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Walser M, Hill S

Effect of ketoconazole plus low-dose prednisone on progression of chronic renal failure

Am J Kidney Dis (Apr) 29:503-513 1997

Ketoconazole was given to patients with progressive chronic renal failure to determine the effect of inhibiting endogenous cortisol production. This study was performed because a previous analysis suggested a relationship between the rate of progression and the rate of 17-hydroxy-corticosteroid excretion. Ketoconazole was given to 20 patients with chronic renal failure due to glomerular disease, interstitial nephritis, diabetes or polycystic kidney disease in a daily dose of 200-600 to suppress cortisol production along with prednisone 2.5 mg/d to prevent corticotropin-mediated pituitary escape. Several protocols were employed but all included comparison of the rate of progression determined by serial GFR determinations (urinary clearance of 99mTC-DTPA) during one or more control periods with the rate during one or more ketoconazole treatment periods. In seven patients with chronic glomerular disease the rate of progression was a loss of 0.62 mL/min/month. Ketoconazole decreased this rate by 66%. In five patients with interstitial nephritis the rate was decreased from -1.19 mL/min/month by 55%. In five diabetics the rate decreased from -1.22 mL/min/month by 77%. However, in four patients with PCKD the rate of progression increased from -0.67 mL/min/month by 99%. Four additional patients were withdrawn from the study because of hepatotoxicity or side effects of nausea and vomiting.

Comment: These are provocative findings. Too small a number of subjects was studied for ketoconazole to be recommended for routine use in patients with chronic renal failure. In addition it must be ascertained whether patients with certain diseases or characteristics, such as those with polycystic kidneys, are merely not benefited by ketoconazole or are actually harmed. This study provides adequate justification for undertaking a more extensive randomized prospective trial of the use of ketoconazole to prevent progression of chronic renal disease.

The mechanism of this effect is not known. Although ketoconazole inhibits cortisol production by inhibiting cytochrome P-450, it is a "dirty" drug in that it has numerous other effects. Walser notes that ketoconazole also inhibits thromboxane production and nitric oxide synthase. Ketoconazole and other cytochrome p-450 inhibitors prevent experimental acute renal injury by preventing degradation of cytochrome p-450 and subsequent release of iron capable of catalyzing oxygen radical formation (Proc Natl Acad Sci USA 91:7002, 1994). Ketoconazole also interferes with the metabolism of a number of drugs, including cyclosporine. This effect has been utilized to reduce the required dose of cyclosporine which is costly (N Engl J Med 333:628, 1995; Am J Nephrol 15:493, 1995). Ketoconazole in a dose of 100-200 mg/d was generally well-tolerated in patients with cardiac or renal transplants.

Currently, there are only a few interventions that have been demonstrated to slow the progression of chronic renal disease. These therapies include dietary protein restriction, blood pressure reduction, angiotensin antagonists, and some calcium channel blockers. For diabetes, controlling blood sugar is also effective. A much larger number of interventions have strong experimental support but have not been subjected to clinical trials. These interventions include antioxidants, sodium bicarbonate, heparin, cholesterol reduction, phosphate restriction, and inhibiting mediators of fibrogenesis (such as TGF-b). This clinical trial is a welcome addition to the nephrology literature. (Mark S. Paller, M.D., University of Minnesota, Minneapolis)

The abstract of this paper is available from the AJKD online at this site.