Iatrogenic hypercalcemia in hemodialysis patients.

Calcium carbonate is frequently used in large doses as a phosphorus binder in hemodialysis patients, which often results in hypercalcemia. In most studies in which calcium carbonate is prescribed to control serum phosphorus levels the patients are not given calcitriol. However, calcitriol may be necessary for suppression of parathyroid hormone. The risk of hypercalcemia when calcium supplements are used in conjunction with calcitriol has not previously been examined in detail. We reviewed the charts of 74 hemodialysis patients (119 patient dialysis years) to determine the relationship of serum calcium to calcitriol, calcium therapy, and PTH levels. Twenty-eight patients (38%) were hypercalcemic at some point. Calcitriol therapy significantly increased the risk of hypercalcemia, independently of calcium therapy (p = 0.032). However, patients on a low dose of calcitriol were more than twice as likely to be hypercalcemic than patients on higher doses. Mean PTH levels were lower in the patients on the lower doses of calcitriol, indicating less severe hyperparathyroid disease. We conclude that hypercalcemia is a common complication in hemodialysis patients on calcitriol and calcium carbonate. Whether lowering the dialysate calcium, as suggested by other investigators, will successfully decrease the risk of hypercalcemia without worsening hyperparathyroidism remains to be determined.

Effects of selective oxidation of 1-34 bovine parathyroid hormone on its renal actions in the rabbit.

Oxidation of both of the methionine residues (positions 8 and 18) in parathyroid hormone (PTH) eliminates many of its biological effects. The present studies were performed to examine the actions of 1,34 bovine PTH and 1-34 bovine PTH oxidized selectively at Met 8, at Met 18, and at both sites on renal electrolyte handling and on adenylate cyclase (AC) stimulation. In clearance studies in anesthetized rabbits, PTH caused a phosphaturia and an anticalciuria. PTH also stimulated renal proximal tubular AC in vitro and increased renal cortical cAMP content in vivo. PTH oxidized at Met 18 was anticalciuric, but not phosphaturic, stimulated renal AC and increased cortical cAMP content. PTH oxidized at Met 8 also produced an anticalciuria without a phosphaturia, but only weakly stimulated AC and did not alter cortical cAMP content. PTH oxidized at both Met 8 and Met 18 was phosphaturic but not anticalciuric, was a weak agonist for AC and decreased cortical cAMP content. In the isolated perfused rabbit proximal straight tubule, PTH inhibited fluid and phosphate transport, whereas the doubly oxidized peptide was inactive. The data are consistent with the possibility that the effects of PTH on renal tubular phosphorus transport are mediated by more than one mechanism and are, in part, independent of the cAMP messenger system.

Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure.

It has been postulated that hyperparathyroidism in chronic renal failure results from hypocalcemia, occurring, in part, from phosphate retention and/or deficient 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] synthesis. However, many studies have failed to demonstrate hyperphosphatemia or low 1,25-(OH)2D levels in patients with mild renal failure. We measured creatinine clearance (CCr), fractional excretion of phosphorus (FEP), and serum phosphorus, ionized calcium, and plasma N-terminal PTH, and 1,25-(OH)2D concentrations in 21 normal subjects and 51 patients with renal failure. Patients with mild renal failure (Ccr, greater than 40 mL/min.1.73 m2) had normal mean serum phosphorus and ionized calcium and decreased mean 1,25-(OH)2D levels compared with those in normal subjects. In patients with moderate renal failure (CCr, 20-40), the mean ionized calcium level was normal, plasma PTH levels and FEP were elevated, and the decrement in 1,25-(OH)2D was more pronounced. The mean ionized calcium level was decreased only in the group of patients with severe renal failure (CCr, less than 20). The 1,25-(OH)2D values correlated positively with CCr and negatively with the log of plasma PTH and serum phosphorus concentrations. Log of plasma PTH correlated negatively with CCr and positively with FEP. The ionized calcium concentration correlated very weakly with CCr and the log of the plasma PTH level. These data demonstrate the presence of hyperparathyroidism, normocalcemia, and 1,25-(OH)2D deficiency in renal failure and are consistent with a role for 1,25-(OH)2D in the suppression of parathyroid activity through as yet unidentified mechanisms.

Chronic effects of nitrendipine on renal hemodynamics and tubular transport.

The effects of nitrendipine (10 mg, during acute clearance experiments) given both acutely and after 2 weeks of administration were examined in normal and hypertensive subjects. At the initiation of therapy, nitrendipine caused an increase in glomerular filtration rate and effective renal plasma flow in the hypertensive, but not in the normal, group. Percentage excretion rates of sodium (%ENa) and phosphate (%EPi) and free water clearance (CW) increased in both groups at the initiation of therapy. After 2 weeks of nitrendipine therapy repeat acute clearance studies showed that the drug no longer increased glomerular filtration rate or effective renal plasma flow in hypertensive subjects, the increases in %ENa and CW persisted in normal subjects and trended upward in hypertensive subjects, and the increase in %EPi persisted in both normal and hypertensive individuals. We conclude that nitrendipine is not sodium retentive after chronic therapy and the acute increase in %ENa, %EPi, and CW after its initial administration suggests a proximal tubular effect.

Effects of elevated lead and cadmium burdens on renal function and calcium metabolism.

To assess the pathophysiologic significance of increased body burdens of lead and cadmium, detailed renal function studies and evaluation of calcium, phosphorus, and vitamin D metabolism were carried out in 38 industrial workers exposed to lead and cadmium for 11 to 37 yr. Body burden of lead, as assessed by x-ray fluorescence measurement of tibia lead content, was elevated in 58% of the men and, when assessed by excretion of lead after Ca-EDTA infusion, was elevated in 36%. Liver or kidney cadmium burden, as assessed by neutron activation analysis, was elevated in 31%. Creatinine clearance was normal in all workers. One worker was hyperuricemic and two were proteinuric; three had increased beta 2 microglobulin excretion and one had diminished urinary acidifying ability. Maximal urinary concentrating ability was abnormal in a significant fraction, i.e., 52% of the men. Individuals with a high lead burden had a slight decrease in mean serum phosphorus but no accompanying phosphaturia. There was no abnormality of serum calcium. Twenty-two percent of subjects were hypercalciuric and two had low vitamin D levels, but these abnormalities bore no relation to heavy metal burden. In this carefully characterized group of men with chronic lead and calcium exposure, definite, if subclinical, effects on renal function and serum phosphorus but not calcium or vitamin D metabolism were demonstrable.

Vitamin D metabolism and expression in rats fed on low-calcium and low-phosphorus diets.

1. Cholecalciferol, radioactively labelled with both (14)C and (3)H, was administered weekly for 7 weeks to rats that had been depleted of vitamin D for 4 weeks before repletion with the radioactive vitamin. This permitted measurement of the steady-state effect on vitamin D metabolism of low-calcium and low-phosphorus regimens, as compared with a normal mineral intake. These dietary manoeuvres were carried out during the last 3 weeks of repletion. Cholecalciferol, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol were determined in plasma, intestine, kidney and bone. Ca(2+)-binding-protein content was measured in intestine and kidneys of comparable animals. 2. In rats on the low-calcium diets, 1,25-dihydroxycholecalciferol concentration was elevated in plasma, bone, kidney and intestine, and intestinal Ca(2+)-binding protein was increased to over twice the concentration found in the control animals. 3. The low-phosphorus regimens led to a decrease in plasma phosphate and 1,25-dihydroxycholecalciferol in all tissues studied, for the latter to the point where it was undetectable in plasma and bone. Intestinal and renal concentrations of Ca(2+)-binding protein were unchanged in the low-phosphate-intake group and decreased in the very-low-phosphate-intake group. 4. It is concluded that in the rat, unlike in the chick, hypophosphataemia is not associated with a stimulation of the production of 1,25-dihydroxycholecalciferol or its expression in the synthesis of Ca(2+)-binding protein. Therefore the plasma phosphate concentration does not appear to be directly involved in the regulation of the functional metabolism of vitamin D.