cyclosporin-g and Kidney-Failure--Chronic

Drugs used to modify the immune response in solid organ transplantation or autoimmune disease may cause dose-related nephrotoxicity. Cyclosporine, FK506, cyclosporine G, and rapamycin have all been studied experimentally and to a more limited extent in patients. This paper summarizes this literature using data from clinically relevant animal models.

Topics: Acute Kidney Injury; Animals; Cyclosporine; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Polyenes; Sirolimus; Tacrolimus

Animal studies have suggested that the analogue cyclosporin G (CyG) may be less nephrotoxic than cyclosporin A (CyA). A pilot study was therefore performed in 10 primary cadaveric renal allograft recipients who were randomized to receive posttransplant immunosuppression with either CyA or CyG. The follow-up time was a minimum of 1 year. One graft was lost in each group. All patients in both groups experienced at least one acute rejection episode. Episodes of acute nephrotoxicity were observed in both groups. Renal function, as assessed by determinations of the serum creatinine level and chromium-ethylene diamine tetra-acetic acid (Cr-EDTA) clearance, did not differ between the two groups. Renal allograft biopsies showed a significantly higher degree of fibrosis in the CyG group than in the CyA group. All CyG-treated patients evidenced laboratory signs of acute liver toxicity, which was dose-dependent and reversible. Today, all CyG-treated patients have been switched to CyA. This study shows that immunosuppression after renal transplantation in man is possible with CyG; however, it does not seem to have any advantages over CyA.

Topics: Adult; Area Under Curve; Creatinine; Cyclosporine; Female; Histocompatibility Testing; HLA-DR Antigens; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pilot Projects

The pharmacokinetics of the cyclosporine A (CsA, Sandimmune) analogue Nva2-cyclosporine, or cyclosporine G (CsG) was investigated in 6 patients with terminal renal failure after a 4-hr intravenous infusion (3.5 mg/kg) and after oral administration (600 mg) of the drug. Blood samples were collected up to 38 hr and CsG concentrations were measured by radioimmunoassay and high-performance liquid chromatography. The resulting pharmacokinetic parameters of CsG were similar to those described for CsA in the same patient population. Based on HPLC determinations, a mean terminal elimination half-life of 18.9 hr was calculated. The total body clearance was 0.55 L/hr/kg, the volume of the central compartment was 0.32 L/kg, and the steady-state volume of distribution was 5.97 L/kg. After oral administration maximum CsG concentrations in blood were reached between 2.5 and 3 hr, and the bioavailability was in the range of 24-55% (mean 36%). The ratios between the polyvalent RIA and HPLC determinations were considerably larger after oral dosing than after i.v. infusion. The blood-to-plasma ratio was 1.23, which is smaller than that observed for CsA. These results suggest that in patients undergoing renal transplantation the same dosing strategies can be applied for CsG as have been established for CsA.

Topics: Adult; Cyclosporine; Cyclosporins; Humans; Kidney Failure, Chronic; Male; Pilot Projects