Experience with cyclosporine in the canary islands

Experience With Cyclosporine in the Canary Islands D. Herna´ndez ABSTRACT Cyclosporine (CsA) is currently the basis of most immunosuppressive protocols after solid organ transplantation. The introduction of Neoral, a new microemulsion formulation of CsA, and more recently a range of adjunctive immunosuppressants have further enhanced short-term efficacy and tolerability of CsA-based immunosuppression. In addition, Neoral C2 monitoring has been shown to have advantages not only in the early posttransplant period, but also for maintenance transplant patients. The major long-term disadvantage associated with CsA is the development of nephrotoxicity and chronic allograft nephropathy (CAN), which is the second major cause of graft failure. Thus, strategies to reduce the risk of CAN include CsA-sparing protocols, use of C2 level monitoring, introduction of non-nephrotoxic adjunctive immunosuppressants, and optimal management of additional risk factors. Other important side effects related to CsA-based immunosuppression include hypertension, diabetes, and hyperlipidemia. Optimal management of these conditions may lead to significant reduction of cardiovascular-related morbidity and mortality following solid organ transplantation.

C

YCLOSPORINE (CsA), a cyclic endecapeptide extracted from Tolypocladium inflatum Gams has played a leading role in anti-rejection therapy after its introduction in 1983.1 Although other immunosuppressants have emerged in the field of solid organ transplantation, CsA is currently the basis of most immunosuppressive protocols and its use continues to expand globally. Indeed, recent data from the United Network for Organ Sharing (UNOS) indicate that in the United States between 1997 and 2000, 60% to 70% of all maintenance patients were treated with CsA-based immunosuppressive therapies.2 During the last decade there have been significant advances in CsA formulation design, therapeutic drug monitoring, and CsA-based combination protocols that have substantially improved transplant outcomes. However, the use of CsA has been associated with drug-related side effects, including nephrotoxicity, which may limit its long-term efficacy. The aim of this review is to summarize current knowledge on CsA-based immunosuppression and to provide the clinician with a guide to the optimal use of this drug after solid organ transplantation.

tion regulator nuclear factor of activated T cells. Likewise, CsA also inhibits activation of the transcription factor NF-␬B, which is required for the induction of various cytokine genes. In particular, IL-2 gene expression is inhibited by CsA, which leads to suppression of T-cell activation; additionally, expression of other cytokines involved in the immune response (IL-6 and IL-8) is also decreased.3 CsA is mainly metabolized by the hepatic cytochrome P450 3A enzyme system. Elimination is primarily biliary with only about 6% of each dose excreted in urine. Neither hemodialysis nor renal failure had any significant effect on CsA clearance.1 The original oil-based oral formulation of the drug (Sandimmun) was characterized by poor and unpredictable absorption, so that intensive monitoring of blood CsA concentrations and frequent dosage changes were required to obtain the desired therapeutic response. In the mid1990s however, a novel microemulsion preconcentrate was introduced (Neoral). This microemulsion has self-emulsifying properties that enhance bioavailability and decrease

IMMUNOSUPPRESSIVE ACTION AND PHARMACOKINETIC PROPERTIES

From the Nephrology Section, Hospital Universitario de Canarias, Tenerife, Spain. Address reprint requests to Domingo Herna´ndez, MD, Nephrology Section, Hospital Universitario de Canarias, Ofra s/n, 38320, La Laguna, Tenerife, Spain. E-mail: dhmarrero@ hotmail.com

CsA inhibits the activation of calcium/calmodulin-activated phosphatase calcineurin via complex formation with cyclophilin, thereby preventing the translocation of the transcrip0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.030 120S

© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 120S⫺124S (2004)

CYCLOSPORINE IN THE CANARY ISLANDS

pharmacokinetic variability between patients. As a consequence, significant increases in AUC and Cmax with Neoral relative to the oil-based formulation have been reported in solid organ transplant patients.2 Obviously, these properties help to maintain adequate blood levels to ensure effective immunosuppression. SHORT-TERM CLINICAL EFFICACY: COMBINING AND COMPARING THERAPIES

CsA has revolutionized the field of organ transplantation. Not only has it significantly improved the short and longterm survival of solid organs, but it also has mitigated the impact of HLA mismatching and the absence of pretransplant blood transfusions. Indeed, CsA use was accompanied by a dramatic decline in morbidity after transplantation, including the rate and severity of allograft rejection.4 In recent years, a variety of new agents such as tacrolimus, mycophenolate mofetil (MMF), sirolimus, everolimus, and specific monoclonal antibodies directed against the IL-2 (basiliximab and daclizumab) have been developed. As expected, special emphasis has focused on the comparison of CsA-based immunosuppression with these new drugs as baseline immunosuppressants. Clinical trials comparing tacrolimus and Neoral have shown similar graft survival and acute rejection rates except in selected populations. Given its higher immunosuppressive potency compared with CsA, tacrolimus has been adopted in most protocols for treatment of patients at high immunologic risk, especially pancreas-kidney or liver transplant and black recipients.2 Nevertheless, in most transplant centers, tacrolimus has not replaced CsA as the major baseline immunosuppressant.5,6 Owing to the improved pharmacokinetic properties of Neoral, this drug has been rapidly accepted by the transplant community since 1994. Multicenter clinical studies have demonstrated that Neoral significantly decreases acute rejection rate among de novo liver, renal and cardiac transplant recipients.1,2,7,8 Despite greater drug exposure with the Neoral formulation than the CsA oil-based formulation, there is no evidence for a significantly increased risk of CsA-related nephrotoxicity. Because of its advantages, Neoral has largely replaced the original formulation as the treatment of choice for patients on CsA-based immunosuppression. During the past few years a number of formulations of CsA with pharmacokinetic characteristics comparable to Neoral have been developed (e.g. CsA-modified-SangStat). So far, however, these new formulations have not demonstrated greater clinical efficacy than CsA-modified-Novartis in clinical trials.1 Although supplementation of CsA-based protocols with MMF has also resulted in a significant reduction in the incidence of acute rejection episodes, no clear advantages for graft or patient survival has been observed.9 Moreover, the addition of MMF to calcineurin inhibitor– based immunosuppressive protocols has been restricted in some trans-

121S Table 1. CsA Target Trough Concentrations During Months 1 to 3 After Transplantation* Type of Organ Transplant

Kidney Kidney Kidney

Immunologic/Nephrotoxicity Risk

Normal High immunologic risk Initial graft nonfunction or older donor age Liver All risk situations Heart All risk situations Lung All risk situations Pancreas/kidney All risk situations

Target Concentration (ng/mL)

100 –200 150 –250 80 –150 150 –250 200 –300 250 –350 200 –300

*These are the concentrations to be used in typical induction protocols.

plant centers to patients known to be at higher risk for severe graft rejection. Basiliximab and daclizumab are promising additions to immunosuppressive protocols because of their virtual absence of side effects. Both have been shown to significantly reduce the incidence of acute rejection episodes when used in the early post transplant period in combination with CsA and prednisone.10,11 Furthermore, they may have a CsAsparing effect when used with MMF and prednisone. Sirolimus and everolimus are being developed as adjunctive to current baseline immunosuppression as well as to replace CsA or tacrolimus. In this regard, two recent studies have confirmed that early CsA withdrawal followed by a sirolimus/steroid-based maintenance regimen resulted in long-term improvement in both renal function and blood pressure, without an increased risk of graft loss or late acute rejection episodes.12,13 To date, however, only a few longterm results with sirolimus/everolimus are available and their future role in baseline clinical immunosuppression is unclear. In summary, standard immunosuppression includes CsA for solid organ transplants and limited information is currently available about the use of other immunosuppressants in calcineurin inhibitor-free immunosuppressive protocols. In the few studies performed to date, a relatively high incidence of acute rejection episodes was observed,1,2 leading to reintroduction of either tacrolimus or CsA in a large proportion of patients. Thus, from a clinical point of view, only CsA and tacrolimus can safely be recommended as baseline immunosuppressants with an acceptable riskbenefit ratio. Finally, there is controversy over whether CsA can be introduced orally from the first day of transplantation. The starting dose as well as the whole blood target concentrations to be aimed at during the first month after transplantation depend on several factors such as the combination of immunosuppressants, the immunologic risk, and/or the presence of delayed graft function. Table 1 provides a guide to different whole blood trough concentrations of CsA for patients with versus without immunologic risk, and following various types of organ transplants.

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122S Table 2. Target Neoral C2 Levels for Liver and Renal Transplant Patients Time Posttransplant (mo)

Liver transplant 0 –3 4–6 ⬎6 Renal transplant 1 2 3 4–6 7–12 ⬎12

Cyclosporine Levels (ng/mL)

1000 800 600 1500 –2000 1500 1300 1100 900 800

Neoral C2 target levels have been established for renal and liver transplant patients. Targets levels should be achieved by day 5 posttransplant for optimal outcome. C2 samples must be taken at 2 hours ⫾ 15 minutes postdose. Adapted with permission from Levy G et al.16

CLINICAL BENEFITS OF NEORAL C2 MONITORING

The rationale for Neoral C2 monitoring is based on the greater sensitivity of the area under the curve for the first 4-hour postdose (AUC0 – 4) for improved prediction of risk for acute rejection and CsA-induced nephrotoxicity compared with traditional C0 monitoring.14 Furthermore, the single sampling point at 2 hours postdose has been identified as an accurate surrogate marker of AUC0 – 4 in a wide range of patient populations. Thus, C2 is the best time point predictor for AUC0 – 4 in all transplant patients populations and seems to be a good pharmacokinetic marker to monitor CsA during the early posttransplant period. Accordingly, management of Neoral dosing using C2 level monitoring in de novo transplant recipient has been largely validated in multiple studies around the world.12 In this regard, a significant reduction of acute rejection rate has been observed in solid organ transplantation when compared with the Sandimmun formulation.7,8,15 Optimal target Neoral C2 levels to prevent acute rejection in renal and liver transplant patients are shown in Table 2.16 The maintenance transplant patient might also benefit clinically from the more precise CsA exposure offered by Neoral C2 monitoring in terms of maintaining adequate immunosuppression while avoiding nephrotoxicity. In this sense, both renal function and blood pressure improvements were seen in a large proportion of maintenance transplant patients who received a dose reduction because of overexposure to Neoral, evaluated by C2 monitoring.14 Following the recommendations of the CONCERT (Consensus on Neoral C2: Expert Review in Transplantation) Conference, Neoral C2 is considered the optimal method to monitor CsA microemulsion in adult de novo renal and liver transplant patients not only in the early posttransplant period, but also in the maintenance transplant patient.17 As a consequence, Neoral C2 monitoring has now been successfully adopted by transplant centers worldwide.

LONG-TERM CLINICAL EFFICACY IN SOLID ORGAN TRANSPLANTS The Old Question: Is Inadequate Immunosuppression a Key Cause of Chronic Allograft Rejection?

Since 1998 there has been a substantial increase in short and long-term survival of renal grafts from both cadaveric and living donors.18 Since CsA became widely used after its introduction in the mid-1980s, this drug has greatly contributed to these results. However, every year between 4% to 6% of grafts are lost due to CAN. Several immune and non-immune risk factors have been linked to chronic rejection, including suboptimal immunosuppression. Indeed, CsA dosages of less than 5 mg/kg/d have been identified as a risk factor for chronic rejection.19 More recently, Opelz G and Do ¨hler B observed that renal transplant patients receiving CsA 3 to 6 mg/kg/d at 1 year posttransplantation had the best graft survival rate at 10 years posttransplantation. There was evidence of under-immunosuppression at doses of ⬍3 mg/kg/d and over-immunosuppression at doses of ⬎6 mg/kg/d20 (Fig 1). Poor patient compliance, inadequate absorption, and pharmacokinetic variability have been recognized as important limitations to effective treatment with this drug.21 Thus, it is possible that posttransplant Neoral C2 monitoring might avoid these handicaps. Finally, the maintenance of CsA minimum target blood levels in stable graft recipients may facilitate steroid withdrawal, mainly in patients with life-threatening complications such as hepatitis B infection or tumor. Calcineurin inhibitors are associated with efficacy-limiting adverse effects, particularly nephrotoxicity, which may modify their benefits for long-term graft survival. In up to 6% of the total worldwide renal transplant population, chronic renal allograft dysfunction may be caused solely by chronic CsA nephropathy.22 It has also been estimated that up to 7% of adult recipients of cardiac allografts who have been exposed to CsA for at least 3 years will develop CsA-related end-stage renal failure.23 In consonance with these facts, two studies have shown a similar long-term graft survival rate between patients with and without CsA (prednisone plus azathioprine) after kidney transplantation. Chronic nephropathy was the leading cause of graft failure among recipients on CsA therapy.24,25 Moreover conversion from CsA to a calcineurin inhibitor-free immunosuppression resulted in reduced incidence of CAN.26 One plausible explanation is that CsA stimulates transforming growth factor (TGF) production, and this fibrogenetic cytokine is involved in the pathogenesis of CAN. The significant reduction in TGF-beta plasma levels observed after treatment with an angiotensin II receptor antagonist (losartan) supports this argument,27 but further studies are needed to clarify this issue. MINIMIZING CALCINEURIN INHIBITORS

Chronic deterioration of renal function represents a major limitation to the long-term success of many organ transplants. Calcineurin inhibitors are important factors contrib-

CYCLOSPORINE IN THE CANARY ISLANDS

123S

Fig 1. Graft survival rates of first cadaver kidney transplants according to CsA dose at 1 year after transplantation. Number of patients treated in each group are indicated. Reprinted with permission from Opelz G and Do¨hler B.20

uting to renal dysfunction and nephrotoxicity that is histologically and clinically indistinguishable from CAN.28,29 This observation has prompted some investigators to reduce or avoid CsA in their anti-rejection protocols to prevent or minimize the risk of CAN. Indeed, a number of randomized clinical trials have been conducted to evaluate this therapeutic option. In this sense, a meta-analysis of randomized, controlled trials examined either prednisone or CsA withdrawal on incidence of acute rejection and renal allograft failure.30 The results of this study indicated that both prednisone and CsA withdrawal were associated with a higher incidence of acute rejection, but CsA withdrawal did not seem to increase the rate of graft failure even in studies with long-term-follow-up. More recently, a randomized clinical trial showed that early tapering of CsA can be safely accomplished in renal transplant patients who are stable on a triple drug regimen with MMF, thereby resulting in improved renal function, lipid profile, and blood pressure.31 Likewise, among patients with biopsy-proven CAN or renal dysfunction may undergo CsA reduction with addition of MMF, or alternatively substitution of rapamicin after CsA withdrawal.12,29 Others, however, have not observed such benefits; CsA withdrawal at 6 months after transplantation has resulted in a significantly increased incidence of biopsy-proven acute and chronic rejection.32 This controversy suggests that there is a need to identify patients at increased risk for acute rejection or chronic nephropathy after tapering of immunosuppressive medications. In this respect, it has been reported that a protocol biopsy at more than 1 year after transplantation, even in patients with optimal renal function, may be helpful. Patients with biopsy-proven chronic CsA nephropathy may undergo substantial CsA reduction if they never have experienced an acute rejection episode, renal

dysfunction, or major histologic lesions during follow-up.28 Hence, it is inferred that CsA withdrawal or reduction in selected patients may not necessarily entail a greater risk of long-term graft failure. SIDE EFFECTS

The major long-term safety problems associated with CsAbased immunosuppression include nephrotoxicity, hypertension, diabetes mellitus, and dyslipidemia.1,2 Acute nephrotoxicity is reported to affect 25% to 37% of kidney, heart, or liver transplant recipients under CsA and may respond to dose reduction. However, up to 15% of patients progress to permanent renal dysfunction. CsA stimulates angiotensin II and augments thromboxane A2 production, which produces not only vasoconstriction but also proliferation of vascular smooth-muscle cells and fibrosis. Dietary supplementation with n-3 polyunsaturated fatty acids, calcium antagonists and angiotensin II receptor 1 antagonists have been used to minimize CsA-induced nephrotoxicity, although their efficacy is not totally proven.33–35 Hypertension is common among transplant recipients under CsA treatment (65% to 85%). The mechanisms underlying CsA-associated hypertension are unclear, but it has been suggested to include an imbalance between vasoconstrictor and vasodilator endothelial substances. Although there is no hypertension therapy specific for solid organ recipients, antihypertensive therapy may be initiated with calcium antagonists or angiotensin converting-enzyme inhibitors (ACEI) with addition of further agents to reduce blood pressure to the adequate target level. ACEI might also contribute to a significant reduction of hypertensionrelated left ventricular hypertrophy.36,37 Likewise, reduc-

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tion of CsA dose or conversion to tacrolimus may help to decrease blood pressure.38 CsA contributes to hyperlipidemia after transplantation, which has been associated with cardiovascular complications and CAN.39 This side effect might be more pronounced in kidney recipients with normal pretransplant weight, as recently reported.40 The mechanisms are complex and not fully understood, but aggressive treatment of this disorder is clearly indicated. Conversion to tacrolimus may be indicated in some cases. Posttransplant diabetes mellitus (PTDM) is associated with steroids and calcineurin inhibitors. Incidence varies from 2% to 53% according to definition and duration of follow-up. Although a greater exposure achieved with Neoral has been suggested as a risk factor for PTDM,41 the risk for developing this disorder at 1 year after transplantation is up to five times greater with tacrolimus compared with CsA immunosuppression. Development of PTDM is associated with impaired long-term graft and patient survival, as well as an increased risk of cardiovascular complications. Thus, efforts must be expanded to minimize the impact of this condition on transplant outcomes. In this regard, an international consensus guideline has been recently performed to achieve this aim.42 Taken together, hypertension and metabolic abnormalities may lead to increased cardiovascular morbidity and mortality after transplantation. Additionally genetic factors such as the ACE/DD genotype might contribute to higher cardiovascular risk in these patients.43 Finally, other serious adverse effects, such as hepatoxicity, neurologic abnormalities, bone disorders, or gastrointestinal complications, although less frequent, must also be taken in account to decide the appropriate CsA-based regimen. FUTURE TRENDS

Until alternatives to allo-donor organ transplantation are developed, anti-rejection therapy remains necessary. Despite its side effects, CsA remains the cornerstone of immunosuppressive therapy. There is a strong tendency toward tailoring medication to individual patient requirements, drug-dose reduction, C2 monitoring and combination therapy, all of which seem likely to be adopted as the standard of care in the immediate future. The revolution in molecular genetics and pharmacogenomics promises to lead to the development of new agents that target specific pathways in the immune response to the allograft. The transplant community will undoubtedly benefit from relevant advances in many existing and future fields of research. REFERENCES 1. Kahan BD: New Engl J Med 321:1725, 1989 2. Winkler M: BioDrug 14:185, 2000 3. Dunn CJ, Wagstaff AJ, Perry CM, et al: Drugs 61:1957, 2001 4. Chan L, Gaston R, Hariharan S: Am J Kidney Dis 38(suppl 6):S2, 2001 5. Meier-Kriesche H-U, Kaplan B: Am J Transplant 2:100, 2002

HERNA´ NDEZ 6. Bunnapradist S, Daswani A, Takemoto SK: Transplantation 76:10, 2003 7. Belitsky P: Transplant Proc 32(suppl 3A):10S, 2000 8. Valantine H: Transplant Proc 32(suppl 3A):27S, 2000 9. Hernandez D, Garcia-Lo ´pez F: Nefrologia 23:211, 2003 10. Kahan BD, Rajagopalan PR, Hall M: Transplantation 67: 276, 1999 11. Nashan B, Light S, Hardie IP, et al: Transplantation 67:110, 1999 12. Oberbauer R, Kreis H, Johnson RW, et al: Transplantation 76:364, 2003 13. Stallone G, Di Paolo S, Schena A, et al: Transplantation 15:998, 2003 14. Cole E, Maham N, Cardella C, et al: Transplantation 75:2086, 2003 15. Levy GA: Transplant Proc 32(suppl 3A):2S, 2000 16. Cole E, Midtvedt K, Johnston A, et al: Transplantation 73(suppl):S19, 2002 17. Levy G, Thervet E, Lake J, et al: Transplantation 73(suppl): S12, 2002 18. Hariharan S, Johnson CP, Bresnahan BA, et al: N Engl J Med 342:605, 2000 19. Tejani A, Sullivan EK: Pediatr Transpl 4:107, 2000 20. Opelz G, Do ¨hler B: Transplantation 72:1267, 2001 21. Kahan BD, Welsh M, Urbauer DL, et al: J Am Soc Nephrol 11:1122, 2000 22. Mattos AM, Olyaei AJ, Bennett WM: Am J Kidney Dis 35:333, 2000 23. Goldstein DJ, Zeuch N, Sehgal V, et al: Transplantation 63:664, 1997 24. Marcen R, Pascual J, Teruel JL, et al: Transplantation 72:57, 2001 25. Grimbert P, Baron C, Fruchaud G, et al: Transpl Int 15:550, 2002 26. Bakker RC, Hollander AAMJ, Mallat MJK, et al: Kidney Int 64:1027, 2003 27. Campistol JM, Inigo P, Larios S, et al: Nephrol Dial Transplant 16(suppl 1):114, 2001 28. Gotti E, Perico N, Perna, et al: J Am Soc Nephrol 14:755, 2003 29. Weir MR, Ward MT, Blahut SA, et al: Kidney Int 59:1567, 2001 30. Kasiske BL, Chakkera HA, Louis TA, et al: J Am Soc Nephrol 11:1910, 2000 31. Sschnuelle P, van der Heide JH, Tegzess A, et al: J Am Soc Nephrol 13:536, 2002 32. Gregoor PHJGS, Se´vaux RGL, Ligtenberg G, et al: J Am Soc Nephrol 13:1365, 2002 33. Herna´ndez D, Guerra R, Milena A, et al: Nephrol Dial Transplant 17:897, 2002 34. Rodicio JL, Morales JM, Alcazar JM, et al: J Hypertens 11(suppl):S49, 1993 35. Noris M, Azzollini N, Pezzotta A, et al: J Am Soc Nephrol 12:1937, 2001 36. Herna´ndez D, Lacalzada J, Salido E, et al: Kidney Int 58:889, 2000 37. Midtvedt K, Ihlen H, Hartmann A, et al: Transplantation 72:107, 2001 38. Artz MA, Boots JM, Ligtenberg G, et al: J Am Soc Nephrol 14:1880, 2003 39. Moore R, Hernandez D, Valantine H: Drug Saf 24:755, 2001 40. Herna´ndez D, Alvarez A, Torres A, et al: Transplant Proc 35:1727, 2003 41. Cosio FG, Pesavento TE, Osei K, et al: Kidney Int 59:732, 2001 42. Davidson J, Wilkinson A, Dantal J, et al: Transplantation 75(10 suppl):SS3, 2003 43. Herna´ndez D, Linares J, Salido E, et al: Transplant Proc 37:3686, 2001