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Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

Eduard M. Scholten^*, Ajda T. Rowshani, Serge Cremers, Frederike J. Bemelman, Michael Eikmans, Erik van Kan^||, Marko J. Mallat^*, Sandrine Florquin^¶, Janto Surachno, Ineke J. ten Berge, Ingeborg M. Bajema and Johan W. de Fijter^*

^* Nephrology, Clinical Pharmacy and Toxicology, and Pathology, Leiden University Medical Center, Leiden, and Departments of Nephrology and Clinical Immunology, ^|| Clinical Pharmacy and Toxicology, and ^¶ Pathology, Academic Medical Center, Amsterdam, The Netherlands

Address correspondence to: Dr. Johan W. de Fijter, Department of Nephrology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Phone: +31-71-5262418; Fax: +31-71-5248118; E-mail: jwdefijter{at}lumc.nl

Received for publication March 14, 2006. Accepted for publication July 4, 2006.

Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve–controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (r = –0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673