Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection

Abstract

BackgroundLate antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR.MethodsStudy subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15–75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m2 at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy.ResultsA total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m2 per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01–1.3), p = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1–1.4), p = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation.ConclusionOur study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation–likely representing a confounder in pre-sensitized recipients–were strongly associated with worse transplant outcomes.

Morphologic and Molecular Features of Antibody-Mediated Transplant Rejection: Pivotal Role of Molecular Injury as an Independent Predictor of Renal Allograft Functional Decline

“…Our approach, which involved the use of linear mixed models incorporating a substantial number of creatinine measurements (a median of 49 measurements per patient), allowed us to examine associations for both baseline eGFR and eGFR slopes. In line with previous research [4,8], we observed a significant decline in renal functional following ABMR diagnosis, with an average eGFR slope of −5.4 mL/min/1.73 m [2] per year. Through this detailed examination of the eGFR course, we were able to distinguish between processes contributing to the dynamic progression of graft dysfunction, which might be amenable to intervention, and processes related to the irreversible loss of nephrons.…”

“…Our present study aimed to address this gap and provide additional insights into the relationship between IRRAT score and both the baseline eGFR and its slope. Previous studies have demonstrated a close association between the eGFR slope in ABMR, serving as a potentially valuable surrogate endpoint, and long-term graft survival [ 4 , 8 ]. As expected, our mixed model analysis revealed associations between IRRAT score and baseline eGFR, and univariable Cox regression demonstrated a strong association between IRRAT score and graft loss (2.7-fold risk; p < 0.001).…”

“…Surprisingly, none of the tested factors independently predicted eGFR slope, which itself emerged as a robust surrogate of graft survival [ 4 ]. Second, in a study of 70 ABMR patients conducted at our unit, graft survival was found to be associated with cg, while the only biopsy-based predictor of eGFR slope was the diagnosis of concurrent glomerulonephritis [ 8 ]. In a study of 278 patients with active ABMR, Viglietti et al [ 9 ] established a dynamic composite prediction score integrating various factors, such as eGFR and interstitial fibrosis/tubular atrophy at the time of diagnosis, along with changes in eGFR, peritubular capillaritis, and DSA levels post-treatment.…”

Clinical Impacts of Allograft Biopsy in Renal Transplant Recipients 10 Years or Longer After Transplantation

“…To evaluate the effect of treatment modification on hard outcomes, such as kidney failure with replacement therapy, we selected the eGFR slope among various surrogate endpoints, instead of albuminuria change, since urinary protein was negative in most KTRs, except for those with recurrent nephritis. Moreover, the association between graft outcome and eGFR slope for at least 12 months after biopsy has been confirmed recently in KTRs [ 16 ]. This result supports the validity of eGFR slope as a surrogate endpoint for graft survival.…”