Cyclosporine-induced Nephrotoxicity Research Articles

Does nifedipine protect against cyclosporin-induced nephrotoxicity?

Does nifedipine protect against cyclosporin-induced nephrotoxicity?

Biochemical mechanisms underlying cyclosporine-induced nephrotoxicity. Effect of concomitant administration of prednisolone.

Biochemical mechanisms underlying cyclosporine (CsA)-induced nephrotoxicity and the effect of concomitant administration of prednisolone (Pr) on the nephrotoxicity were studied. Male Wistar rats were treated with the vehicles used for CsA and Pr administration (group 1), Pr alone (group 2), CsA alone (group 3), or CsA plus Pr (group 4), respectively. The dose of CsA was 5 mg/kg/day, i.p. for the initial 7 days, and was decreased to 2.5 mg/kg/day i.p. thereafter. The dose of Pr was always maintained at one-tenth of that of CsA. At 10, 30, and 90 days after the initiation of these treatments, blood urea nitrogen (BUN) and serum levels of creatinine and CsA were determined. The syntheses of DNA, RNA, and protein, Na+, K+-adenosine triphosphate (ATP)ase activity, and ATP content were measured using homogenates of the renal cortex obtained from each experimental group. At an early stage (at 10 and 30 days) of CsA administration, the impairment of renal function and inhibition of the synthesis of DNA and RNA appeared in groups 3 and 4. The magnitude of these changes was found to be greater in group 3 (CsA alone) than in group 4 (CsA plus Pr). Group 3 also showed a significant reduction of Na+, K+-ATPase activity as well as ultrastructural abnormalities. At a later stage (at 90 days), however, such differences in nephrotoxicity between groups 3 and 4 were not detected. These results strongly suggest that inhibition of the synthesis of DNA and RNA and the activity of enzymes related to the functions of cell membrane, such as Na+, K+-ATPase, may be involved in the occurrence of CsA-induced nephrotoxicity. The present results also suggest that the concomitant administration of Pr with CsA may reduce the nephrotoxicity of CsA at early stages of CsA administration, but this preventive effect of Pr may disappear if the administration of CsA is prolonged.

Nifedipine Appears to Prevent Cyclosporin-Induced Nephrotoxicity

Nifedipine Appears to Prevent Cyclosporin-Induced Nephrotoxicity

Cyclosporine nephrotoxicity: sodium excretion, autoregulation, and angiotensin II.

Cyclosporine-induced nephrotoxicity (CIN) was studied in rats treated for 7 days with cyclosporine (10 mg x kg-1 x day-1 im) or vehicle (CON). CIN rats displayed characteristic reductions in glomerular filtration (GFR) and renal blood blood flow (RBF), and electron microscopy showed injury to proximal cells. Metabolic studies (7 day) showed significantly lower renal sodium excretion in conscious CIN rats compared with CON. In anesthetized rats at similar blood pressures, nephron GFR (SNGFR) was lower in CIN than CON, but fractional Na reabsorption was similar. In CIN, SNGFR, measured proximally to block flow to the sensing site of tubuloglomerular feedback (TGF) at the macula densa, was not significantly different than distal SNGFR. The rate of distal fluid delivery was significantly lower in CIN than in CON. Inhibition of the renin-angiotensin system (RAS) with captopril (CAP, 10 mg/kg iv), or saralasin (SAR, 0.3 mg x kg-1 x h-1 iv) caused marked arterial hypotension in CIN and a fall in renal vascular resistance (RVR). With arterial pressure controlled, CAP or SAR increased GFR and RBF, and reduced RVR in CIN, but did not reverse the renal deficits compared with similarly treated CON. RBF autoregulation in CIN was impaired between 90 and 140 mmHg but was partially restored by CAP. We conclude that both the filtered load and excretion rate of sodium in CIN are significantly reduced compared with controls, that SNGFR in CIN is not depressed by TGF in response to elevated distal fluid delivery, and that the RAS is not a primarily mediator of the renal vasoconstriction in CIN.

Pharmacodynamics of cyclosporine-ketoconazole interaction in mice. Combined therapy potentiates cyclosporine immunosuppression and toxicity.

We have previously studied the pharmacokinetics of the cyclosporine-ketoconazole interaction and shown that ketoconazole inhibits the metabolism of cyclosporine in mice. In the present study we investigated the pharmacodynamics of the interaction and found that ketoconazole increased the immunosuppressive activity and toxicity of cyclosporine in vivo. Mice were treated orally with cyclosporine (25-200 mg/kg/day), ketoconazole (100 mg/kg/day), drug vehicle, or drug combination for 14 days. Immunosuppression was studied by assaying radiometrically the delayed hypersensitivity response in mice that were sensitized and challenged to keyhole limpet hemocyanin. The dose-response curve for cyclosporine was shifted to the left when cyclosporine and ketoconazole were coadministered compared with treatment with cyclosporine alone. The dose that produced 50% of the maximal immunosuppression (ED50) for cyclosporine alone was 89 mg/kg/day, whereas the ED50 for cyclosporine, when combined with ketoconazole, was 33 mg/kg/day. Ketoconazole alone was not immunosuppressive. Toxicity was measured by the length of survival during a ten-day period of treatment. Animals receiving both drugs had a significantly lower survival: the ten-day survival of animals treated with 200 mg/kg/day of cyclosporine was 100% in the absence of ketoconazole treatment and 62.5% with 100 mg/kg/day of ketoconazole. The results of our study have two important implications. First, the effect of ketoconazole on cyclosporine immunosuppression is quantitatively similar to its effect on cyclosporine kinetics. Because of this two- to three-fold increase in both unchanged cyclosporine blood levels and immunosuppression, our results suggest that unchanged cyclosporine--not its metabolites--is the primary pharmacological agent of cyclosporine in vivo immunosuppression. Second, to avoid cyclosporine-induced nephrotoxicity, it has been recommended that the dosage of cyclosporine be decreased when this drug combination is used clinically. The results of this study suggest that a decrease in cyclosporine dosage will not lower the level of immunosuppression in these patients.

Increased serum beta 2 microglobulin during rejection, cyclosporine-induced nephrotoxicity, and cytomegalovirus infection in renal transplant recipients.

In 83 renal transplant recipients, serum beta 2 microglobulin (beta 2m) levels were significantly elevated during pretransplant uremia, rejection, cyclosporine-induced nephrotoxicity, and infections. In patients with normal serum creatinine, 74% had elevated serum beta 2m levels. None of the cyclosporine-treated patients had normal levels of beta 2m. Patients with stable renal allograft function receiving cyclosporine showed significantly higher serum beta 2m (P less than 0.001) and serum creatinine (P less than 0.01) levels than azathioprine treated patients. Patients with an irreversible rejection showed significantly higher serum concentrations of beta 2m than patients experiencing a reversible rejection (P less than 0.001). During cytomegalovirus (CMV) infection the serum beta 2m levels were elevated compared with other infections (P less than 0.001), while the serum creatinine was not. However, infected patients had higher serum levels of beta 2m and creatinine than patients with stable renal allograft function (P less than 0.001). Serum beta 2m may therefore be useful in the early diagnosis of CMV infection. To conclude, serum beta 2m levels cannot distinguish between rejection, cyclosporine nephrotoxicity, or infection.

Cyclosporin-induced nephrotoxicity

Cyclosporin-induced nephrotoxicity

Amelioration of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism

The aim of this study was to determine the effect of altered hepatic drug metabolism on the nephrotoxic and immunosuppressive properties of cyclosporin A (CsA) in the rat. From a consideration of the structures of those CsA metabolites identified so far, it seemed probable that the metabolism of CsA would occur at the hepatic cytochrome P-450 (cyt P-450) enzyme system. CsA (50 mg/kg/24 hr) administered orally for 14 days resulted in significant increases in both serum urea concentration and urinary N-acetyl-β- d-glucosaminidase activity, accompanied by renal proximal tubular vacuolation. The concomitant administration of either Aroclor 1254 (25 mg/kg/24 hr, i.p.) or phenobarbitone (PB) (40 mg/kg/24 hr, i.p.) but not 3-methylcholanthrene (3-MC) (15 mg/kg/72 hr, i.p.) resulted in abolition of the nephrotoxicity, assessed both biochemically and histologically, whilst the suppressive effect on the humoral response to SRBC was unaltered. Phenobarbitone also significantly decreased serum CsA concentrations. These results suggest that the PB-inducible set of cyt P-450 isoenzymes may be responsible or partly responsible for hepatic CsA metabolism.

Cyclosporin-induced nephrotoxicity

Cyclosporin-induced nephrotoxicity