Rethinking Chronic Allograft Nephropathy

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, with typical features on biopsy (see below). One can designate graft loss due to CAN, and can define progressive CAN by an arbitrary change over time. Such definitions avoid the problem of defining chronic rejection so rigorously that one excludes much of the population of interest. Magnitude of the Problem of CAN The two largest problems in renal transplantation are organ availability and late graft loss. A transplant is beneficial compared to remaining on the waiting list (15) and is the treatment of choice for end-stage renal disease. However, the average cadaver donor transplant fails at about 10 CAN is the cause of to a transplant and a major cause of end-stage renal disease in the developed the number of on and kidneys for CAN to the of and renal in the with renal transplants in have and immunosuppression has acute rejection but has little effect on CAN and late graft loss. CAN is in cadaver donor transplants than donor transplants but the clinical course is in donor transplants it is The of CAN The of CAN is nonspecific and of specific The CAN atrophy, interstitial fibrosis, and in and is the basis for the of CAN for CAN are at CAN lesions including the lesions often the of CAN overlap the lesions in the aging kidney Thus, many kidneys now the for CAN at the of The of CAN lesions in cadaver transplants is about to by but it is not in much was at the of The key feature may be atrophy, with a in renal is an increase in interstitial and in but it is to the increase in and the of in the because the kidney has in size A of the by may be specific for CAN and is The injury rejection has been with transplant on the that the and interstitial fibrosis. This may not be and is not a for CAN or chronic with and lesions of the arterial lesions in CAN have been as and to the lesions in chronic rejection of in However, such are lesions are in CAN that are not in donor kidneys and one of the strong of CAN lesions is with donor age the of graft at mo is determined by the donor in transplants by the transplant disease is and not the process are differences in the and transplant but these may reflect the age of the or the of Thus, the arterial changes in kidney transplants and in transplants may of the arterial disease with in cell and and in the the of the loss of in is due to failure of the to in response to and exhaustion of the normal due to endothelial to from growth of from the failure of the of the to as it should in response to Thus, the on the intimal changes should be by the concept of a of arterial In CAN, renal function and with the of the the chronic allograft at correlates with transplant function at and with graft However, it is with progression than does the or which the of but are and Load of CAN has emerged from the human renal transplant late graft loss is due to CAN, the risk factors for late allograft failure can be as a for CAN. that the of graft failure in are as of the tissue the rejection and the load or stress on the organ factors for renal graft The of the are two of input chronic changes from stresses and in the and the acute that in and The of and or for donor are the importance of acute and chronic input In the the usually and now are to be with and The is that nonspecific input injury is rejection as the major process CAN and graft Chronic age is the of poor graft and CAN lesions with donor age from an of graft function and The aging kidney functional in due to age and age-related such as and disease loss of renal is with of the The number of due to and the remaining glomerular is not a major in age-related changes for that in The of from in the to 10 to in the to the CAN are prominent in the aging kidney. The lesions with renal but it is not that nephron loss or of cells in the probably as a response to injury. of donor age explain about of the in kidney transplant The of donor aging have been to be due to nephron However, the of donor age and other input are than the of nephron such as donor size and which to of the Thus, changes in the aging kidney probably to the than nephron dose per we this may be a in in the than due to nephron In other the age of the and the number of may graft In renal the of a of the has been as the basis for This may not be due to in and because may not be the of graft The extent of may better renal tissue in In the gender and size of the donor the but and size differences probably reflect nephron dose and are as load factors. Acute graft function is a strong of graft acute injury related to the and transplant it is that preexisting chronic changes such as increase This reflects the of the kidney with chronic stress to acute injury, as in acute renal failure of other has been to injury, but is than One key may be renal injury due to which can now be in and is and in many in the reflects the of many death, donor maintenance, and preservation, the and arterial in the the is in with perhaps because rejection can as acute tubular grafts from compared with transplants the of the stresses of and other risk factors for function and suggesting that current conditions for and are not The of renal to the 1960s and to be the of and should be stress be Moreover, the in organ have been to the function of the at the of renal stresses may with the chronic input stresses in the kidneys with age-related from of by have better than from from events features of the donor the such as may the of the factors such as of death, and age-related disease the of these with large renal hypertension, and little disease are compared to are to be and to have hypertension, and disease. We to the models for these and acute rejection have a major effect on graft Acute rejection or not well to the early of CAN. In progression of CAN is with of an ongoing immune to and Such are to be and the and of and cells in CAN remains the was The about the of acute rejection in CAN have in recent from acute rejection correlates with from CAN and from late graft loss. The rejection that with late graft loss by impaired function or recurrent and rejection acute rejection early and late and graft rejection by immunosuppression has effect than on CAN and late graft loss to The such as A and have to or renal function or graft despite reducing the rate of acute over for reducing CAN but these may reflect of compared with in the early and have not been in recent in the Transplant such as donor and due to have a on graft in cadaver transplant at least as strong as or other immune The of per se is by the that transplants as well as one related donor transplants and better than cadaver transplants kidneys rejection may in be a for input injury and and rejection may for of the effect of graft even acute rejection are that the of are with can acute rejection even late and may to the failure of to transplant This may explain to have effect on transplant than is a in the treatment of and Input Injury with Immune with have acute rejection and grafts function usually rejection The of and rejection poor for immune problems in kidneys with acute input injury in the of rejection in but may be a increase in immune in A of of injury a of events that to a response to tissue injury and not to the injury response The immune is by such that in normal tissue to be and in tissue is the injury is to and an immune response perhaps in due to Injury may as an of in epithelium and endothelium as well as and cells Injury and inflammation immune in the the immune Acute input injury rejection, and rejection injury inflammation and immune injury The importance of this in clinical transplantation remains of chronic allograft nephropathy (CAN) fibrous intimal tubular atrophy, and interstitial fibrosis. intimal tubular with interstitial acute input by increase rejection, the chronic stresses such as age-related changes may is that donor and parenchyma has features of chronic inflammation, with cells than and in the of vessels, and and in endothelial and of many The and lesions immune However, in human transplants the of donor age and disease are but their with rejection is Load The nonimmune factors to graft the of progression of chronic renal disease in Thus, current on size and hypertension, proteinuria, and Such or stress the inflammation, and immune of the is better in of an effect usually to nephron dose (see factors to patient and other factors such have immune and to or and the nephron or has been as a risk for progression of renal disease and CAN. large size and gender graft in it is not that these reflect CAN in the donor size and glomerular as in However, the of gender and size are compared with the of donor age and and is little that is a of progression in human CAN, or even that CAN A large of tissue to the may the immune In tissue correlates with the immune and and an may to the of transplants nephron may inflammation, as has been in models from are with in graft in of and the Transplant is not this reflects an risk of CAN. may be with chronic rejection of transplants and transplants of has been with the of chronic rejection, but such observations are by the of clinical with and with Thus, the case that human CAN remains in CAN, in and treatment may CAN. can cause arterial disease in is A and has been for However, of kidney with by in and to or in the In grafts with proteinuria, the may be to the this cannot renal injury, it may to progression in in the is with CAN and late graft failure as a cause or an The in by treatment is in the the of the of in the recurrent rejection impaired graft function, and such as and with is a to the extent to which of can CAN in this that to CAN. and are risk factors for the of and are in transplant and to patient from disease The of in the of CAN is from the of correlates with CAN but cause CAN remains with graft in renal biopsies in one but other have not a The of and may with graft failure in kidney transplants and in transplant Thus, by with CAN. present, with is not for allograft but should be other risk factors are are about of in with the of One problem for that or cause CAN is such be in the transplant the host input and immune stress in the transplant them to from and of and The of from the and to CAN is to CAN excludes of drug The typical of renal from is in which thickening with with changes, and of cells on and of the with of and glomerular may stable due to growth and in suggest that or can increase CAN are early of toxicity, but or may the of immune injury The of the of reflect this beneficial and of the of of an and of CAN is not of correlates with chronic rejection in one suggesting that is This should be in other in one population with graft loss but it has been to that the and of these graft Thus, it remains in renal transplants or to the problem of progressive loss of function due to CAN, or chronic of or other CAN. the in the In these are two immune and The immune is that on graft function are due to immune Thus, nonspecific tissue injury the which the of The process be recurrent clinical or acute rejection or a immune process such as alloantibody The for the immune is the of kidneys with in the and Thus, load factors can be by the kidney immune injury is increase acute rejection even late and the of to increase with time. The strong of in cadaver transplantation for the immune The is the nonimmune that rejection is one of many which a chronic nonimmune The that acute rejection by immunosuppression has little effect on graft this as are which that early rejection is it is Rejection that fails to to may be with CAN because the failure to kidneys exhaustion of their repair due to the cumulative of the Thus, acute rejection in such kidneys little to the is to explain of the human and a of these is the In the that of the is a effect of chronic and acute input and of immune and effect of load factors. The effect of input and immune injury may be to stress the tissue and by the aging as of Chronic with of Chronic models of chronic human a human disease that years or within or months. the model has been to the are on the that a which the human disease have a This is and the of animal models to human over a much is This has been by et al. in the of animal models of and The animal models may be from the human diseases. age or to human CAN but are not well in other are major differences in the response to injury and in the aging process kidneys have a to a which does not in injury in kidney transplants triggers a chronic process with prominent which is but is not the human of injury that are by chronic for human CAN are not usually in and or even donor donor donor hypertension, death, preservation, graft animal models the donor transplants in death, minimal injury, and chronic disease. kidneys the typical of human renal the of Thus, CAN in animal models to be by immune and by immune the human In recent in clinical to the of animal models to the of human the the and the of in of such as the renal effect of in nephropathy and by animal and animal models of acute rejection have been for The is that we to animal models but that may not be models of the human models should be that the of human CAN. the of animal models of CAN, we on them to in of CAN in animal models to be by immune such as and Thus, immune in animal models often allograft or CAN, or or injury in kidneys and in in a intimal thickening and with on immunosuppression CAN may the by and has a of other on CAN models treatment and of immune The kidney is the for of nephron which to proteinuria, and inflammation In renal and changes CAN in with the of growth factors such as growth and transforming growth and The events are not by the donor a of molecular are as or mediators of lesions. the can or growth of arterial cells on the availability of specific of tissue may be and the determine the effect of and as well as cell may be early and of and many other be for to be to the human process of CAN. a of and the of CAN that of aging and age-related recent on the cell of aging and senescence may be cells in are usually limited in their number of cell This finite has been the the limit the of this the cell many and usually This is one of senescent in cells. such as or may be is as cell has that determine their is an state that cells with potential for to avoid the that are in senescence are the and cell at which are to cells to growth as a response to Recent a limited number of other in the of such as cells or the the a of and the which the response to and the of the which growth is one of the The is the of at the of with specific is to the problem that the of cannot be and is with and to the of from recognized as In the problem of is by a as well as by other for In is and with may be other in as a because the and the cell is has been in human and in aging in and may explain the senescence is determined by including the of number of cell of and the level of injury and The to senescence in is on the donor age at the of and stress in tissue to can the process of senescence may be for and have and have human which senescence is senescence in vitro and organ aging in but it is to that the aging of a tissue reflect changes in key cells within that which change the In an epithelium or an the of the tissue is limited by the ability of cells to maintain the tissue and and to it acute injury. In arteries, the endothelial cells may be cells the of in and and of the In or exhaustion of the endothelial for repair and of the may the (FIT) lesions. age is limited by endothelial is a feature of the aging kidney and is by disease such as The endothelial cells to and injury may their ability to of the arterial in fibrosis. may be other cells in the the cells. events may be to in the of injury and repair may the limit of the of the epithelium to repair, to Thus, senescence of key cells be the tissue Injury of such as and inflammation the cells can the injury and the inflammation with minimal the epithelium cannot the inflammation and in perhaps because the injury response cannot be by of Thus, fibrosis may for fibrosis of the senescence A for Chronic The human observations are as specific lesions human CAN from aging or age-related diseases. The concept of chronic rejection as an immune disease as by Hume, Porter, Jeannet, and their colleagues does not the current disease of CAN, much of which reflects nonimmune factors. The of acute rejection by immunosuppression has effect on CAN than age and organ CAN. of acute rejection correlates with CAN. (6) CAN. (7) models of chronic rejection not reflect the of human CAN. We suggest that nonimmune injury, and rejection renal tissue a to a state of of finite repair potential that we renal senescence This is by progressive and endothelial with fibrosis. is by age-related the injury, rejection, and load factors such as hypertension, and This is by the of the donor and may CAN not a disease but a that kidneys or by the stresses on the the per nephron may the process to in but this is a of and endothelial of the model for CAN including of inflammation and recent the concept that stresses of transplantation can In the cells about a of is not to that the stress of renal transplantation key renal cells to their The of renal failure in normal aging even with a kidney that the aging process normal load conditions is by acute nonspecific injury or immune injury. This is with the of renal failure in with one kidney for organ the of donor and the relatively effect of kidneys Thus, the of a nephron the of these is not a compared with input immune the of end-stage renal disease of in the suggest that injury repair be limited in old kidneys stresses due to a renal disease. In this model of CAN and for that in normal the interstitial and intimal fibrosis are to be to the exhaustion of the and endothelial that is to from in does not change the senescent changes are in the endothelium and the The response to injury may be or injury inflammation and with little fibrosis the epithelium and fibrosis are the process is When for tissue are senescence of inflammation may with immune response to immune of the and promote rejection, or may an stress on the tissue which senescence and triggers fibrosis. The of inflammation fibrosis, as an stress on the and the specific immune and of a of CAN The model the prominent effect of donor age and the effect of nonspecific injury and rejection, and for the overlap the lesions of CAN and of aging and of other renal diseases. The model should on the cell of the and endothelial cells in CAN and for that in other chronic renal diseases. A kidney transplant is a The and and useful and ability to The such a to and the of the In a we a We and to useful We two old to one the on the kidneys with and that may a few years not be but to with end-stage disease as a finite but useful to than we to such and with may be to the state of senescent change in donor the on a The such as may to much a kidney has we should the senescence by to acute input stress to the tissue exhaustion may be kidneys be to because immune and are in the kidney to stress may be by of immunosuppression may be useful for kidneys with changes, perhaps agents. We should and and should be with of fibrosis be In fibrosis in CAN is the cells in the and their to repair, and remodel fibrosis may the by further and to the other of fibrosis be two kidneys to one has been but this many with The of kidneys from a donor to one host is to but may be on a in the progression of CAN is due to a in the kidney than to the of two kidneys be than two kidneys from a donor should be to one in the of a clinical in which the of transplants can be compared with that of two one kidney. Such a renal than which the number of grafts due to patient clinical the is to transplant kidney one with and that the kidneys have and of these have for progression in chronic renal disease that cannot be the stress of a the repair potential of the cells and to with fibrosis. of the kidney an of these We are to and for of of this and the it and to and for