Low calcium diet in hypercalciuric calcium nephrolithiasis: first do no harm

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (1000 mg elemental calcium together with a standard breakfast) was studied in 13 healthy male controls and 21 recurrent idiopathic renal calcium stone formers, 12 with hypercalciuria (UCa x V > 7.50 mmol/24 h) and nine with normocalciuria. In controls, serum 1,25(OH)2 vitamin D3 (calcitriol) remained unchanged 6 h after oral calcium load (50.6 +/- 5.1 versus 50.9 +/- 5.0 pg/ml), whereas it tended to increase in hypercalciuric (from 53.6 +/- 3.2 to 60.6 +/- 5.4 pg/ml, P = 0.182) and fell in normocalciuric stone formers (from 45.9 +/- 2.6 to 38.1 +/- 3.3 pg/ml, P = 0.011). The total amount of urinary calcium excreted after OCL was 2.50 +/- 0.20 mmol in controls, 2.27 +/- 0.27 mmol in normocalciuric and 3.62 +/- 0.32 mmol in hypercalciuric stone formers (P = 0.005 versus controls and normocalciuric stone formers respectively); it positively correlated with serum calcitriol 6 h after calcium load (r = 0.392, P = 0.024). Maximum increase in urinary calcium excretion rate, delta Ca-Emax, was inversely related to intact PTH levels in the first 4 h after calcium load, i.e. more pronounced PTH suppression predicted a steeper increase in urinary calcium excretion rate. Twenty-four-hour urine calcium excretion rate was inversely related to the ratio of delta calcitriol/deltaPTHmax after calcium load (r = -0.653, P = 0.0001), indicating that an abnormally up-regulated synthesis of calcitriol and consecutive relative PTH suppression induce hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence of absorptive hypercalciuria in tuberculosis patients

In patients with granulomatous diseases, disturbances in calcium metabolism have been described. The aim of the study was to evaluate alterations in calcium metabolism in patients with tuberculosis. Forty patients with tuberculosis (TB) were studied in a baseline state (calcium intake 1000 mg/day). Fourteen of these patients were also studied after restrictive calcium diet (400 mg/calcium/day) and after a load of oral calcium of 1000 mg. In all the studies, calcium and phosphorus were measured in serum and urine, and parathyroid hormone (PTH) in plasma. In addition, serum 25OHD and 1,25(OH)2D (calcitriol) levels were measured in the baseline state and after the restrictive diet. In the baseline state, 25OHD levels were lower and urinary calcium higher in TB patients than in the control group. No patients had hypercalcemia, but hypercalciuria was present in 10 patients (25%). The patients with tuberculosis were divided according to the presence or absence of hypercalciuria. In both groups, the 25OHD levels were lower than in controls. Hypercalciuric patients had lower plasma parathyroid hormone levels and higher serum calcitriol levels than the control group and the TB patients without hypercalciuria. Urinary calcium excretion after a calcium load was higher in TB patients with hypercalciuria than in controls. A positive correlation was found between the calcitriol levels and postcalcium load urinary calcium excretion in patients with calcium hyperabsorption. These data indicate that absorptive hypercalciuria is frequently observed in patients with TB and is possible due to inappropriately high serum calcitriol levels.     

Observations on the different calcium metabolic patterns in sarcoidosis. A metabolic and kinetic study

Combined calcium balance and 47Ca turnover studies in sarcoidosis (4 patients) and vitamin D intoxication (1 patient) disclosed three different patterns of calcium metabolism. On patient with sarcoidosis had a normal metabolism of calcium, and two patients presented the usual pattern of intestinal hyperabsorption, hypercalcemia, and hypercalciuria. The fourth patient with sarcoidosis and the patient with vitamin D intoxication, both studied during spontaneous remissions, presented the third pattern. The main features here were hypercalcemia despite normal intestinal absorption of calcium, enlarged exchangeable calcium pool, accelerated accretion and resorption rates, hypercalciuria, and a distinctly negative calcium balance. This pattern of remission seems to represent a mobilization of extraosseous or metastatic calcifications, rather than a resorption of bone calcium.     

Assessment of parathyroid gland function: predictive value of a nomogram

Recent developments in measurement of intact parathormone (PTH) has enabled to generate a nomogram for parathyroid function. Blood levels of PTH can thus be interpreted in relation to calcemia. Intact PTH and calcium were assayed in blood from 99 healthy subjects studied under fasting conditions; 26 subjects were also studied during hyper- and hypocalcemia, induced by calcium and EDTA infusions, respectively. Serum levels of intact PTH which had been obtained in 99 patients were then analysed retrospectively by comparison with the nomogram. Patients whose intact PTH levels lie above the normal zone of the nomogram produce too much PTH relative to the blood calcium level (hyperparathyroidism); those falling under the normal zone produce too little (hypoparathyroidism).     

Pathogenesis of idiopathic calcium nephrolithiasis: update 1997

Idiopathic calcium nephrolithiasis (ICN) is a frequent disease in Western countries. The physicochemical theory of lithogenesis, which explains stone formation by the precipitation, growth, and crystalline aggregation of lithogenic salts in the urine, has contributed greatly to the understanding of the pathogenesis of calcium urolithiasis. However, several aspects are still unexplained; the co-existence of familial occurrence, primary tubular dysfunctions with ICN, and anomalies in the systemic handling of oxalate and calcium led to the development of a cellular hypothesis of ICN. A number of cellular defects in the handling of ions has been reported that involves both anion and cation transport. These anomalies are probably the expression of a still unknown cellular defect in idiopathic calcium stone formers. We suggested that an anomaly in the cell membrane composition might be responsible for the complex array of cell ion flux abnormalities observed in ICN. Recently, a disorder in the n-6 polyunsaturated fatty acid series has been described; it is characterized by a lower linoleic acid content and a higher arachidonic acid concentration in both plasma and erythrocyte membrane phospholipids of renal calcium stone patients. This anomaly could cause an increased activity of ion carriers; furthermore, it may lead to increased prostaglandin synthesis and to secondary phenomena at the kidney, skeletal, and intestinal level. As a consequence, critical conditions for lithogenesis in the kidney may ensue. The data suggest a common pathogenesis for hypercalciuria and hyperoxaluria. The systemic defect in the phospholipid arachidonic acid level may be both of dietary or genetic origin; experimental data suggest that the increase in delta-6 desaturase activity, the limiting enzyme in the metabolic pathway of polyunsaturated fatty acids, might be relevant to the pathogenesis of lipid abnormalities observed in nephrolithiasis and to the pathogenesis of ICN and its related problems (at the kidney, intestinal, and bone level).     

Pathogenesis of renal calculi in distal renal tubular acidosis. Possible role of parathyroid hormone

Elevated circulating levels of immunoreactive parathyroid hormone (PTH), hypercalciuria and renal calculi were found in 3 patients with distal renal tubular acidosis (RTA). Treatment with alkali resulted in a fall of PTH toward normal and a reduction in urinary calcium, but the frequency of urolithiasis was unchanged. In one patient in whom prolonged follow-up was possible, a subtotal parathyroidectomy was performed. This was followed by virtual cessation of stone formation despite persistence of the acidification defect. This study suggests that RTA may be associated with secondary hyperparathyroidism and that the consequent elevation in PTH may play a contributory role in the pathogenesis of renal calculi.     

Elevated serum-calcium and parathormone-levels in HIV afflicted female heroin addicts

Alterations of calcium and bone metabolisms have been observed in numerous studies of small groups of male HIV-infected patients. However, our knowledge regarding the manifestation of AIDS-associated hypoparathyroidism in female subjects is limited. In order to investigate the influence of heroin on the calciotropic hormones we performed a cross-sectional study on 45 female patients with proven HIV infection. The following criteria were used for exclusion from the study: age less than 20/ more than 50 years; confinement to bed; wasting symptoms; treatment with agents containing ketoconazole, renal or hepatic insufficiency; clinical or echographic signs of liver cirrhosis; endocrine diseases, or treatment with drugs known to influence calcium metabolism. A reduced parathormone (PTH) level was found among the female HIV-infected patients. Additional long-term use of heroin resulted in a significant increase of PTH compared to sex- and age matched controls and a second group of non-HIV-afflicted heroin dependent females. Significantly lowered serum magnesium concentrations were found in all three groups. Both serum calcium and urinary excretion of calcium were elevated in the group of HIV-infected heroin addicts and were independent from low vitamin D3 levels (1,25-dihydroxycholecalciferol) and alterations of protein metabolism. Therefore, it is concluded that the changes of PTH secretion are mainly due to mechanisms both of the impaired immune defense of HIV-infected females and the additional effect of opiates.     

High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro

Phosphate retention plays an important role in the pathogenesis of secondary hyperparathyroidism in patients with renal failure. In in vitro studies, high extracellular phosphate levels directly stimulate PTH secretion in rat and bovine parathyroid tissue. The present study evaluates the effect of high phosphate levels on the secretion of PTH and the production of prepro PTH mRNA in human hyperplastic parathyroid glands. The study includes parathyroid glands obtained from patients with primary adenomas and from hemodialysis and kidney-transplant patients with diffuse and nodular secondary hyperplasia. The experiments were performed in vitro using small pieces of parathyroid tissue. The ability of high calcium levels to decrease PTH secretion was less in adenomas than in secondary hyperplasia; among the secondary hyperplasia, nodular was less responsive to an increase in calcium than diffuse hyperplasia. In diffuse hyperplasia, PTH secretion was increased in response to 3 and 4 mM phosphate compared with 2 mM phosphate, despite a high calcium concentration in the medium; prepro PTH mRNA levels increased after incubation in 4 mM phosphate. Similar results were obtained with nodular hyperplasia, except that the elevation of PTH secretion in response to 3 mM phosphate did not attain statistical significance. In adenomas, high calcium concentrations (1.5 mM) did not result in inhibition of PTH secretion, independent of the phosphate concentration, and the prepro PTH mRNA was not significantly increased by high phosphate levels. In conclusion, first, the PTH secretory response to an increase in calcium concentration is less in nodular than diffuse hyperplasia; second, high phosphate levels directly affect PTH secretion and gene expression in patients with advanced secondary hyperparathyroidism.     

Calciotropic hormones and nephrolithiasis

In recurrent calcium stone formers interfering factors or changes in receptor sensitivity may alter the interrelationships among calcium-regulating hormones, and hormonal behavior often does not fit with the theoretical assumptions. The vitamin D system appears to have the most important metabolic and clinical effects. Abnormal up-regulation of the synthesis of calcitriol and the consequent parathyroid hormone (PTH) suppression can induce hypercalciuria. Consequently, the hypocalciuric effect of thiazide would be caused by an enhanced response to PTH and by a reduction in 1,25(OH)2-vit D. A negative role of vitamin D on the skeleton has been observed in the presence of a negative calcium balance. Moreover, vitamin D also plays a role in urine oxalate excretion. PTH seems not to be directly stimulated in hypercalciuria and recurrent calcium nephrolithiasis, and patients with hyperparathyroidism and recurrent calcium nephrolithiasis show a similar degree of bone demineralization, irrespective of the presence of absence of the so-called 'primary hyperparathyroidism.' Calcitonin plays a contributory role in the pathogenesis of recurrent calcium nephrolithiasis that seems to be strictly related to dietary calcium intake. A higher sensitivity of thyroid C cells, particularly in absorptive hypercalciuric patients, could be related to the pathogenesis of hypercalciuria and contribute to its persistence.     

How should the efficacy of prenatal care be tested in twin gestations?

The aim of the present study was to test the hypothesis that the decreased renal tubular reabsorption of calcium observed in estrogen deficiency is associated with a local regulation of either PTHrP or PTH/PTHrP receptor genes in the kidney. Rats were randomly sham-operated (S) or ovariectomized receiving either vehicle (OVX) or 4 microg E2/kg/day (OVX+E4) or 40 microg E2/kg/d (OVX+E40) during 14 days using alzet minipumps. Plasma PTH and calcium levels were lower in untreated OVX animals than in all other groups (P < 0.01). Plasma PTH was higher in OVX+E40 than in OVX+E4 (P < 0.05). PTHrP mRNA expression in the kidney was unaffected by ovariectomy but was increased in OVX+E40 (0.984 +/- 0.452 for PTHrP/GAPDH mRNAs expression vs. 0.213 +/- 0.078 in sham, P < 0.01). PTH/PTHrP receptor mRNA expression and the cAMP response of renal membranes to PTH were unaffected by ovariectomy and estrogen substitution. In conclusion, renal PTHrP and PTH/PTHrP receptor mRNAs are not modified by ovariectomy. However, 17beta-estradiol increases renal expression of PTHrP mRNA without evident changes in its receptor expression and function. This may help to explain the pharmacological action of estrogen in the kidney, especially how it prevents the renal leak of calcium in postmenopausal women.     

A definition of catheter-related infection

A 5 year old boy with normal phenotype and normal renal function presented tetany. Hypocalcemia and hyperphosphatemia, with increased serum levels of parathyroid hormone (PTH) were detected in serial measurements. Pseudohypoparathyroidism was diagnosed. This disease presents the biochemical abnormalities of hypoparathyroidism (hypocalcemia, hyperphosphatemia) with peripheral resistance to PTH activity. The patient was treated effectively with calcium and vitamin D supplements. The causes of hypocalcemia related to parathyroid gland activity are reviewed and the physiopathology of pseudohypoparathyroidism is described.     

Idiopathic hypercalciuria in childhood

This review describes the supposed mechanisms leading to idiopathic hypercalciuria (IHU) in childhood, further the diagnostic criteria and the proposed treatment modalities are discussed. IHU is not only one of the main causes of renal stone disease in children but it's also at the origin of the postglomerular haematuria and the frequency-dysuria syndrome. Its role in the development of osteoporosis in adults is also documented. The diagnosis of raised calcium excretion is based on age specific values during early infancy. In older children and adults a urinary calcium/creatinine ratio exceeding 0.6 mmol/mmol is regarded as elevated. Dietary calcium restriction can no longer be recommended for the treatment of IHU because it results in secondary hyperoxaluria and on the long-term causes decreased bone mineral density. Patients should be kept on dietary sodium restriction and high fluid intake. In cases IHU associated with recurrent episodes of macroscopic haematuria or recurrent stone disease a therapeutic trial with hydrochlorothiazide in the dose of 0.5-1 mg/kg/day with potassium-citrate supplementation and possibly magnesium citrate should be started. In some special forms of hypercalciuria such as the X-linked recessive nephrolithiasis syndrome or Bartter syndrome the localization and in some cases even the molecular mechanism of the events leading to increased calcium excretion are elucidated. In IHU enhanced Ca(++)-ATPase, and Na-Li countertransport activity and decreased Na+/K+ ATPase activity were described in the erythrocyte membrane model. It is expected that with the molecular genetic development the clinical classification of the hypercalciuric syndromes will become a rational genome-based one.     

Secondary hyperparathyroidism is an expected consequence of parathyroidectomy for primary hyperparathyroidism: a prospective study

BACKGROUND: Parathyroidectomy for primary hyperparathyroidism (PHPT) can cause secondary hyperparathyroidism, with increased serum parathyroid hormone (PTH) and normal or low serum calcium concentrations. METHODS: A prospective study investigated 78 consecutive patients who underwent exploration for PHPT. Serum intact PTH and total calcium concentrations were measured the evening after operation and ionized Ca++ the following morning. These levels were reassayed 1 week later. RESULTS: Before operation, the mean PTH level was 138 +/- 15 pg/mL, total calcium concentration was 11.6 +/- 0.1 mg/dL, and ionized Ca++ concentration was 1.44 +/- 0.02 mmol/L. On the night of the operation, the PTH level was 11 +/- 2 pg/mL, and the total calcium concentration was 8.9 +/- 0.1 mg/dL. Fifty-five patients had hypoparathyroidism, with a PTH level less than 10 pg/mL. The day after the operation, the ionized Ca++ level was 1.14 +/- 0.01 mmol/L. One week later, PTH, ionized Ca++, and total serum calcium concentrations returned to normal levels. In 9 patients (12%), PTH levels were increased (98 +/- 16 pg/mL), although ionized Ca++ concentrations were normal (1.18 +/- 0.02 mmol/L), demonstrating secondary hyperparathyroidism. Risk factors for postoperative secondary hyperparathyroidism included older age, symptomatic hyperparathyroidism, higher preoperative PTH and alakaline phosphatase levels, and lower serum phosphorous levels. In 70% of these patients, PTH levels returned to normal in 3 to 12 months. CONCLUSIONS: Secondary hyperparathyroidism occurs in 12% of patients after surgical treatment of PHPT. It is transient, possibly compensating for relative hypocalcemia.     

Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor

The calcium-sensing receptor (CaSR) regulates PTH secretion to control the extracellular calcium concentration in adults, but its role in fetal life is unknown. We used CaSR gene knockout mice to investigate the role of the CaSR in regulating fetal calcium metabolism. The normal calcium concentration in fetal blood is raised above the maternal level, an increase that depends upon PTH-related peptide (PTHrP). Heterozygous (+/-) and homozygous (-/-) disruption of the CaSR caused a further increase in the fetal calcium level. This increase was modestly blunted by concomitant disruption of the PTHrP gene and completely reversed by disruption of the PTH/ PTHrP receptor gene. Serum levels of PTH and 1, 25-dihydroxyvitamin D were substantially increased above the normal low fetal levels by disruption of the CaSR. The free deoxypyridinoline level was increased in the amniotic fluid (urine) of CaSR-/- fetuses; this result suggests that fetal bone resorption is increased. Placental calcium transfer was reduced, and renal calcium excretion was increased, by disruption of the CaSR. These studies indicate that the CaSR normally suppresses PTH secretion in the presence of the normal raised (and PTHrP-dependent) fetal calcium level. Disruption of the CaSR causes fetal hyperparathyroidism and hypercalcemia, with additional effects on placental calcium transfer.     

Are we mismanaging calcium and phosphate metabolism in renal failure?

Secondary hyperparathyroidism and renal osteodystrophy are the consequences of abnormal calcium, phosphate, and calcitriol metabolism ensuing from renal failure. Evidence suggests that calcium balance tends to become negative as we grow older than 35 years of age; however, the current dialysis modalities provide patients regardless of age with excessive calcium during dialysis. Administration of calcitriol in the management of hyperparathyroidism further increases the calcium and phosphate absorption. Furthermore, the current thrice-weekly renal replacement therapies fail to remove the daily absorbed phosphate, and we have to use calcium carbonate as a primary phosphate-binding agent to reduce intestinal phosphate absorption. The large calcium mass transfer and phosphate retention could lead to soft tissue calcification, especially in older end-stage renal disease (ESRD) patients. Consequently, only by maintaining a negative calcium balance during renal replacement therapy can we safely use calcitriol and calcium carbonate for the management of secondary hyperparathyroidism. Recent studies have indicated that phosphate restriction alone independent of plasma calcitriol or calcium can lower plasma parathyroid hormone (PTH) in renal failure and prevent hyperplasia of parathyroid glands. Therefore, phosphate control perhaps is the most important means to prevent secondary hyperparathyroidism. Previous studies have shown that ferric compounds are potent phosphate-binding agents; hence, these compounds warrant further trial in the management of phosphate metabolism in renal failure.     

Recovery of free ADP, Pi, and free energy of ATP hydrolysis in human skeletal muscle

BACKGROUND: Recent studies have demonstrated that a high concentration of phosphate directly stimulates parathyroid hormone (PTH) secretion. High serum levels of phosphate are usually observed in patients with end-stage renal disease. The aim of the present study was to evaluate whether serum phosphate concentration had an acute effect on PTH secretion in hemodialysis patients. The levels of serum phosphate were manipulated during the hemodialysis session by using a phosphate free dialysate or a dialysate with a high content of phosphate. METHODS: Ten stable hemodialysis patients with PTH values above 300 pg/ml were included in the study. A PTH-calcium curve was obtained during both high phosphate and phosphate free hemodialysis. RESULTS: The serum phosphate concentration remained high (2.17 +/- 0.18 mM) throughout the high phosphate hemodialysis and decreased progressively to normal levels (1.02 +/- 0.06 mM) during the phosphate free hemodialysis. The serum PTH levels at maximal inhibition by hypercalcemia (minimal PTH) were greater during the high phosphate than the phosphate free hemodialysis (413 +/- 79 vs. 318 +/- 76 pg/ml, P < 0.003). In all patients the values of minimum PTH were greater during the high phosphorus than the phosphorus free hemodialysis. The values of maximally stimulated PTH during hypocalcemia and the set point of the PTH-calcium curve were similar during the high phosphate and the phosphate free hemodialysis. CONCLUSION: The maintenance of high serum phosphorus levels during hemodialysis prevented, in part, the inhibition of PTH secretion by calcium, which strongly suggests that in hemodialysis patients high serum phosphate contributes directly to the elevation of PTH levels despite normal or high serum calcium concentration.     

Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism

The relative contributions of increased parathyroid cell mass and altered control mechanisms of parathyroid hormone (PTH) secretion in secondary hyperparathyroidism are still controversial. In this study, endogenous pulsatile PTH secretion was analyzed by the multiparameter deconvolution technique to differentiate alterations in cell mass-dependent (PTH burst mass) and regulation-dependent (frequency, synchrony, calcium responsiveness) PTH release in uremic patients. PTH concentration versus time profiles were obtained in 13 uremic and 16 healthy adults under baseline conditions and during acute hypo- and hypercalcemia. Plasma PTH half-life was increased in patients compared with control subjects (4.7+/-1.9 versus 2.6+/-0.1 min, P < 0.005). The baseline PTH secretion rate was elevated eightfold in the patients as a result of an increased PTH mass secreted per burst (17.1+/-4.7 versus 2.0+/-0.4 pM, P = 0.0001), higher burst frequency (8.0+/-0.3 versus 6.8+/-0.3 h(-1), P < 0.01), and a higher tonic secretion rate (343+/-99 versus 30+/-4 pM/h, P = 0.0001). Acute hypocalcemia elicited an immediate, frequency- and amplitude-mediated selective increase in the pulsatile secretory component, which was fractionally weaker in patients (+595%) than control subjects (+1755%, P < 0.001). The acceleration and the amplification of PTH bursts were 35 and 60% lower in the patient group. Acute hypercalcemia suppressed total PTH secretion by 79% in control subjects but only by 63% in patients (P < 0.002). PTH burst frequency was reduced during hypercalcemia by 30% in control subjects, but remained unchanged in patients. In conclusion, uremic hyperparathyroidism is mediated by a marked increase in glandular secretion, but also by reduced PTH elimination. The increased spontaneous PTH burst frequency and the blunted responsiveness to changes in Ca2+ indicate partial uncoupling of hyperplastic parathyroid glands from the physiologic regulatory mechanisms that direct pulsatile PTH release.