Banff 2022 Vascularized Composite Allotransplantation Meeting Report: Diagnostic criteria for vascular changes.

As more data become available, the Banff 2007 working classification of skin-containing vascularized composite allograft (VCA) pathology is expected to evolve and develop. This report represents the Banff VCA Working Group's consensus on the first revision of the 2007 scoring system. Prior to the 2022 Banff-CanXadian Society of Transplantation Joint Meeting, 83 clinicians and/or researchers were invited to a virtual meeting to discuss whether the 2007 Banff VCA system called for a revision. Unanimously, it was determined that the vascular changes were to be included in the first revision. Subsequently, 2 international online surveys, each followed by virtual discussions, were launched. The goals were (1) to identify which changes define severe rejection, (2) to grade their importance in the evaluation of severe rejection, and (3) to identify emerging criteria to diagnose rejection. A final hybrid (in-person and virtual) discussion at the Banff/Canadian Society of Transplantation Joint Meeting finalized the terminology, the definition, a scoring system, and a reporting system of the vascular changes. This proposal represents an international consensus on this topic and establishes the first revision of the Banff 2007 working classification of skin-containing vascularized composite allograft pathology.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.

Renal tubular cell binding of ß-catenin to TCF1 versus FoxO1 is associated with chronic interstitial fibrosis in transplanted kidneys.

ß-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of ß-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. ß-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of ß-catenin/TCF1 versus ß-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, all P < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%, P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of ß-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.

Blocking thrombospondin-1 signaling via CD47 mitigates renal interstitial fibrosis.

Acute kidney injury triggers a complex cascade of molecular responses that can culminate in maladaptive repair and fibrosis. We have previously reported that the matrix protein thrombospondin-1 (TSP1), binding its high affinity its receptor CD47, promotes acute kidney injury. However, the role of this pathway in promoting fibrosis is less clear. Hypothesizing that limiting TSP1-CD47 signaling is protective against fibrosis, we interrogated this pathway in a mouse model of chronic ischemic kidney injury. Plasma and renal parenchymal expression of TSP1 in patients with chronic kidney disease was also assessed. We found that CD47-/- mice or wild-type mice treated with a CD47 blocking antibody showed clear amelioration of fibrotic histological changes compared to control animals. Wild-type mice showed upregulated TSP1 and pro-fibrotic markers which were significantly abrogated in CD47-/- and antibody-treated cohorts. Renal tubular epithelial cells isolated from WT mice showed robust upregulation of pro-fibrotic markers following hypoxic stress or exogenous TSP1, which was mitigated in CD47-/- cells. Patient sera showed a proportionate correlation between TSP1 levels and worsening glomerular filtration rate. Immunohistochemistry of human kidney tissue demonstrated tubular and glomerular matrix localization of TSP1 expression in patients with CKD. These data suggest that renal tubular epithelial cells contribute to fibrosis by activating TSP1-CD47 signaling, and point to CD47 as a potential target to limit fibrosis following ischemic injury.

The meaning of borderline rejection in kidney transplantation.

Borderline T cell-mediated rejection is a diagnostic category of the Banff schema that uses a lower diagnostic threshold. Subclinical borderline T cell-mediated rejection detected by surveillance sampling is not entirely benign. Studies demonstrate increased rates of late rejection, progressive nephron loss, functional impairment, donor-specific antibody formation, and allograft failure. It can be conceptualized as a failure to control the cellular alloimmune response. Mixed results are reported for its treatment, and randomized controlled trials are needed.

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

Relative survival and quality of life benefits of pancreas-kidney transplantation, deceased kidney transplantation and dialysis in type 1 diabetes mellitus-a probabilistic simulation model.

For patients with type 1 diabetes mellitus who progress to the point of requiring renal replacement therapy, the relative benefits of simultaneous pancreas and kidney transplantation (SPK) and deceased donor kidney transplantation across different age categories compared to dialysis are uncertain. Using Australian and New Zealand registry data from 2006 to 2016, a probabilistic Markov model (n = 10 000) was built comparing patient survival between SPK and deceased donor kidney transplantation with dialysis. Compared to dialysis, the average life years saved (LYS) and quality-adjusted life years (QALY) for SPK and deceased donor kidney transplantation were 5.48 [95% CI 5.47, 5.49] LYS and 6.48 [6.47, 6.49] QALY, and 3.38 [3.36, 3.40] LYS and 2.46 [2.45, 2.47] QALY, respectively. For recipients aged 50 years or younger, receiving a deceased donor kidney, the average incremental gains compared to dialysis were 4.13 [4.10, 4.16] LYS and 2.99 [2.97, 3.01] QALY, and for recipients older than 50 years, 3.05 [3.02, 3.08] LYS and 2.25 [2.23, 2.27] QALY. Compared to dialysis, SPK transplantation incurs the greatest benefits in LYS and QALY for patients with type 1 diabetes requiring renal replacement therapy. Patients older than 50 years still experience survival benefits from deceased donor kidney transplantation compared to dialysis.

Promotion of ß-catenin/Foxo1 signaling ameliorates renal interstitial fibrosis.

Transforming growth factor ß (TGF-ß) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-ß to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. ß-catenin is a common co-factor in most TGF-ß signaling pathways. ß-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that ß-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas ß-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that ß-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-ß1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-ß with a small molecule inhibitor of ß-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest ß-catenin/Foxo as a therapeutic target in kidney fibrosis.

Does tubulitis without interstitial inflammation represent borderline acute T cell mediated rejection?

Tubulitis without interstitial inflammation (Banff i0), termed "isolated tubulitis" (ISO-T), has been controversially included within the Banff "borderline" category of acute T cell mediated rejection (TCMR). This single-center, retrospective, observational study of 2055 consecutive biopsies from 775 recipients, determined the clinical significance of ISO-T. ISO-T prevalence was 19.1%, comprising mild tubulitis (i0t1) in 97.2%. Independent clinical predictors of tubulitis were HLA mismatch, prior TCMR and antibody-mediated rejection, pulse corticosteroids, and BKVAN (P = .006 to P < .001 by multivariable analysis). Histological associations of tubulitis included interstitial inflammation, peritubular capillaritis, tubular atrophy, and SV40T (P = .005 to <.001). The dominant pathological diagnoses in ISO-T (n = 393) were interstitial fibrosis/tubular atrophy (IF/TA, 44.5%) or normal/minimal (31.8%). Subanalysis of ISO-T from indication biopsies (n = 107) found acute tubular injury (37.4%), IF/TA (28.0%), normal/minimal (12.1%), acute rejection (9.3%, vascular or antibody), chronic-active TCMR (2.8%), and BKVAN (5.6%). Allograft function of ISO-T frequently improved, affected by early biopsy timing and underlying disease diagnosis. Subsequent histology of 1197 ISO-T biopsy-pairs was generally benign. The 1- and 5-year death-censored graft survivals of ISO-T were 98.8% and 92.7%. In summary, tubulitis without inflammation does not represent borderline TCMR. We suggest its removal from the borderline category, and reinstatement of i1 as the diagnostic threshold.

The clinical and pathological significance of borderline T cell-mediated rejection.

The pathological diagnosis of borderline rejection (BL-R) denotes possible T cell-mediated rejection (TCMR), but its clinical significance is uncertain. This single-center, cross-sectional cohort study compared the functional and histological outcomes of consecutive BL-R diagnoses (n = 146) against normal controls (n = 826) and acute TCMR (n = 55) from 551 renal transplant recipients. BL-R was associated with the following: contemporaneous renal dysfunction, acute tubular necrosis, and chronic tubular atrophy (P < .001); progressive tubular injury with fibrosis by longitudinal sequential histology (45.3% at 1 year); increased subsequent acute rejection (39.4%), allograft failure (P < .001), and patient mortality (P = .007). BL-R detected by biopsy indicated for impaired function was followed by suboptimal functional recovery (46.3%), persistent inflammation (27.2%), and acute rejection episodes (50.0%) despite antirejection treatment in 83.3%. By 1 year after BL-R, the incidence of new-onset microvascular inflammation (9.3%), C4d staining (22.3%), transplant glomerulopathy (13.3%), and de novo donor-specific antibodies (31.5%) exceeded normal controls (P < .05-.001). BL-R inflammation in protocol biopsy persisted in 28.0% and progressed to acute rejection in 32.6%; however, it resolved in 61.6% of the untreated cases. In summary, BL-R is a heterogeneous diagnostic grouping, ranging from mild inconsequential inflammation to clinically significant TCMR, which is capable of immune-mediated tubular injury resulting in inferior functional, immunological, and histological consequences.

The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion.

Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA. The prevalence and intensity of i-IFTA increased with developing chronic fibrosis and correlated with inflammation, tubulitis, and immunosuppression era (P < .001). Tacrolimus era-based immunosuppression was associated with reduced histologic inflammation in unscarred and scarred i-IFTA compartments, ameliorated progression of IF, and increased conversion to inactive IF/TA (compared with cyclosporine era, P < .001). Prior acute (including borderline) TCMR and subclinical TCMR were followed by greater 1-year i-IFTA, remaining predictive by multivariate analysis and independent of humoral markers. One-year i-IFTA was associated with accelerated IF/TA, arterial fibrointimal hyperplasia, and chronic glomerulopathy and with reduced renal function (P < .001 versus no i-IFTA). In summary, i-IFTA is the histologic consequence of active T cell-mediated alloimmunity, representing the interface between inflammation and tubular injury with fibrotic healing. Uncontrolled i-IFTA is associated with adverse structural and functional outcomes.

Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study.

BACKGROUND: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis. METHODS: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702. FINDINGS: We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve [AUC] 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972). INTERPRETATION: Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis. FUNDING: National Institutes of Health.

Bortezomib in ABO-incompatible kidney transplant desensitization: a case report.

Positive B cell crossmatch accompanied by high levels of pre-transplant human leukocyte antigen donor-specific antibodies are associated with adverse graft outcomes in kidney transplant recipients. Targeting plasma cells, the main antibody producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We report using a combination of bortezomib and plasmapheresis to desensitize a highly sensitized kidney transplant recipient for an ABO-incompatible living donor kidney transplant. The flow cytometric B cell crossmatch was positive on presentation. After treatment, the anti-A titres fell from 1:64 to 1:4, and a negative B flow cytometric crossmatch was achieved prior to transplantation. The combined approach of bortezomib to abrogate antibody production at the plasma cell level, followed by plasmapheresis and low-dose intravenous immunoglobulin to remove in-circulation alloantibodies, has proven to be effective in our case. Bortezomib may play a role in highly sensitized renal transplants.

Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study.

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients. DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials). PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021. MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys. TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.

Diagnosis and prevention of chronic kidney allograft loss.

Kidney transplantation is the best possible treatment for many patients with end-stage renal failure, but progressive dysfunction and eventual allograft loss with return to dialysis is associated with increased mortality and morbidity. Immune injury from acute or chronic rejection and non-immune causes, such as nephrotoxicity from calcineurin inhibitors, ischaemia-reperfusion injury, recurrent glomerular disease, and allograft BK viral infection, are potential threats. Serial monitoring of renal function enables early recognition of chronic allograft dysfunction, and investigations such as therapeutic drug concentrations, urinalysis, imaging, and a diagnostic biopsy should be undertaken before irreversible nephron loss has occurred. Specific interventions targeting the pathophysiological cause of dysfunction include strengthening of immunosuppression for chronic rejection, or calcineurin inhibitor minimisation, substitution, or elimination if nephrotoxicity dominates. Recommended proactive preventive measures are control of hypertension, proteinuria, dyslipidaemia, diabetes, smoking, and other comorbidities. Strategies to maintain transplant function and improve long-term graft survival are important goals of translational research.

Glomerular C4d Immunoperoxidase in Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy.

Introduction: The diagnosis of late antibody-mediated rejection (AMR) is compromised by frequent absence of C4d in peritubular capillaries (C4dptc), termed "C4d-negative" AMR. We hypothesized that glomerular capillary C4d (C4dglom) reflected endothelial interaction with antibody and could improve immunologic classification of transplant glomerulopathy (TG). Methods: We evaluated C4d using immunoperoxidase in 3524 consecutive, kidney transplant biopsies from a single center. Results: C4dglom was detected in 16.5% and C4dptc in 9.9% of biopsies. C4dglom occurred in 60.3% of TG (n = 174) and was absent in normal glomeruli. Epidemiologic risk factors for C4dglom were younger, female, living-donor recipients with early AMR, prior treated rejection, and late presentation using multivariable analysis. Semiquantitative C4dglom score correlated with donor specific antibody (DSA) level, C4dptc, microvascular inflammation (MVI), Banff cg scores, renal dysfunction, and proteinuria. Principal component analysis colocalized C4dglom with histologic AMR. Multivariable analysis of TG found DSA, C4dptc, and post-transplant time associated with C4dglom. Addition of C4dglom into Banff chronic AMR schema improved its diagnostic sensitivity for TG (verified by electron microscopy [EM]) from 22.2% to 82.4% and accuracy from 59.6% to 93.9%, compared with Banff 2019 using only C4dptc. Tissue C4dglom and chronic AMR diagnosis incorporating C4dglom were associated with death-censored allograft failure in TG (P < 0.001), independent of the severity of glomerulopathy and chronic interstitial fibrosis. Conclusion: C4dglom is a promising diagnostic biomarker of endothelial interaction with antibody which substantially improved test performance of the Banff schema to correctly classify TG by pathophysiology and prognosticate graft loss. We recommend routine C4d immunoperoxidase to minimize underdiagnosis of late AMR in TG.

The Pathological and Clinical Diversity of Acute Vascular Rejection in Kidney Transplantation.

BACKGROUND: Vascular rejection (VR) is characterized by arteritis, steroid resistance, and increased graft loss but is poorly described using modern diagnostics. METHODS: We screened 3715 consecutive biopsies and retrospectively evaluated clinical and histological phenotypes of VR (n = 100) against rejection without arteritis (v0REJ, n = 540) and normal controls (n = 1108). RESULTS: Biopsy sample size affected the likelihood of arterial sampling, VR diagnosis, and final Banff v scores ( P < 0.001). Local v and cv scores were greatest in larger arteries (n = 258). VR comprised 15.6% of all rejection episodes, presented earlier (median 1.0 mo, interquartile range, 0.4-8 mo) with higher serum creatinine levels and inferior graft survival, versus v0REJ ( P < 0.001). Early VR (≤1 mo) was common (54%) and predicted by sensitization, delayed function, and prior corticosteroid use, with associated acute dysfunction and optimal therapeutic response, independent of Banff v score. Late VR followed under-immunosuppression in 71.4% (noncompliance 38.8%, iatrogenic 32.6%), and was associated with chronic interstitial fibrosis, incomplete renal functional recovery and persistent inflammation using sequential histopathology. The etiology was "pure" antibody-mediated VR (n = 21), mixed VR (n = 36), and "pure" T cell-mediated VR (n = 43). Isolated VR (n = 34, Banff i < 1 without tubulitis) comprised 24 T cell-mediated VR and 10 antibody-mediated VR, presenting with mild renal dysfunction, minimal Banff acute scores, and better graft survival compared with inflamed VR. Interstitial inflammation influenced acute renal dysfunction and early treatment response, whereas chronic tubulointerstitial damage determined long-term graft loss. CONCLUSIONS: VR is a heterogenous entity influenced by time-of-onset, pathophysiology, accompanying interstitial inflammation and fibrosis. Adequate histological sampling is essential for its accurate diagnostic classification and treatment.