George Gavellas

Metabolic Consequences of Oral Administration of 24,25-Dihydroxycholecalciferol to Uremic Dogs

24,25-dihydroxycholecalciferol [24,25-(OH)(2)D(3)], once considered a relatively inert metabolite of vitamin D(3), has been recently recognized as a metabolically active product in some species. In previous studies, we have shown that infusion of 24,25(OH)(2)D(3) into the thyroid artery of normal dogs results in prompt and complete suppression of parathyroid hormone (PTH) secretion. In this study, we have examined the metabolic consequences of oral administration of this metabolite in dogs with experimentally induced renal hyperparathyroidism. Dogs with comparable degrees of renal insufficiency (glomerular filtration rate, 10-15 ml/min) were treated for 3 wk with daily doses of either 2 mug of 24,25(OH)(2)D(3) or 50% ethanol, the vehicle in which the metabolite was suspended. After a 6-wk recovery period, treatments were reversed: dogs who had previously served as controls received the metabolite while dogs previously treated with metabolite received the vehicle. Administration of 24,25(OH)(2)D(3) resulted in a 40-60% decrease of immunoreactive PTH. This was associated with a small (0.1-0.2 mg/dl) but unequivocal decrease of serum ionized calcium. Calcium balance, which was slightly negative under control conditions, became slightly but definitively positive on treatment with 24,25(OH)(2)D(3). All other parameters measured, including total serum calcium, magnesium, phosphorus, creatinine, electrolytes, phosphorus excretion, and phosphorus balance, remained unchanged. The data support the hypothesis that 24,25(OH)(2)D(3) not only decreases PTH secretion but also functions as an anabolic hormone in bone under the conditions of this experiment.

The calcemic and phosphaturic effects of parathyroid hormone in the normal and uremic dog

The responsiveness of bone and kidney to highly purified bovine PTH was evaluated in normal (N) and uremic dogs. One group of uremic dogs (uremic-constant solute intake; U-CSI), maintained on a diet containing 1500 mg of phosphorus (P) daily developed the adaptive increases in phosphate excretion (FEPO4) and PTH levels characteristic of uremia. A second group of uremic dogs (uremic-proportional reduction of solute; U-PRS), in which dietary P intake was reduced in proportion to the reduction in GFR, exhibited normal FEPO4 and PTH values. During PTH infusion tubular reabsorption of phosphate per nephron mass decreased 2.5 mg100 ml in U-PRS but only 1.4 in U-CSI (p < .001) and 1.1 in N (p < .001). After PTH the calcemic response was significantly and equally decreased in both U-CSI and U-PRS compared to N. In conclusion, the blunted calcemic response to PTH in uremia does not appear to be the only or predominant factor in the pathogenesis of hyperparathyroidism since the uremic dog treated with proportional reduction of phosphorus intake, which maintains a normal PTH level, also demonstrates this abnormality. The PTH-induced rise in phosphate excretion in the uremic nephron depends on the pre-existing degree of inhibition of renal tubular phosphate reabsorption. Finally, the uremic animals in which an adaptive phosphaturia was prevented (U-PRS) exhibited a magnified response in phosphate excretion per nephron to exogenous PTH infusion.

Effect of Protein Diets on the Renal Function of Baboons (Papio hamadryas) With Remnant Kidneys: A 5-Year Follow-up

To assess the progression of renal disease and the effects of protein intake in a species phylogenically close to humans, 14 adolescent baboons (Papio hamadryas) were subjected to infarction of one third of the left kidney and, 2 months later, to right nephrectomy. They were then randomized to a synthetic protein diet containing either 8% or 25% casein. Hemodynamic and metabolic measurements were obtained in awake animals every 4 months. Modest proteinuria developed immediately after left kidney infarction, and hypertension after right nephrectomy. Proteinuria and hypertension, however, were similar in both groups and did not progress for the next 60 months. Inulin clearance markedly increased with implementation of the synthetic diet in baboons given 25% protein, in contrast to animals given 8% protein, averaging 46.6 +/- 4.7 mL/min versus 28.2 +/- 2.6 mL/min, respectively, after 4 months. The glomerular filtration rate (GFR) changed little immediately thereafter and, at 1 year, averaged 43.0 +/- 1.4 mL/min and 28.0 +/- 4.3 mL/min, respectively. During the next 4 years, however, inulin clearance steadily decreased in baboons fed 25% protein. The inverse correlation between inulin clearance and time of follow-up was y = 48.5 - 0.36x (r = -0.879, P < 0.001) in baboons fed 25% protein and y = 29.0 - 0.11x (r = -0.625, P < 0.02) in baboons fed 8% protein. Nevertheless, after 5 years, the mean GFR was still significantly greater in animals given the 25% protein diet than in baboons fed 8% protein, averaging 29.1 +/- 0.6 mL/min and 24.1 +/- 1.0 mL/min, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of Secondary Hyperparathyroidism by Cimetidine in Chronically Uremic Dogs

Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536+/-70 muleq/ml (mean+/-SE) (nl < 100 muleq/ml) before treatment to 291+/-25 muleq/ml at 12 wk (P < 0.001) and 157+/-32 muleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7+/-0.9 mg/dl to 3.4+/-0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4+/-4.3 pg/ml to 51.8+/-2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (-347+/-84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141+/-409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion. These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.

Effects of cimetidine on parathyroid hormone in chronic uremia.

Recent case reports suggest suppression of immunoreactive parathyroid hormone (iPTH) with cimetidine in two patients with primary hyperparathyroidism. In both patients peptic ulcer disease led to medical treatment with cimetidine. In the first patient given oral cimetidine (800 mg then 400 mg daily) for 8 months, iPTH decreased from 20 times to 6 times normal1. No changes in serum calcium and phosphorus occurred, but inhibition of gastric acid secretion and ulcer healing were demonstrated. In the second patient, a woman with a parathyoid adenoma, cimetidine treatment (1200 mg daily) was associated with a decrease in iPTH levels from a value 2.5 times normal to a normal value2,3. Concommittantly, serum calcium decreased from 11.3 mg/dl to 10.3 mg/dl and serum phosphorus increased from 2.1 mg/dl to 2.7 mg/dl. One month after discontinuation of cimetidine therapy iPTH had rebounded to values thrice normal and serum calcium and phosphorus were 10.8 and 2.3 mg/dl, respectively.

Interrelations Between Phosphorus, Calcium, Parathyroid Hormone, and Phosphate Excretion in the Normal and Uremic Dog

Phosphorus homeostasis is maintained in animals and man by excretion through the kidneys of the same amount of phosphorus absorbed from the intestines on an ongoing basis. There is apparently little impairment of gastrointestinal phosphorus absorption in uremia (1); yet phosphorus balance is well maintained in animals and man with advancing chronic renal disease. This balance is accomplished by progressive increases in fractional excretion of phosphate (\((F{{E}_{P{{O}_{4}}}})\)) by the kidneys and associated increases in para-thyroid hormone (PTH) secretion (2–5).