Ketoconazole (Nizoral) has been used extensively to treat fungal infections for a number of years. Ketoconazole also is used in renal transplant recipients to reduce the rate of metabolism of cyclosporine, thereby lowering the dosage requirement of this expensive drug.
Ketoconazole inhibits the synthesis of cortisol, the main glucocorticoid hormone produced by the adrenal cortex. High rates of production of cortisol are associated with faster progression of chronic renal failure, while low rates of cortisol production are associated with slow progression or no progression.
These observations led us to the hypothesis that ketoconazole administration on a long-term basis might slow the progression of renal failure. One problem with this concept is the well-known "escape" phenomenon: When cortisol production is inhibited, adrenocorticotrophic hormone (ACTH), derived from the pituitary gland, increases and stimulates the adrenal gland to produce more cortisol. We have found that this "escape" can be prevented by administering a low dose (2.5 mg per day) of prednisone (a synthetic glucocorticoid) at the same time. ACTH levels do not rise, and the block in cortisol synthesis persists.
Ketoconazole has other effects that might lead to slower progression of renal disease.
We have published the results of our study on the effect of ketoconazole (200 mg per day) plus low-dose prednisone (2.5 mg per day) in 27 patients with chronic renal failure. In diabetic nephropathy, glomerular diseases, and interstitial nephritis, we observed distinct slowing of progression. In polycystic kidney disease, however, progression was not slowed and may have been accelerated. A discussion of long-term results of taking ketoconazole plus low-dose prednisone in two patients with diabetic kidney disease follows.
Eve Magee, a 47-year-old black curriculum specialist in the Baltimore City school system, was referred in April 1998. She had been diabetic for 19 years, and had been on insulin for several years. Kidney involvement was first detected one year earlier, but high blood pressure had been present for two years, treated with a variety of drugs. Serum creatinine most recently was reported as 4.7 mg per dl, and urine protein as 1.9 g per day. For seven months she had been getting injections of erythropoietin. She was free of symptoms, except for some numbness and tingling in her feet. Her mother and a sister were diabetic, too. Physical exam was negative except for systolic hypertension (blood pressure 170/65) and ankle swelling. Laboratory reports came back as follows: serum creatinine 3.9 mg per dl, serum urea nitrogen 69 mg per dl, urine protein 2.53 g per day, glomerular filtration rate 11 ml per min. She was instructed on a very-low-protein diet (0.3 g per kg) and told how to get essential amino acids. Three weeks later serum urea nitrogen had fallen to normal (23 mg per dl). At this point she was started on ketoconazole and low-dose prednisone. We did not measure her rate of loss of kidney function first during a control period, because of the severity of her renal failure. She took 200 mg per day of ketoconazole and 2.5 mg per day of prednisone daily for the next four years. The only problem that arose was that the transplant service had worked her up for a transplant and called to tell her that a kidney had become available. Since she had no symptoms and was not progressing, she declined. However, she recently developed pneumonia, and never regained her vigor afterward. She finally went on dialysis, having deferred it for about four years.
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