Francis E. Cuppage

pH-Dependent Accumulation of Clindamycin in a Polycystic Kidney

We determined the concentrations of clindamycin and gentamicin in fluid aspirated from 16 cysts of a surgically excised polycystic kidney. The patient had received both drugs intravenously for seven days before nephrectomy. The cysts were grouped into proximal (pH greater than 6.5) and distal (pH less than 6.5) types according to the pH of the fluid. In nine proximal cysts the mean concentration of gentamicin was 1.3 +/- 0.2 and that of clindamycin was 9.2 +/- 2.3 micrograms/mL. In seven distal cysts the gentamicin concentration was 0.7 +/- 0.2 micrograms/mL and the clindamycin concentration was 34.0 +/- 5.2 micrograms/mL. Plasma gentamicin was 3.8 (peak) and 1.9 (trough) micrograms/mL, and clindamycin was 3.9 micrograms/mL (random). Clindamycin cyst concentrations showed an inverse correlation with cyst fluid pH (r2 = 0.78). These studies confirm that in autosomal dominant polycystic kidney disease (ADPKD), certain cysts develop steep pH gradients between fluid and plasma and indicate that intracystic pH determines the extent to which basic lipophilic antibiotics accumulate in the fluid. Lipid-soluble antibiotics with relatively alkaline pKaS may be useful in the treatment of infected renal cysts.

Nephrotoxicity of Intravenously Injected Cadmium-Metallothionein: Critical Concentration and Tolerance

The nephrotoxicity of Cd-metallothionein (Cd-MT) was examined after iv administration of various dosages to mice. The lowest dosage of Cd-MT that produced renal injury was 0.2 mg Cd/kg. This dosage of Cd-MT resulted in 10 micrograms Cd/g in the kidneys 24 hr after administration. A time-course experiment utilizing a higher (0.3 mg Cd/kg) nephrotoxic dose of Cd-MT demonstrated that the renal Cd concentration at 4 and 12 hr was much higher than the critical concentration, but thereafter decreased to about 10 micrograms Cd/g wet tissue by 24 hr. Thus, Cd in excess of 10 micrograms/g appears to damage the kidney and then distributes to other tissues and/or is excreted into urine. When a total of 0.3, 0.4, and 0.8 mg of Cd/kg as Cd-MT was administered in divided dosages over 4 days, as much as 30 micrograms Cd/g was detected in the kidney but no renal injury was observed. Thus, the critical concentration for producing renal injury after acute administration of Cd-MT is estimated to be approximately 10 micrograms Cd/g wet weight. However, with repeated exposure to Cd-MT, this acute critical concentration can be exceeded without producing renal injury, as tolerance to the nephrotoxic effects of Cd-MT develops.

Hypocomplementemic glomerulonephritis in an infant and mother. Evidence for an abnormal form of C3

A mother developed hematuria during the fourth month of pregnancy, and her nursing infant son from this otherwise uncomplicated pregnancy developed hematuria at 3.5 months of age. Both had a mild glomerulonephritis characterized by mesangial prominence, focal thickening and mottling of the glomerular basement membrane and electron-dense deposits, predominantly in the intramembranous and subendothelial positions. Immunofluorescence studies revealed striking accumulations of C3 and other complement components associated with alternative complement pathway activation within glomeruli, and the presence of small or equivocal amounts of immunoglobulin. C1q, C4 and factor B were not detectable. The glomerular lesion was accompanied by hypocomplementemia. Sera of both mother and infant displayed half normal levels of C3 and factor B, increased levels of C4, and normal levels of 12 other complement proteins. High normal or slight elevation in nephritic factor-like activity was observed in serial serum samples. Studies suggested that this mother and son represent the second kindred having an abnormal form of C3 which produces an alternative complement pathway C3 convertase, C3b, Bb, resistant to control by factor H. No additional affected family members were identified. The course of the nephritis over 7 years without drug therapy has been mild with resolving hematuria and no abnormal proteinuria or decrease in creatinine clearance.

Urinary Lipid Bodies in polycystic Kidney Disease

Urinary doubly refractile lipid bodies (oval fat bodies) are observed most frequently in patients with heavy proteinuria resulting from glomerular disease. We observed doubly refractile lipid bodies (DRLB) in the urine sediment of 60% of 35 patients with autosomal dominant polycystic kidney disease (ADPKD). All patients had clinical courses typical of ADPKD, and none exhibited the features of a second, unrelated renal disease. DRLB in the urine were correlated with a urine dipstick protein reading exceeding trace. Age, sex, BP, and serum creatinine concentration were not associated with the presence of DRLB in the urine. Examination of cyst fluid obtained from kidneys of six ADPKD patients revealed DRLB in 80% of cyst fluid samples that contained degraded blood (so-called chocolate cysts). The DRLB in cyst fluid were morphologically indistinguishable from those observed in urine, and DRLB from both sources were stained with oil red O. We conclude that urinary DRLB are a clinical feature of ADPKD.