Hypocalcemic tetany and metabolic alkalosis in a dialysis patient: an unusual event.

The case is described of a 29-year-old man with renal failure and recurrent hyperparathyroidism who 3 weeks postparathyroidectomy developed hypocalcemic tetany because he was taking one-half the prescribed dose of calcitriol. He interpreted his symptoms as those of potassium intoxication and self-administered almost 1,500 mEq sodium bicarbonate. The increase in plasma sodium and osmolarity led to increased fluid intake, and at presentation he had an ionized calcium of 0.50 mmol/L, K 5.3 mmol/L, Na 148 mmol/L, total CO2 52.6 mmol/L, pO2 51.2 mm Hg, and pH of 7.61. He had gained 7 kg in weight. All abnormalities were corrected by dialysis, using initially a calcium-free dialyzate with extra calcium infused. The case illustrates the effect of alkalosis in reducing the amount of calcium that exists in ionized form, and it is suggested that complexing of calcium as calcium bicarbonate together with the pH change contributed to the decrease in ionized calcium. It is also an example of the hazards of treating patients who devise their own therapeutic regimens.

Renal cell carcinoma presenting as nephrotic syndrome complicated by acute renal failure.

A case of minimal change nephropathy occurring in association with a renal cell carcinoma is presented and discussed. The case was unusual in that it was associated with acute renal failure necessitating hemodialysis for five weeks. The renal failure resolved but the nephrotic state persisted in spite of therapy with prednisone then cyclophosphamide. The literature on nephrotic syndrome causing acute renal failure and its association with solid tumors is briefly reviewed.

Unilateral radiation nephropathy--the long-term significance.

Eighteen patients with gastrointestinal and retroperitoneal non-Hodgkin's lymphoma received abdominal radiotherapy as their primary treatment. Each patient received a total tumor dose of 2200 to 4500 cGy in 5 to 9 weeks to the whole or half of one kidney. Nine patients developed unilateral radiation nephropathy demonstrable on post-treatment evaluation with 99m Tc glucoheptonate blood flow, delayed static scan, and an I-131 radio-hippurate renal perfusion study. The tests were periodically repeated over periods ranging from 5 to 8 years. Six patients with nephropathy and 4 patients without nephropathy were followed 5 years or longer. The minimum nephro-pathogenic irradiation dose was 2200 cGy delivered in 59 days. The incidence of nephropathy is higher with increase in the total dose. Short term recovery in function was observed in 3 patients and long-term complete recovery was observed in one patient. Atrophic renal change was irreversible and progressive in 3 patients over a 6 to 7 year follow-up period. In this group of patients, an abnormal creatinine clearance and serum beta-2 microglobulin level was indicative of vascular damage. Elevated arterial blood pressure was seen in 5 patients. All were controlled medically, without nephrectomy. There was no other clinically significant problem resulting from the unilateral nephropathy in this group of patients.

Kinetic disposition of intravenous ceftriaxone in normal subjects and patients with renal failure on hemodialysis or peritoneal dialysis.

The kinetic disposition of a single intravenous dose of ceftriaxone (250 to 665 mg) was studied in six normal subjects and nine patients with renal insufficiency and normal hepatic function. In normal subjects, ceftriaxone was eliminated with a t1/2 beta of 5.2 h (range, 4.1 to 5.8). The total body clearance (Qb) was 13.5 ml/kg per h (range, 8.4 to 23.3), and renal clearance was 8.3 ml/kg per h (range, 5.8 to 13.3). In patients with severe renal insufficiency requiring peritoneal or hemodialysis, the mean t1/2 beta was prolonged to 13.4 h (range, 7.7 to 15.8) and the mean Qb was reduced to 6.9 ml/kg per h (range, 3.4 to 12.8). The apparent volumes of distribution (Vc and Vss) were not different from those determined in normal subjects. Peritoneal dialysis did not remove ceftriaxone. The dialysate of three patients on continuous peritoneal dialysis did not contain any measureable ceftriaxone, and the kinetic disposition in these patients was similar to the hemodialysis patients between their dialysis treatment. During a 4-h hemodialysis session, the total body clearance of ceftriaxone was reduced, perhaps secondary to a decrease in hepatic blood flow induced by the hemodialysis procedure. After a 12- or 24-h dose regimen, predicted trough concentrations of ceftriaxone in plasma at steady state derived from kinetic data generated from the study and assuming linear pharmacokinetic behavior were well above the minimum inhibitory concentrations of most sensitive bacteria, suggesting the feasibility of a once-a-day dosage regimen especially for patients with severe renal insufficiency.

Action of phosphorus on calcium release in isolated perfused rat tails.

A bone perfusion system using isolated rat tails was developed to study the action of inorganic phosphorus (Pi) on calcium (Ca) release in bone. Rats were either pre-labelled with 45Ca to study calcium removal from bone or 45Ca was added to the perfusate to study Ca deposition into bone. When perfusate Pi was increased from 3.5 to 5.25 mg/dl, a marked inhibition of 45Ca release was demonstrated. 85Sr microspheres, used to demonstrate differences in the flow of perfusate between bone and soft tissue, showed that the Pi effect was not due to alterations in perfusate flow to bone. Increasing the perfusate Pi concentration from 3.5 to 7 mg/dl did not increase 45Ca deposition into bone, nor did it affect baseline or PTH-stimulated cyclic AMP production. The Pi effect was inhibited by reducing the perfusate temperature to 4 degrees C, by using an anerobic perfusate, adding iodoacetate to the perfusate, and finally, by pre-treating the rats with actinomycin D prior to the experiment. Thus, in this model an increase in the Pi concentration of the perfusate inhibits Ca release from bone but does not increase Ca uptake by bone. The inhibitory effect appears to be dependent on normal cell metabolism.

The role of phosphorus in the genesis of azotemic osteodystrophy.

There is good evidence for a role for phosphate retention in the genesis of secondary hyperparathyroidism. It exerts its effect directly by lowering the ionized calcium, thereby stimulating parathyroid secretion, and indirectly by causing skeletal resistance to the calcemic action of parathyroid hormone. The resistance phenomenon may be due in part to a direct effect of phosphorus on the skeletal resorbing action of parathyroid hormone and in part to an indirect effect of phosphorus on 1,25(OH)2D3 production. As well as causing parathyroid resistance, low serum 1,25(OH)2D3 is also responsible for decreased calcium absorption and may have a role in the mineralization disturbance seen in most cases of severe uremia. In the occasional instance, hypophosphatemia induced by phosphate-binding agents may contribute to uremic osteomalacia.

Evidence that resistance to the calcemic action of parathyroid hormone in rats with acute uremia is caused by phosphate retention.

An animal model was developed to examine the cause of resistance to the calcemic action of PTH in renal failure. Thyroparathyroidectomized (TPTX) rats were repeatedly reinfused with their excreted urine, over a 5-hour period, to produce an acute uremic animal with normal kidneys. Nonuremic controls were infused with equivalent volumes of a simple electrolyte solution. Using this model, we have demonstrated impaired calcemic response to PTH (Lilly Parathyroid Extract, 80 U/100 g) in urine-infused rats compared with electrolyte-infused rats. The final plasma calcium concentrations were 12.0 +/- 0.3 and 14.9 +/- 0.3 mg/dl, respectively (P less than 0.001). The cause of this impaired calcemic response was investigated by reinfusing rats with their own urine that had been pretreated with either activated charcoal or zirconium oxide in two different anionic forms, or urine that had been ultrafiltrated through an Amicon membrane of which the stated molecular-weight cut-off of the smallest pore-size membrane was 500 daltons. It was found that charcoal and ultrafiltration techniques had no effect, whereas the zirconium oxide treatment completely corrected the impaired calcemic response and returned the plasma phosphorus to a concentration similar to that in nonuremic controls. This can be explained by the fact that the principal effect of zirconium oxide on urine is to remove inorganic phosphate. Other groups of TPTX rats given PTH extract were infused with an electrolyte solution containing varying amounts of phosphate up to a maximum similar to the amount that a urine-infused rat would receive. A highly significant inverse relationship was found between the dose of phosphate infused with the electrolyte solution and the measured calcemic response to PTH. This relationship is represented by the following equation: calcium (mg/dl) = 14.84 - 0.139 inorganic phosphate; r = 0.915, P less than 0.001. From these series of studies, we conclude that phosphate retention is the cause of resistance to the calcemic action of PTH extract in this acute uremic model.

Resistance to parathyroid hormone in renal failure: role of vitamin D metabolites.

Resistance to the calcemic action of parathyroid extract (PTE) was shown in thyroparathyroidectomized rats after 5 hr of renal failure that was induced by either bilateral nephrectomy (NPX) or ureter ligation (UL). Studies were carried out to investigate the relationship of parathyroid resistance to the vitamin D status of the animal. Concentrations of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) and 24,25-dihydroxycholecalciferol (24,25(OH)2D3) were similar in pooled sera samples from rats either UL or sham-operated and treated with PTE. Pretreatment with oral 25-hydroxycholecalciferol or with a combination of i.v. 24,25(OH)2D3 and 1,25(OH)2D3 prior to UL failed to alter the resistance. Resistance was also present in a group in vitamin-D-deficient rats. A similar group given 1 microgram of vitamin D2 showed more parathyroid resistance than did the group not given vitamin D2. In chronic renal failure of 28 day's duration, parathyroid resistance was again demonstrated, but, in contrast to the acute renal failure models, this was partly corrected by prior 1,25(OH)2D3 administration. These studies show that parathyroid resistance is not caused by an abnormality of vitamin D metabolism in the acute renal failure model, and we suggest that the phenomenon is due to the accumulation of one or more uremic factors.

The calcium and vitamin D status in an elderly female population and their response to administered supplemental vitamin D3.

Recent reports have implicated the importance of impaired calcium absorption, inadequate dietary vitamin D, and low serum vitamin D levels in the genesis of metabolic bone diseases in the elderly. This study evaluated the dietary intakes of calcium and Vitamin D, calcium absorption, and serum 25 hydroxycholecalciferol (25 OH D) levels in a population of women (mean age 83 yrs) compared to healthy volunteers (mean age 35 yrs). Dietary intakes of both calcium and vitamin D and serum 25 OH D levels were found to be comparable in both groups. Calcium absorption was normal in the subjects studied and did not change significantly after two 2-week periods of oral supplementation with vitamin D3 in doses of 500 I.U./day and 10,000 I.U./day, although the serum 25 OH D levels rose significantly and comparably in both groups. Thus other etiological factors may play relevant roles in the causation of bone diseases in the elderly and unless deficient dietary or serum vitamin D levels are demonstrated, empirical supplementation with vitamin D should not be undertaken. The differences of the above findings from previously published data are discussed.

The use of high calcium dialysate in the treatment of renal osteomalacia.

Four chronic haemodialysis patients suffering from osteomalacia were treated by increasing their dialysate calcium concentration from 1-40 to 2-15 mM/I. Bone biopsies were taken before and after 22 weeks of this treatment and a further biopsy was taken in one patient after 52 weeks. Symptomatic cure occurred in one patient with mild osteomalacia and some improvement osteomalacia and hyperparathyroidism. Bone biopsies showed slight improvement in the patient with mild osteomalacia after 22 weeks, and considerable improvement after 25 weeks. In the patient with mixed histology, the osteitis fibrosa subsided and the osteomalacia became a little worse after 22 weeks. There was no histologic improvement in the two patients with severe osteomalacia after 22 weeks. It is concluded that high calcium dialysis is not an effective treatment for renal osteomalacia.

What is tertiary hyperparathyroidism?

Five patients who had gross abnormalities of calcium and phosphorus metabolism due to long standing renal failure are described to illustrate the difficulties with the term "tertiary hyperparathyroidism". One patient who had unequivocal biochemical tertiary hyperparathyroidism was found histologically to have nodular hyperplasia of all four glands even though one gland weighed twice as much (12g) as the combined weight of the other three. Another patient was not hypercalcaemic but had all the other features of the condition including rapid onset of osteitis fibrosa, vascular calcification and a probable parathyroid adenoma, with hyperplasia of the three glands. The other three had hypercalcaemia only after a reduction in the plasma inorganic phosphorus due either to renal transplantation or aluminum hydroxide therapy. The bone histology of the five patients varied from severe osteomalacia to severe osteitis fibrosa. A consideration of the factors involved in causing hypercalcaemia in these patients and a review of the literature leads to the conclusion that the term tertiary hyperparathyroidism is often misleading and best avoided.

Actinomycin D in the treatment of Paget's disease of bone.

Fifteen patients with Paget's disease of bone were treated with actinomycin D for periods of up to 15 months. It was found that actinomycin D is effective in reducing the pain but not the neurological effects of Paget's disease. Careful adjustment of dose according to weight and initial response is necessary to prevent gastrointestinal side effects. If this is done, the risk of hepatic, renal, or haematological side effects is negligible.