This report was reviewed for medical and scientific accuracy by Richard A. Mann, MD, MS, Associate Professor of Medicine, Microbiology and Molecular Genetics; Medical Director, Kidney/Pancreas Transplant Program, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Expert Commentary

E. Steve Woodle, MD, FACS, Professor of Surgery, Department of Surgery; Director, Division of Transplantation; Chairman, Board of Directors, Israel Penn International Transplant Tumor Registry; University of Cincinnati College of Medicine, Cincinnati, Ohio

Since the introduction of cyclosporine nearly two decades ago, calcineurin inhibitors have become an integral component of maintenance immunosuppressive regimens in renal transplantation. Cyclosporine and tacrolimus are very effective in reducing the incidence of acute rejection after renal transplantation, and both have demonstrated the ability to prolong long-term patient and graft survival in renal transplant recipients.^1,2 However, tacrolimus has been shown to be significantly more effective in preventing acute rejection than cyclosporine.^1,3,4

Evidence is emerging that early renal function, within the first year after renal transplantation, is an important parameter influencing long-term graft survival.^5,6 Thus, the choice of immunosuppressive regimen must be guided not only by its ability to prevent rejection but also by its effect on renal function.⁶ The nephrotoxic effects of cyclosporine are functional (acute) and structural (chronic) consisting of renal afferent vasoconstriction resulting in the development of afferent arteriolopathy, glomerulosclerosis, tubular atrophy, and interstitial fibrosis.⁷ Until recently, the nephrotoxic effects of cyclosporine and tacrolimus were assumed to be similar. This belief was supported by evidence of nephrotoxicity with tacrolimus in early clinical trials, which used higher doses of tacrolimus than those currently recommended.^8,9 The reported incidence of tacrolimus-induced nephrotoxicity has decreased over the years, presumably a result of more appropriate (lower) dosing.¹⁰ Long-term data confirm cyclosporine and tacrolimus differ in their propensity to induce nephrotoxicity.¹¹

Recently, efforts have been directed toward immunosuppressive regimens that minimize nephrotoxicity. One approach involves the use of alternate immunosuppressive agents, such as sirolimus or mycophenolate mofetil, to allow gradual reduction of calcineurin inhibitor doses.¹¹ These investigational immunosuppressive regimens must be interpreted carefully in light of potential insufficient immunosuppression. Indeed, recent data have demonstrated that patients who fail to return to baseline renal function after experiencing an acute rejection have only a 50.4% chance of graft survival at 6 years.¹² Additional studies are needed to assess the long-term safety and efficacy of calcineurin inhibitor-minimization strategies.

This Transplantation Express Report^TM describes the integral role of calcineurin inhibitors in immunosuppressive regimens for renal transplantation.

Trends in Calcineurin Inhibitor Utilization for Renal Transplantation

In 1993, 95% of patients undergoing a renal transplant received immunosuppressive therapy with cyclosporine, while only 2% received tacrolimus (not yet approved by the FDA).¹³ Over the next 10 years, however, a shift toward greater utilization of tacrolimus in renal transplantation was observed. The use of cyclosporine decreased to 30% in 2002, while the use of tacrolimus increased to 63% of renal transplant recipients (Figure 1).

A similar trend was observed for maintenance immunosuppression therapy in the first year post-transplantation. In 1992, 96% of patients received cyclosporine as maintenance immunosuppressive therapy, while only 3% received tacrolimus (not yet approved by the FDA).¹³ By 2001, 64% of renal transplant recipients received tacrolimus.

These trends may be related to several factors including lower rates of acute rejection and lower rates of steroid-resistant rejection under tacrolimus therapy. ^1,14

Renal Function - An Important Predictor of Long-term Allograft Survival

Although long-term graft survival in renal transplantation has improved,¹⁵ late loss of renal allografts (more than one year after transplantation) still occurs with an annual rate of loss from 3% to 5%.¹⁶ Although late loss of renal allograft can result from subacute, chronic alloimmune responses, additional factors can contribute to chronic allogenic nephropathy and subsequent graft loss, including hypertension, hyperlipidemia, and nephrotoxicity.⁶ Importantly, evidence now indicates that changes in renal function occurring 6 to 12 months after transplantation can be used to identify patients at high risk for graft loss,⁵ thus providing clinicians with an opportunity to optimize immunosuppressive therapy.

Serum creatinine levels can be monitored to detect early changes in renal function. In one retrospective survey of over 105,000 renal transplant recipients, 6- and 12-month serum creatinine levels, as well as the change between 6 and 12 months, were strongly associated with long-term graft survival.⁵ An elevated serum creatinine (>1.5 mg/dL) at 6 and 12 months, and an increase in serum creatinine increases of ≥0.3 mg/dL between 6 and 12 months after transplantation, were associated with a decline in long-term graft survival. Combined data from multicenter trials of tacrolimus- and cyclosporine-based immunosuppressive regimens support these findings, demonstrating that serum creatinine in the first 6 to 12 months after transplantation is an important predictor of 3-year graft loss and should be a surrogate endpoint for long-term graft loss.¹⁷

Comparative Effects of Calcineurin Inhibitors on Long-term Allograft Function and Survival

The calcineurin inhibitors have differing effects on long-term renal allograft function. While not observed in short-term (6- to 12-month) clinical trials,^1,4 these differences are evident when long-term data from larger clinical studies are analyzed. A recent study of 40,963 first-time recipients of a renal allograft, with graft survival of at least 2 years as reported in the United States Renal Data System (USRDS), explored the relationships between immunosuppressive therapy, kidney function, and graft survival.¹¹ The results of that study demonstrated that tacrolimus had a more favorable effect on kidney allograft function than either conventional cyclosporine or cyclosporine microemulsion. In a univariate analysis of annualized change in glomerular filtration rate (GFR), only tacrolimus was associated with improved function (+0.76 mL/min/1.73m²/year). In contrast, annualized GFR declined for both conventional cyclosporine (-0.62 mL/min/1.73m²/year) and cyclosporine microemulsion (-0.80 mL/min/1.73m²/year) (Table 1).

Using multiple linear regression analysis, an increase in GFR was observed in tacrolimus-treated patients (+1.60 mL/min/1.73m²/year, 95% Confidence Interval [CI], 1.22-1.97; P<.001) compared with those patients who received cyclosporine microemulsion. In contrast, a decline in GFR was observed in conventional cyclosporine-treated patients (-0.16 mL/min/1.73m²/year, 95% CI, -0.003 to -0.32; P = .04) compared with those patients who received cyclosporine microemulsion. The purine metabolism inhibitors, azathioprine and mycophenolate mofetil, were also associated with declines in GFR (univariate analysis; -1.14 and -1.03 mL/min/1.73m²/year, respectively), with those patients receiving mycophenolate mofetil demonstrating slower decline in GFR than those patients receiving azathioprine (multiple linear regression analysis; +0.61 mL/min/1.73m²/year, 95% CI, 0.14-1.08; P = .01).

Given the importance of the relationship between improved allograft function and graft survival, long-term data are critical in fully assessing this relationship. In an extension of a phase III multicenter comparative trial of tacrolimus and cyclosporine,¹ tacrolimus was associated with reduced rates of graft failure (requirement for graft nephrectomy, permanent return to dialysis, or crossover to other study treatment due to rejection) and treatment failure (graft loss or discontinuation of randomized immunosuppressant) compared with cyclosporine at 5 years.² Although graft survival rates were statistically equivalent in patients treated with cyclosporine and tacrolimus, when refractory rejection resulting in crossover from one calcineurin inhibitor to the other was counted as a graft loss, graft survival rates at 3 years were 81.3% with tacrolimus use and 70.2% with cyclosporine (P = .0102) and at 5 years were 63.8% with tacrolimus use and 53.8% with cyclosporine (P = .014). Median serum creatinine levels were higher among cyclosporine-treated patients than tacrolimus-treated patients. At 5 years, serum creatinine levels were 1.4 mg/dL and 1.7 mg/dL among tacrolimus- and cyclosporine- treated patients, respectively (P = .0014). Moreover, significantly fewer patients treated with tacrolimus developed serum creatinine levels >1.5 mg/dL (40.4% vs 62.0%; P = .0017).

Reducing Adverse Events in Renal Transplantation

Earlier attempts to withdraw steroids in patients on cyclosporine-based immunosuppressive regimens resulted in an unacceptably high rate of rejection; especially in high risk groups such as African-Americans.¹⁸ With the advent of newer, more potent immunosuppressive agents such as tacrolimus, steroid-sparing immunosuppression treatment regimens have gained renewed interest. These regimens are associated with improved safety, including a reduced incidence of post-transplant diabetes mellitus, dyslipidemia, hypertension, and lower levels of low-density lipoprotein (LDL)-cholesterol, with comparable efficacy (patient and graft survival) when compared with immunosuppressive regimens that utilize long-term administration of corticosteroids.^19-21 A recent interim analysis of corticosteroid withdrawal within 7 days post-transplant further support these outcomes revealing low overall acute rejection rates, excellent patient and graft survival, and low incidence of post-transplant diabetes mellitus.²² It should be noted that most of these studies excluded high risk patients and that further studies are required to determine the optimal timing, and appropriate patient population, for steroid withdrawal. The reduction in adverse events, especially adverse cardiovascular events, is of critical importance in improving long-term patient and graft survival in renal transplant recipients. At the present time, half of all kidney allografts that are lost are lost due to the death of the patient and approximately half of these deaths are the result of cardiovascular disease.¹⁶

Emerging Strategies to Reduce Nephrotoxicity

In an attempt to further reduce nephrotoxicity in renal transplant recipients, recent efforts have focused on minimizing the dose of calcineurin inhibitors. Ciancio and colleagues compared 1-year patient and graft survival among 150 patients randomized to decreasing doses of tacrolimus in combination with sirolimus (Group A; n = 50), decreasing doses of tacrolimus in combination with mycophenolate mofetil (Group B; n = 50), or decreasing doses of cyclosporine microemulsion in combination with sirolimus (Group C; n = 50).²³ Target tacrolimus trough levels were 10, 8, and 6 ng/mL at 1 month, 6 months, and 12 months, respectively, for Group A; and 10 and 8 ng/mL at 1 month and 12 months, respectively, for Group B. Target cyclosporine microemulsion trough levels were 225 and 175 ng/mL at 1 month and 12 months, respectively, for Group C. Maintenance sirolimus target trough levels were 8 ng/mL in Groups A and C. Each treatment group received daclizumab induction therapy and maintenance methylprednisolone. Patient and graft survival were not significantly different among the treatment groups (patient survival at 12 months, 96%, 92%, and 98%; graft survival at 12 months, 96%, 90%, 92% for Groups A, B, and C, respectively). Changes in renal function over the course of 1 year (mean serum creatinine and mean creatinine clearance) were not statistically different between the treatment groups; however, in comparison with the average of the means of Groups A and C, the creatinine clearance in Group B was significantly higher at 6 and 12 months (P = .03 and P = .04, respectively) (Table 2). In other words, the creatinine clearance in Group B did not show a downward trend during the first 12 months.

Although the percentage of patients with lymphoceles among treat-ment groups was not significantly different (P = .27), there was a slight trend toward a higher incidence in groups that received sirolimus (15% for Groups A and C combined vs 6% for Group B; P = .11). At 12 months, patients in groups that received sirolimus were more likely to require antilipid therapy for elevated cholesterol or triglycerides (80%, 54%, and 16% for the cyclosporine microemulsion/sirolimus, tacrolimus/sirolimus, and tacrolimus/mycophenolate mofetil groups, respectively; P<.00001). The incidence of new onset post-transplant diabetes mellitus was greater in the cyclosporine microemulsion/sirolimus treatment group (33%) than either of the tacrolimus treatment groups (17% and 14% in Groups A and B, respectively; P = .06 for simultaneous comparison of all 3 treatment groups).

Although strategies to minimize the dose of calcineurin inhibitors appear to be effective, further studies are needed to assess the risk/benefit ratio of such approaches over longer periods of time.

Conclusion

Calcineurin inhibitors remain the cornerstone of maintenance immunosuppressive therapy following renal transplantation, as they have demonstrated beneficial effects on both short- and long-term graft and patient survival. Recent data suggest that tacrolimus and cyclosporine have disparate effects on renal function that could potentially influence long-term outcomes. Additional studies are needed to fully elucidate these differences and to determine optimal dosing strategies for calcineurin inhibitors.

References

1. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997;63:977-983.
2. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002;73:775-782.
3. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation. 1997;64:436-443.
4. Margreiter R; European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet. 2002;359:741-746.
5. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62:311-318.
6. First MR. Renal function as a predictor of long-term graft survival in renal transplant patients. Nephrol Dial Transplant. 2003;18(Suppl 1):i3-6.
7. Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation. 2000;69(12 suppl):SS5-10.
8. Textor SC, Wiesner R, Wilson DJ, et al. Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. Transplantation. 1993;55:1332-1339.
9. Canzanello VJ, Textor SC, Taler SJ, et al. Renal sodium handling with cyclosporine A and FK506 after orthotopic liver transplantation. J Am Soc Nephrol. 1995;5:1910-1917.
10. Jurewicz WA. Immunological and nonimmunological risk factors with tacrolimus and Neoral in renal transplant recipients: an interim report. Transplant Proc. 1999;31:64S-66S.
11. Gill JS, Tonelli M, Mix CH, Johnson N, Pereira BJ. The effect of maintenance immunosuppression medication on the change in kidney allograft function. Kidney Int. 2004;65:692-699.
12. Meier-Kriesche H-U, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4:378-383.
13. Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, Bustami RT, Dyke DB. Immunosuppression: practice and trends. Am J Transplant. 2004;4(Suppl 9): 38-53.
14. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation. 2000;69:834-841.
15. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605-612.
16. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580-590.
17. Fitzsimmons W, Thompson D, Hariharan S, Van Veldhuisen P. Serum creatinine as a surrogate endpoint for graft loss in kidney transplantation: validation efforts from multicentre trials. Am J Transplant. 2002;2(Suppl 3):272. Abstract 533.
18. Ahsan N, Hricik D, Mata A, et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil - a prospective randomized study. Transplantation. 1999;68:1865-1874.
19. Squifflet JP, Vanrenterghem Y, van Hooff JP, Salmela K, Rigotti P; European Tacrolimus/MMF Transplantation Study Group. Safe withdrawal of corticosteroids or mycophenolate mofetil: results of a large, prospective, multicenter, randomized study. Transplant Proc. 2002;34:1584-1586.
20. Boots JMM, Christiaans MHL, van Duijnhoven EM, van Suylen RJ, van Hooff JP. Early steroid withdrawal in renal transplantation with tacrolimus dual therapy: a pilot study. Transplantation. 2002;74:1703-1709.
21. ter Meulen CG, van Riemsdijk I, Hené RJ, et al. Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: a prospective, randomized, multicenter study. Transplantation. 2004;4:803-810.
22. Woodle ES, for the Fujisawa Steroid Withdrawal Study Group. A prospective, randomized, double blind multicenter study of early (7 day) cortico-steroid cessation vs. long term low dose corticosteroid therapy under tacrolimus and mycophenolate mofetil therapy with antibody induction in renal transplant recipients. American Transplant Congress 2004, May 14-19, 2004, Boston, Massachusetts. Abstract 1528.
23. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation. 2004;77:252-258.

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Disclosure

E. Steve Woodle, MD, FACS
Grant/Research Support&#8212Aventis, Fujisawa Healthcare, Inc., Genzyme, Roche

Richard A. Mann, MD, MS
Grant/Research Support-Fujisawa Healthcare, Inc.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; Millennium CME Institute, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Transplantation Express Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report^TM was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2004 Millennium CME Institute, Inc. and UMDNJ-Center for Continuing and Outreach Education

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