Studies of the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man.

We carried out clearance studies in nine healthy adults and four patients with hypoparathyroidism before and after inducing stable metabolic acidosis with either NH(4)Cl or acetazolamide. Clearances were repeated in seven normal subjects and three of the patients 3 days after stopping these agents.During acidosis in the normal subjects, serum ultrafilterable calcium concentration rose significantly, but inulin clearance fell to a greater extent, so that the calculated filtered load of calcium fell significantly. Despite this, urinary calcium excretion rose. Urinary calcium excretion remained elevated in the recovery studies when the serum ultrafilterable calcium concentration and filtered load of calcium had returned to control levels. Evidence is presented indicating that the increased calcium excretion which occurred during acidosis and recovery clearances was not due to natriuresis or to increased excretion of complexing anions. The comparable results in the four patients with hypoparathyroidism, two of whom also had hypothyroidism, suggest that the capacity to alter secretion rates of parathyroid hormone, thyrocalcitonin or both is not a critical determinant of the augmented rates of calcium excretion during acidosis.We conclude that metabolic acidosis produces increased urinary calcium excretion by causing decreased renal tubular calcium reabsorption. Evidence is presented which suggests that this is a direct effect of metabolic acidosis on metabolic processes within renal tubular cells.

The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease.

Small but statistically significant negative calcium balances were found in each of eight studies in seven patients with chronic azotemic renal disease when stable metabolic acidosis was present. Only small quantities of calcium were excreted in the urine, but fecal calcium excretion equaled or exceeded dietary intake. Complete and continuous correction of acidosis by NaHCO(3) therapy reduced both urinary and fecal calcium excretion and produced a daily calcium balance indistinguishable from zero. Apparent acid retention was found throughout the studies during acidosis, despite no further reduction of the serum bicarbonate concentration. The negative calcium balances that accompanied acid retention support the suggestion that slow titration of alkaline bone salts provides an additional buffer reservoir in chronic metabolic acidosis. The treatment of metabolic acidosis prevented further calcium losses but did not induce net calcium retention. It is suggested that the normal homeostatic responses of the body to the alterations in ionized calcium and calcium distribution produced by raising the serum bicarbonate might paradoxically retard the repair of skeletal calcium deficits.

The effect of glucose on urinary cation excretion during chronic extracellular volume expansion in normal man.

Both glucose administration and extracellular volume expansion augment urinary calcium and magnesium excretion. While volume expansion also augments sodium excretion, glucose induces an antinatriuresis. To examine the interrelationships of volume expansion and of glucose administration on sodium, calcium, and magnesium excretion, the effects of glucose were evaluated during clearance studies in the same subjects before and after chronic extracellular volume expansion produced by desoxycorticosterone acetate (DOCA) and a normal dietary sodium intake. The augmentation of U(Ca)V and U(Mg)V by glucose was simply additive to the increments in divalent cation excretion caused by "escape" from the sodium-retaining effects of DOCA. Glucose administration reduced U(Na)V, an effect exaggerated after DOCA escape and associated with reductions in volume/glomerular filtration rate (V/GFR) and C(Na) + C(H2O)/GFR, suggesting augmented proximal tubular reabsorption. Before glucose, U(Na) was inversely correlated with U(G), and after glucose administration C(Na)/GFR was inversely correlated with T(G)/GFR. We propose that the availability of glucose in the proximal tubule stimulates Na reabsorption while delaying development of a chloride diffusion potential, thereby inhibiting tubular reabsorption of Ca and Mg.

Infantile polycystic kidney disease in the adult.

We evaluated an adult with polycystic kidney disease that had been present since birth. Our evidence indicates that this patient is a unique example of survival into adult life of the recessively inherited, infantile form of polycystic kidney disease.

Effect of glucocorticoids on WBC counts in splenectomized renal transplant recipients.

Change in peripheral blood WBC and differential cell count in response to oral glucocorticoids (steroids) was examined in 36 stable renal transplant patients receiving their usual steroid dose on a daily or alternate-day steroid schedule. Three hours following steroid therapy mean WBC count had increased significantly. Mean change in WBC count was +2,400 cells/cu mm with individual values ranging from -600 to +8,000/cu mm. No differences were observed between patients receiving daily or alternate-day regimens. Changes in WBC count were due almost entirely to an increase in segmented granulocytes and a decrease in lymphocytes. there was no correlation between dose of steroid and WBC responses. However, when retested, a given patient's WBC response to a given dose of steroid was reproducible. Differences between patients, with respect to WBC response to steroids, could not be explained by differences in azathioprine dose and was not related to initial WBC count hematocrit value, age, duration of transplant, or levels of serum creatinine, BUM, or serum phosphorus. Because of the clinical importance of the WBC count in the renal transplant recipient and the potential for large and unpredictable changes in WBC count in response to steroids, WBC and differential cell count should be obtained before the morning steroid dose.

A model for planning health care in patients with end-stage renal disease.

Treatment modalities of end-stage renal disease (ESRD) patients include in-center dialysis, home dialysis, and kidney transplant. We present a model to account for all aspects of modality use to aid in planning regional facilities. Five years of data for 979 patients on dialysis in Wisconsin between 1970 and 1975 are used. The model shows movement (transit probabilities) from one modality to another, eg, transition from in-center dialysis to transplantation, and data were used to derive all transitional probabilities characterizing patient movement from one modality to another. Model and probabilities were used to predict number of patients in each modality in 1976, and the model was used to predict number of patients in each treatment modality through 1990. These figures may be used for planning regional facilities. Extrapolation of this model and derived probabilities for nationwide projections may be possible.

Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25-OH-vitamin D.

We evaluated the effects of dietary PO4 restriction on 25-OH-Vitamin D3 metabolism, serum iPTH levels, and mineral balances in healthy women and men. PO4 balances were progressively negative because of fecal losses without sex difference. Turnover of the plasma 25-OH-D pool was increased from 5.8 +/- 0.4 to 12 +/- 1.2 nmol/day; P less than 0.001, despite a fall in serum iPTH of -1.1 +/- 0.3 mulEq/ml; P less than 0.01. In both sexes, net intestinal calcium and magnesium absorption increased in proportion to a more rapid turnover of the plasma 25-OH-D pool, implying increased renal 1,25-(OH)2-D3 production. By contrast, there was a striking sex difference in the response of serum PO4 to dietary PO4 deprivation; the levels falling progressively in women, but remaining at control levels in men. Women demonstrated progressive hypercalciuria and negative Ca balances while in men the increments in intestinal Ca absorption were approximately matched by the increments in urinary Ca excretion so that Ca balances were not different from zero.

The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism.

We observed that plasma 1,25-(OH)2-D concentrations average 87 +/- 30 SD pmol/l in 48 healthy adults without a personal or family history of kidney stones. Plasma 1,25-(OH)2-D concentrations were significantly elevated among 26 patients with recurrent calcium-containing renal stones and hypophosphatemia: 150 +/- 74 pmol/l; P less than 0.001, and among 9 patients with proven parathyroid adenoma and hypophosphatemia: 200 +/- 54 pmol/l; P less than 0.001. Plasma 1,25-(OH)2-D levels in these 3 groups were inversely correlated with serum phosphate concentration: plasma 1,25-(OH)2-D, pmol/l = 282 - 141 X serum PO4, mmol/l; r = 0.51; P less than 0.001. During dietary PO4 deprivation lasting 11 to 16 days in 10 healthy women, serum PO4 fell and plasma 1,25-(OH)2-D concentrations rose whereas in 8 healthy men neither serum PO4 nor 1,25-(OH)2-D concentrations changed. The change from control in plasma 1,25-(OH)2-D levels were correlated with the change from control in serum PO4 concentrations: delta1,25-(OH)2-D, pmol/l = 1 - 82 X delta serum PO4 mmol/l; r = 0.59; P less than 0.01. We conclude that reductions in serum PO4 concentrations, either directly or indirectly, stimulate renal synthesis of 1,25-(OH)2-D in humans.

The lack of effect of chronic metabolic acidosis on 25-OH-vitamin D metabolism and serum parathyroid hormone in humans.

We evaluated the turnover of the plasma 25-OH-vitamin D pool, acid, and mineral balances in paired balance studies of 6 normal subjects during normal acid base conditions and during stable chronic metabolic acidosis induced by NH4Cl. Positive acid balances and negative Ca balances due to hypercalciuria were observed as previously reported. Plasma 25-OH-D pool turnover averaged 6.1+/-0.4 nmol/day during control and did not change during acidosis (6.5 +/- 0.5 nmol/day) nor were any significant increments in net intestinal absorption of Ca, PO4, or Mg, the physiological expression of vitamin D action, observed during acidosis. In 3 other subjects, repetitive measurements of serum iPTH during 7 control days and 24 days of stable NH4Cl acidosis showed no changes. We interpret the data to support the hypothesis that neither PTH nor vitamin D and its metabolites mediates the increase in net bone resorption that must accompany chronic metabolic acidosis.

The interrelationships among prolactin, 1,25-dihydroxyvitamin D, and parathyroid hormone in humans.

Serum PRL, parathyroid hormone (PTH), and plasma 1,25-dihydroxyvitamin D [1,25(OH)2D]concentrations were measured in 6 women and 2 men with hyperprolactinemia, 6 normal men and 7 normal women, 4 men and 4 women with primary hyperparathyroidism, and 16 men and 4 women with Ca nephrolithiasis. Plasma 1,25(OH)2D and serum parathyroid hormone (PTH) concentrations were normal in the women and men with hyperprolactinemia. In patients with primary hyperparathyroidism and elevated serum PTH, plasma 1,25(OH)2D concentrations were elevated but serum PRL levels were normal. Likewise, serum PRL levels were normal in patients with Ca nephrolithiasis who had significantly elevated plasma, 1,25(OH)2D concentrations and normal serum PTH concentrations. Thus, hyperprolactinemia due to pituitary adenoma or idiopathic hypersecretion is not accompanied but elevated plasma concentrations of 1,25(OH)2D.

Synthesis and metabolic clearance of 1,25-dihydroxyvitamin D as determinants of serum concentrations: a comparison of two methods.

We evaluated endogenous renal 1,25-dihydroxyvitamin D (1,25-OH)2D) synthesis by compartmental analysis of the plasma disappearance of injected [3H]1,25-dihydroxyvitamin D3 in 11 subjects with serum 1,25-(OH)2D concentrations varying from 9-154 pM (normal, 89 +/- 25 pM). Estimated renal synthesis ranged from 2-180 pmol/kg . day. Serum 1,25-(OH)2D concentrations in these subjects best fit a log function of renal synthesis: serum 1,25-(OH)2D, pM = -13 + 74 log renal 1,25-(OH)2D production, picomoles per kg/day (r = 0.91). We also evaluated serum 1,25-(OH)2D concentrations in 6 healthy subjects who had been given 0.6, 1.2, or 1.8 nmol calcitriol every 6 h during a period 6--12 days after hormone administration was begun. Steady serum 1,25-(OH)2D concentrations 2, 4, and 6 h after the last calcitriol dose were achieved in proportion to log dose: serum 1,25-(OH)2D, pM = -12 + 103 log 1,25-dihydroxyvitamin D3 dose, picomoles per kg/day (r = 0.94). Estimated 1,25-(OH)2D production rates using these two methods and assuming a normal serum 1,25-(OH)2D concentration of 89 pM range from 10--24 pmol/kg . day or, for a 70-kg subject, 0.6--1.7 nmol/day or 0.25--0.7 microgram/day. Metabolic clearance of 1,25-(OH)2D appears to be accelerated when production rates are increased.

Metabolism and excretion of 3H-1,25-(OH)2-vitamin D3 in healthy adults.

The synthesis of very high specific activity 25-OH-vitamin D3 (78 Ci/mmol) has made possible the study of the metabolism and plasma disappearance of 3H after a single dose of 3H-1,25-(OH)2-D3 in quantities that are only 10-20% of the endogenous plasma pool. We studied seven healthy adults who were given doses of 1,25-(OH)2-D3 ranging from 30-2300 pmol. Plasma disappearance was rapid with only 14 +/- 2% of administered 3H remaining in the plasma pool 4 h after labeling. Plasma metabolite profiles during the first 4 h showed only 1,25-(OH)2-D3. Thereafter, significant amounts of other metabolites were detected. The 6-day cumulative excretion of 3H in urine and feces (virtually all associated with metabolites of 1,25-(OH)2-D3) averaged 16 +/- 3% and 49 +/- 11% of the dose, respectively. Compartmental analysis of the isotope data for two subjects who received the smallest doses of 1,25-(OH)2-D3 indicated that endogenous renal 1,25-(OH)2-D3 synthesis rates approximate 0.8-2.4 nmol/day (0.3-1.0 microgram/day).

Vitamin D metabolites and parathyroid hormone in Cushing's syndrome: relationship to calcium and phosphorus homeostasis.

We studied the effects of glucocorticoid excess on calcium and phosphorus homeostasis in relation to vitamin D metabolites and parathyroid hormone (PTH) in seven patients with spontaneous ACTH-dependent Cushing's syndrome. Remission of hypercortisolism resulted in a significant increase in tubular reabsorption of phosphate [from 76 +/- 4% to 89 +/- 2% (mean +/- SEM); P less than 0.01] and serum phosphorus (from 3.1 +/- 0.1 to 4.2 +/- 0.2 mg/dl; P less than 0.005). Serum calcium did not change, although there was a reduction in daily urinary calcium excretion from 0.23 +/- 0.02 to 0.107 +/- 0.02 mg calcium/mg creatinine. Serum immunoreactive PTH (iPTH) levels were normal during Cushing's syndrome (34 +/- 5 microleq/ml), but fell significantly after remission to 22 +/- 2 microleq/ml (P less than 0.05). This small decrease in iPTH did not correlate with the improvement of phosphate homeostasis. Plasma 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH2)D] concentrations in Cushing's syndrome did not differ from measurements in 97 normal subjects. After treatment, 25OHD did not change, but 1,25-(OH)2D fell in each patient from a mean of 44 to 22 pg/ml (P less than 0.02). 1,25-(OH)2D was inversely correlated with serum phosphorus (r = 0.59; P less than 0.01), but did not correlate with iPTH. The known impairment of intestinal calcium absorption in Cushing's syndrome cannot be attributed to a decrease in the circulating levels of 1,25-(OH)2D. Endogenous hypercortisolism decreases tubular phosphate reabsorption and serum phosphorus, increase tubular phosphate reabsorption and serum phosphorus, increases iPTH, and results in an increase in 1,25-(OH)2D. These events may contribute to the severe loss of bone mass in such patients and may account for the calciuria and phosphaturia of Cushing's syndrome.

A human parathyroid carcinoma that produces parathyroid hormone: long term maintenance in tissue culture.

Parathyroid carcinoma cells from a pulmonary metastasis of a patient with a serum Ca of 17 mg/dl and an immunoreactive parathyroid hormone (PTH) of 6.4 ng eq bovine (b) PTH/ml (normal 40--400 pg/ml) have been maintained in tissue culture for more than 2 1/2 years. The cells secrete PTH into the culture media that 1) during immunoassay dilutes in parallel to human hyperparathyroid serum, 2) has a molecular weight similar to intact highly purified bPTH, and 3) stimulates bone resorption in a manner that is equivalent and additive to synthetic bPTH-(1--34).

Plasma 1,25-(OH)2-vitamin D concentrations and net intestinal calcium, phosphate, and magnesium absorption in humans.

We evaluated the relationship between plasma concentrations of the renal hormone 1,25-(OH)2-vitamin D and net intestinal absorption of Ca, PO4, and Mg in vitamin D-replete patients eating similar diets, who had undetectable, normal or elevated plasma 1,25-(OH)2-D levels, Net intestinal Ca absorption was positively correlated to plasma 1,25-(OH)2-D concentrations: percentage dietary Ca absorbed = 10 + 0.17 x plasma total 1,25-(OH)2-3, pmole/liter, r = + 0.58; P less than 0.001. By contrast, there was no significant correlation between PO4 or Mg absorption and plasma 1,25-(OH)2-D concentrations. Moreover, significant quantities of PO4 and Mg were absorbed in the absence of detectable plasma 1,25-(OH)2-D. We conclude that net intestinal Ca absorption is critically dependent upon the availability of the renal hormone 1,25-(OH)2-D in vitamin D-replete humans when dietary Ca intake is normal. By contrast, other factors must play a dominant role in regulating net intestinal PO4 and Mg absorption.

Habitual excessive dietary salt intake and blood pressure levels in renal transplant recipients.

We observed that renal transplant recipients with good graft function (mean serum creatinine level 1.5 mg/dl +/- 0.5 SD, N = 68) had dietary salt intakes (estimated from serial measurements of 24-hour sodium excretion rate) which averaged 43 percent higher than that of a comparable group of healthy subjects. There was no correlation between blood pressure levels and salt intake and, despite the high dietary salt intake, hypertension was present in only 29 patients and was usually mild; mean systolic and diastolic blood pressures were 132 +/- 10 mm Hg and 89 +/- 7 mm Hg, respectively while the patients were receiving antihypertensive medication (median number of standard doses of antihypertensive medication was 1.0 doses/patient patient per day). These observations suggest that high dietary salt intake does not exert a powerful blood pressure elevating effect, since any effect of high dietary salt intake to raise blood pressure should have been magnified in the renal transplant recipients because of their reduced renal mass and their chronic glucocorticoid therapy.

Moderate hypocalcemia due to normal serum 1,25-dihydroxyvitamin D levels in an asymptomatic kindred with familial hypoparathyroidism.

Hypoparathyroidism was diagnosed in nine members of a kindred of three generations. This study investigated why these persons were asymptomatic and without developmental abnormalities, in contrast to the common presentation of idiopathic hypoparathyroidism. In the hypocalcemic subjects, serum calcium level was 7.4 +/- 0.8 mg/dl (mean +/- SD) and ionized serum calcium level was 3.48 +/- 0.21 mg/dl. Immunoreactive parathyroid hormone values were inappropriately low. Injection of EDTA in one patient lowered ionized calcium levels, but immunoreactive parathyroid hormone values did not rise. Serum levels of 1,25-dihydroxyvitamin D and other vitamin D metabolites were normal or elevated and substantially higher than in other hypoparathyroid states. The normally observed positive correlation between the fasting urinary calcium/creatinine ratio and serum 1,25-dihydroxyvitamin D that reflects the dependence of net bone resorption on 1,25-dihydroxyvitamin D was upheld in hypoparathyroid patients. It is proposed that the subjects with familial hypoparathyroidism in this kindred had moderate asymptomatic hypocalcemia without developmental abnormalities because normal or elevated serum 1,25-dihydroxyvitamin D levels enhanced intestinal calcium absorption. This may represent one point in the spectrum of idiopathic hypoparathyroidism. Alternately, both the moderate degree of hypocalcemia and the normal serum calcitriol values could have been related to mild, partial hypoparathyroidism, which could have been inherited in this kindred.

The effect of parathyroidectomy on the recurrence of nephrolithiasis.

Little information is available on the long-term influence of parathyroidectomy on the rate of renal stone formation in patients with primary hyperparathyroidism (pHPT) and nephrolithiasis. The reported occurrence of renal stone disease in untreated patients with pHPT is 15% to 30%. A registry of 258 pHPT patients who underwent parathyroidectomies at the Milwaukee Regional Medical Center has allowed continued follow-up of the 71 (28%) pHPT patients with associated renal stone disease. Patients have been followed up for an average of 5 years (range, 1 to 15 years) since surgery. The rate of renal stone formation before and after parathyroidectomy was compared. Identification of a "new" renal stone was defined as passage and collection, extraction, or radiographic visualization of stones. All 71 pHPT patients with stone disease had hypercalcemia and inappropriately elevated parathyroid hormone concentrations, and after parathyroidectomy these values returned to normal in 69 of 71 patients. Since undergoing parathyroidectomy, only 4 patients have passed renal stones. The rate of stone formation per patient per year was 0.36 before and 0.02 after surgery (p less than 0.001). Surgical correction of pHPT significantly reduced the rate of stone formation.

Cyclosporine therapy and refractory Pneumocystis carinii pneumonia. A potential association.

In surveillance of 75 patients receiving renal transplants in 1984 at our institution, five cases of Pneumocystis carinii pneumonia were detected. All five cases occurred in a subgroup of 11 patients who had received cyclosporine. A retrospective epidemiologic survey of the infected patients revealed all five were heterosexual white men with onset of Pneumocystis pneumonia two to six months after cadaveric transplantation. All received cyclosporine and corticosteroids, and four of five patients also received azathioprine; none was neutropenic or had evidence of concurrent cytomegalovirus infection. Only one of these patients responded to therapy with sulfamethoxazole and trimethoprim, one patient responded to pentamidine therapy, and the remaining three patients died. Cyclosporine use may be related to development of Pneumocystis infections that are refractory to conventional antiprotozoal therapy, and transplantation programs should closely survey patients for such complications.

Is there a disorder of phosphate metabolism in idiopathic hypercalciuria?

Hypophosphatemia either as a consequence of secondary hyperparathyroidism or as a consequence of a primary defect in phosphate metabolism appears to be a well established abnormality among subsets of patients with idiopathic hypercalciuria and nephrolithiasis. The detailed biochemical events that lead to hypophosphatemia in those patients who exhibit a primary abnormality of phosphate metabolism remain to be clarified.