Morphological and biochemical effects of gentamicin and cyclosporin-A on urinary cell phospholipids and phospholipases in man.

Abstract

The morphology, lipid composition, and activity of sphingomyelinase (E.C. 3.1.4.12) and phospholipases A (E.C. 3.1.1.32) and C (E.C. 3.1.4.3) were studied in the urinary cells from four normal subjects, four patients receiving gentamicin (G), and four patients receiving cyclosporin-A (CsA). We report that abnormal urinary excretion of proximal tubular cells occurred in patients receiving G and CsA. Membrane-enclosed sudanophilic material and numerous vacuoles were found in the cytoplasm of the proximal tubular cells from both patients receiving G and those receiving CsA. Patients receiving G shed higher levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and sphingomyelin (SM) in the order of 78%, 38%, and 30% relative to normal. In contrast, the excretions of phosphatidylinositol (PI) and PC were 50% and 30% lower, respectively, in patients receiving CsA as compared to control. Sphingomyelin levels, however, were moderately elevated in these patients' urinary renal tubular cells. The activity of acid sphingomyelinase was one half the normal level in the cells of patients receiving G and CsA. The most striking result was a tenfold decrease in the activity of neutral sphingomyelinase in patients receiving G. In contrast, the activity of neutral sphingomyelinase in patients receiving CsA was similar to control. Phospholipase A activity was decreased and increased 35% and 15%, respectively, in urinary proximal tubular cells from patients receiving G and CsA. We conclude that deficient neutral sphingomyelinase activity precedes phospholipid (PL) overloading and gross pathological changes in patients receiving gentamicin but not in patients receiving cyclosporin-A.