Cytochrome P450-dependent arachidonic acid metabolism in human kidney cortex from several postmortem subjects has been characterized. Using HPLC and GC/MS, four cytochrome P450-arachidonic acid metabolites were tentatively but not unequivocally identified as epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHT) and 19- and 20-hydroxyeicosatetraenoic acids, suggesting the involvement of two major cytochrome P450 enzymes, epoxygenase and omega/omega-1 hydroxylases. This pattern of metabolism was similar to that found in rabbit and rat kidneys. The formation of these metabolites was dependent on the presence of NADPH and inhibited by IgG of NADPH-cytochrome P450 (c) reductase. Immunologic studies of renal cytochrome P450 epoxygenase demonstrated that antibodies prepared against human-purified hepatic cytochrome P450 epoxygenase recognized renal enzyme protein and inhibited the enzyme activity by 92%. In contrast, control immunoglobulin did not inhibit renal cytochrome P450 epoxygenase. Antibody inhibition of renal cytochrome P450 epoxygenase demonstrated a degree of conservation of both enzyme proteins between liver and kidney. Antibodies against lauric acid omega/omega-1 hydroxylases (P450 omega) inhibited the formation of omega/omega-1 hydroxylase products, 19- and 20-HETEs. Identical qualitative patterns of arachidonic acid metabolites were observed in all cortical microsomes studied. Interindividual variations were observed in the cytochrome P450-dependent arachidonic acid metabolism, and the activities ranged from 0.031 to 5.027 nmol arachidonic acid converted/mg protein/30 min. which is about a 150-fold difference. However, when the specific activities for total cytochrome P450-dependent arachidonic acid metabolism were calculated, two separate groups could be distinguished, high and low metabolizers of arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

The auditory sensitivity of 67 patients with chronic end-stage renal failure was assessed. In order to determine the incidence of hearing loss and to describe the impairment and possible contributing factors, one group of 39 patients was assessed prior to treatment by hemodialysis. Twelve of these subjects were then followed for 1 year as they are treated by hemodialysis. The remaining 27 patients, not treated by hemodialysis, were also retested in one year. A second group of 28 patients who ad been receiving hemodialysis over periods of 1 1/2, 3, and 6 years was also evaluated. A high incidence of high-frequency impairment was obtained which could not be attributed to age, noise exposure, ototoxicity, or hereditary. An association between this high-frequency impairment and both the renal disease and its treatment was suggested. Clinically significant sensorineural hearing loss did not appear associated with non-genetic kidney disease.

The development of hypertiglyceridemia was studied in 38 patients who were at different deteriorative stages of chronic renal insufficiency, as measured by corrected creatinine clearance. Patients in the mild stages of chronic renal insufficiency showed a 53% decrease in postheparin lipolytic activity, and no change in plasma triglyceride levels. In the moderate and severe stages, plasmia triglycerides were significantly elevated but there was no further decrease in PHLA. Those patients undergoing chronic hemodialysis showed a further increase in plasma triglycerides and postheparin lipolytic activity decreased to near zero. Serum electrophoretic studies indicated that in the moderate and severe stages of chronic renal insufficiency, prior to initiating hemodialysis, the chylomicron and very low density lipoprotein fraction were elevated. In those patients receiving chronic hemodialysis hyperchylomicronemia was the predominant finding.

Some chronic renal failure patients maintained on dialysis have uncontrollable hypertension. Those with elevated renin levels require bilateral nephrectomies prior to kidney transplant to avoid nephrosclerosis. The morbidity and mortality from surgical nephrectomies are high. In 2 such patients we embolized the renal arteries with gelfoam and successfully occluded all the major vessels. One patient became normotensive. The second remained hypertensive and had increased renin levels, probably on the basis of ischemia. Subsequent surgical nephrectomies demonstrated completely occluded segmental branches but only focal areas of infarction. Collateral blood supply determines the success of the procedure.

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