Pathogenesis and management of an important posttransplant complication

Chronic allograft nephropathy: pathogenesis and management of an important posttransplant complication

Aull, Meredith J

Chronic allograft nephropathy is a devastating complication of kidney transplantation that is responsible for a significant proportion of graft loss. This complication is characterized by a progressive decline in kidney function, which is not attributable to a specific cause. Many risk factors exist for the development of chronic allograft nephropathy, including donor-, recipient-, and transplant-related factors (eg, use of calcineurin inhibitors and acute rejection episodes), as well as comorbid conditions such as hypertension and hyperlipidemia. There is no definitive treatment for this complication; management has focused on minimization or withdrawal of calcineurin inhibitors in conjunction with addition of sirolimus or mycophenolate mofetil. Alterations in the immunosuppressive regimen must be done cautiously, as precipitating acute rejection will cause further damage to the allograft. Optimal control of blood pressure, particularly with the use of agents such as angiotensin II receptor blockers, in conjunction with management of dyslipidemia may be effective concurrent therapies in patients with chronic allograft nephropathy. (Progress in Transplantation. 2004;14:82-88)

Newer, more potent immunosuppressive agents introduced in the last decade have significantly improved acute rejection rates after kidney transplantation; however, this has not translated into significant improvements in long-term graft survival. Acute rejection within the first posttransplant year decreased from 38.5% of kidney transplant recipients in 1991 to 16.6% of recipients in 2000.1 However, current 5-year graft survival rates are 63.3% and 76.5% in deceased donor and living donor transplants, respectively.1 Leading causes of kidney graft loss after the first posttransplant year now include death with a functioning graft and chronic allograft nephropathy (CAN).1,2 According to data from 1994 to 1998, graft loss from CAN accounted for more than 30% of the losses that occurred between posttransplant years 1 and 3.2

Formerly known as chronic rejection, the term “chronic allograft nephropathy” evolved over time as it became evident that the chronic changes to the kidney allograft are mediated by both immune and nonimmune factors. CAN has been described as the progressive decline in allograft function that occurs months or years after transplantation and is not caused by acute rejection, recurrence of original disease, surgical complications, or other identifiable factors.3 Clinical manifestations of CAN include deterioration in kidney function (as evidenced by a slow, progressive increase in serum creatinine and decline in glomerular filtration rate [GFR]), proteinuria (usually 1-2 g/day), and arterial hypertension. Histologically, biopsies of kidney allografts with CAN reveal features such as inflammation, fibrosis, glomerulosclerosis, tubular atrophy, and vascular smooth muscle proliferation.4,5 The Banff criteria are used to grade the severity of CAN on the basis of the extent of interstitial fibrosis and tubular atrophy found upon biopsy.4 Table 1 contains the grading system used to stratify the severity of CAN in the Banff 97 classification.

Significance of Chronic Allograft Nephropathy in Kidney Transplantation

Many studies have been performed to assess the incidence of CAN and to identify the factors involved in the pathogenesis of this complication. In one single-center retrospective analysis6 of 2140 kidney transplant recipients, the 5-year incidence of biopsy-proven CAN was 12.2%. In this study, there were no significant differences in CAN rates observed among cadaveric donor (13.2%), living related donor (nonidentical; 15.9%), and living unrelated donor (12.0%) kidney transplants. The 5-year incidence in HLA-identical living donor transplants was 0%; however, these recipients did develop CAN later, with 25% of grafts ultimately lost to CAN. Overall, CAN was the cause of graft loss in 32% of failures: 28% cadaveric, 51% one-haplotype living related, 45% living unrelated, 25% identical; P = .001. This cause of graft loss was only slightly less than death with a functioning graft, which was responsible for graft loss in 34% of cases: 37% cadaveric, 24% one-haplotype living related, 28% living unrelated, 35% identical; P = NS. Overall, the development of CAN led to a 10.5-fold increase in graft loss.6

Acute rejection within the first 6 to 12 months after transplantation has been identified as one of the strongest risk factors for the development of CAN.7,8 Sijpkens and colleagues9 studied 654 cadaveric kidney transplant recipients with grafts functioning for 6 months or more. Of these, 54 (8.3%) were diagnosed with progressive kidney dysfunction unrelated to calcineurin inhibitor nephrotoxicity or recurrent disease. The strongest risk factor for development of CAN was acute rejection occurring more than 3 months after transplantation; other factors included younger recipient age and higher panel reactive antibody level at time of transplantation. The FK506 study group found an increased incidence of CAN in patients who had acute rejection within the first posttransplant year.10 Another prospective, single-center analysis did not find acute rejection to be a risk factor; however, chronic graft changes did correlate with lipid abnormalities and the chronic allograft damage index, as assessed by kidney biopsy.11 The lipid abnormalities included significantly higher triglycerides, total cholesterol, and low-density lipoprotein in patients whose allograft function deteriorated in comparison to those whose graft function remained stable (P > or =.02 for each marker).

An additional factor that appears to have an important role in the development of CAN is transforming growth factor [beta]^sub 1^ (TGF-[beta]^sub 1^), a profibrotic and proinflammatory cytokine that has been implicated in the development of graft fibrosis.12 Levels of TGF-[beta]^sub 1^ may be increased by angiotensin II and cyclosporine, having implications for the management of patients with CAN.

In a study of 2140 kidney transplant recipients, Krieger and colleagues6 identified risk factors for the development of CAN, including retransplantation, acute rejection, panel reactive antibody value, serum creatinine at discharge, serum creatinine at 1 year, delayed graft function, HLA-B and HLA-DR mismatches, recipient age and black race, donor age and black race, cold ischemia time, and cytomegalovirus infection. Table 2 contains the many factors that have been implicated in the development of CAN.

The chronic damage that occurs in CAN may occur relatively early in the posttransplant period. Nicholson and colleagues13 demonstrated that analysis of certain markers in kidney biopsies performed at 6 months after transplantation might serve as surrogate markers for the development of chronic changes. The authors performed immunostaining for several factors involved in the tissue remodeling process (collagen III, smooth muscle actin, infiltrating leukocytes, and tenascin). Levels of collagen III were elevated in the biopsies of patients who later developed CAN and the percentage of collagen III in the biopsy correlated with GFR. Patients with high levels of collagen III had a mean GFR of 30.8±3.6 mL/min, compared with 44.8±3.6 mL/min in those with lower levels of collagen III (P = .01). Measurement at this early time may allow more opportunity to modify the immunosuppressant regimen to prevent further progression of the histologic changes.

Another article in this issue focuses on the use of calcineurin inhibitor-sparing and withdrawal protocols to prevent the development of CAN. The remainder of this article will focus on some of the strategies that may be used in managing patients with CAN, as well as review some other approaches that may prove valuable in the prevention of this devastating complication.

Impact of Calcineurin Inhibitors on the Development of Chronic Allograft Nephropathy

Many of the studies examining CAN have been in populations receiving cyclosporine-based immunosuppression regimens; however, it is obviously important to determine the significance of CAN in patients receiving tacrolimus-based regimens as well. Murphy and colleagues14 performed a prospective randomized trial to analyze the impact of calcineurin inhibitor on the development of CAN. One-year protocol biopsies of 102 patients receiving either tacrolimus- or cyclosporine-based immunosuppression were evaluated for allograft interstitial extracellular matrix proteins, which are indicators of fibrosis shown to be surrogate markers for CAN.13 This study found that patients receiving the cyclosporine-based regimens were at higher risk for developing fibrosis of the kidney allograft (P = .002 compared to patients receiving tacrolimus).14 This difference occurred despite similar baseline demographics, clinical characteristics of donor and recipient, delayed graft function rates, acute rejection rates (including steroid-resistant acute rejection episodes), serum creatinine and GFRs at 1 year after transplantation. Calcineurin inhibitor-associated adverse effects included hyperlipidemia with cyclosporine and impaired glucose tolerance with tacrolimus; the authors point out that the hyperlipidemia associated with cyclosporine likely contributed to the increased rate of fibrosis seen on biopsy, demonstrating that the adverse effect profile of these agents may contribute to the development of fibrosis.14

Analysis of 2-year protocol biopsies from 144 recipients of cadaveric kidney transplants who were enrolled in the FK506 Kidney Transplant Study found significant CAN in both tacrolimus- and cyclosporine-treated recipients; however, the rate was lower in tacrolimus-treated patients (62.0% vs 72.3%; P = NS).10 The mean chronic lesion scores were similar, indicating the presence of histopathologic changes that included little or mild interstitial fibrosis, tubular atrophy, or intimal thickening in both groups. It was noted than CAN was increased in patients receiving a kidney from an older donor, in patients with calcineurin inhibitor-induced nephrotoxicity, in those who developed cytomegalovirus infection, and in those who had an acute rejection episode in the first posttransplant year.10

Strategies for Management of Chronic Allograft Nephropathy

Calcineurin Minimization or Withdrawal in Conjunction With Mycophenolate Mofetil

Long-term outcomes associated with calcineurin minimization or withdrawal in patients with biopsy-proven CAN were studied in 118 kidney transplant recipients at the University of Maryland.15 Interventions included calcineurin-inhibitor dose reduction (n = 100; close decreased by 50%) and discontinuation (n = 18); the decision was arbitrary and based on HLA matching and degree of kidney dysfunction. To compensate for the reduced immunosuppression, mycophenolate mofetil was either added or maximized to a dose of 2 grams per day, and all patients received low-dose prednisone. In addition, a majority of the patients had received induction therapy with antilymphocyte agents. The patient population consisted primarily of male African American recipients of cadaveric grafts, with a mean serum creatinine level of 2.8 mg/dL before intervention (mean time since transplantation was 853 days). Thirty-three patients had 1 or more kidney biopsies to evaluate increases in serum creatinine alter intervention; acute rejection occurred in 18 of 118 patients (15.3%) and the majority of rejections were graded as mild and easily treated with corticosteroids. Approximately 50% of patients experienced improvement, or at the very least, lack of further deterioration in kidney function during the study period. These observations are based on serum creatinine level, however, not repeat kidney biopsy. Although most patients did not tolerate the 2 grams per day of mycophenolate because of adverse effects, all patients tolerated at least 1 gram per day. The authors stress the importance of careful management of other potential risk factors for graft deterioration, including blood pressure, hypercholesterolemia, and blood glucose.

The use of mycophenolate mofetil to substitute for cyclosporine in patients with chronic allograft dysfunction has also been studied by the MMF “Creeping Creatinine” Study Group.16 In this study, 143 patients with biopsy-proven chronic allograft dysfunction were randomized to receive mycophenolate mofetil and cyclosporine withdrawal (n = 73) or to continue receiving cyclosporine (n = 70). Kidney function stabilized in 58% of mycophenolate mofetil/cyclosporine withdrawal patients compared to 28% of patients continuing to receive cyclosporine (P

Calcineurin Minimization or Withdrawal in Conjunction With Sirolimus

Potential benefits of using sirolimus to treat CAN were observed in early trials of sirolimus, in which improvements in kidney function were noted in patients receiving combined therapy with sirolimus and cyclosporine compared to patients receiving full-dose cyclosporine therapy. In an analysis of 446 kidney transplant recipients treated with sirolimus, Kahan et al17 found a significantly lower rate of CAN at 3 years after transplantation in recipients treated with low-exposure cyclosporine/sirolimus than in patients receiving high-exposure cyclosporine/sirolimus or cyclosporine/prednisone regimens.17 Results of the European Rapamune Maintenance Regimen Study show that at 2 years, serum creatinine and systolic blood pressure in patients withdrawn from cyclosporine alter the third postoperative month were significantly better than in patients remaining on the cyclosporine/sirolimus combination.18 Patients remaining on the cyclosporine regimen had more complications, including hypertension, abnormal kidney function, and nephropathy.18

Because of these findings, recent research in the area of CAN has focused on the use of sirolimus to prevent CAN and/or delay progression once the diagnosis of CAN is established. Sirolimus has been studied using various approaches, the most common of which include use as a calcineurin-sparing agent and to completely withdraw calcineurin inhibitors from the immunosuppressive regimen.

In a study of 19 patients with chronic allograft dysfunction, Citterlo et al19 performed sharp withdrawal of calcineurin inhibitor with addition of sirolimus. Target trough levels for sirolimus were 8 to 10 ng/mL; calcineurin inhibitor was stopped the evening before the first dose of sirolimus in the majority of patients, and patients were continued on their maintenance steroid doses. The kidney transplant recipients had a median serum creatinine level of 2.85 mg/dL at the time of intervention, and were an average of 104±73 months after transplantation. Conversion was based on progressive declining kidney function, as defined by a serum creatinine of 2.0 to 4.5 mg/dL and/or proteinuria greater than 500 mg/day. Renal biopsy showing fibrosis, tubular atrophy, and intimal hyperplasia was also used as an indication for conversion to sirolimus. At 6 months after conversion, there were no episodes of acute rejection; however, there was a significant increase in both total cholesterol and triglyceride levels. Response to conversion included amelioration of kidney dysfunction in 36% of patients and stabilization in 21%, whereas 43% experienced continued deterioration. Results showed that patients who had improvement or stabilization in kidney function were converted at a significantly lower serum creatinine than those who showed continued decline in function (2.6 vs 3.3 mg/dL; P

Saunders and colleagues20 studied 31 kidney transplant recipients with biopsy-proven CAN. Patients were randomized to receive either cyclosporine dose reduction with (n = 16) or without (n = 15) addition of sirolimus 2 mg/day. All patients had a kidney biopsy and GFR measurement at study entry and again at 6 months. Cyclosporine dose reduction included a 40% decrease in dose to achieve a target trough of 50 to 75 ng/mL; goal sirolimus trough was 5 to 15 ng/mL. Prednisone was continued at the previous dose, and azathioprine was discontinued in the 19 patients who were taking it before study entry. There were no episodes of acute rejection; however, GFR decreased significantly in patients receiving sirolimus, whereas it remained stable in patients who received cyclosporine dose reduction alone. In addition, the sirolimus-treated patients showed no improvement in the molecular and histologic tests performed on the biopsy tissue. Adverse effects more common in sirolimus-treated patients included arthralgia, gastrointestinal symptoms, and increased triglycerides.

Ruiz and colleagues21 studied a subgroup of 57 patients who were enrolled in a randomized trial of cyclosporine plus sirolimus (n = 29) versus cyclosporine plus sirolimus, with cyclosporine elimination at 3 months after transplantation (n = 28). These 57 patients had 2 biopsies performed, one at the time of transplantation and another at 1 year after transplantation. Biopsies were assessed for the presence and progression of chronic lesions that existed at the time of transplantation, as well as for the development of new CAN. Patients in the cyclosporine elimination group had a lower rate of both progression of chronic lesions and new CAN. The lower rate of progression in the chronic lesions occurred even though patients in the cyclosporine elimination group had higher chronicity scores at baseline. The development of new CAN was 65% in patients continuing on cyclosporine versus 30.8% of those undergoing cyclosporine elimination (P

Amm and colleagues22 performed a retrospective review of 57 patients with clinical features of CAN who received substitution of sirolimus for calcineurin inhibitors. Sirolimus was introduced and followed by a 6-week overlap with calcineurin inhibitors; sirolimus target trough level was 5 to 10 ng/mL. Mean baseline serum creatinine at time of sirolimus introduction was 2.5 mg/dL and some patients had proteinuria. All patients had at least 6 months of follow up. Overall, stabilization of creatinine occurred in 36% (creatinine at baseline 2.5±1.1 mg/dL vs 2.5±1.4 at follow-up; P = NS), improved in 38% (2.4±0.7 vs 1.9±0.7; P

Overall, the use of sirolimus appears to be beneficial in attenuating CAN, although the most benefit appears to be derived from early withdrawal of cyclosporine and/or conversion to sirolimus occurs when the creatinine is mildly elevated. The risk of acute rejection with sirolimus appears to be low after calcineurin withdrawal; the rate of acute rejection is similar between patients receiving sirolimus that remain on cyclosporine compared to those who are withdrawn from cyclosporine. It is possible that the failure of some cyclosporine/sirolimus20 combinations is the result of potentiation of the nephrotoxic effects of cyclosporine by a pharmacokinetic interaction with sirolimus, which increases renal exposure to cyclosporine without necessarily showing equal increases in scrum concentrations.23 Because of the role of hyperlipidemia in the development of CAN, it remains to be seen if sirolimus-induced increases in the lipid profile will have an impact on the continued progression of CAN in the long term.

Everolimus

Preclinical studies of everolimus, a novel proliferation inhibitor, suggest that this agent may inhibit the development of chronic rejection in solid organ transplant recipients.24 These effects may stem from the ability of everolimus to spare cyclosporine exposure, as well as the agent’s beneficial impact on comorbid conditions such as hypertension and hyperlipidemia; however, the exact mechanism has not been elucidated. Rat models of kidney transplantation using everolimus in animals with CAN have shown positive results that may translate into similar findings in human studies.25 Everolimus delayed the progression of CAN when it was introduced to the animals at the time when CAN has been documented to occur in the model; proteinuria, glomerulosclerosis, and inflammatory infiltrates were significantly lower than control animals not receiving everolimus. In addition, animals with delayed introduction of everolimus also showed significant improvement in protcinuria, CAN grade, and glomerulosclerosis. These beneficial effects are believed to stem from the antiproliferative and apoptosis-enhancing effects of everolimus.25 Although it is too early to determine the effects of everolimus on CAN, it appears that this agent may have a role in future therapies for CAN.

Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Chronic Allograft Nephropathy

The beneficial effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) on blood pressure and proteinuria in kidney transplant recipients are well described.26-29 These effects, in combination with the effect that blockade of angiotensin II may have on TGF-[beta]1 levels, may confer additional benefit to the patient with CAN. Historically, there has been some hesitation to use ACEI and ARBs in kidney transplant recipients because of fears of causing decline in renal function, hyperkalemia, and anemia. However, several small studies have demonstrated the safety and efficacy of ACEI and ARBs in the transplant recipient, including patients with CAN. These studies have shown effective blood pressure control and/or reduction in proteinuria without detrimental effects on renal function or other significant adverse effects.26-28 Lin and colleagues29 demonstrated that patients treated with ACEI or ARBs, when compared to patients not receiving these agents, had a lower incidence and slower progression of renal insufficiency; there was also a significant decrease in the combined endpoint of graft failure or death in patients receiving the ACEI or ARB.

Several studies have also looked specifically at the effects of ACEI and ARBs on levels of TGF-[beta]^sub 1^, given their potential benefits in mediating the detrimental effects of TGF-[beta]^sub 1^ on the development of CAN. El-Agroudy and colleagues30 studied 162 hypertensive living donor kidney transplant recipients receiving cyclosporine-based immunosuppression and randomized patients into 3 groups that included anti-hypertensive therapy with an ARB, an ACE inhibitor, or a calcium channel blocker. Forty-seven of the recipients had CAN before study entry, as demonstrated by the baseline kidney biopsy; however, results did not specifically address the outcome in this subgroup of patients. Only the ARB group, who received therapy with losartan, had a significant decrease in TGF-[beta]^sub 1^ levels, urinary protein excretion, as well as a lower rate of histopathologic progression (on the basis of amount of interstitial fibrosis present upon biopsy). The group receiving ACEI therapy did have significantly lower proteinuria; however, the effects on TGF-[beta]^sub 1^ levels were temporary and nonsignificant. The authors note that this effect might be clue to relatively low doses of the ACEI in the group. On the other hand, because ACE inhibition does not fully block the production of angiotensin II owing to existence of alternate pathways, the use of ARBs may be the better choice because they block the angiotensin II receptor.

Campistol and colleagues31 found that patients with documented CAN (n = 14) have higher levels of TGF-[beta]^sub 1^ than control groups without CAN (n = 25; 15 kidney transplant recipients with normal renal function and 10 healthy volunteers), and that treatment with losartan caused a decrease in levels, which reached those of the control transplant recipients without CAN. It is not known whether the effects of ARBs on TGF-[beta]^sub 1^ will translate into a decline in the rate of progression of CAN. Interestingly, the same group also demonstrated the ability of losartan to decrease TGF-[beta]^sub 1^ in patients with normal renal function, leading to the assumption that use of ARBs may offer additional benefit in preventing the development of CAN.32

Other Interventions

There are limited data to suggest that use of hydroxymethylglutaryl-CoA reductase inhibitors for the treatment of hyperlipidemia may also reduce the incidence of acute and chronic rejection in transplant recipients. In a prospective randomized trial conducted by Katznelson,33 heart transplant recipients receiving pravastatin for hyperlipidemia were compared with a control group not receiving this drug. A decrease in clinically severe acute rejection and a statistically significant increase in 1-year graft survival (94% vs 78% in control group; P=.02) was seen in pravastatin-treated patients. These patients also had lower incidence and progression of transplant coronary vasculopathy. Kidney transplant recipients were also studied and had a lower rate of acute rejection in comparison to controls (25% vs 58%; P=.01). On the basis of these results, the authors conclude that hydroxymethylglutaryl-CoA reductase inhibitors may have immunosuppressive properties that may be beneficial in reducing chronic rejection in transplant recipients.

Murphy and colleagues34 found that administration of aspirin, 150 mg per day, in the first 3 months after kidney transplantation (n=105) decreased the incidence of CAN (at 1-year protocol biopsy), when compared to an untreated historical control group (n= 121). Although this decrease did not reach statistical significance (16% in aspirin group vs 26% in historical control; P=.08), it may be an important therapy to study further, considering the beneficial effects of aspirin in preventing cardiovascular events in this high-risk population.

Conclusion

There is no ideal intervention to attenuate CAN once it occurs; therefore, it is practical to focus on preventing its development or slowing its progression. Although only few of the risk factors for CAN are modifiable, focusing on those that can be managed after transplantation is the best hope to prevent CAN. Preventing acute rejection, as the newer immunosuppressive agents are excellent at doing, or treating it aggressively if it does occur, is an important first step. Cautious modification of the immunosuppressant regimen to reduce or eliminate exposure to calcineurin inhibitors may help to prevent graft fibrosis, while addition of nonnephrotoxic agents such as sirolimus or mycophenolate may be considered after carefully balancing the risk of acute rejection.

In addition, effective management of comorbid disease states such as hypertension and hyperlipidemia is essential. Employing an angiotensin II receptor blocker for blood pressure management in patients that are beyond the perioperative period may help to improve long-term renal function as a result of the class effect on lowering blood pressure, decreasing proteinuria, and decreasing levels of TGF-[beta]^sub 1^. The impact of sirolimus-induced hyperlipidemia in patients with CAN is yet to be established; however, effective management of the hyperlipidemia with HMG-CoA reductase inhibitors is warranted. In addition to the cardiovascular benefits of lipid control using HMG-CoA reductase inhibitors, it is possible that these agents may confer protection from development of CAN.

As data supporting the use of sirolimus or everolimus continue to accumulate, these agents may play a major role in the prevention and treatment of CAN. However, large, prospective studies need to be performed to determine the best strategy for preventing and managing this important cause of graft loss.

References

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6. Krieger NR, Becker BN, Heisey DM, et al. Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts. Transplantation. 2003;75:1677-1682.

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12. Campistol JM, Inigo P, Larios S, Bescos M, Oppenheimer F. Role of transforming growth factor-b1 in the progression of chronic allograft nephropathy. Nephrol Dial Transplant. 2001;16(suppl 1):114-116.

13. Nicholson ML, Bailey E, Williams S, Harris KPG, Furness PN. Computerized histomorphometric assessment of protocol renal transplant biopsy specimens for surrogate markers of chronic rejection. Transplantation. 1999;68:236-241.

14. Murphy GJ, Waller JR, Sandford RS, Furness PN, Nicholson ML. Randomized clinical trial of the effect of microemulsion cyclosporine and tacrolimus on renal allograft fibrosis. Br J Surg. 2003;90:680-686.

15. Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int. 2001;59:1567-1573.

16. Dudley CRK, for the MMF “Creeping Creatinine” Study Group. MMF substitution for CsA is an effective and safe treatment of chronic allograft dysfunction; results of a multicenter randomized controlled study [abstract 41]. Am J Transplant. 2002;2(suppl 3):148.

17. Kahan BD, Knight R, Schoenberg L, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc. 2003; 35(suppl 3A):25S-34S.

18. Oberbauer R, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation. 2003;76:364-370.

19. Citterlo F, Scata MC, Violi P, et al. Rapid conversion to sirolimus for chronic progressive deterioration of the renal function in kidney allograft recipients. Transplant Proc. 2003;35:1292-1294.

20. Saunders RN, Bicknell GR, Nicholson ML. The impact of cyclosporine dose reduction with or without the addition of Rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy. Transplantation. 2003; 75:772-780.

21. Ruiz JC, Campistol JM, Mota A, et al. Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Transplant Proc. 2003;35:1669-1670.

22. Amm JM, Ramamurthy G, Degala A, et al. Rapamycin substitution for calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy: a report of 57 cases [abstract 235]. Am J Transplant. 2003;3(suppl 5):211.

23. Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol. 2001;12:1059-1071.

24. Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit. 2002;24:53-58.

25. Lutz J, Zou H, Liu S, Antus B, Heemann U. Apoptosis and treatment of chronic allograft nephropathy with everolimus. Transplantation. 2003;76:508-515.

26. Muirhead N, House A, Hollomby DJ, Jevnikar AM. Effect of valsartan on urinary protein excretion and renal function in patients with chronic renal allograft nephropathy. Transplant Proc. 2003;35:2412-2414.

27. Stigant CE, Cohen J, Vivera M, Zaltzman JS. ACE inhibitors and angiotensin II antagonists in renal transplantation: an analysis of safety and efficacy. Am J Kidney Dis. 2000;35:58-63.

28. Omoto K, Tanabe K, Tokumoto T, et al. Use of candesartan cilexitil decreases proteinuria in renal transplant patients with chronic allograft dysfunction. Transplantation. 2003;76: 1170-1174.

29. Lin J, Valeri AM, Markowitz GS, et al. Angiotensin converting enzyme inhibition in chronic allograft nephropathy. Transplantation. 2002;73:783-788.

30. El-Agroudy AE, Hassan NA, Foda MA, et al. Effect of angiotensin II receptor blocker on plasma levels of TGF-[beta]^sub 1^ and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol. 2003;23:300-306.

31. Campistol JM, Inigo P, Jimenez W, et al. Losartan decreases plasma levels of TGF-[beta]^sub 1^ in transplant patients with chronic allograft nephropathy. Kidney Int. 1999;56:714-719.

32. Inigo P, Campistol JM, Lario S, et al. Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-[beta]^sub 1^ plasma levels in a crossover trial in renal transplant recipients. Transplantation. 2001;12:822-827.

33. Katznelson S, Kobashigawa JA. Dual roles of HMG-CoA reductase inhibitors in solid organ transplantation: lipid lowering and immunosuppression. Kidney Int. 1995; 52:S112-115.

34. Murphy GJ, Taha R, Windmill DC, Metcalfe M, Nicholson ML. Influence of aspirin on early allograft thrombosis and chronic allograft nephropathy following renal transplantation. Br J Surg. 2001;88:261-266.

Meredith J. Aull, PharmD

New York Presbyterian Hospital, New York, NY

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