Deterioration Of Kidney Allograft Function Research Articles

PIRCHE-II scores prove useful as a predictive biomarker among kidney transplant recipients with rejection: An analysis of indication and follow-up biopsies.

BackgroundIndication biopsies for deterioration of kidney allograft function often require follow-up biopsies to assess treatment response or lack of improvement. Immune-mediated injury, namely borderline rejection (BLR), T-cell mediated rejection (TCMR), or antibody-mediated rejection (ABMR), results from preformed or de novo alloreactivity due to donor and recipient HLA-mismatches. The impact of HLA-mismatches on alloreactivity is determined by highly immunogenic HLA-epitopes.MethodsWe analyzed 123 kidney transplant recipients (KTRs) from 2009 to 2019 who underwent a first indication and a follow-up biopsy. KTRs were divided into three groups according to the first biopsy: No rejection (NR)/BLR (n=68); TCMR (n=21); ABMR (n=34). The HLA-derived epitope-mismatches were calculated using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm.ResultsGroup NR/BLR: KTRs with higher total PIRCHE-II scores were more likely to develop TCMR in the follow-up biopsy (p=0.031). Interestingly, these differences were significant for both HLA-class I- (p=0.017) and HLA-class II-derived (p=0.017) PIRCHE-II scores. Group TCMR: KTRs with ongoing TCMR in the follow-up biopsy were more likely to show higher total PIRCHE-II scores (median 101.50 vs. 74.00). Group ABMR: KTRs with higher total PIRCHE-II scores were more likely to show an increase in the microvascular inflammation score in the follow-up biopsy. This difference was more pronounced for the HLA-class II-derived PIRCHE-II scores (median 70.00 vs. 31.76; p=0.086).ConclusionsPIRCHE-II scores may prove useful as a biomarker to predict the histopathological changes of immune-related injury from a first indication to a follow-up biopsy. This immunological risk stratification may contribute to individualized treatment strategies.

Risk Prediction for Delayed Allograft Function: Analysis of the Deterioration of Kidney Allograft Function (DeKAF) Study Data.

Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population but not individual risk. We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF = 20.4%) and investigated potential improvements. We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable with that reported by Irish et al. For cohorts excluded by Irish: (a) in pump-perfused kidneys, the IC overestimated DGF risk; (b) in simultaneous pancreas kidney transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF-excluding those with single dialysis in the first 24 h posttransplant-we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC-predicted risk. The IC can be a useful population guide for predicting DGF in the population for which it was intended but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease.

Complement Components in the Diagnosis and Treatment after Kidney Transplantation-Is There a Missing Link?

Currently, kidney transplantation is widely accepted as the renal replacement therapy allowing for the best quality of life and longest survival of patients developing end-stage renal disease. However, chronic transplant rejection, recurrence of previous kidney disease or newly acquired conditions, or immunosuppressive drug toxicity often lead to a deterioration of kidney allograft function over time. Complement components play an important role in the pathogenesis of kidney allograft impairment. Most studies on the role of complement in kidney graft function focus on humoral rejection; however, complement has also been associated with cell mediated rejection, post-transplant thrombotic microangiopathy, the recurrence of several glomerulopathies in the transplanted kidney, and transplant tolerance. Better understanding of the complement involvement in the transplanted kidney damage has led to the development of novel therapies that inhibit complement components and improve graft survival. The analysis of functional complotypes, based on the genotype of both graft recipient and donor, may become a valuable tool for assessing the risk of acute transplant rejection. The review summarizes current knowledge on the pathomechanisms of complement activation following kidney transplantation and the resulting diagnostic and therapeutic possibilities.

Incidence, risk factors, and long-term outcomes associated with antibody-mediated rejection - The long-term Deterioration of Kidney Allograft Function (DeKAF) prospective cohort study.

Major gaps remain in our understanding of antibody-mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long-term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean±SD) 4.85±1.86years of follow-up. Time to AMR was 0.97±1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel-reactive antibody >0%, positive T- or B-cell cross-match, and delayed graft function. Compared with no AMR, the adjusted time-dependent hazard ratio for death-censored graft failure is 10.1 (95% confidence interval, 6.5-15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90days after transplant), and 24.0 (14.0-41.1) for late AMR (≥90days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100days or no improvement in estimated glomerular filtration rate by 42days. Long-term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long-term allograft survival.

HLA antibodies are associated with deterioration of kidney allograft function irrespective of donor specificity

BackgroundDonor-specific antibodies are associated with high immunological risk and poor allograft outcome. Risk and clinical relevance of non-donor-specific HLA antibodies is less clear. MethodsA retrospective single-center study was conducted in all patients receiving a first kidney transplant at the University hospital of Zürich between 01/2006 and 02/2015. Patients were stratified into 3 groups having either no HLA antibodies at all (NoAB), HLA antibodies with donor specificity (DSA) and HLA antibodies without donor specificity (NonDSA). Allograft outcome was assessed using the slope of the estimated glomerular filtration rate (eGFR slope) starting at 12 months after transplantation. ResultsDuring a median follow-up of 1808 days HLA antibodies were detected in 106 of 238 eligible patients (44%). Out of these, 73 patients (69%) had DSA and 33 patients (31%) had NonDSA only. Medium-term allograft function, as determined by eGFR slope over three years, improved in patients with NoAB (months 12–48: +0.7 ml/min/1.73 m2) but deteriorated significantly in patients with both DSA (months 12–48: −1.5 ml/min per1.73 m2/year, p = 0.015) and NonDSA (months 12–48: −1.8 ml/min per1.73 m2/year, p = 0.03) as compared to the group with NoAB. ConclusionBoth, donor-specific and non-donor-specific HLA antibodies are associated with medium-term kidney allograft dysfunction as compared to patients with no HLA antibodies.

Inflammation in areas of fibrosis: The DeKAF prospective cohort.

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsy specimens has been associated with decreased death-censored graft survival (DC-GS). Additionally, an i-IFTA score≥2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i-IFTA and t-IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90days posttransplant (n=598); mean (SD) 1.7±1.4years posttransplant. I-IFTA, present in 196 biopsy specimens, was strongly correlated with t-IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score=0. Unlike previous studies, i-IFTA=1 (vs 0) was associated with worse 3-year DC-GS: (i-IFTA=0, 81.7%, [95% CI 77.7 to 85.9%]); i-IFTA=1, 68.1%, [95% CI 59.7 to 77.6%]; i-IFTA=2, 56.1%, [95% CI 43.2 to 72.8%], i-IFTA=3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i-IFTA with decreased DC-GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T-IFTA was similarly associated with decreased DC-GS. Of these indication biopsies, those with i-IFTA≥2, without meeting other criteria for CA TCMR had similar postbiopsy DC-GS as those with CA TCMR. Those with i-IFTA=1 and t≥2, ti≥2 had postbiopsy DC-GS similar to CA TCMR. Biopsies with i-IFTA=1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i-IFTA and t-IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.

Urinary microbiome associated with chronic allograft dysfunction in kidney transplant recipients

We performed a study to identify differences in the urinary microbiome associated with chronic allograft dysfunction (CAD) and compared the urinary microbiome of male and female transplant recipients with CAD. This case-control study enrolled 67 patients within the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort at two transplant centers. CAD was defined as a greater than 25% rise in serum creatinine relative to a 3month post-transplant baseline. Urine samples from patients with and without CAD were analyzed using 16S V4 bacterial ribosomal DNA sequences. Corynebacterium was more prevalent in female and male patients with CAD compared to non-CAD female patients (P=0.0005). A total 21 distinct Operational Taxonomic Unit (OTUs) were identified as significantly different when comparing CAD and non-CAD patients using Kruskal-Wallis (P<0.01). A subset analysis of female patients with CAD compared to non-CAD females identified similar differentially abundant OTUs, including the genera Corynebacterium and Staphylococcus (Kruskal-Wallis; P=0.01; P=0.004, respectively). Male CAD vs female CAD analysis showed greater abundance of phylum Proteobacteria in males. There were differences in the urinary microbiome when comparing female and male CAD patients with their female non-CAD counterparts and these differences persisted in the subset analysis limited to female patients only.

Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing.

An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned >3 Mb of 28 genes and identified 18,661 genetic variants (3,961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p=0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p=0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation.

Long-term Graft Survival After Kidney Allograft Torsion: Rapid Diagnosis and Surgical Management Key to Reversibility of Injury

IntroductionKidney allograft torsion (KAT) is a rare complication of kidney transplantation (KT) that occurs when the transplanted kidney rotates around its vascular pedicle, which may result in a catastrophic compromise of the graft's blood supply, deterioration of kidney function, and eventually premature graft death. Case ReportWe report the case of a patient who had an acute kidney injury (AKI) episode from KAT. Her diagnosis was ascertained expeditiously and she had prompt surgical management. Five years after the KAT event, her baseline creatinine (Cr) stabilized around 1.6 mg/dL and she has achieved >8-year graft survival. DiscussionThis case illustrates the reversibility of injury that can occur after a KAT event with a commensurate return to baseline kidney function when KAT is promptly diagnosed and treated. A high index of suspicion of this uncommon but catastrophic complication of KT must be maintained to achieve desirable long-term outcomes. A diagnosis of KAT must be considered when routine etiologies of an acute deterioration of kidney allograft function have been excluded. Finally, prophylactic nephropexy must be strongly considered with intraperitoneal placement of a kidney allograft to avoid KAT.

Increased Plasma Tissue Inhibitors of Metalloproteinase Concentrations as Negative Predictors Associated With Deterioration of Kidney Allograft Function Upon Long-Term Observation

Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post–renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = −0.43; P < .0001 and rs = −0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = −0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury.

The impact of apoptosis and inflammation gene polymorphisms on transplanted kidney function

The progressive deterioration of kidney allograft function leads in most cases to transplant failure. Polymorphisms in genes encoding for inflammatory and apoptosis molecules may be one possible explanation for interindividual differences in kidney transplant outcomes. The objective of our work was to identify the possible effect of interleukin 6 (IL-6), transforming growth factor beta 1 (TGFB1), and Fas on graft function. A case-control study was carried out to assess potential associations between polymorphisms in inflammation- and apoptosis-related genes and the risk for chronic impairment of kidney graft function. The study included 376 cadaveric kidney recipients, 256 of them with stable graft function and 120 who experienced renal deterioration during the follow-up period of 2.6 ± 1.4 years. Genotyping of IL-6/G-174C, TGFB1/L10P, TGFB1/R25P, and Fas/G-670A polymorphisms was performed by PCR-RFLP and direct sequencing. Considering the single IL-6, TGFB1, and Fas polymorphisms, we found similar allelic and genotype frequencies between the 2 groups. To test the hypothesis of mutual effects of polymorphisms, multiple logistic regression was performed incorporating data for all the possible dual genotypic associations. The association of IL-6 high producer and Fas low producer genotype resulted in a protective effect against graft dysfunction (OR=0.79; 95% C.I.=0.72-0.86). This study did not find significant associations of apoptosis and inflammation gene polymorphisms with transplanted kidney function in Italian renal transplant recipients. However, our data seem to indicate that the carriage of IL-6 high producer/Fas low producer genotype has a protective effect against graft function loss.

Increased Plasma Timps Concentrations as the Negative Predictor Associated with Deterioration of Kidney Allograft Function in the Long-Term Observation

Introduction: Chronic allograft injury (CAI) is the most frequent cause of kidney graft loss, and presents with progressive graft impairment. Chemokines, cytokines and MMPs/TIMPs system play the role in fibrosis development. The aim of the study was to assess the importance of MMPs/TIMPs, IL-6 and CCL2 (previously MCP-1) in renal transplant recipients (RTR) with long-term allograft function (over 1 year) with impaired graft function Methods: 150 RTR (male 66%, aged 49,2 ± 11,5 y.), at mean 73,4 ± 41,2 months (range 12-240) after kidney transplantation and 37 healthy volunteers (male 54%, aged 48,4 ± 14,1 y.) as controls, were assessed for plasma and urine MMP-2, MMP-9, TIMP-1, TIMP-2, IL-6 and CCL2. Investigated factors were evaluated by ELISA, and urine concentrations were standardized to urine creatinine. Depending on allograft function 45 RTR had eGFR > 60 ml/min/1,73m2, and 104 RTR had eGFR < 60 ml/min/1,73m2, respectively. The data are presented as mean ± SD or median and 95% Cl for the median. The Mann-Whitney U test (for independent samples) was applied, and differences with p < 0,05 were considered statistically significant. Results: 1. RTR compared with controls had significantly lower eGFR (48 ± 16 and 73 ± 10 ml/min/1,73m2; p = 0,0001) and increased concentrations of plasma and urine IL-6 (p = 1,8e-0,5 and p = 0,0001), MMP-9 (p = 0,0015 and p = 0,003), TIMP-1 (p = 2,2e-16 and p=3,4e-05), TIMP-2 (p = 0,003 and p = 0,02), respectively, as well as lower plasma MMP-2 (p = 7,5e-06) and urine CCL2 (p = 3,3e-05) concentrations. 2. RTR with impaired graft function (eGFR < 60 ml/min/1,73m2) compared with RTR with preserved graft function (eGFR > 60 ml/min/1,73m2) had higher median plasma TIMP-1 (165 ng/ml, 95%Cl 151 - 171 ng/ml vs 124 ng/ml, 95%Cl: 115 - 141 ng/ml; p < 0,0001) and TIMP-2 (93 ng/ml, 95%Cl: 88 - 99 ng/ml vs 79 ng/ml, 95%Cl: 76 - 88 ng/ml; p = 0,0005) concentrations and trend to higher median urine IL-6 concentration (0,9 pg/ml, 95%Cl: 0,6- 1,3 pg/ml vs 0,4 pg/ml, 95%Cl: 0,3 - 0,9 pg/ml; p = 0,054). 3. There were no significant differences in plasma and urine CCL2, MMP-2, MMP-9 and plasma IL-6 concentrations between RTR with preserved and impaired graft function. Conclusion: RTR compared with healthy controls had significantly higher plasma and urine IL-6, urine CCL2 concentrations and unsettled MMPs/TIMPs system RTR with impaired graft function had significantly increased plasma TIMP-1, TIMP-2 and trend to increased urine IL-6 concentrations compared with RTR with preserved graft function.