Animal model of aluminum-induced osteomalacia: role of chronic renal failure.

Both aluminum toxicity and a relative deficiency of parathyroid hormone have been implicated in the development of osteomalacia in dialysis patients. To study the effect of intraperitoneal (IP) aluminum injections on bone histology and parathyroid hormone and to determine if chronic renal failure accentuates aluminum toxicity, rats were divided into five groups: normals (N); low dose aluminum (LDA), 0.1 mg IP aluminum daily; high dose aluminum (HDA), 1.0 mg IP aluminum daily; chronic renal failure (CRF); and chronic renal failure plus high dose aluminum (CRF-HDA). At the conclusion of the study, there were no differences between N and LDA rats. Between the other groups, marked differences were observed. Compared to N rats, the relative osteoid volume (P less than 0.02) and the osteoid seam width (P less than 0.001) were increased in HDA, CRF, and CRF-HDA rats. Percent resorption and osteoclasts/mm2 were increased in CRF rats (P less than 0.02) and decreased in HDA rats (P less than 0.05). Compared to N rats, the amino terminal parathyroid hormone was decreased in HDA rats (P less than 0.02) despite the presence of hypocalcemia. These data suggest that (1) aluminum toxicity produces osteomalacia; (2) a relative parathyroid hormone deficiency may be a contributory factor; (3) chronic renal failure increases the severity of aluminum-induced osteomalacia; and (4) chronic renal failure alone does not result in osteomalacia.

Effects of acute and chronic splenectomy on experimental acute renal tubular lesions.

The first half of this study describes the effects of acute splenectomy on epinephrine-induced ATL in the dog. Renal morphology and hematocrit were compared in 12 dogs without splenectomy (group I), six dogs with antecedent splenectomy (group II), and seven dogs with antecedent splenectomy after splenic contraction was induced by topical application of epinephrine (group III). Splenectomy was performed in groups II and III 20 to 30 min prior to epinephrine infusion; all three groups received equal infusions (4 microgram/kg/min) for 6 hr before the kidneys were harvested. ATL and renal congestion were consistently severe in group I but infrequent and less severe in groups II and III. The second half of this study describes the apparent protective effect of chronic (2-week) splenectomy on epinephrine-induced ATL. Renal morphology and hematocrits were compared in 13 intact dogs (group IV) and 10 dogs splenectomized 2 weeks before the epinephrine infusion (group V). The severity of the ATL and the degree of renal congestion were significantly less in the chronically splenectomized dogs. This chronic protection afforded by acute and chronic splenectomy observed after epinephrine infusion remains unclear.

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.

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.