The effect of two different cyclosporine formulations on the long‐term progression to chronic rejection in renal allograft recipients
Authors: Goel Mahesh , Flechner Stuart M , Ischikawa Akira , Induhara Ramaih , Mastroianni Barbara , Savas Kathy , Modlin Charles , Goldfarb David , Feng Jingyuan , Cook Daniel J , Novick Andrew C 
Published: March 2003

Abstract: Introduction: The introduction of the microemulsion formulation of cyclosporine (CsA) (Neoral – NEO) has been shown to provide improved absorption and less intrapatient variability than the previous formulation (Sandimmune – SIM) in kidney transplant recipients. It has been suggested that the use of the microemulsion formulation results in less acute rejection, and therefore permits better long‐term transplant outcomes. Our aim was to determine whether the microemulsion formulation of cyclosporine has reduced the long‐term (5 yr or more) rates of chronic rejection (allograft nephropathy) in a renal transplant population.

Methods: The study population included 792 (508 cadaveric and 284 living donor) transplants performed in 786 patients at the Cleveland Clinic Foundation and its affiliate hospitals between July 1, 1987 and July 1, 1998. Patients who were less than 18‐yr‐old or had less than 12 months of graft function were excluded from the analysis. Over 90% of the cadaveric and 11% of the live donor recipients were given an induction antibody. A total of 591 patients were given the SIM formulation and 201 the NEO formulation of cyclosporine. Additional maintenance therapy included either azathioprine or mycophenolate mofetil, and steroids. All patients were followed to graft loss, death, or return to dialysis. The NEO group was followed until December 2001. The diagnosis of acute rejection was biopsy confirmed in >92% of cases. Chronic rejection was identified by clinical and biopsy criteria. Demographic and clinical data was collected from medical records, interviews, and phone contact with patients and treating physicians.

Results: The mean follow‐up was 84 ± 31 months for the SIM group, and 54 ± 14 months for the NEO group. At 70 months there was no significant difference (p = 0.17) – actuarial patient survival between the SIM (90.7%) vs. the NEO (93%) treated patients. In addition, at 70 months there was no significant difference (p = 0.55) in death censored actuarial graft survival between the SIM (84.3%) and the NEO treated (85.7%) patients. The acute rejection‐free rate was 10% higher for the NEO vs. the SIM patients (79 vs. 69%, p = 0.0004). Chronic rejection was diagnosed in 141 of 591 (24%) of the SIM patients and in 56 of 201 (28%) of the NEO patients (p = ns). At 5 yr the mean serum creatinine (mg/dL) was 2.07 ± 1.69 for the SIM and 2.15 ± 1.61 for the NEO patients (p = ns).

Conclusions: The use of the microemulsion formulation of CsA has led to the improved delivery of the parent drug, and a decrease in the number of acute rejection episodes post‐transplant. However, patient and graft survival, renal function, and progression to chronic allograft nephropathy at 5 yr were no different. The advantages of greater drug exposure from the microemulsion formulation may be counterbalanced by increased drug induced nephrotoxicity over time.