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Better understanding of the contribution of donor aging and comorbidity factors of expanded criteria donors (ECD) to the clinical outcome of a transplant is a challenge in kidney transplantation. We investigated whether the features of donor-derived stromal vascular fraction of perirenal adipose tissue (PRAT-SVF) could be indicative of the deleterious impact of the ECD microenvironment on a renal transplant. A comparative analysis of cellular components, transcriptomic and vasculogenic profiles was performed in PRAT-SVF obtained from 22 optimal donors and 31 ECD deceased donors. We then investigated whether these parameters could be associated with donor aging and early allograft dysfunction. When compared with the PRAT-SVF of non-ECD donors, ECD PRAT-SVF displayed a lower proportion of stromal cells, a higher proportion of inflammatory NK cells. The global RNA sequencing approach indicated a differential molecular signature in the PRAT-SVF of ECD donors characterized by the over-expression of CXCL1 and IL1-β inflammatory transcripts. The vasculogenic activity of PRAT-SVF was highly variable but was not significantly affected in marginal donors. Periorgan recruitment of monocytes/macrophages and NK cells in PRAT-SVF was associated with donor aging. The presence of NK cell infiltrates was associated with lower PRAT-SVF angiogenic activity and with early allograft dysfunction evaluated on day 7 and at 1 month post-transplant. Our results indicate that human NK cell subsets are differentially recruited in the periorgan environment of aging kidney transplants. We provide novel evidence that PRAT-SVF represents a non-invasive and timely source of donor material with potential value to assess inflammatory features that impact organ quality and function.

Acute T cell-mediated rejection (TCMR) is one of the most important causes of kidney graft injury and loss; however, in-depth transcriptomic analyses of relevant tissues and circulating immune cells are limited. In this study, we conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells and spatial transcriptomics using kidney allograft biopsy samples. The scRNA-seq study included four patients with borderline rejection or biopsy-proven TCMR and two with no evidence of TCMR. For spatial analysis, we compared tissue specimens from one patient diagnosed with borderline rejection and another patient with TCMR to their time-zero protocol biopsies. Six regions of interest per biopsy section were selected, focusing on the evident T-cell infiltration area in the tubulointerstitium and glomeruli. Integrating two methodologies, we pinpointed CD8 + effector memory T cell (T EM ) expression profiles and key upregulated genes, including LTB, GZMK, PSME2, UBE2L6, and STAT1. Among them, STAT1 was confirmed as a hub gene through network and pathway analysis. Immunohistochemistry and immunofluorescence on kidney allograft tissue validated the co-expression of STAT1 with CD8, indicating an active inflammatory response. Our findings suggest the presence of a CD8 + STAT1 + T EM subset with features of clonal expansion, providing additional insight into the immunological processes associated with TCMR.

Background Early diagnosis of kidney allograft dysfunction is crucial for the management and long-term survival of transplanted kidneys. We investigated whether neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) are capable of being used as novel biomarkers of acute kidney allograft dysfunction. Methods We measured serum and urine NGAL, urine IL-18, and urine L-FABP levels on the first 3 days after transplantation. To assess the diagnostic sensitivity of these biomarkers, a receiver-operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) was calculated to quantify the accuracy of the parameter. Sections from paraffin-embedded biopsy specimens were examined by immunohistochemistry for NGAL expression. Results Twelve cases were clinically diagnosed as acute rejection (AR) by renal biopsy. Urine NGAL was the most sensitive of these markers for detection of acute kidney allograft dysfunction. The cutoff value of urine NGAL was 66.0 ng/ml, with an AUC of 0.79 (95 % CI 0.68–0.88). Sensitivity of serum NGAL was about the same as urine NGAL with an AUC of 0.75 (0.64–0.85). IL-18 and L-FABP were 0.584 (95 % CI 0.433–0.725) and 0.612 (95 % CI 0.460–0.749), respectively. NGAL was more useful than other biomarkers to detect AR of kidney allograft dysfunction. NGAL staining intensity was significantly increased in the proximal tubules of the transplants with AR than in transplants that were not acutely rejected. Conclusion Urine NGAL level was found to be the most sensitive biomarker of acute kidney allograft dysfunction after living-donor kidney transplantation.

Desmopressin acetate (DDAVP), a selective agonist of type 2 vasopressin receptors, is sometimes used prior to percutaneous renal biopsy to reduce the risk of bleeding complications. DDAVP increases free water reabsorption in renal collecting ducts, potentially leading to water intoxication or dilutional hyponatraemia. We present two cases, where DDAVP was used prior to percutaneous renal transplant biopsy and was associated with severe hyponatraemia and neurological sequelae. With DDAVP being advocated in many centres prior to percutaneous renal biopsy, these cases highlight the need for increased awareness regarding side effects. In this report, we provide suggestions on strategies to minimize hyponatraemia in this context.

Transplantation from a non‐identical donor initiates a recipient immune response directed toward donor antigens, manifest as rejection, and expressed as differing pathophysiological syndromes. Primary non‐function due to hyperacute rejection from preformed antibodies is rare, compared with more common ischemia–reperfusion injury. Early acute T‐cell mediated interstitial rejection usually resolves with pulse corticosteroids, whereas vascular, antibody‐mediated, severe interstitial or recurrent rejections result in allograft damage, functional impairment, and require additional therapies. Progressive allograft dysfunction is detected by serial monitoring of serum creatinine, investigated by assessment of therapeutic drug levels, urinalysis, imaging, and timely diagnostic biopsy. Chronic rejection or late acute rejection from non‐adherence can cause irreversibly damage leading to graft failure. Non‐immune causes of dysfunction include ischemia–reperfusion injury, ureteric obstruction, vascular impairment, calcineurin inhibitor nephrotoxicity, recurrent glomerular disease, and BK viral nephropathy. A specific etiologic diagnosis is needed for rational and specific treatment directed towards the dominant pathophysiological cause of dysfunction.

Reported as the third most common cause of graft failure (after death with a functioning graft and interstitial fibrosis and tubular atrophy), recurrent disease is an important and often overlooked cause of graft dysfunction and eventual graft loss. This is compounded in patients transplanted without a clear biopsy‐proven diagnosis to explain their original disease. Thus, recurrent disease requires a high index of suspicion and a clinician willing actively expose the root cause of a failing allograft. This chapter will review the aetiology, clinical presentation, and investigation of recurrent disease in the kidney and pancreas grafts after transplantation. Recurrence of specific forms of glomerulonephritis and autoimmune disease in the pancreas are addressed individually, together with a review of current understanding on disease pathogenesis and an evaluation of current therapeutic options.

Kidney allograft biopsies provide assessment regarding diagnostic, prognostic, and theranostic considerations. However, most diagnosis is based on consensus, exemplified by cellular rejection possessing interstitial inflammation, tubulitis, and arteritis. Antibody‐mediated rejection is identified by microcirculation injury (capillaritis and glomerulitis), peritubular capillary C4d, and donor‐specific antibody. Antibody‐mediated rejection, particularly with chronicity like transplant glomerulopathy, and recurrent/de novo glomerular disease represent two major causes for late allograft loss. Differential diagnostic considerations include tubular injury, polyomavirus nephritis, and post‐transplant lymphoproliferative disease. Recent developments in assessing molecular phenotypes provide novel pathogenetic insights and potentially provide more precise diagnostic stratification of diseases and personalized therapies.

Kidney transplantation remains the most effective treatment for end-stage renal disease (ESRD). However, long-term graft survival is still limited by chronic allograft dysfunction (CAD), which is primarily characterized by renal interstitial fibrosis (RIF). The development of RIF is an actively regulated and progressive process involving both immune and non-immune mechanisms. Within the renal microenvironment, multiple cell populations interact to form a self-reinforcing profibrotic network that ultimately drives irreversible fibrotic remodeling. Despite increasing mechanistic insights, the precise modes of multicellular crosstalk remain incompletely understood, and effective targeted therapies are still lacking in clinical practice. In this review, we systematically summarize the dynamic interactions among immune cells, renal epithelial cells, and stromal cells during renal allograft interstitial fibrosis. By integrating recent advances at the cellular and molecular levels, we identify key regulatory nodes within this multicellular network and discuss emerging therapeutic targets and precision intervention strategies aimed at inhibiting profibrotic signaling, alleviating pathological tissue remodeling, and improving long-term graft function and survival.

Advanced renal failure remains a major global health burden. Mitochondrial dysfunction is frequently observed during progressive kidney injury and chronic allograft dysfunction (CAD), but observational data cannot distinguish causal involvement from secondary consequences. We applied a multi-omic genetic prioritization framework to evaluate whether inherited variation affecting mitochondrial gene regulation is associated with a proxy phenotype for advanced renal failure and fibrotic allograft remodeling. We integrated cis-mQTL (DNA methylation), cis-eQTL (gene expression), and cis-pQTL (plasma protein) data for MitoCarta3.0 genes with a UK Biobank GWAS of kidney transplant recipient status (369 cases, 397,602 controls) as a proxy endpoint for advanced renal failure. Summary-data-based Mendelian randomization (SMR; Wald ratio) was performed using a single lead cis-QTL instrument per gene per layer, with HEIDI heterogeneity testing and Bayesian colocalization to assess whether molecular QTL and outcome signals were consistent with a shared causal variant (PPH4 ≥ 0.70). Because no association survived false discovery rate (FDR) correction across the mitochondrial gene set, we used a tiered, exploratory prioritization scheme based on nominal MR evidence and colocalization. Instrument strength metrics (F-statistics and R²) are reported. At a nominal threshold (  < 0.05; none surviving FDR < 0.05), we observed suggestive SMR associations in the methylation and expression layers, with generally weaker signals in the protein layer. Integrating MR evidence with colocalization support prioritized eight mitochondrial candidate genes ( / , , , , , , , and ). Translational evaluation showed dysregulation of several prioritized candidates in human CAD allograft tissues and in a murine allogeneic kidney transplantation model of chronic allograft fibrosis. In TGF-β-stimulated HK-2 cells, mitochondrial dysfunction accompanied profibrotic responses, and functional perturbation supported as a plausible node linking mitochondrial bioenergetics to fibrotic remodeling. Given the limited number of outcome cases, the proxy nature of transplant recipient status, and no FDR-significant associations, the genetic results should be interpreted as exploratory and hypothesis-generating rather than causal proof. Nonetheless, multi-omic genetic prioritization with kidney-relevant experimental data highlights mitochondrial pathways as plausible contributors to advanced renal failure and fibrotic allograft remodeling, motivating replication in larger outcome GWAS and kidney-relevant QTL resources.