Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity

Abstract

Since the introduction of cylcosporine into clinical use, a major area of concern within the transplant community has been the fear of chronic nephrotoxicity. Although progressive renal damage does appear to occur in native kidneys of heart and liver transplant patients receiving cyclosporine, it has been our contention that its use is not a major cause of deterioration in renal allografts. We therefore undertook a study of 91 consecutive renal transplants performed over a three-year period with a minimum graft survival of 1 year and a follow-up of 7-9 years. Serial serum creatinine values, iothalamate clearances and cyclosporine levels were obtained at 3 months after transplantation and yearly thereafter. Biopsies were performed on all grafts that had failed as well as on the majority of patients with deteriorating renal function, and were interpreted by two nephropathologists. As measured by iothalamate clearances, 65 % of the patients in this series exhibited absolutely stable renal function despite the maintenance of cyclosporine levels of more than 200 ng/ml for 7-9 years. Since these stable patients did not reveal any decline in renal function, it therefore follows that they did not experience chronic cyclosporine nephrotoxicity. Furthermore, none of the patients with declining renal function or with failed grafts showed any evidence of nephrotoxicity on biopsy. Chronic cyclosporine nephrotoxicity may be a cause of declining function or graft loss with renal transplant recipients, but if so, it is exceedingly rare.

Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology

“…When an insensitive surrogate marker such as serum creatinine or GFR is used (22), the apparent prevalence is less common (7,8,23). In nonrenal solid organ transplantation (2,21,24) or with CsA treatment for autoimmune diseases not involving the kidney (25), declining renal function attributable to CsA nephrotoxicity is becoming an increasingly recognized and common problem.…”

Randomized, International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis

“…Inadequate or variable CsA exposure is now believed to be a key determinant of acute rejection, which in turn is closely linked to the development of chronic rejection, the principal cause of late graft loss (19,(25)(26)(27)(28)(29)(30)(31)(32). Recent studies have shown that patients differ substantially in the relative absorption of CsA from cyclosporine microemulsion, providing a logical basis for the definition of patient risk categories according to absorber status (15,21).…”

Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse-sample Predictors During the First 3 Months after Renal Transplantation

“…Inadequate or variable CsA exposure is now believed to be a key determinant of acute rejection, which in turn is closely linked to the development of chronic rejection, the principal cause of late graft loss; early and long-term graft survival may therefore both be critically dependent upon achieving and maintaining adequate CsA exposure in the early posttransplant period (4,(26)(27)(28)(29)(30). This nested pharmacokinetic study was conducted in the first 3 months post-transplant in renal transplant patients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression to determine the relationship between cyclosporine dose and pharmacokinetics and to determine the optimal predictors for absorption profiling in clinical practice.…”