods: In this observational cohort study, tacrolimus trough-level variability was used as the predictor of all-cause allograft failure (defined as return to dialysis) and patient survival (all-cause mortality)., Results: In total, 394 transplants were included in the analysis. Sixty-two transplants failed during the study. Tacrolimus trough-level variability across quartile groups were: Q1 median variability 12.5 %, range 4.76-15.71 % (n = 99), Q2 median variability 18.17 %, range 15.74-21.29 % (n = 96), Q3 median variability 24.63 % range 21.42-28.88 % (n = 100), Q4 median variability 36.91 %, range 28.91-81.9 % (n = 99). Higher tacrolimus trough-level variability was associated with inferior allograft survival in univariate models [hazard ratio per quartile increase (HR), 1.46, 95 % CI 1.16-1.83, p value = 0.001] and multivariate models (HR 1.36, 95 % CI 1.05-1.78, p value = 0.019). Higher tacrolimus trough-level variability was not associated with patient survival; univariate model (HR 1.25, 95 % CI 0.90-1.74, p value = 0.17), multivariate model (HR 1.25, 95 % CI 0.86-1.83, p value = 0.23)., Conclusions: Inferior renal allograft survival was observed in recipients with higher variability in tacrolimus trough-levels.

Purpose: Chronic allograft nephropathy (CAN) is widely accepted as the leading cause of renal allograft loss after the first year post transplantation. This study aimed to identify urinary biomarkers that could predict CAN in transplant patients., Experimental Design: The study included 34 renal transplant patients with histologically proven CAN and 36 renal transplant patients with normal renal function. OrbiTrap MS was utilized to analysis a urinary fraction in order to identify other members of a previously identified biomarker tree . This novel biomarker pattern offers the potential to distinguish between transplant recipients with CAN and those with normal renal function., Results: The primary node of the biomarker pattern was reconfirmed as β2 microglobulin. Three other members of this biomarker pattern were identified: neutrophil gelatinase-associated lipocalin, clusterin, and kidney injury biomarker 1. Significantly higher urinary concentrations of these proteins were found in patients with CAN compared to those with normal kidney function., Conclusions and Clinical Relevance: While further validation in a larger more-diverse patient population is required to determine if this biomarker pattern provides a potential means of diagnosing CAN by noninvasive methods in a clinical setting, this study clearly demonstrates the biomarkers' ability to stratify patients based on transplant function., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: Long-term survival of renal allografts has improved over the last 20 years. However, less is known about current expectations for long-term allograft function as determined by estimated glomerular filtration rate (eGFR). The aim of this study was to investigate factors which affect graft function at 5 years' post-renal transplantation. The statistically significant factors were then used to construct a predictive model for expected eGFR at five years' post-transplant., Methods: We retrospectively reviewed all adult patients who received a renal transplant in the Republic of Ireland between 1990 and 2004. Data collected included era of transplantation (1990-1994, 1995-1999, 2000-2004), donor and recipient age and gender, number of human leucocyte antigen mismatches, cold ischemia time (CIT), number of prior renal transplants, immunosuppressive regimen used and acute rejection episodes. Estimated GFR was calculated at 5 years after transplantation from patient data using the Modified Diet in Renal Disease (MDRD) equation. Consecutive sampling was used to divide the study population into two equal unbiased groups of 489 patients. The first group (derivation cohort) was used to construct a predictive model for eGFR five years' post-transplantation, the second (validation cohort) to test this model., Results: Nine hundred and seventy eight patients were analyzed. The median age at transplantation was 43 years (range 18-78) and 620 (63.4%) were male. One hundred and seventy five patients (17.9%) had received a prior renal transplant. Improved eGFR at five years' post-transplantation was associated with tacrolimus-based combination immunosuppression, younger donor age, male recipient, absence of cytomegalovirus disease and absence of acute rejection episodes as independently significant factors (p < 0.05). The predictive model developed using these factors showed good correlation between predicted and actual median eGFR at five years. The model explained 20% of eGFR variability. The validation model findings were consistent with the derivation model (21% variability of eGFR explained by model using same covariates on new data)., Conclusion: The predictive model we have developed shows good correlation between predicted and actual median eGFR at five years' post-transplant. Applications of this model include comparison of current and future therapy options such as new immunosuppressive regimens.

Kidney transplantation has become the preferred method of renal replacement. However, the rate of long term allograft survival has not changed over the last decade. Donor and recipient genetic interplay influences kidney transplant outcome but our knowledge of these complex interactions is limited. Until recently, investigations have been limited to small candidate gene studies, usually restricted to allograft recipients. Genome-wide association studies have been slow to emerge in transplantation but the first has recently been reported and will be reviewed here. Much larger studies involving donor and recipients pairs are ongoing. We are now entering the era of epigenetics and whole genome sequencing which will hopefully provide a more in-depth knowledge of the genetic influences on renal transplant outcome. This may lead to a more accurate assessment of post-transplant risk, potentially allowing for the development of risk predication models leading to a more personalized approach to kidney transplant care. In this article, we examine the current and emerging literature in the field and discuss the limitations of current studies and technologies.

Background: We examined, through genome-wide association studies (GWAS), the correlation between recipient genetic variation and renal function at five yr., Methods: Our cohort contained 326 Irish, first time, kidney-only, deceased donor, transplant recipients on calcineurin inhibitors (263 had a functioning graft at five yr) between 1993 and 2002. Outcomes were creatinine at five yr and long-term graft function., Results: Two variants were identified showing borderline genome-wide significance - one on chromosome 18 (p = 4.048e-08, rs6565887) and another on chromosome 14 (p = 7.631e-08, rs3811321). Individually, the two SNPs explained up to 8.8% and 11.29% of five-yr creatinine variance, respectively, while together they explained up to 17.4% of trait variance. Both variants were predictors of long-term allograft function (p = 0.004, 70% vs 30% survival at 10 yr). The chromosome 14 variant is located in the intergenic region of the T-Cell Receptor Alpha locus., Conclusions: Using a genome-wide approach, we have identified two associations with five-yr creatinine levels in renal transplant recipients treated with calcineurin inhibitors. Independent replication is now warranted to clarify the clinical significance of these results., (© 2013 John Wiley & Sons A/S.)

Early transplant failure is a devastating outcome after kidney transplantation. We report the causes and consequences of deceased donor renal transplant failure in the first 30 d at our center between January 1990 and December 2009. Controls were adult deceased donor transplant patients in the same period with an allograft that functioned >30 d. The incidence of early graft failure in our series of 2381 consecutive deceased donor transplants was 4.6% (n = 109). The causes of failure were allograft thrombosis (n = 48; 44%), acute rejection (n = 19; 17.4%), death with a functioning allograft (n = 17; 15.6%), primary non-function (n = 14;12.8%), and other causes (n = 11; 10.1%). Mean time to allograft failure was 7.3 d. There has been a decreased incidence of all-cause early failure from 7% in 1990 to <1% in 2009. Patients who developed early failure had longer cold ischemia times when compared with patients with allografts lasting >30 d (p < 0.001). Early allograft failure was strongly associated with reduced patient survival (p < 0.001). In conclusion, early renal allograft failure is associated with a survival disadvantage, but has thankfully become less common in recent years.

It is recognized that cytomegalovirus (CMV) infection in transplant recipients may lead to graft loss. Prophylaxis with acyclovir has therefore gained widespread acceptance, but the debate on whether this intervention improves long term graft survival continues. All patients who received renal grafts at the National Renal Transplant Centre, Dublin, between January 1992 and December 1999 were retrospectively analyzed. During this time period, patients who were CMV positive and/or had received grafts from CMV-positive donors were administered prophylactic oral acyclovir 800 mg thrice daily, adjusted for calculated creatinine clearance, from the first day post-transplantation. This treatment was continued for three months unless the graft failed or the patient developed CMV disease or died. Graft and patient outcomes were compared in recipients who received acyclovir with those who did not. Over the study period, 935 patients received renal transplants in our center, of whom 487 were administered acyclovir. The incidence of CMV disease was 3.3 cases per 100 patients per annum in those who required prophylaxis. Despite prophylaxis, graft outcomes were found to be significantly worse (p value < 0.001) in the group that qualified for acyclovir. We conclude that acyclovir provides incomplete protection from the negative impact of CMV on graft survival.

Accelerated acute humoral rejection (AHR) continues to occur in renal transplantation despite improved crossmatching, with potentially devastating consequences. Between 1 June 1998 and 31 December 2000, 440 renal transplants were performed in our center. AHR was diagnosed by the demonstration of typical pathological features on renal histology and positive direct immunofluorescence or detection of anti-HLA antibodies in serum. AHR developed in 20 (4.5%) of our renal transplant recipients, nine male and eleven female at an average of 16.3 days post transplantation. All of these patients had a negative current cytotoxic crossmatch prior to transplantation. The median serum creatinine at diagnosis was 5.96 mg/dL, and 83% of these individuals developed oliguric renal failure requiring dialysis after having initially attained good graft function (median of best serum creatinine before AHR was 2.64 mg/dL). The 18 recipients who had not infarcted their grafts at the time of diagnosis of AHR received plasmapheresis in conjunction with intensification of their immunosuppressive regimen. This regimen was successful in reversing AHR in 78% of those treated with apheresis. In the 14 responders, graft survival at 6 months was 100% and at 12 months was 91%. Median serum creatinine at 6 and 12 months was 1.26 and 1.33 mg/dL, respectively. Patients received an average of 8.1 plasma exchanges. However, responders received a significantly higher frequency of plasmapheresis (P =.0053), despite undergoing a similar number of exchanges overall. Plasmapheresis appears to be an effective modality for reversing AHR and maintaining graft function., (Copyright 2003 Wiley-Liss, Inc.)

ABSTRACT: Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis. [ABSTRACT FROM AUTHOR]