RENAL TRANSPLANT PROTOCOL BIOPSIES: A SURROGATE BIOMARKER FOR LATE GRAFT LOSS

Protocol Renal Allograft Biopsies and the Design of Clinical Trials Aimed to Prevent or Treat Chronic Allograft Nephropathy. Transplantation 2000; 69: 1849. Serón D, Moreso F, Ramón JM, Hueso M, Condom E, Fulladosa X, Bover J, Gil-Vernet S, Castelao AM, Alsina J, and Grinyó JM. Surrogate biomarkers are sets of parameters of a disease or a disease activity that are used to prognosticate the long-term outcome or the response to therapy of that particular disease. Their use in clinical medicine is presently receiving much attention from government agencies, industry, and academia because they allow us to do clinical trials that require a much shorter follow-up period than the classical trials with a “real” biological end point. Of course, the disadvantage of the use of surrogate end points is that they are less robust. In renal transplantation, chronic rejection or chronic allograft nephropathy (CAN) is the most prevalent cause of graft dysfunction and graft loss in the first posttransplantation decade, for which there is no treatment. It is defined operationally as a gradual decline in function after the first 3 months in the absence of other obvious causes. Once the diagnosis has been made, the course is variable albeit that it results in graft failure in over 80% of cases. An early surrogate biomarker that predicts late failure is of obvious value for the design of intervention studies. In this issue, Dr Serón et al. report the Barcelona experience with posttransplantation protocol biopsies at 3 months as a marker for the 10-year outcome. Stable patients with a serum creatinine level of <300 μmol/L and less than 1 g of proteinuria/24 hr were included, and the biopsy specimen was categorized according to the Banff schedule. It is of note that the inclusion of patients with a serum creatinine level of <300 μmol/L represents almost the entire range of glomerular filtration rates expected in renal transplant patients. At 3 months, 38% of biopsy specimens had evidence of CAN, while 7.5% showed renal transplant vascular disease. This prevalence seems high, but in a set of pretransplantation biopsy specimens already 15% displayed histopathological features resembling CAN. The CAN lesions, rather than any acute rejection injury, correlated with long-term prognosis: patients with no CAN had a 10-year graft survival of 95.4% compared with 82.3% in patients with interstitial fibrosis and 41.3% in patients with both interstitial and vascular lesions. The authors calculated that a study powered to show a 50% reduction in the incidence of CAN at 3 months would require the enrollment of about 300 patients. This article corroborates other studies that have shown the association between CAN in protocol biopsy specimens and late prognosis. The Helsinki group demonstrated in a cohort of patients with more or less normal graft function at 2 years that the chronic allograft histological examination score was the single most important predictor of CAN and graft loss (1). Similarly, Dimény et al. (2) found that the 6-month chronic biopsy score correlated with graft function and loss at 2 or 3 years after transplantation. Other investigators focused on interstitial fibrosis and found a good correlation of an enlarged interstitial volume fraction at 6 months and impaired graft survival at 6 years, whereas the 1-month score was not useful (3). Although the Barcelona group showed a significant correlation between the 3-month score and prognosis, as did a study from Winnipeg (4), the 6-month biopsy may prove to be a more reliable marker. In addition to surveillance biopsies, the value of other biomarkers for long-term prognosis are currently under study and include the histopathologic pattern of early acute rejection episodes, the composition of the cellular infiltrate in such rejection biopsy specimens, patterns of changes in the glomerular filtration rate, and the urinary protein excretion profile as well as the expression pattern of intragraft cytokine or extracellular matrix genes. Although several individual markers may show a good correlation with late graft loss, it would seem that a combination of biomarkers will allow the most accurate prognostication. For example, in the Helsinki study, the combination of histological examination on surveillance biopsy specimens in combination with functional parameters gave a better prognostication than histological examination alone (1). Within the group of CAN, renal transplant vascular disease has the worst prognosis. To analyze the factors associated with CAN alone or in combination with transplant vascular disease, Dr Serón at al. performed a logistic regression analysis and found that donor age, cold ischemia time, acute rejection history, and mean cyclosporine levels predict CAN without renal transplant vascular disease, whereas the total serum cholesterol before transplantation was the only independent predictor of CAN with vascular lesions. However, it is likely that other factors than hypercholesterolemia also correlate with the development of transplant vascular disease. In our own material, we identified recipient age of less than 50 years, preceding vascular rejection episodes, proteinuria, and a serum creatinine level >150 μmol/L as independent risk factors for transplant vascular disease albeit that these factors also correlated with chronic interstitial lesions. On the other hand, significant risk factors for transplant glomerulopathy included proteinuria and poor sharing for cross-reactive HLA class I determinants (our unpublished data). Kupin et al. (5) reported that more black recipients, grafts from female donors, and preceding steroid-sensitive rejection episodes were associated with transplant glomerulopathy, whereas the degree of HLA mismatching was higher in patients with graft tubulointerstitial fibrosis. The suggestion that the risk factors for various forms of CAN are different has not received much attention but seems to imply that the pathogenesis of the various forms of CAN may be different. Only with the widespread introduction of surveillance biopsies and sophisticated analyses regarding patterns of gene expression in the various conditions will we be able to define appropriate surrogate markers for various forms of late graft loss.

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