At the End of the Day, Should We Consider Chronic Histological Lesions?

In this issue, Naesens et al. (1) evaluate the impact on long-term graft survival of various chronic histological lesions obtained from for cause biopsies performed 1 year after transplantation in a large group of approximately 1,200 kidney transplant recipients transplanted between 1991 and 2001. By confronting a detailed histological analysis with actualized Banff scores and high-quality statistical multivariate analyses, this study will undoubtedly contribute to better characterize the complex interplay of various injuries leading to late graft loss. The main novel result is that chronic histological damage is a significant determinant of kidney transplant outcome, independent of specific diagnoses. Of note, previous literature on the causes of graft loss attributed one single cause to each graft loss (2, 3). Naesens et al. hypothesized that the complex history of a transplant is a better predictor of graft outcome than any specific disease in itself. Multivariate Cox proportional hazards analysis clearly illustrated that renal allograft loss, chronic histological damage, and specific disease processes have additive and independent impact on graft outcome. Though graft loss is multifactorial, the Naesens et al.’s study confirms that rejection phenomena are the main contributor of graft loss, with T cell–mediated rejection, changes suggestive of antibody-mediated rejection (ABMR) and transplant glomerulopathy being the prominent features in 52.8% on the last biopsies before graft loss. This is in perfect agreement with the study from the Edmonton group where 64% of graft loss were caused by ABMR (including ABMR, mixed rejections or probable ABMR) (3) and from the Mayo Clinic study where 35.2% of graft losses were attributed to rejection (including ABMR, T cell–mediated rejection, chronic damage associated with recurrent rejections, and transplant glomerulopathy) (2). Of course, one should remind that the Belgian cohort was transplanted in an earlier era, between 1991 and 2001, where not all patients were treated with the current immunosuppressive regimens. The Naesens study further contributes to better characterize the complex interplay of different injuries leading to late graft loss. Their analysis of the last indication biopsy before graft loss revealed that the most biopsies show an ongoing specific disease (69.4%) or chronic scarring likely caused by prior specific diseases (7.6%). Finally, only 6.9% of cases demonstrated chronic damage in the last biopsy before graft loss, without specific disease in the past. These results seem in accordance with the previous studies that show the importance of specific histological diagnoses for graft outcome and reinforce the message that advanced scarring is associated in most cases with an identifiable cause (2, 3). Obviously, the chronic damage observed in a late indication biopsy often in association with a specific disease is not necessarily caused by that specific disease and could also be related to prior (other) specific diseases and even to a nonspecific fibrogenic process (aging, calcineurin inhibitor (CNI) nephrotoxicity). In addition, a specific disease can evolve over time. For instance, a BK virus associated nephropathy can resolve and led to non-specific allograft scarring lesions. Naesens et al. demonstrate that this nonspecific scarring chronic damage is significantly associated with worse outcome. Evaluating the impact of individual elementary lesions in the last biopsy on graft outcome, Naesens et al. found that interstitial infiltrate, interstitial fibrosis / tubular atrophy (IF/TA), chronic glomerular, C4d deposition, and arteriolar hyalinosis (ah) were independently associated with postbiopsy death-censored graft survival. Surprisingly, although the first four lesions were positively associated with bad outcome, ah was associated with better outcome. This association could have been fortuitous if not already reported in the similarly designed DEKAF study, where the diagnosis of “CNI nephrotoxicity” (presumably partly by histology of ah) was associated with better outcome than no CNI nephrotoxicity (4) and in an independent study of the Edmonton group (5). This suggests that the timing of the biopsies, and the study design, affected this result and could be responsible for the discrepancies. Even if it is tempting to speculate that patients with a higher exposure to CNIs may have had a better control of the immune response, this unexpected finding warrants further study. In addition, the Naesens et al.’s study shows that despite the strong association between IF/TA and ah, IF/TA is associated with worse outcome, whereas ah is associated with improved outcome. This suggests that chronic interstitial, chronic tubular, and ah elementary lesions should not been associated in one non-specific diagnosis group, or even in a CNI toxicity group, because it could be tempting.

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