This report was reviewed for medical and scientific accuracy by David A. Laskow, MD, Chief, Kidney/Pancreas Transplant Service, Associate Professor of Surgery, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

Chronic allograft nephropathy is a major cause of late graft loss following renal transplantation.¹ While a variety of factors likely contribute to chronic allograft nephropathy, immunosuppression-related nephrotoxicity is a potentially modifiable contributing factor. Cyclosporine side effects such as nephrotoxicity and hypertension contribute to chronic graft failure.² The nephrotoxic effects of cyclosporine are functional (acute) and structural (chronic) consisting of renal efferent vasoconstriction resulting in the development of afferent arteriolopathy, glomerulosclerosis, tubular atrophy, and interstitial fibrosis.³ Cyclosporine-induced hypertension is associated with volume expansion and inappropriate systemic vasoconstriction.⁴ Not only does the hypertension associated with cyclosporine have a detrimental effect on graft survival,^5,6 it is likely to contribute to the high cardiovascular morbidity in renal transplant recipients.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 utilized higher doses than those currently recommended.^8,9 The reported incidence of tacrolimus-induced hypertension and nephrotoxicity has decreased over the years, presumably a result of more appropriate (lower) dosing.¹⁰ Tacrolimus use has been associated with improved graft and patient survival compared to cyclosporine. It has been proposed that reduced nephrotoxicity associated with tacrolimus may contribute to these improved outcomes.

Effect of Calcineurin Inhibitors on Acute Renal Hemodynamics

Both functional and structural changes in renal function have been reported in renal transplant recipients receiving maintenance immunosuppressive therapy with cyclosporine or tacrolimus. Early studies suggested that both cyclosporine and tacrolimus were equally nephrotoxic.^11,12 These data, however, do not consider the relative contribution of immunosuppression to these toxicities. This is difficult to determine due to multiple confounding factors present in this population (eg, other medications, renal ischemia resulting from the graft procedure, concomitant diseases/conditions). Few studies have attempted to differentiate immunosuppression-related changes in renal function from chronic renal allograft nephropathy. Furthermore, the mechanisms of immunosuppression-related nephrotoxicity are poorly understood.

One study was recently conducted in healthy subjects in an attempt to determine the effects of cyclosporine and tacrolimus in the absence of confounding factors.¹³ Results suggest that tacrolimus is less nephrotoxic than cyclosporine in this patient population. Eight healthy subjects participated in this open-label study. Cyclosporine and tacrolimus were administered to each patient for two weeks in a randomized, crossover fashion. Treatments were separated by a washout period of at least one week and doses were adjusted to maintain target trough levels within the currently accepted therapeutic range for each agent (100-200 ng/mL and 5-15 ng/mL for cyclosporine and tacrolimus, respectively).

Tacrolimus did not affect renal hemodynamics or blood pressure in healthy subjects (Figure 1). Glomerular filtration rate and effective renal plasma flow were maintained with tacrolimus therapy (glomerular filtration rate at baseline and after 2 weeks of tacrolimus administration 98В±9 mL/min/1.73 m² and 93В±7 mL/min/1.73 m², respectively; effective renal plasma flow at baseline and after 2 weeks of tacrolimus administration 597В±108 mL/min/1.73 m² and 588В±103 mL/min/1.73 m², respectively; P = Not Significant (NS) for change from baseline). Furthermore, tacrolimus did not adversely affect blood pressure (mean arterial pressure 93В±8 mm Hg at baseline and 96В±11 mm Hg after tacrolimus administration; P = NS) or renal vascular resistance (87В±19 mm Hg*min/L/1.73 m² at baseline and 89В±20 mm Hg*min/L/1.73 m² after tacrolimus administration; P = NS).

In contrast, cyclosporine administration led to significant reductions in glomerular filtration rate (85В±10 mL/min/1.73 m²; <.05 vs baseline), effective renal plasma flow (438В±84 mL/min/1.73 m²; P<.01 vs baseline and tacrolimus), significant increases in mean arterial pressure (108В±10 mm Hg; P<.05 vs baseline and tacrolimus), and renal vascular resistance (144В±45 mm Hg*min/L/1.73 m²; P<.01 vs baseline and tacrolimus).

These findings demonstrate that the calcineurin inhibitors differ in their propensity to cause acute changes in renal hemodynamics in the absence of confounding factors. While results of this study suggest that tacrolimus may cause less acute and chronic nephrotoxicity, additional studies are needed to fully elucidate the differential effects.

Emerging Strategies to Reduce Nephrotoxicity
In an attempt to further reduce nephrotoxicity in renal transplant recipients, recent efforts have focused on calcineurin inhibitor minimization- and avoidance-based immunosuppressive regimens. In a study of 525 renal allograft recipients (primary 90%; cadaveric 89%), Johnson et al examined early cyclosporine withdrawal from a cyclosporine-sirolimus-corticosteroid-immunosuppressive regimen and found in 430 (82%) randomized patients that early cyclosporine withdrawal resulted in significant improvements in both renal function and blood pressure, with no difference in patient and graft survival at 12 months¹⁴ and 24 months¹⁵ and without increased risk of graft loss or late acute rejection (acute rejection after randomization 5.1% vs 9.8%) at 24 months.¹⁵ Thrombocytopenia, hypokalemia, and abnormal liver function tests were reported significantly more frequently with the sirolimus-corticosteroid regimen.¹⁵ In a preliminary finding, Stegall et al found that using sirolimus in combination with thymoglobulin, mycophenolate mofetil, and prednisone resulted in low acute cellular rejection rates while avoiding calcineurin inhibitors.¹⁶ Although these data show promise, further evidence is necessary to determine how these strategies will impact overall renal transplant management.

Tacrolimus is Associated with Improved Graft Survival

Two recent analyses of data from the large United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database have demonstrated an association between tacrolimus use and reduced graft loss. A study conducted by Cherikh and colleagues (2003) analyzed data from the UNOS/OPTN database to obtain substantial statistical power to assist in validating observed immunosuppressive outcomes.¹⁷ Researchers examined data from 19,246 primary cadaveric kidney transplants performed during 1995 and 1998 using a multivariate Cox regression analysis. The objective of the study was to determine the relative efficacy of four discharge immunosuppressive regimens: cyclosporine plus azathioprine (n = 6,754), cyclosporine plus mycophenolate mofetil (n = 9,784), tacrolimus plus azathioprine (n = 490), and tacrolimus plus mycophenolate mofetil (n = 2,218).

In the absence of delayed graft function and early acute rejection, the latter three regimens were associated with reduced risk of long-term graft loss or death as compared to the baseline regimen of cyclosporine plus azathioprine (Figure 2). The tacrolimus plus mycophenolate mofetil treatment arm was associated with the greatest reduction (20%) in risk of graft loss (P<.001). Moreover, the risk of mortality was reduced by 14% with cyclosporine plus mycophenolate mofetil, 33% with tacrolimus plus azathioprine, and 29% with tacrolimus plus mycophenolate mofetil compared to cyclosporine plus azathioprine.

At 36 months, adjusted graft survival was 90.5% (95% Confidence Limit (CL), 89.5-91.4), 91.4% (95% CL, 90.6-92.3), 92.1% (95% CL, 90.5-93.8), and 92.4% (95% CL, 91.3-93.4) in the cyclosporine plus azathioprine, cyclosporine plus mycophenolate mofetil, tacrolimus plus azathioprine, and tacrolimus plus mycophenolate mofetil groups, respectively. Similar findings were reported at 60 months (graft survival rates of 83.1% (95% CL, 81.5-84.7), 84.8% (95% CL, 83.3-86.2), 86.0% (95% CL, 83.1-88.9), and 86.3% (95% CL, 84.5-88.2) with cyclosporine plus azathioprine, cyclosporine plus mycophenolate mofetil, tacrolimus plus azathioprine, and tacrolimus plus mycophenolate mofetil, respectively). While the presence of delayed graft function and early acute rejection increased the risk of graft loss in all groups, the extent of these increases were less in the cyclosporine plus mycophenolate mofetil (97%), tacrolimus plus azathioprine (80%) and tacrolimus plus mycophenolate mofetil (75%) groups than in the cyclosporine plus azathioprine group (120%). The adjusted 36- and 60-month graft survival rates declined to 80.2% (95% CL, 77.8-82.7) and 66% (95% CL, 66.7-70.4) with cyclosporine plus azathioprine, 82.1% (95% CL, 79.9-84.4) and 69.5% (95% CL, 66.0-73.1), with cyclosporine plus mycophenolate mofetil, 83.5% (95% CL, 80.0-87.2%) and 71.7% (95% CL, 66.2-77.6) with tacrolimus plus azathioprine, and 83.9% (95% CL, 81.6-86.4) and 72.4% (95% CL, 68.6-76.4) with tacrolimus plus mycophenolate mofetil. These findings were not significantly influenced by age, race/ethnicity, the presence of diabetes, or panel reactive antibodies >80%. Furthermore, the use of induction therapy did not improve graft or patient survival.

Evidence of Reduced Graft Loss with Tacrolimus

Additional evidence of the efficacy of tacrolimus on graft survival was reported by Bresnahan and colleagues at the American Transplant Congress 2003.¹⁸ This large, independent review of 46,128 kidney transplants (cadaveric 30,549; living donor 15,579) reported to UNOS/OPTN between 1995 and 2000 demonstrated an association between tacrolimus use and improved short-term endpoints (graft loss, patient death, acute rejection, serum creatinine) and composite endpoints (combination of at least one of 1-year short-term endpoints) as compared to cyclosporine-based regimens. The use of tacrolimus resulted in reduced graft loss (odds ratio 0.902, 95% Confidence Interval (CI) 0.832-0.977, P = .0117), acute rejection (odds ratio 0.926, 95% CI, 0.883-0.972, P = .0019), and reduced risk of elevated serum creatinine (>1.5 mg/dL) (odds ratio 0.716, 95% CI, 0.682-0.752, P<.0001) (Table 1). Importantly, patients treated with tacrolimus-based regimens were less likely to experience graft loss, death, acute rejection, or elevated serum creatinine (odds ratio 0.751, 95% CI, 0.718-0.786; P<.0001) than patients treated with cyclosporine-based regimens.

The 1-, 3-, and 5-year unadjusted actuarial graft survival for cadaveric recipients with tacrolimus-based regimens was 91.8%, 81.1%, and 69.8%, respectively. The corresponding values for cyclosporine-based therapy were 90.3%, 79.9%, and 67.5%, respectively (P<.0001). These findings were independent of other risk variables such as transplant year, panel reactive antibodies, delayed graft function, and mycophenolate mofetil use. Investigators noted that with each transplant year reported to UNOS/OPTN, there was an increase in the proportion of patients receiving tacrolimus. It is likely that the reduced risk of graft loss with tacrolimus (as compared to cyclosporine) observed in these studies is related to the reduced propensity of tacrolimus to elevate systemic blood pressure and induce nephrotoxicity.

Conclusion

Ideally, immunosuppressive therapies should suppress rejection while preserving organ function. In the absence of confounding factors related to renal transplantation, tacrolimus preserves renal function at near baseline levels. In renal transplant recipients, tacrolimus-based regimens are associated with improved graft and patient survival compared to cyclosporine-based therapies. As nephropathy is a major cause of graft failure, it is likely that the improved renal safety observed with tacrolimus contributes to more positive long-term outcomes.

References

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4. Textor SC, Canzanello VJ, Taler SJ, et al. Cyclosporin-induced hypertension after transplantation. Mayo Clin Proc. 1994;69:1182-1193.
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11. 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.
12. Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas AJ. One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group. Transplantation. 1996;15:1576-1581.
13. Klein IHHT, Abrahams A, van Ede T, HenР№ RJ, Koomans HA, Ligtenberg G. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation. 2002;73:732-736.
14. Johnson RW, Kreis H, Oberbauer R, Brattstrom C, Claesson K, Eris J. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation. 2001; 72:777-786.
15. Oberbauer R, Kreis H, Johnson RW, 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.
16. Stegall MD, Larson TS, Prieto M, et al. Kidney transplantation without calcineurin inhibitors using sirolimus. Transplant Proc. 2003;35(3 suppl):S125- S127.
17. Cherikh WS, Kauffman HM, Maghirang J, Bleyer AJ, Johnson CP. A comparison of discharge immunosuppressive drug regimens in primary cadaveric kidney transplantation. Transplantation. 2003;76:463-470.
18. Bresnahan BA, Cherikh WS, Cheng Y, Siddiqi NA, Hariharan S. Short-term benefit of tacrolimus vs cyclosporine therapy after renal transplantation: an analysis of UNOS/OPTN database. Presented at the American Transplant Congress 2003: The Fourth Joint American Transplant Meeting. May 30-June 4, 2003, Washington, DC. Abstract 1213.

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Disclosure

David A. Laskow, MD
Grant/Research Support-Fujisawa Healthcare, Inc., Novartis; Speakers Bureau-Fujisawa Healthcare, Inc., Roche

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

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

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; MMC, 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™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education