The late loss of kidney allografts is a major and largely unsolved problem in transplantation (Tx). Chronic renal allograft dysfunction can have different etiologies. Besides immunological processes of rejection, nonimmunologic factors, including donor age, brain death, hypertension, prolonged warm and cold ischemia times, hyperfiltration, recurrent renal diseases or calcineurin inhibitor toxicity, are known to be associated with fibrosis and can influence long-term graft survival (1,2). However, only little is known about the specific chain of events resulting in allograft fibrosis.
Chronic rejection (CR), characterized histologically by transplant arteriopathy, transplant glomerulopathy and fibrotic changes of the tubulointerstitial space, is the leading cause of late graft loss following solid organ transplantation (3,4). The most important injury to a kidney transplant is caused by cellular and/or humoral allo-responses best characterized in the setting of acute rejection. In particular, acute rejection episodes with transplant endarteritis (TXA, Banff type II acute rejection) seem to play a central role in the development of chronic rejection and graft loss (3,5,6). TXA often only incompletely responds to anti-rejection therapy including anti-lymphocytic preparations (5,7,8). Endarteritis in its early stage shows infiltration of mononuclear inflammatory cell elements. The recruitment of myofibroblasts into the inflamed intimal layers results in the accumulation of extracellular matrix components, i.e. sclerosing vasculopathy with concentric intimal fibrosis. Arterial intimal sclerosis can progress (chronic progressive rejection) in the setting of persistent or repetitive intimal inflammation, e.g. due to recurrent or smoldering rejection, which ultimately leads to significant luminal narrowing and impaired blood flow (3,4,9).
In humans, most data on CR is limited as histological studies are typically performed on biopsy cores taken for diagnostic purposes in complex clinical situations. Often, protocol biopsies do not meet the Banff criteria of specimen adequacy, i.e. >7 glomeruli and at least one artery (10,11). Thus, TXA and CR with sclerosing vasculopathy may be underestimated (3,7). In a retrospective review of a large series of kidney transplants in rhesus monkeys, Schuurman et al. (12) concluded that CR could develop in a high percentage of animals (up to 85%) within 60 days post-Tx under suboptimal baseline immunosuppression. Based on these observations, we designed a unique study to specifically induce CR in young, healthy cynomolgus monkey renal allograft recipients. We wanted to test the feasibility of our CR study design, to compare observations with human CR, and to describe key morphological aspects of arterial intimal thickening associated with sclerosis.