Urinary zinc excretion following infusions of zinc sulfate, cysteine, histidine, or glycine.

Zinc sulfate (40 mg elemental zinc) or one of three amino acids (5 or 10 g cysteine, 10 g histidine, or 10 g glycine) was infused into anesthetized dogs over a 60-min period. Plasma concentrations and urine excretions of zinc and five other cations, and glomerular filtration rates were determined before, during, and after these infusions. Infusions of zinc sufficient to produce a 20-fold increase in total plasma zinc concentrations had little effect on urinary zinc excretions (threefold increase) or plasma ultrafilterable zinc concentrations. Ten grams of cysteine urinary zinc excretions more than 100-fold, 5 g of cysteine increased zinc excretions more than 30-fold, 10 g of histidine increased zinc excretions sixfold, and 10 g of glycine had no effect. Cysteine infusions appeared to produce a net tubular secretion of zinc. Only histidine appeared to increase serum ultrafilterable zinc concentrations significantly. It would appear that plasma and urine concentrations of certain amino acids, specifically cysteine and histidine, along with polypeptides and other metabolites containing these amino acids, may be major determinants of urinary zinc excretion.

Serum concentrations and urinary excretions of zinc in cirrhosis, nephrotic syndrome and renal insufficiency.

Serum zinc conentrations are decreased in patients with a variety of clinical disorders including cirrhosis, nephrotic syndrome and renal insufficiency. Urinary zinc excretions are increased in the first two disease states. Symptoms of acute zinc deficiency (anorexia, dysfunction of smell and taste and mental and cerebellar disturbances) and chronic zinc deficiency (growth retardation, anemia, testicular atrophy and impaired wound healing) are common in these patients. It remains unresolved whether these low serum zinc concentrations in these disease states are indicative of true symptomatic or asymptomatic zinc deficiency, or merely reflect a decrease in available zinc-binding proteins, as well over 90% of serum zinc is bound to protein in normal subjects. The correlation between serum zinc and albumin concentrations, reportedly the major zinc-binding protein, is unimpressive. Studies of serum and urine binding of added radiozinc65 using Sephadex G-200 gel column chromatography and polyacrylamide gel electrophoresis suggest most of the radiozinc is bound to a protein with a molecular weight near albumin (68,000). Polyacrylamide gel electrophoresis suggests this might be a prealbumin. The low serum zinc concentration in the patient with nephrotic syndrome does not appear to be due to loss of zinc bound to urinary protein.

An etiology of nephrotic syndrome in chronic interstitial nephritis (pyelonephritis); an electron microscopic study.

Renal tissues were studied using electron microscopy (EM) and immunofluorescence microscopy (IFM) from three patients who were found to have chronic interstitial nephritis (pyelonephritis) by light microscopy (LM). By LM, 90% of the glomeruli in two patients and all glomeruli in one patient were normal. By EM, glomerular capillaries in all patients revealed generalized fusion of epithelial foot processes. In two patients, IFM for immunoglobulins, third component of complement and fibrinogen were negative. These two patients received corticosteroids for 6 to 12 weeks. In one, proteinuria markedly decreased (from 17.9 to 1.1 gm) in four weeks and in the other follow-up studies of renal histology revealed normal glomeruli and partial restoration of foot processes by LM and EM respectively. Thus, this study offers evidence for lipoid nephrosis (or minimal lesion disease) as an etiology of nephrotic syndrome in chronic interstitial nephritis (pyelonephritis). The impaired renal function in these patients is attributed to tubulo-interstitial disease rather than glomerular pathology. It remains to be determined whether the two disparate pathological conditions have coexisted or chronic interstitial nephritis had led to the appearance of lipoid nephrosis through an unidentified mechanism.

Rapid development of glomerular crescents in epinephrine-infused dogs.

A serendipitous finding in the kidneys examined by light, electron, and immunofluorescence microscopy (LM, EM, and IFM, respectively) in mongrel dogs infused intravenously with epinephrine (4 microgram per kg per min) alone or in combination with therapeutic agents over a six hour period was proliferating epithelial cells in Bowman's space and adhesion to the Bowman's membrane (crescent). This lesion was observed in 10 of 17 dogs. In five, over 50 percent of the glomeruli were involved. In seven additional dogs infused with epinephrine, renal biopsy studies (LM) at 0, 3 and 6 hr periods revealed crescents only in the six hr specimens. By EM, the crescents were composed of actively proliferating epithelial cells with many large mitochondria containing conspicuous intramitochondrial particles. Fibrin was found within glomerular and peritubular capillaries, within tubules but rarely in the crescent. IFM revealed granular deposits of IgG only in the glomerular basement membrane and mesangium. Other changes included necrosis of the tubules in all dogs receiving epinephrine alone and necrosis of arterioles in some of the dogs studied. Dogs receiving normal saline infusions (control) did not reveal any abnormalities in the kidney. This model should prove useful in determining the morphogenesis of crescent formation and in evaluating the effect of therapeutic agents in the prevention of this lesion.

Effects of acetylsalicylic acid, dipyridamole, and hydrocortisone on epinephrine-induced myocardial injury in dogs.

A reproducible model for producing diffuse myocardial injury (epinephrine infusion) has been developed to study the cardioprotective effects of agents or maneuvers which might alter the evolution of acute myocardial infarction. Infusions of epinephrine (4 mug per kilogram per minute for 6 hours) increased radiocalcium uptakes into intact myocardium and each of its subcellular components with the mitochondrial fraction showing the most consistent changes when compared to saline-infused control animals (4,957 vs. 827 counts per minute per gram of dried tissue or fraction). Myocardial concentrations of calcium also increased significantly (12.0 vs. 5.0 mg.per 100 Gm. of fat-free dry weight). Infusions of calcium chloride sufficient to raise serum calcium concentrations 2 mEq. per liter failed to increase calcium influx into the myocardial cell. Mitochondrial radiocalcium uptakes were significantly decreased in animals pretreated with acetylsalicylic acid or dipyridamole or when hydrocortisone was added to the epinephrine infusion (2,682,2,803, and 3,424 counts per minute per gram of dried fraction, respectively). Myocardial calcium concentrations also were decreased (11.2, 8.3, and 8.9 mg. per 100 Gm. of fat-free dry weight, respectively) in the three treatment groups, being significantly decreased only in the last two. Evidence of microscopic damage was graded as less severe in the three treatment groups. Acetylsalicylic acid, dipyridamole, and hydrocortisone all appear to have cardioprotective effects when tested in this model.

Focal glomerular sclerosis.

Focal glomerular sclerosis was diagnosed in nine patients by renal biopsy. Proteinuria, hematuria, hypertension, and slowly progressive renal insufficiency unresponsive to corticosteroid and immunosuppressive therapy were consistent clinical findings. Focal, segmental, and global glomerular sclerosis with intraluminal deposits of hypereosinophilic and strongly PAS-positive material, intracapillary foam cells, and moderate interstitial involvement were consistent morphologic findings. The importance of this clinicopathologic entity in the spectrum of renal diseases has only recently been appreciated.

Case report. Severe hyperuricemia, hypokalemic alkalosis and tubulointersitial nephritis.

A patient with severe idiopathic hyperuricemia and hypokalemic alkalosis was followed over a one-year period. A tubulointersitial nephritis consistent with hypokalemic nephropathy was found on biopsy. However, the possibility that the hyperuricemia contributed to the hypokalemia and renal lesion cannot be excluded. Inappropriate urinary loss of potassium could be prevented by administration of spironolactone or triameterene. Six months after initiation of allopurinol therapy with reduction of serum uric acid concentrations to normal concentrations, this potassium wasting was substantially decreased.

Natriuresis and carbohydrate-induced antinatriuresis in fasted, hydrated hypertensives.

After an overnight fast and oral hydration with water, hypertensive subjects developed a significant natriuresis (mean urine sodium excretions increased from 130 to 291 mueq/min. The incidence of a natriuresis (greater than 200 mueq sodium excreted per minute) was 75% in the hypertensive group (16 subjects) compared to 27% in a previously studied normotensive group (22 subjects). The incidence of a carbohydrate-induced antinatriuresis (greater than 30% decrease in urinary sodium excretion) was 62% in the hypertensive group compared to 41% in the normotensive group. No decrease in plasma volume (131I-labeled albumin concentration) due to a shift of solute and water intracellularly could be documented to explain the antinatriuretic effect of glucose. An incidental observation was a significant decrease in plasma zinc concentrations after glucose ingestion.