P. O. Schwille

Double-Blind Study with Thiazide in Recurrent Calcium Lithiasis

The effect of 25 mg. hydrochlorothiazide twice daily on the meta-phylaxis of recurrent calcium lithiasis was compared to placebo in a double-blind study during 1 year in 51 patients. A distinct and continuous decrease in urinary calcium excretion occurred only in patients given hyrochlorothiazide. On the other hand, both groups showed a slight increase in total serum calcium levels, unchanged values for ionized and ultrafilterable calcium, and decreased urinary excretion of oxalate during the study. The activity products of calcium oxalate and calcium phosphate also were decreased in both groups but remained within the metastable range. Spontaneous passage of renal stones occurred during treatment in 6 patients given placebo and in 6 treated with hydrochlorothiazide despite decreased urinary calcium excretion in the latter group. The findings show the specific effect of hydrochlorothiazide treatment to be a decrease in urinary calcium excretion in patients with calcium lithiasis, while other changes appear to be nonspecific effects of treatment.

Citrate in Urine and Serum and Associated Variables in Subgroups of Urolithiasis

Outpatient renal stone formers belonging to the established urolithiasis subgroups and controls were examined with respect to urinary and serum citrate (Cit) and several associated variables. Only in the normocalciuric majority of calcium and in uric acid stone formers was Cit in 24-hour urine decreased, but was normal in 2-hour fasting morning, and in 3-hour postprandial urine following a Cit-free test meal. Serum Cit was elevated in normocalciuria, renal and resorptive hypercalciuria. This Cit constellation was associated with either normal (absorptive, renal hypercalciuria) or low (normocalciuria, uric acid stone formers) parathyroid gland function as assessed by serum parathyroid hormone and nephrogenous urinary cyclic AMP, except in patients with primary hyperparathyroidism. In 2-hour morning urine the magnesium/creatinine ratio (normocalciuria) and ammonia excretion (uric acid stone formers) were decreased, while ammonia in 24-hour urine was low in all stone formers. It is suggested that Cit metabolism is altered in renal stone disease in general, and that in normocalciuria, stone inhibitors (Cit; magnesium) may be deficient.

Magnesium, citrate, magnesium citrate and magnesium-alkali citrate as modulators of calcium oxalate crystallization in urine: observations in patients with recurrent idiopathic calcium urolithiasis

The effects of magnesium (Mg) and citrate on the metastable limit of calcium oxalate (CaOx) solubility (synonym: tolerable oxalate TO) were examined in artificial urine and in postprandial urine of male patients with idiopathic calcium urolithiasis (ICU). In artificial urine increasing pH, Mg and citrate elevate TO, decrease CaOx supersaturation only marginally, but elevate considerably free citrate; the effect of Mg alone was small in comparison with citrate alone, and the effects of both substances appeared additive. In ICU patients, matched for sex, age and CaOx supersaturation to non-stone-forming controls, TO was decreased (mean values 0.33 vs. 0.52 mM/l in controls, P < 0.05). Additional significant (P < 0.05) differences were found between ICU and controls: the former exhibited increased CaOx crystal growth, decreased crystal agglomeration time, a more acidic urinary pH, increased concentrations of free calcium and free Mg, and decreased free oxalate and free citrate. After ingestion of a urine-acidifying test meal, or this meal supplemented with either neutral Mg citrate or Mg-alkali citrate, by three groups of male ICU patients, matched for age and CaOx supersaturation, only the last-named preparation evoked an increase in TO and a decrease in crystal diameter, while the normally occurring pH decline from fasting urine was virtually abolished, and the ratios urinary Mg/citrate and calcium/citrate tended towards low values. In contrast, Mg citrate increased crystal agglomeration time, while changes in the other parameters were only insignificant. The crystals formed in urine were CaOx di- and monohydrate (by electron microscopy), and energy dispersive X-ray analysis showed calcium peaks exclusively. However, chemical analysis of crystals verified the presence not only of oxalate and calcium, but also of Mg, phosphate, citrate, and urate; moreover, these crystal constituents seemed to be influenced by Mg citrate and Mg-alkali citrate in different ways. It was concluded that (1) Mg and citrate are effectors of TO in artificial and natural urine; (2) in ICU, low TO and other disturbed CaOx crystallization parameters appear related to the prevailing low urinary pH and low free citrate; (3) Mg-alkali citrate inhibits CaOx crystallization, probably via actions of the citrate, but not the Mg. Because of the eminent role of Mg in human health and ICU, further studies on crystallization after oral intake of Mg in the form of citrate are warranted.

Osteopenia following total gastrectomy in the rat--state of mineral metabolism and bone histomorphometry.

Total gastrectomy (GX) in humans is frequently followed by osteopenia, but the details are unclear. The present investigations in the rat were aimed at elucidating its pathogenesis. Seventeen weeks after GX, we evaluated Ca, Mg and P metabolism as well as bone parameters, including fluorochrome-based bone histomorphometry. In GX rats, fecal Mg was increased, but intestinal absorption of P, Ca, and Mg was within normal limits, as was the urinary excretion of Ca, Mg, hydroxyproline and the pyridinium cross-links. In contrast, urinary P as well as cyclic AMP were significantly increased. In serum of GX rats, gastrin and 25-hydroxyvitamin D (25-OHD) were decreased, and Ca, Mg, P, parathyroid hormone (PTH), calcitonin, and the bone marker osteocalcin were normal, whereas 1,25-dihydroxyvitamin D [1,25(OH)2D] was significantly increased. GX rats had significantly reduced bone density and mineral content, severe high-turnover osteopenia, characterized by normal width but significantly decreased maturation time of osteoid, increased bone formation rate, and increased numbers of osteoclasts. We concluded that after GX (1) there is high-turnover osteopenia with normal mineralization and other histomorphometric features resembling those seen in states with hyperphosphaturia and subsequent hypervitaminosis D; (2) normal serum PTH levels and several indirect indicators of parathyroid gland function argue against the presence of (secondary) hyperparathyroidism, whereas increased bone mobilization due to elevated 1,25(OH)2D explains the maintenance of homeostasis of serum minerals, especially Ca, at the expense of bone mineral; (3) a complex interplay of mineral-metabolic effectors exists, among which low 25-OHD-PTH-independent renal phosphate losses, and high 1,25(OH)2D are prominent features. The presented animal model is recommended for future research in this area.

Gastric Fundectomy in the Rat: Effects on Mineral and Bone Metabolism, with Emphasis on the Gastrin–Calcitonin–Parathyroid Hormone–Vitamin D Axis

Abstract. In humans, gastric surgery results in in osteopenia via mechanisms that are insufficiently understood; surgery-induced changes in the hormonal axes involving the stomach, thyroid, and the parathyroids may play a role. To study this in more detail, we evaluated calcium (Ca), magnesium (Mg), and phosphorus (P) metabolism as well as physical, chemical, and histomorphometric bone parameters in rats rendered hypergastrinemic by fundectomy (FX). In independent experiments, the response to an oral Ca challenge was investigated in intact rats versus FX, and in thyroidectomized versus thyroid-intact FX rats. Sixteen weeks following FX, body weight was approximately 80% that of sham-operated controls. In urine, P excretion was elevated fivefold, the pH was significantly decreased, and cAMP excretion was elevated as compared with controls; serum parathyroid hormone (PTH), calcitonin, 25OHD, Ca, Mg, and P were normal; gastrin and 1,25(OH)2D were elevated. On the basis of bone ash mineral content, FX rats developed significant osteopenia, and histomorphometry indicated only slightly elevated bone turnover and mineralization. Following oral Ca, thyroid-intact FX rats developed hypercalcemia, serum gastrin decreased, and calcitonin increased significantly; in thyroidectomized FX rats, calcitonin remained at baseline levels although there was a similar degree of hypercalcemia; PTH decreased during the hypercalcemic period in both groups. Serum gastrin did not correlate with calcitonin or PTH, and in multivariate regression analysis the only predictor of serum 1,25(OH)2D was urinary phosphorus. It was concluded that in the FX rat (1) osteopenia is not caused by intestinal Ca malabsorption, vitamin D, Ca deficiency, or secondary hyperparathyroidism; (2) osteopenia may be related to PTH-independent urinary hyperexcretion of P, followed by a rise of serum 1,25(OH)2D; (3) the existence of endocrine axes among gastrin, calcitonin, and PTH cannot be substantiated. FX osteopenia appears to be related to gastric acid abolition, and the reactive hypergastrinemia probably stabilizes the mass and turnover of bone.

Postprandial Hyperoxaluria and Intestinal Oxalate Absorption in Idiopathic Renal Stone Disease

Calcium and oxalate were studied in daily, fasting and postprandial urine specimens from healthy subjects and patients with idiopathic renal calcium stones in response to a test meal free of oxalate, and supplemented with calcium and 14carbon-oxalic acid. The data showed that the amount of oxalate in fasting urine of patients with stones did not differ from that in controls. Generally, patients with stones had considerable postprandial hyperoxaluria in terms of excretion and concentration, associated with a significantly higher degree of supersaturation with regard to calcium oxalate compared to controls. These findings were paralleled by decreased intestinal absorption of 14carbon-oxalate and by unchanged 24-hour urinary oxalate. Although the source of increased postprandial oxalate in patients with stones is not clear the possibility of enhanced de novo synthesis from oxalate precursors is discussed. In patients with different types of calciuria the 2 main risk factors (hyperoxaluria and hypercalciuria) for the process of stone formation are recognizable more readily in the postprandial urine specimens than in fasting or daily urine specimens.

Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: attenuation by ascorbic acid supplementation of a test meal.

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m2] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P ≤ 0.05 vs controls)., whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize postload phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38,r = -0.44,P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and —within limits — glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some preexisting basic abnormality of cell metabolism in RCU.

Composition of renal stones and their frequency in a stone clinic: Relationship to parameters of mineral metabolism in serum and urine

SummaryStone analyses (kidney, upper urinary tract) of the department of Urology, University of Erlangen, from a four-year-period (1974–1977) have been recorded with emphasis to stone composition, sex and age of the pertinent stone forming patients.During this time period there were no substantial changes as regards the per cent frequency of the various stone types. The most frequent type was calcium oxalate (CaOx), followed by uric acid, calcium phosphate (CaP), struvite and cystine. Stone analyses were mostly requested for patients between 46 and 55 years of age. Stone incidence in our clinic is calculated to be 1.22 times higher in males than females, especially beyond 36 years of age. The frequency peaks are: pure (=100 per cent) CaOx 36–45 years; CaOx with additional mineral phases (mostly CaP) 46–55 years; uric acid 56–65 years; CaP 26–35 years.From those patients who underwent further investigations in searching for metabolic abnormalities serum concentrations, urine mineral clearances in fasting urine samples, and activity products of stone forming mineral phases in sequentially collected specimens from 24 h and 2 h fasting urine had been measured and compared with values from healthy control subjects. In urolithiasis (idiopathic) there is a normal parathyroid hormone blood level, a generally lower serum inorganic phosphate and magnesium concentration.In pure (=100 per cent) CaOx and uric acid lithiasis serum uric acid and creatinine are higher than in controls, urine pH and calcium clearance in some groups are different too. Clearances of magnesium, uric acid, phosphate, sodium are within normal limits in urolithiasis. When expressing the propensity to form stones in terms of activity products, then only uric acid lithiasis deviates substantially from normal. All other stone types differ only slightly or not at all from each other and controls respectively.It is concluded that 1) in our geographic region the various stone types prevail in different age periods; 2) there are distinct alterations of parameters of mineral metabolism in urolithiasis; 3) measuring urine clearances may lead to assume falsely normal mean urine excretion of stone forming constituents.

Nephrocalcinosis and hyperlipidemia in rats fed a cholesterol- and fat-rich diet: association with hyperoxaluria, altered kidney and bone minerals, and renal tissue phospholipid-calcium interaction.

Abstract To determine whether an “atherogenic” diet (excess of cholesterol and neutral fat) induces pathological calcification in various organs, including the kidney, and abnormal oxalate metabolism, 24 male Sprague-Dawley rats were fed either normal lab chow (controls, n=12) or the cholesterol- and fat-rich experimental diet (CH-F, n=12) for 111 ± 3 days. CH-F rats developed dyslipidemia [high blood levels of triglycerides, total, low-density lipoprotein (LDL)-, very low-density lipoprotein (VLDL)-, high-density lipoprotein (HDL)-bound cholesterol, total phospholipids], elevated serum total alkaline phosphatase and lactate dehydrogenase (LDH) levels, in the absence of changes in overall renal function, extracellular mineral homeostasis [serum protein-corrected total calcium, magnesium, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D)], plasma glycolate and oxalate levels. There was a redistribution of bone calcium and enhanced exchange of this within the extraosseous space, which was accompanied by significant bone calcium loss, but normal bone histomorphometry. Liver oxalate levels, if expressed per unit of defatted (DF) dry liver, were three times higher than in the controls. Urinary glycolate, oxalate, calcium and total protein excretion levels were elevated, the latter showing an excess of proteins >100 kD and a deficit of proteins >30–50 kD. Urinary calcium oxalate supersaturation was increased, and calcium phosphate supersaturation was unchanged. There were dramatically increased (by number, circumference, and area) renal calcium phosphate calcifications in the cortico-medullary region, but calcium oxalate deposits were not detectable. Electron microscopy (EM) and elemental analysis revealed intratubular calcium phosphate, apparently needle-like hydroxyapatite. Immunohistochemistry of renal tissue calcifications revealed co-localization of phospholipids and calcium phosphate. It is concluded that rats fed the CH-F diet exhibited: (1) a spectrum of metabolic abnormalities, the more prominent being dyslipidemia, hyperoxaluria, hypercalciuria, dysproteinuria, loss of bone calcium, and calcium phosphate nephrocalcinosis (NC); and (2) an interaction between calcium phosphate and phospholipids at the kidney level. The biological significance of these findings for the etiology of idiopathic calcium urolithiasis in humans is uncertain, but the presented animal model may be helpful when designing clinical studies.

Intestinal calcium absorption during hyperinsulinemic euglycemic glucose clamp in healthy humans.

SummaryThe influence of postprandial-like plasma insulin levels on intestinal calcium absorption (CaA) was studied in 9 health men. On separate occasions, they received either an i.v. infusion of 40 mU/m2 minute synthetic human insulin as well as a variable glucose infusion in order to clamp the plasma glucose at the baseline level (=glucose clamp), or insulin- and glucose-free vehicle infusions (=vehicle). During these infusions, an oral load containing 326 mg Ca in the form of Ca chloride was administered and CaA was determined thereafter with a47Ca/85Sr double tracer method. During glucose clamp, mean plasma insulin was 172 ±(1 SEM) 10 as compared to 6±1 μU/ml during vehicle infusions. During the clamp, 3-hour cumulative CaA rose significantly by 14% as compared to vehicle (39.2±2.5 vs. 34.4±2%,P<0.02). At the same time, serum potassium and phosphorus dropped significantly, whereas serum parathyroid hormone (PTH) and 1,25(OH)2D levels were unchanged as compared to vehicle. The urinary excretions of potassium, sodium, and inorganic phosphorus as well as the urinary specific activity of47Ca, dropped significantly during glucose clamp, whereas the urinary excretion of cAMP was unchanged as compared to vehicle. The results suggest that, under the conditions of euglycemic hyper-insulinemic clamp, insulin stimulates CaA of healthy humans in a PTH- and 1,25(OH)2D-independent manner. Insulin may thus possibly be regarded as a factor participating in the regulation of CaA in humans.