Progression of Interstitial Fibrosis and Tubular Atrophy in Low Immunological Risk Renal Transplants Monitored by Sequential Surveillance Biopsies: The Influence of TAC Exposure and Metabolism.

Betty Chamoun,Maite Salcedo,Eva Castellá,Xavier Guri,Ignacio Cidraque,Irina B Torres,Nestor G Toapanta,Daniel Seron,Alejandra Gabaldón,Joana Sellarés,Francesc Moreso,Manel Perelló

doi:10.3390/jcm10010141

Abstract

The combination of tacrolimus (TAC) and mycophenolate is the most widely employed maintenance immunosuppression in renal transplants. Different surrogates of tacrolimus exposure or metabolism such as tacrolimus trough levels (TAC-C0), coefficient of variation of tacrolimus (CV-TAC-C0), time in therapeutic range (TTR), and tacrolimus concentration dose ratio (C/D) have been associated with graft outcomes. We explore in a cohort of low immunological risk renal transplants (n = 85) treated with TAC, mycophenolate mofetil (MMF), and steroids and then monitored by paired surveillance biopsies the association between histological lesions and TAC-C0 at the time of biopsy as well as CV-TAC-C0, TTR, and C/D during follow up. Interstitial inflammation (i-Banff score ≥ 1) in the first surveillance biopsy was associated with TAC-C0 (odds ratio (OR): 0.69, 95% confidence interval (CI): 0.50–0.96; p = 0.027). In the second surveillance biopsy, inflammation was associated with time below the therapeutic range (OR: 1.05 and 95% CI: 1.01–1.10; p = 0.023). Interstitial inflammation in scarred areas (i-IFTA score ≥ 1) was not associated with surrogates of TAC exposure/metabolism. Progression of interstitial fibrosis/tubular atrophy (IF/TA) was observed in 35 cases (41.2%). Multivariate regression logistic analysis showed that mean C/D (OR: 0.48; 95% CI: 0.25–0.92; p = 0.026) and IF/TA in the first biopsy (OR: 0.43, 95% CI: 0.24–0.77, p = 0.005) were associated with IF/TA progression between biopsies. A low C/D ratio is associated with IF/TA progression, suggesting that TAC nephrotoxicity may contribute to fibrosis progression in well immunosuppressed patients. Our data support that TAC exposure is associated with inflammation in healthy kidney areas but not in scarred tissue.

Highlights

Introduction ditions of the Creative CommonsAt-Renal transplantation is the best treatment for end-stage renal disease, since it is associated with a better long-term patient survival and a higher quality of life at a lower cost than dialysis techniques [1]
We explore the association between histological lesions and different surrogates of tacrolimus exposure/metabolism in a cohort of low immunological risk renal transplants treated with prolonged-release TAC (PR-TAC), mycophenolate mofetil (MMF), and steroids monitored by paired surveillance biopsies
We considered low immunological risk renal transplants, which are defined as the absence of donor-specific HLA antibodies at the time of transplant or having received a desensitization treatment before transplant in the case of living donors treated with prolonged-release tacrolimus (PR-TAC), mycophenolate mofetil (MMF)

Summary

Introduction

Renal transplantation is the best treatment for end-stage renal disease, since it is associated with a better long-term patient survival and a higher quality of life at a lower cost than dialysis techniques [1]. Since the beginning of the present century and following tribution (CC BY) license International guidelines (Kidney Disease: Improving Global Outcomes; KDIGO) maintenance immunosuppression in most renal transplant units is based on the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) either with or without low-dose steroids [2]. One important limitation for this strategy is that TAC is a drug with a narrow therapeutic window, and the optimal whole blood target levels (TAC-C0 ) during follow up have not been properly defined. Registry studies have shown an association between low TAC exposure and poorer long-term graft survival [4]. High TAC exposure has been associated with nephrotoxicity, viral infections, and cancer among other toxicities [5,6]

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