Jacob Lemann

The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis.

Acute acid loads have been shown to titrate extraand intracellular buffers (1, 2). The state of titration of these buffers is reflected by the level of serum bicarbonate. With sustained acid loading, serum bicarbonate ultimately stabilizes at some reduced level despite continuing acid retention, indicating that an additional buffer system is titrated. It has been suggested that such additional quantities of buffer could arise from the slow dissolution of bone mineral during chronic metabolic acidosis (3). The present metabolic balance studies were carried out to study further the relationship between acid retention and calcium balance during chronic ammonium chloride acidosis.

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.

Studies of the mechanism by which phosphate infusion lowers serum calcium concentration.

It has long been known that oral or intravenous administration of phosphate salts lowers the serum calcium concentration in normal animals (1, 2) and in hypercalcemic human subjects (3-5). Recently , interest has been renewed in the clinical use of phosphate therapy to control life-threatening hypercalcemia because of the relative in-effectiveness or toxicity of other modes of therapy (6, 7). In 1962, Dent (5) reported dramatic lowering of the serum calcium concentration in a patient with hyperparathyroidism during the intravenous infusion of sodium phosphate and sustained lowering of serum calcium by continuing oral doses of phosphate in another patient with hyperpara-thyroidism. Since then, Goldsmith and Ingbar (8) have demonstrated the clinical effectiveness and apparent safety of both oral and intravenous phosphate therapy in the management of hyper-calcemia accompanying a variety of diseases. Most of the investigators who have shown that phosphate administration lowers serum calcium concentration have suggested that this effect is the result of the precipitation of calcium phosphate salts in the body. The present studies were carried out to further test this hypothesis. If phosphate infusion lowers serum calcium concentration by causing calcium phosphate salt precipitation, then. a) phosphate infusion should * tend to lower serum calcium concentration in all subjects, regardless of the presence or absence of those endocrine organs normally involved in the regulation of the serum calcium; b) a simultaneous increase in calcium excretion should not account for the fall in serum calcium occurring during phosphate infusion; and c) the degree by which serum calcium concentrations fall should be a function of the extent to which the solubility product of some calcium phosphate salt is exceeded during the infusion of phosphate. The results of the present experiments satisfy all of these postulates and strongly support the hypothesis that phosphate infusion lowers serum calcium concentration as a result of CaHPO4 precipitation. Methods Studies were carried out in 22 patients divided into four groups: 1) eight control subjects without disorders of calcium homeostasis, 2) three patients with hypopara-thyroidism on adequate calcium and vitamin D therapy, 3) four patients with primary hyperparathyroidism, and 4) seven patients with hypercalcemia in association with malignant tumors of the breast or lung or with multiple myeloma. All were hospitalized in the Marquette University Clinical Research Center, where they received constant diets. Calcium and phosphorus intakes were constant for each subject but varied from subject to subject, ranging from 10 to 26 mmoles …

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.

Possible Role of Carbohydrate-Induced Calciuria in Calcium Oxalate Kidney-Stone Formation

Abstract Since nutrient ingestion has been shown to augment urinary calcium excretion in normal subjects, we compared the effect of ingestion of glucose or sucrose on urinary calcium excretion in normal subjects, those who form calcium oxalate kidney stones and their relatives. Patients and relatives had significantly higher urinary calcium excretion rates in control periods than normal subjects, but considerable overlap was present. After sugar ingestion each patient and relative achieved higher rates of calcium excretion than any normal subject. In addition, the patients and relatives had a greater antidiuresis after sugar and achieved much higher urinary calcium concentrations. Coupled with higher basal rates of urinary calcium excretion, the exaggerated augmentation of calcium excretion after carbohydrate ingestion could favor calcium salt precipitation in patients who form stones and in their relatives.

The transtubular potassium concentration in patients with hypokalemia and hyperkalemia.

It is advantageous to make an independent assessment of the potassium (K) secretory process and the luminal flow rate in the renal cortex to evaluate K handling by the kidney during hypokalemia or hyperkalemia. The transtubular potassium concentration gradient (TTKG) is a semiquantitative index of the activity of the K secretory process. The purpose of this study was to define expected values for the TTKG in normal subjects with hypokalemia or following an acute K load. During hypokalemia of non-renal origin, the TTKG was 0.9 +/- 0.2; in contrast, the TTKG was significantly higher during the hypokalemia of hyperaldosteronism, 6.7 +/- 1.3. The TTKG was 11.8 +/- 3.6, 2 hours after normokalemic subjects received 0.2 mg 9 alpha-fludrocortisone (9 alpha-F). To obtain expected values during hyperkalemia, normal subjects ingested 50 mmol potassium chloride; 2 hours later, the TTKG was 13.1 +/- 3.8. Therefore, the expected value for the TTKG must be interpreted relative to the concentration of K in the plasma. Circumstances were also defined where the TTKG is low despite hyperaldosteronism, namely, during a water diuresis and pre-existing hypokalemia.

The calciuria of increased fixed acid production in humans: Evidence against a role for parathyroid hormone and 1,25(OH)2-vitamin D

SummaryWe measured mineral and acid balances, serum iPTH, urinary cAMP/creatinine, and plasma concentrations of 25OHD and 1,25(OH)2D in 7 healthy adults during control conditions and during increased fixed acid production achieved either by the administration of NH4Cl (N=3) or by increased dietary protein intake (N=4). When acid production was increased, the subjects were in positive acid balance and negative Ca balance because of increased urinary Ca excretion. Serum iPTH fell slightly but urinary cAMP and the plasma levels of vitamin D metabolites did not change. We conclude that the accelerated skeletal and urinary losses of Ca that occur when fixed acid production is increased are not contributed to nor compensated for by the parathyroid-vitamin D endocrine systems.

Use of the Serum Creatinine to Estimate Glomerular Filtration Rate in Health and Early Diabetic Nephropathy

We evaluated 100/serum creatinine, 24-hour creatinine clearance, and simultaneously measured creatinine clearance or creatinine clearance estimated by the formula devised by Cockcroft and Gault in comparison with measurements of glomerular filtration rate (GFR) using iothalamate among 136 patients with diabetic nephropathy. We also evaluated 100/serum creatinine, simultaneously measured creatinine clearance or creatinine clearance estimated by the Cockcroft and Gault formula in comparison with measurements of GFR using inulin among 88 healthy adults, 21 hypercalciuric kidney stone formers and their hypercalciuric relatives, and one man with chronic nephritis. Creatinine clearances measured simultaneously were closely correlated to GFR (r = 0.93) as were creatinine clearances, estimated by the Cockcroft and Gault formula (r = 0.84) when GFR ranged from 16 to 175 mL/min (0.27 to 2.92 mL/s). These observations confirm the clinical use of either creatinine clearances during water diuresis or estimates of creatinine clearance by the Cockcroft and Gault formula in the assessment of kidney function.

Hypercalciuria and Stones

Hypercalciuria, defined as the urinary excretion of more than 0.1 mmol Ca/kg/d (4 mg/kg/24 h), is observed in approximately 50% of patients with calcium oxalate/apatite nephrolithiasis and is one of the risk factors for stone formation. Urinary Ca excretion rates among such patients are higher than normal, despite comparable ranges of glomerular filtration rate (GFR) and serum ultrafiltrable Ca concentrations, and thus glomerular filtration of Ca, suggesting that hypercalciuria is the result of inhibition of net tubular Ca reabsorption. Although increased dietary NaCl or protein intake and reduced K intake increase urinary Ca excretion rates, urinary Ca excretion rates are higher among hypercalciuric stone formers than among normal subjects in relation to comparable ranges of urinary Na, SO4 (as a reflection of protein intake), or K excretion rates, indicating that these dietary factors are not primarily responsible for hypercalciuria. Hypophosphatemia is observed among a subset of hypercalciuric patients and consequent activation of 1,25-(OH)2-D synthesis increases intestinal Ca absorption and urinary calcium excretion. Other hypercalciuric patients exhibit augmented intestinal Ca absorption without elevated plasma 1,25-(OH)-2-D levels, suggesting that either the capacity of 1,25-(OH)2-D to upregulate its own receptor in the intestine or 1,25-(OH)2-D-independent intestinal Ca transport are responsible for increased Ca absorption and hypercalciuria. Hypercalciuric patients also exhibit accelerated radiocalcium turnover, negative Ca balances, reduced bone density, delayed bone mineralization, fasting hypercalciuria, and increased hydroxyproline excretion, all of which reflect participation of the skeleton and presumably a more generalized acceleration of Ca transport. Hypercalciuria may be familial.(ABSTRACT TRUNCATED AT 250 WORDS)

Preeclampsia Related to a Functioning Extrauterine Placenta: Report of a Case and 25-Year Follow-up

We report the case of a patient with preeclampsia due to an extrauterine, intra-abdominal pregnancy. After the fetus was delivered, but while the functioning placenta remained in the abdomen, preeclampsia, which was documented by clinical data and a kidney biopsy, persisted until the placenta was removed 99 days postpartum. A kidney biopsy 21 months postpartum was normal. Twenty-five years later, her kidney function and blood pressure were normal. The observation of this patient supports the view that the placenta must be intact for the development of preeclampsia and is the first description of endotheliosis in a kidney biopsy from a hypertensive woman with an intra-abdominal pregnancy.