The EKiTE network (epidemiology in kidney transplantation - a European validated database): an initiative epidemiological and translational European collaborative research

Background: Kidney transplantation is considered to be the treatment of choice for people with end-stage renal disease (ESRD). However, due to the shortage of available organs and the increase in the ESRD prevalence in Europe, it is essential to improve transplantation outcomes by studying the related prognostic factors. Today, there is no European registry collecting data to perform such clinical epidemiology studies. Main body: Entitled EKiTE, for European cohort for Kidney Transplantation Epidemiology, this prospective and multicentric cohort includes patients from Spanish (Barcelona), Belgian (Leuven), Norwegian (Oslo) and French (Paris Necker, Lyon, Nantes, Nancy, Montpellier, Nice and Paris Saint Louis) transplantation centers and currently contains 13, 394 adult recipients of kidney (only) transplantation from 2005 and updated annually. A large set of parameters collected from transplantation until graft failure or death with numbers of post-transplantation outcomes. The long-term follow-up and the collected data enable a wide range of possible survival and longitudinal analyses. Conclusion: EKiTE is a multicentric cohort aiming to better assess the natural history of the ESRD in European kidney transplant recipients and perform benchmarking of clinical practices. The data are available for clinical epidemiology studies and open for external investigators upon request to the scientific council. Short-term perspectives are to extend EKITE network to other European countries and collect additional parameters in respect of the common thesaurus

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury.

Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury initiated by ischemia/reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was substantially enriched with long chain fatty acids (FAs). We identified a renal FA-related gene signature with low levels of carnitine palmitoyltransferase 2 (Cpt2) and acyl-CoA synthetase medium chain family member 5 (Acsm5) and high levels of acyl-CoA synthetase long chain family member 4 and 5 (Acsl4 and Acsl5) associated with IRI, transition to chronic injury, and established chronic kidney disease in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-Acsl4+Acsl5+Acsm5- PTCs failing to recover from IRI as identified by single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed to CPT2 repression, which, in turn, promoted lipids' accumulation, drove profibrogenic epithelial phenotypic changes, and activated the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation engaged an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule, sustaining the progression to chronic kidney allograft injury

Intragraft antiviral-specific gene expression as a distinctive transcriptional signature for studies in polyomavirus-associated nephropathy

Background: polyomavirus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. To identify PVAN-specific gene expression and underlying molecular mechanisms, we analyzed kidney biopsies with and without PVAN. Methods: the study included 168 posttransplant renal allograft biopsies (T cell-mediated rejection [TCMR] = 26, PVAN = 10, normal functioning graft = 73, and interstitial fibrosis/tubular atrophy = 59) from 168 unique kidney allograft recipients. We performed gene expression assays and bioinformatics analysis to identify a set of PVAN-specific genes. Validity and relevance of a subset of these genes are validated by quantitative polymerase chain reaction and immunohistochemistry. Results: unsupervised hierarchical clustering analysis of all the biopsies revealed high similarity between PVAN and TCMR gene expression. Increased statistical stringency identified 158 and 252 unique PVAN and TCMR injury-specific gene transcripts respectively. Although TCMR-specific genes were overwhelmingly involved in immune response costimulation and TCR signaling, PVAN-specific genes were mainly related to DNA replication process, RNA polymerase assembly, and pathogen recognition receptors. A principal component analysis (PCA) using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific genes (RPS15, complement factor D, lactotransferrin, and nitric oxide synthase interacting protein) by quantitative polymerase chain reaction and confirmation by immunohistochemistry of 2 PVAN-specific proteins with antiviral function (lactotransferrin and IFN-inducible transmembrane 1) was done. Conclusions: in conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, PVAN-specific genes were identified with well-known antiviral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design

Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation

Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.Copyright © 2022 Roufosse, Becker, Rabant, Seron, Bellini, Böhmig, Budde, Diekmann, Glotz, Hilbrands, Loupy, Oberbauer, Pengel, Schneeberger and Naesens

Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.Copyright © 2022 Seron, Rabant, Becker, Roufosse, Bellini, Böhmig, Budde, Diekmann, Glotz, Hilbrands, Loupy, Oberbauer, Pengel, Schneeberger and Naesens

The association between use of proton-pump inhibitors and excess mortality after kidney transplantation:A cohort study

Background Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs. Methods and findings We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7-9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38-2.52, P 20 mg omeprazole equivalents/ day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48-3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23-2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation. Conclusions We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs

A Peripheral Blood Diagnostic Test for Acute Rejection in Renal Transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93759/1/j.1600-6143.2012.04253.x.pd

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFN gamma-stimulated endothelial cells

IFN gamma enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFN gamma. We also assessed if NOD affects IFN gamma mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNF alpha and IFN gamma and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFN gamma stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFN gamma to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models