Rethinking Chronic Allograft Nephropathy: The Concept of Accelerated Senescence

Abstract

Chronic rejection or chronic allograft nephropathy (CAN) is the major cause of failure of kidney transplants other than patient death, and has been extensively reviewed (1,2,3,4,5). CAN is characterized by functional impairment with nonspecific pathology: tubular atrophy, interstitial fibrosis, and fibrous intimal thickening (FIT) in the arteries, with variable glomerular lesions. The risk of CAN correlates with the input, immune, and load stresses experienced by that kidney. Input refers to the preexisting chronic conditions in the donor (aging, hypertension) plus the acute injury related to the transplant process (brain death, donor maintenance, organ removal, preservation, implantation, reperfusion). Immune stress is due to rejection by antibody or cellular mechanisms, determined by histocompatibility, presensitization, host responsiveness, and the effectiveness of and compliance with immunosuppression. Load reflects hypertension, donor-recipient size disparity, proteinuria, hyperlipidemia, drug toxicity, and infectious agents. Load factors such as donor size and gender probably reflect differences in nephron dose and are relatively weak, suggesting that nephron number does not explain the strong effect of input and immune factors. What distinguishes the transplant from normal tissue is the level of injury. Injury depletes the finite ability of the tissue to repair, and triggers inflammation, which may further stress the parenchyma and vessels, increase immune recognition, and promote fibrosis. In this article we review the problem of human CAN and propose a model in which the cumulative burden of injury and age exhausts the ability of key cells in epithelium or endothelium to repair and remodel to maintain tissue integrity. We term this exhaustion “senescence” to emphasize the importance of donor aging and the overlap of the pathologic lesions with age-related changes, and to suggest analogy with senescent changes observed in cell culture. When the potential of a tissue to repair is exhausted, the endothelial functions decline and the epithelium atrophies; injury-induced inflammation persists, permitting transforming growth factor-β and other mediators to create fibrosis. Thus, fibrosis may be a default for the failure of normal healing. CAN can be minimized by reducing the burden of injury due to immune and nonimmune mechanisms, but grafts with age- and injury-induced changes may still be useful despite their limitations, and few should be discarded. Recent advances in the cellular basis of senescence in vitro may hold clues to the molecular events that limit the repair of key cells. Development of the Concept of Chronic Rejection and CAN The concept of chronic rejection emerged gradually in the 1950s and 1960s. Acute homograft (now allograft) rejection was well known in the late 1950s in the early clinical experience, and few kidneys survived even for months. In 1955 Hume et al. (6) reported a case in which rejection developed within 5½ mo, with obliteration of the arteries. Systematic investigation of late rejection by Porter et al. (7) and Jeannet et al. (8) revealed that arterial intimal fibrosis was frequent and probably represented a reaction to immune injury, perhaps due to alloantibody (7,9). This may explain the belief that chronic rejection is alloantibody-mediated. Transplant glomerulopathy distinct from recurrent glomerulonephritis was recognized by the late 1960s and early 1970s (10,11,12,13), and is a variable feature of CAN. However, these early observations by Hume, Porter, Jeannet, and their colleagues in transplants on minimal immunosuppression bear little resemblance to the type of late graft loss in the 1990s. The syndrome of obliterative arterial disease progressing over months is now rare, and the clinical course of CAN is usually indolent, with graft loss often many years posttransplant. The arterial lesions are often not prominent in biopsies early in the course. However, the old Hume-Porter-Jeannet syndrome remains the basis of the current animal models of chronic rejection, making them of limited relevance to the clinical problem of CAN. The Problem of Definition We avoid the term chronic rejection because it implies an ongoing immune response that cannot be proven. We cannot determine the extent of immune involvement in CAN at present, and the risk factors indicate a large nonimmune component. Previous efforts to define chronic rejection as a distinct disease often included an arbitrary rate of progression. Such definitions exclude kidneys with poor but stable function, while including kidneys with better function that have experienced recent deterioration. Moreover, progression is often irregular (14), and progression per se is not a criterion for defining other renal diseases. We define CAN as a state of impaired renal allograft function at least 3 mo posttransplant, independent of acute rejection, overt drug toxicity, and recurrent or de novo specific disease entities, wit