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.

Evidence for proximal tubular cell origin of a sarcomatoid variant of human renal cell carcinoma.

A pure sarcomatoid variant of renal cell carcinoma obtained from a hydronephrotic kidney of an elderly white female was grown in tissue culture. Two parallel cell lines, one from the primary neoplasm and the other from a seeded metastasis within the same kidney have been cultured for more than 60 passages over a period of three years. Structural and functional studies of this neoplasm confirmed that it originated from proximal tubular cells.

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.

The alternate complement pathway. A possible role in a patient with focal glomerular sclerosis.

A boy had focal segmental glomerular sclerosis after the resolution of an unusual transient functional defect in activation of the alternate complement pathway. Prior to 1 year of age, the patient suffered repeated serious bacterial infections that were associated with an inability to opsonize Escherichia coli ON 2 in vitro. Serum levels of complement components were normal. Shortly after resolution of the complement defect, nephrotic syndrome developed. Properdin and C3 were identified in sclerotic glomeruli, which suggests that the ability to activate the alternate complement pathway played a role in the pathogenesis of glomerular sclerosis.

Bolus corticosteroids and cyclophosphamide for initial treatment of Wegener's granulomatosis.

Wegener's granulomatosis, a necrotizing vasculitis involving primarily the upper and lower respiratory tract and the kidney, may be rapidly fatal. We describe two children with Wegener's granulomatosis in whom we observed dramatic improvement within 72 hours following bolus corticosteroid therapy combined with cyclophosphamide.

Ultrastructure and function of cysts from human adult polycystic kidneys.

Twenty cysts from five patients with adult polycystic kidney disease were evaluated morphologically by electron microscopy and functionally by cyst fluid chemical analysis in order to correlate the structure with the function of the cyst wall. Thirteen proximal cysts, as defined by cyst fluid/serum sodium ratios of 0.8 to 1.2, were lined by epithelial cells with open or short closed apical junctions that appeared permeable to lanthanum. In contrast, seven distal cysts, as defined by cyst fluid/serum sodium ratios of less than 0.4, were lined by epithelial cells with long closed apical junctions that appeared impermeable to lanthanum. Cell organelles showed no distinction between proximal and distal cysts. Cyst basement membranes appeared abnormal, but there was no consistent pattern. The fluid of proximal cysts contained lower creatinine, potassium, and hydrogen ion, and higher chloride concentrations than did the distal cysts. These studies provide morphologic and chemical evidence consistent with te view that cysts originate from nephrons. Moreover, the maintenance of the epithelial lining and transmembrane solute gradients over many years extending up to and beyond the development of renal insufficiency suggests that the cysts function as nephronsthrughout the life of the patient.

Effect of basement membrane and colloid osmotic pressure on renal tubule cell volume.

Renal tubule cell volume is thought to be kept constant by a cation pump. When active transport is blocked, intracellular impermeant solutes cause cells to swell. Cell size is then determined by transmembrane hydrostatic and colloid osmotic forces. We studied the importance of passive transmembrane forces in determining cell size in isolated rabbit proximal straight tubules (PST). We blocked active solute transport with ouabain and evaluated subsequent changes in cell size by measuring outer diameter of nonperfused tubules. Tubules in a ouabain and 6 g/100 ml protein bath swelled only 40% above control. However, removal of the tubule basement membrane with collagenase dissipated a transmembrane hydrostatic pressure and caused more swelling. Final cell volume was determined largely by bath protein concentration. Tubules in ouabain and collagenase swelled enormously in hyponcotic protein, moderately in isoncotic protein, and could be shrunk below control in hyperoncotic protein. Intracellular colloid osmotic pressure was estimated to exceed 38 cmH20. We conclude that hydrostatic and colloid osmotic forces are major determinants of cell size in isolated PST treated with ouabain.

Gentamicin nephrotoxicity. II. Physiological, biochemical and morphological effects of prolonged administration to rats.

The purpose of this investigation was to determine the morphological, physiological and biochemical effects of gentamicin upon the rat kidney following prolonged administration of the antibiotic. Sprague-Dawley and Fischer 344 strain rats were given 3, 10, 20 or 40 mg gentamicin per kg body weight per day for 28 days. Morphologic alterations were evaluated by light and electron microscopy. Functional parameters included glomerular filtration rate, PAH secretion, renal plasma flow, sodium reabsorption, potassium excretion, urine volume and protein, and serum urea nitrogen. Oxidative metabolism of mitochondrial fractions from renal cortical homogenates was evaluated by oxygen uptake and P:O ratios. The results indicate focal proximal tubular injury, decreased tubular maximum secretion of PAH, and altered oxidative metabolism at the higher dose levels of gentamicin. Neither elevations of serum urea nitrogen nor alterations in glomerular filtration rate, renal plasma flow, or sodium or potassium excretion were observed. Thus, it appears that high dose levels (40 mg per kg per day) alter the structure and function of some proximal tubular segments when administered over prolonged periods. The alterations appear reversible. Although nephro-toxicity is identified under these conditions in rats, extrapolation to human patients usually receiving much lower doses must be guarded.

Gold nephropathy. Ultrastructural, fluorescence, and microanalytic studies of two patients.

Renal biopsy specimens from two patients with gold nephropathy showed two distinctly different types of alterations. The first demonstrated lesions suggestive of immunologic injury primarily to the glomerulus and identical with membranous glomerulonephritis. The second had no evidence of immunologic injury, but contained extensive vacuolar degeneration of proximal tubular epithelial cells. Ultrastructurally, the vacuoles contained lipid materials and occupied the basal portion of the cells. Other tubular cells contained numerous "gold-containing" cytosegresomes. In this second specimen, it appeared that the filtered gold had a direct toxic effect on the tubular epithelium and perhaps also on the glomerular capillary wall. These findings suggest that gold nephropathy may indeed be a spectrum of a combination of both direct toxic and immunologic injury to glomeruli and tubules.

Gentamicin nephrotoxicity in rats. I. Acute biochemical and ultrastructural effects.

This investigation characterizes the acute biochemical and ultrastructural alterations within the rat kidney following the single injection of 10, 40, 80, or 160 mg. of gentamicin per kilogram of rat weight. Gentamicin was given intraperitoneally and rats were killed 80 minutes later. To assess a possible inhibitory effect upon protein synthesis 3H-leucine was injected 20 minutes postantibiotic and renal cortex was assayed for whole tissue and the protein fraction amino acid uptake. To exclude the possibility of gentamicin-induced lysosomal membrane instability with subsequent release of acid hydrolases, the activity of acid phosphatase was assayed in the supernatant and the residue of cortical homogenates containing the lysosomal fraction. Ultrastructural changes were concomitantly studied. To determine the intracellular localization of gentamicin, levels of the antibiotic were measured in subcellular fractions of cortical homogenates obtained from rats 2 hours following a single subcutaneous injection of 20 mg. of gentamicin per kilogram of rat weight. No gentamicin-induced alterations either of protein synthesis or of acid phosphatase distribution were demonstrated. Ultrastructural changes were most marked at 160 mg. per kg. consisting mainly of dilation of the endoplasmic reticulum, altered mitochondria, and increased cytosegresomes. Significant quantities of gentamicin were distributed within the nuclear, mitochondrial, and microsomal fractions. These studies indicate that although cytoplasmic alterations are prominent within the proximal tubular epithelial cells, they are not likely the result of either inhibition of protein synthesis or release of acid phosphatase from lysosomes.