Chronic Allograft Nephropathy

Chronic Allograft Nephropathy Pankaj Baluja, Lukas Haragsim, and Zoltan Laszik With the advent of calcineurin inhibitors, the success of kidney and other solid-organ transplants has improved significantly from the standpoint of reducing the incidence of acute rejection. Over the past 2 decades, both short-term allograft survival and acute rejection rates have dramatically improved with improved diagnostic and therapeutic techniques such as standardized pathology scoring; potent antirejection drugs such as anti–thymocyte globulin, interleukin-2 receptor antibodies, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; and improved infection control such as valganciclovir and antifungal therapy. However, long-term graft loss has remained at nearly constant levels over the same period of time, with the average half-life of a deceased-donor kidney transplant in the United States remaining approximately 1 decade. In addition to death with a functioning allograft and calcineurin toxicity, a chronic fibrotic process— known at various times as chronic rejection, chronic allograft dysfunction, and chronic allograft nephropathy (CAN)—account for the leading causes of transplant failure. © 2006 by the National Kidney Foundation, Inc. Index Words: Chronic rejection; kidney transplantation; chronic kidney disease; transplant failure.

C

hronic allograft nephropathy (CAN) is defined as renal allograft dysfunction that occurs at least 3 months after transplantation and independent of acute rejection, drug toxicity, or other disease. The condition typically presents as progressive deterioration of graft function, evidenced by slowly rising plasma creatinine, proteinuria, and worsening of hypertension.1-4 These clinical manifestations are associated with pathologic changes in the blood vessels, glomeruli, interstitium, and tubules.4-8 CAN lacks a single predominant etiology but instead appears to be the cumulative result of a series of pathologic insults. Although much remains to be studied, mechanisms for the evolution of CAN have been proposed. The initiating event is believed to be endothelial injury, inflammation, and cytokine release. Intimal thickening of the arteries and arterioles ensues, leading to narrowing of the vascular lumina with resultant ischemia, focal glomerulosclerosis, and interstitial fibrosis. The nonsclerotic glomeruli undergo compensatory hypertrophy, with locally increased From the Department of Medicine, University of Oklahoma, Oklahoma City, OK; and Department of Pathology, University of Oklahoma, Oklahoma City, OK. Address Correspondence to Lukas Haragsim, MD, Associate Professor of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1301-0009$32.00/0 doi:10.1053/j.ackd.2005.11.004

56

glomerular filtration rate, which cause further injury to the glomerular capillary endothelium and eventual mesangial cell proliferation and matrix accumulation. Although pathological changes occur in all renal compartments, the principal cause of kidney dysfunction is believed to be the involvement of blood vessels and glomeruli.9-12 More recently, development of CAN has been divided into 2 main phases of injury. The first phase consists of immune-mediated tubulointerstitial injury, in which a state of “subclinical” rejection exists and histologic changes of acute rejection may be present without the associated clinical findings. This sustained injury, along with ischemia-reperfusion injury, provides the background upon which progressive vascular, glomerular, and interstitial changes occur. The second phase of injury appears to be less dependent on immune factors and more so on duration of calcineurin-inhibitor therapy and resulting toxicity and other factors, such as hypertension, donor age, delayed graft function, and recurrence of kidney disease in the recipient.13-15

Histopathology The principal morphologic features of CAN are progressive interstitial fibrosis, tubular atrophy, and glomerulosclerosis. The severity of CAN can be graded histologically according to the Banff Classification of Renal Allograft Pathology (Table 1).8 Although the severity of

Advances in Chronic Kidney Disease, Vol 13, No 1 (January), 2006: pp 56-61

Chronic Allograft Nephropathy

Table 1. Diagnostic Categories for Chronic Allograft Nephropathy (CAN) According to the Banff 97 Classification of Renal Allograft Pathology

57

Risk Factors

tissue injury is graded in all 4 renal compartments, the extent/severity of interstitial fibrosis, tubular atrophy, and tubular loss are the predominant features for determination of the degree of CAN. The pathologic changes (Fig 1) that affect the various tissue components are as follows:

The pathogenesis of CAN has been established as a multifactorial and sequential process, which broadly may be categorized as either immunologic or nonimmunologic. These processes play a synergistic role in the development of the disease.2,16,17 Among the factors categorized as causes of immune-mediated injury, prevention of acute rejection, adequate acute immunosuppression, avoidance of prior sensitization, and HLA matching have been among the most important considerations in the initial phases of transplant. A single episode of acute rejection within the first year of transplantation, regardless of subsequent adequate immunosuppression, is associated with a significantly higher incidence of CAN.18-23 Long-term studies have shown that recipients without an episode of acute rejection have less than 1% incidence of CAN.18,19 The same studies further stratified recipients with a history of

1. Vascular changes include subintimal accumulation of connective tissue that involves interlobular arteries and arterioles, resulting in luminal narrowing. 2. Glomerular changes include thickening of the glomerular capillary walls. with reduplication of the glomerular capillary basement membranes and glomerulomegaly secondary to mesangial matrix accumulation and cellular proliferation. In the more advanced stages, global glomerulosclerosis may develop. 3. Interstitial fibrosis involves a varying amount of the interstitium with or without focal inflammatory cellular infiltrates. Interstitial fibrosis may also occur secondary to chronic tacrolimus/cyclosporine nephrotoxicity. Concomitant changes in tubules and glomeruli, if present, may help to distinguish CAN from that of drug toxicity. 4. Tubular atrophy/tubular cell dropout is considered a rather nonspecific finding and may occur for a number of reasons other than CAN, including chronic cyclosporine/tacrolimus nephrotoxicity. However, splitting of the peritubular capillary basement membranes on electron microscopy is considered to be a characteristic feature of CAN.

Figure 1. Electron microscopy of the glomerular capillary walls in chronic allograft nephropathy (CAN), with reduplication of the glomerular capillary basement membranes (GCBMs). Prominent reduplication of the GCBMs is seen with mesangial cellular interposition and narrowing of the glomerular capillary lumen. Widening of the mesangial area caused by matrix deposition also occurs.

Grade I

II III

Histopathologic Findings Mild interstitial fibrosis and tubular atrophy (a) without or (b) with specific changes that suggest chronic rejection Moderate interstitial fibrosis and tubular atrophy (a) or (b) Severe interstitial fibrosis and tubular atrophy and tubular loss (a) or (b)

Data from Racusen et al.8

58

Baluja, Haragsim, and Laszik

acute rejection into (1) those with living-related v deceased-donor organs and (2) those in whom the episode of rejection occurred within or after 60 days of transplant. The highest incidence of CAN (60%) occurred in the group of recipients with deceased-donor organs, and those in acute rejection occurred more than 60 days after transplantation. The importance of this finding has not gone unnoticed. The principal change in approach to management of transplant patients over the past 2 decades has been to minimize the incidence of acute rejection. Other features that confer increased risk of CAN include increased severity of acute rejection, multiple episodes of acute rejection, and episodes of late acute rejection (1 year after transplantation). Long-term studies have also indicated an increased risk of graft loss for those with prior sensitization to HLA class antigens.24 This finding has been reflected as an increased waiting period and decreased statistical chance of obtaining an allograft for those who have been highly sensitized because of previous exposure (eg, blood transfusion or previously mismatched allograft).25 Correspondingly, a statistically significant difference is seen in the 3-year graft survival rates of those who receive HLA identical grafts as opposed to those with complete mismatch,26 particularly in short-term survival with HLA-B and DR matching and improved long-term survival with HLA-A matching.27 Of note is the importance of lymphocyte antigens as measured by the panel reactive antibody; increased reactivity increases the risk of graft loss. With this evidence, avoidance of sensitization is critical in those anticipated to require transplantation. The development of donorspecific antibodies after transplantation and the subsequent slow, insidious damage from the humoral immune system is currently an area of intense debate and research. Beyond immune-mediated factors are others that confer increased risk of CAN. Among the causes that increase the risk of acute rejection are brain death and ICU hospitalization of the donor.14,29,30 In both situations, physiologic stress leads to catecholamine release, vasoconstriction, and endothelial injury. Subsequent cytokine release and complement ac-

tivation cause T-cell–mediated injury of the allograft even before transplantation. Specifically, elevated intracranial pressure and subsequent brain death may also cause the allograft to be more susceptible to injury via recipient T-cell activation.31,32 In addition to the cause of donor death, the actual life span of the graft is also strongly predicted by the time taken for the graft to resume function. Delayed graft function is a significant risk factor for CAN, the risk of which is increased with ischemia and reperfusion injury.32 The most frequent cause of delayed graft function remains acute tubular necrosis secondary to relative ischemia in the immediate posttransplantation period. Transport time/cold ischemia has also been noted to increase the incidence of CAN, an effect that is most prominent in cadaver and living HLA-mismatched organs and is overcome by 6-antigen HLA matching. 33,34 Infections, particularly viral and bacterial pathogens that directly infect the allograft, contribute to the development and progression of CAN. In addition to activating mediators of inflammation, infection also enhances the expression of MHC II molecules within the endothelium of the allograft and allows donor antigen presentation and an enhanced immune response after transplantation, with subsequent allograft damage and decreased graft survival.29-32,35 For example, cytomegalovirus (CMV) infection of the donor or recipient portends a particularly high incidence of graft failure. 36 The role of recurrent transplant pyelonephritis is less well studied. The above factors do favor the role of impaired allograft function in the early stages after transplantation as a predictor of the eventual outcome, but chronic factors must be considered as well. Perhaps the most common among these chronic factors is glomerular hyperfiltration and hypertrophy.37-39 Secondary to the injury mechanisms within the first year, an allograft frequently undergoes glomerular hyperfiltration and subsequent hypertrophy as a compensatory phenomenon, similar to that seen in a native kidney. Mesangial changes occur, and an initial pattern of focal glomerulosclerosis is seen and may eventually lead to histopathologic changes similar to those seen in membranoproliferative glomer-

Chronic Allograft Nephropathy

ulonephritis (MPGN). Although an association with allograft dysfunction has been suggested with disparity between donor and recipient size, insufficient evidence is available to make a causal relation. Although a single cause of glomerular hyperfiltration remains elusive, uncontrolled hypertension is believed to contribute.40-42 The proposed mechanism is believed to be hypertensioninduced or exacerbated hyalinosis (originally cause by immune response). As a result, the resistance of the renal microvascular bed increases significantly, which may then lead to the histologic pattern of glomerulosclerosis. Finally, one of the major causes of longterm graft failure is calcineurin-inhibitor toxicity. Both cyclosporine and tacrolimus revolutionized transplantation by significantly reducing the incidence of acute rejection. The results achieved by the use of these medications had raised hopes of a corresponding decline in chronic graft dysfunction and graft loss. Retrospective analysis has shown that such an outcome has not been the case.43 Rather, prolonged use of the drugs may cause significant toxicity and histopathologic changes that, although similar to CAN, can be distinguished from CAN as defined above. A considerable amount of recent research has gone into the development of new immunosuppressants that not only will achieve the necessary levels of immunosuppression but also will have significantly lower toxicity and result in better long-term graft survival. The most promising immunosuppressants appear to be mycophenolate and rapamycine. Multiple trials are currently underway that compare varying duration of therapy of calcineurin inhibitors as well as varying combinations of other immunosuppressants, including mycophenolate mofetil, prednisone, and rapamycin. Other factors that play a smaller role in the development of CAN cannot be ignored. Among these factors is recurrent or de novo disease, particularly focal segmental glomerulosclerosis. Recurrent or de novo glomerulonephritis also appears to offset the benefit obtained by well-matched HLA grafts on the half-life of allografts. The age of the donor also plays a role, with an increased incidence of graft rejection and failure in organs from do-

59

nors above 60 years of age. Additionally, donor illness,28 the transplantation center,44 and duration of dialysis before transplantation45 have an affect on long-term graft survival.

Therapeutic Implications The emphasis for nephrologists remains prevention, when possible, of the onset and progression of CAN. One suggestion is the use of “protocol” kidney biopsies. These biopsies are performed at routine intervals, regardless of renal function during the first 1 to 2 years after transplantation to monitor subclinical acute rejection or the initial presence of chronic damage to the allograft before it becomes clinically apparent, by a rise in serum creatinine or proteinuria. However, protocol biopsies have not been systematically evaluated, and concerns about the known complications of biopsy routinely applied to all patients remain. Urinary markers for acute rejection have been studied, and markers for early chronic damage are being evaluated. Thus, because of the multiple factors that contribute to the pathogenesis and the lack of definitive diagnostic techniques, an integrated clinical approach toward prevention must address the major risk factors. The importance of minimizing the risk of acute rejection within the first year has been established, and adequate immunosuppression with calcineurin inhibitors as a part of the regimen remains a mainstay of treatment. However, newer regimens may allow calcineurin withdrawal, minimization, or substitution on a routine basis in the future. Longterm immunosuppression has been the subject of intense study and although no consensus regimen has been developed, those that include mycophenolate mofetil or sirolimus in place of calcineurin inhibitors after the first year have been associated with decreased incidence of biopsy-proven arteriopathy46 and higher creatinine clearance,47 without significantly increased risk of acute rejection.48,49 Beyond the institution of appropriate immunosuppressive therapy, emphasis on patient adherence should not be overlooked. Additionally, to minimize immune-mediated allograft failure, avoidance of sensitization and a careful pretransplant immunologic assess-

60

Baluja, Haragsim, and Laszik

ment (particularly to avoid donor-specific antibodies in patients with a second transplant) are necessary. Although aggressive control of blood pressure is considered universally important in all approaches to management of allografts, recent evidence suggests that, in selected patients, the judicious use of ACE-I/ARB was associated with a better creatinine clearance and decreased incidence of death and allograft failure.50,51 Although studied in a limited population, the benefit of this class of antihypertensive agents may indeed extend beyond diabetic nephropathy. Other risk factors within the control of the nephrologists remain the general care of the patient, including management of dyslipidemia, diabetes, and other comorbid conditions. Finally, early identification of decline in kidney function and a prompt evaluation of the cause of the dysfunction should be accomplished to institute appropriate management to slow and perhaps halt the progression of CAN. In general, this intervention should happen before the patient’s kidney function has chronically declined more than 30%. In summary, CAN remains one of the crucial challenges in the management of patients with kidney failure. No universally accepted algorithm exists, but careful monitoring of kidney function, avoidance of nephrotoxic insults, control of risk factors, and the use of novel immunosuppressive medications remain the best hope for improving long-term patient and allograft survival.

References 1. Hostetter TH: Chronic transplant rejection. Kidney Int 46:266-279, 1994 2. Carpenter CB: Long-term failure of renal transplants: Adding insult to injury. Kidney Int 48:40, 1995 3. Halloran PF, Melk A, Barth C: Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol 10:167-181, 1999 4. Manoco AP, Burke JF, Ferguson RM, et al: Current thinking on chronic renal allograft rejection: Issues, concerns, and recommendations from a 1997 roundtable discussion. Am J Kidney Dis 33:150-160, 1999 5. Yakupoglu U, Baranowska-Daca E, Rosen D, et al: Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study. Kidney Int 65:2360-2370, 2004 6. Kasiske BL, Kalil RS, Lee HS, et al: Histopathological

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

findings associated with a chronic progressive decline in renal allograft function. Kidney Int 40:514-524, 1991 Gouldesbrough BR, Axelsen RA: Arterial endothelialitis in chronic allograft rejection: A histopathological and immunohistological study. Nephrol Dial Transplant 9:35-40, 1994 Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713-723, 1999 Solez K, Benediktsson H, Cavallo T, et al: Report of the Third Banff Conference on Allograft Pathology (July 20-24, 1995) on classification and lesion scoring in renal allograft pathology. Transplant Proc 28:441444, 1996 Maryniak RK, First MR, Weiss MA: Transplant glomerulopathy: Evolution of morphologically distinct changes. Kidney Int 27:799-806, 1985 Kasiske BL, Kalil RS, Lee HS, et al: Histopathologic findings associated with a chronic, progressive decline in renal allograft function. Kidney Int 40:514524, 1991 Monga G, Mazzucco G, Massina M, et al: Intertubular capillary changes in kidney allografts: A morphologic investigation on 61 renal specimens. Mod Pathol 5:125-130, 1992 Nankivell BJ, Borrows RJ, Chir B, et al: The natural history of chronic allograft nephropathy. N Engl J Med 349:2326-2333, 2003 Matas AJ, Gillingham KJ, Humar A, et al: Immunologic and nonimmunologic factors: Different risks for cadaver and living donor transplantation. Transplantation 69:54, 2000 Andredottir MB, Assman KJ, Koene RA, et al: Immunohistological and ultrastructural differences between recurrent type 1 memranoproliferative glomerulonephritis and chronic transplant glomerulopathy. Am J Kidney Dis 32:582, 1998 Tullius SG, Tilney NL: Both allogen-dependent and -independent factors influence chronic allograft rejection. Transplantation 59:313-318, 1995 Krieger NR, Becker BN, Heisey DM, et al: Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts. Transplantation 75:1677-1682, 2003 Almond PS, Matas A, Gillingham KJ, et al: Risk factors for chronic rejection in renal allograft recipients. Transplantation 55:752-756, 1993 Basadonna GP, Matas AJ, Gillingham KJ, et al: Early versus late acute renal allograft rejection: impact on chronic rejection. Transplantation 55:993-995, 1993 Matas AJ, Gillingham KJ, Payne WD, et al: The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation 57:857-859, 1994 Humar A, Kerr S, Gillingham KJ, Matas AJ: Features of acute rejection that increase risk for chronic rejection. Transplantation 68:1200-1203, 1999 Humar A, Payne WD, Sutherland DE, et al: Clinical determinants of multiple acute rejection episodes in kidney transplant recipients. Transplantation 69:23572360, 2000 Lindholm A, Ohlman S, Albrechtsen D, et al: The impact of acute rejection episodes on long-term graft

Chronic Allograft Nephropathy

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

function and outcome in 1347 primary renal transplants treated by 3 cyclosporine regimens. Transplantation 56:307-315, 1993 Terasaki PI, Ozawa M: Predicting kidney graft failure by hla antibodies: a prospective trial. Am J Transplant 4:438-443, 2004 Cecka JM, Cho L: Sensitization, in Terasaki PI (ed): Clinical Transplants 1988, Los Angeles, CA, UCLA Tissue Typing Laboratory, 1989, p 365 Hata Y, Ozawa M, Takemoto S, et al: HLA matching, in Terasaki PI (ed): Clinical Transplants 1996, Los Angeles, CA, UCLA Tissue Typing Laboratory, 1997, p 381 Zantvoort FA, D’Amaro J, Persijn GG, et al: The impact of HLA-A matching on long-term survival of renal allografts. Transplantation 61:841-844, 1996 Ponticelli C, Villa M, Cesana B, et al: Risk factors for late kidney allograft failure. Kidney Int 62:1848-1854, 2002 van der Hoeven JA, Molema G, Ter Horst GJ, Freund RL: Relationship between duration of brain death and hemodynamic (in)stability on progressive dysfunction and increased immunologic activation of donor kidneys. Kidney Int 64:1874-1882, 2003 Lu CY, Penfield JG, Keilar M, et al: Hypothesis: Is renal allograft rejection initiated by the response to injury sustained during the transplant process? Kidney Int 55:2157-2168, 1999 Parschke J, Vok HD: Brain death-associated ischemia and reperfusion injury. Curr Opin Organ Transplant 9:153, 2004 Yokoyama I, Uchida K, Kobayashi T, et al: Effect of prolonged delayed graft function on long-term outcome in cadaveric kidney transplantation. Clin Transplant 8:101-106, 1994 Peters TG, Shaver TR, Ames JT, et al: Cold ischemia and outcome in 17,937 cadaveric kidney transplants. Transplantation 59:191-196, 1995 Polyak MM, Arrington BO, Stubenbord WT, et al: The influence of pulsatile preservation on renal transplantation in the 1990’s. Transplantation 69:249-258, 2000 Stokes KY, Abdih HK, Kelly CJ, et al: Thermotolerance attenuates ischemia-reperfusion induced renal injury and increased expression of ICAM-1. Transplantation 62:1143-1149, 1996 Waldman WJ, Knight DA: Cytokine-mediated induction of endothelial adhesion molecule and histocompatability leukocyte antigen expression by cytomegalovirus-activated T cells. Am J Pathol 148:105-119, 1996 Bia MJ: Nonimmunologic causes of late renal graft loss. Kidney Int 47:1470-1480, 1995

61

38. Melk A, Gourishankar S, Halloran PF: Long-term effects of nonimmune tissue injury in renal transplantation. Curr Opin Organ Transplant 7:171-177, 2002 39. Bhathena DB: Glomerular size and the association of focal glomerulosclerosis in long-surviving human renal allografts. J Am Soc Nephrol 4:1316-1326, 1993 40. Sanders CEJr, Curtis JJ: Role of hypertension in chronic renal allograft dysfunction. Kidney Int 52:S43S47, 1995 (suppl) 41. Cheigh JS, Haschemeyer RH, Wang JC, et al: Hypertension in kidney transplant recipients. Effect on long-term renal allograft survival. Am J Hypertens 2:341-348, 1989 42. Kasiske BL, Anjum S, Shah R, et al: Hypertension after kidney transplantation. Am J Kidney Dis 43: 1071-1081, 2004 43. Meier-Kriesche HU, Schold JD, Srinivas TR, et al: Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4:378-383, 2004 44. Kim SJ, Schaubel DE, Jeffery JR, et al: Centre-specific variation in renal transplant outcomes in Canada. Nephrol Dial Transplant 19:1856-1861, 2004 45. Opelz G: The benefit of exchanging donor kidneys among transplant centers. N Engl J Med 318:12891292, 1988 46. Melk A, Halloran P: Immunosuppressive agents used in transplantation, in Johnson RJ (ed): Comprehensive Clinical Nephrology, Philadelphia, PA, Mosby, 2000, p 1057 47. Sells RA, Bakran A, Brown MW, et al: A prospective randomized study of CsA monotherapy versus CsA ⫹ mycophenolate mofetil in cadaveric renal recipients. Program and Abstracts of the 3rd International Conference on New Trends in Clinical and Experimental Immunosuppression. Geneva, Switzerland, Feb 12-15, 1998. 48. Weir M, Anderson L, Fink J, et al: A novel approach to the treatment of chronic allograft nephropathy. Transplantation 64:1706-1710, 1997 49. Dudley C, Pohanka E, Riad H, et al: Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: The “Creeping Creatinine” Study. Transplantation 79:466-475, 2005. 50. Lin J, Valeri Am, Markowitz GS, et al: Angiotensin converting enzyme inhibition in chronic allograft nephropathy. Transplantation 73:783-788, 2002 51. Zaltzaman JS, Nash M, Chiu R, et al: The benefits of renin-angiotensin blockade in renal transplant recipients with biopsy proven allograft nephropathy. Nephrol Dial Transplant 19:940-944, 2004