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withdrawn from the study because of hepatotoxicity or side effects of nausea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.