[Phosphocalcium metabolism in patients with calcified valvular bioprosthesis]. / Métabolisme phosphocalcique chez les malades ayant une bioprothèse valvulaire calcifiée.

Calcium and gla-protein content are increased in the calcifications of cardiac bioprostheses. Such calcifications are more frequent during growth, pregnancy and renal failure when bone gla-protein levels are elevated. We investigated whether bone gla-protein and other markers of calcium metabolism play a role in bioprostheses calcifications. Forty-seven patients were separated into 2 groups according to the presence (group A, n = 9) or absence (group B, n = 38) of bioprostheses calcifications, as assessed by echo-doppler and surgery. Plasma levels of calcium, phosphorus, magnesium, creatinine and alkaline phosphatases were measured by standard laboratory methods, parathormone and those of bone gla-protein by specific radioimmunoassays. Results (mean +/- SEM) were compared (group A versus group B, P < 0.01) using Student's test and one-factor variance analysis (ANOVA). Age was similar in both group (53 +/- 12.9 vs 50 +/- 12.3 yrs), whereas duration of implant was greater in group A (104 +/- 12.4 vs 66 +/- 6.5 months, P < 0.01). No statistically significant difference was found between group A and B concerning biochemical and/or hormonal markers of calcium metabolism. These negative results merit to be discussed, and further studies will be needed to explore the potential role of circulating bone gla-protein in bioprostheses calcifications.

Acute variations in extracellular pH modulate transduction pathways of PTH in rat proximal tubule.

An increase in circulating parathyroid hormone (PTH) has been shown to enhance the capacity for the kidney to excrete an acid as well an alkaline load, which suggests that changes in systemic acid-base status may modulate the effect of the hormone on bicarbonate absorption in proximal tubule. In the present study, we tested the possibility that acute variations in extracellular pH (pHe), obtained by modifying bicarbonate concentration at constant PCO2 (40 mmHg), may modulate the responses of intracellular messengers coupled to PTH receptors in a preparation of freshly isolated proximal tubule fragments. Variations in pHe, which induced parallel variations in intracellular pH (pHi), did not affect unstimulated values for adenosine 3',5'-cyclic monophosphate (cAMP) production, inositol trisphosphate accumulation, or cytosolic free Ca2+ concentration. In contrast, reducing pHe from 7.4 to 7.2 elicited a decrease of the PTH-induced cAMP production, whereas increasing pHe from 7.4 to 7.6 enhanced it. The ability for cholera toxin and forskolin (which both bypass PTH receptors) to stimulate cAMP formation was diminished at pHe 7.2 and enhanced at pHe 7.6 (the increase did not achieve statistical significance in the presence of forskolin), suggesting that variations in pHe and/or pHi may affect per se adenylyl cyclase activity. Conversely, reducing pHe from 7.4 to 7.2 enhanced the PTH-induced inositol trisphosphate accumulation and rise in cytosolic free Ca2+ whereas increasing pHe from 7.4 to 7.6 had opposite effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin II and nonpeptide receptor antagonists on transduction pathways in rat proximal tubule.

Because the presence of the angiotensin II (ANG II)-dependent phosphoinositide hydrolysis has been questioned from studies in proximal cells in culture, we looked for this transduction pathway in suspension of freshly isolated rat proximal tubule fragments. ANG II-receptor activation induced a prompt (within 15 s) and sustained increase in [3H]inositol phosphates (IPs; inositol trisphosphate, inositol bisphosphate, and inositol monophosphate). In fura-2-loaded tubules, it elicited a rapid and biphasic rise in cytosolic free calcium ([Ca2+]i) with an early peak (within 15 s) followed by a plateau. The peak was maintained in the absence of extracellular calcium. ANG II-induced inositol trisphosphate and [Ca2+]i rises showed a similar dose dependency, with a 50% effective concentration (EC50) of 2.9 and 5.5 nM, respectively. We checked that ANG II inhibited basal (EC50 4.4 nM) and parathyroid hormone- and forskolin-stimulated cAMP production, the latter effect being inhibited by pertussis toxin pretreatment. The effects of ANG II on IPs and [Ca2+]i were inhibited by the ANG II receptor subtype 1 (AT1) antagonist losartan and not by the ANG II receptor subtype 2 (AT2) antagonists PD 123177 and PD 123319. The effect of ANG II on forskolin-stimulated cAMP was inhibited by losartan and not by PD 123319. In agreement with these results, specific binding of 125I-[Sar1,Ile8]ANG II was markedly inhibited by losartan, whereas PD 123319 had no effect. These results demonstrate that AT1 receptor subtypes are present in intact rat proximal tubule cells and are coupled to both IPs-Ca2+ and cAMP signaling pathways. No evidence for AT2 receptor subtype is found.

[Should the parathyroid function be evaluated in a patient with calcium kidney stones? If so, when and why?]. / Faut-il évaluer la fonction parathyroïdienne d'un patient atteint de lithiase rénale calcique? Si oui, quand et pourquoi?

About 7% of patients with calcium urolithiasis suffer from primary hyperparathyroidism. A systematic search for this diagnosis is therefore mandatory in such patients. Because hypercalcemia is often discrete or intermittent, determinations of calcium levels should be repeated at least thrice. Measurement of ionized calcium levels improves the detection of hypercalcemia. The biological diagnosis is based on the presence of hypercalcemia together with an increased plasma level of 1-84 intact parathormone (PTH). A PTH value still in the normal range but inappropriately elevated in the context of hypercalcemia could be sufficient for the diagnosis of primary hyperparathyroidism.

[Renal acidosis]. / Acidoses rénales.

Normal adults with normal protein intakes have a urinary NH4 excretion of 40 to 50 mmol/24 hours and a variable urinary pH. In cases of metabolic acidosis a urinary pH less than 5.5 suggests an extra-renal origin whilst a urinary pH greater than 5.5 is in favour of renal acidosis, but there are many exceptions to this rule. On the other hand, urinary NH4 excretion is always greater than 70 mmol/24 hours in the first case and less than 40-50 mmol/24 hours in the second; and the use of the urinary anionic gap (Na + K - Cl), negative in the first case and positive in the second, enables the two situations to be distinguished. The acidosis of nephron reduction is easily recognised in cases of severe renal failure with an increase in unmeasured plasma anions whilst tubular acidoses are accompanied by a hyperchloremia. Measurement of fractional HCO3 excretion after an oral loading dose of NaHCO3, preferably by TmCHO3 with respect to GFR, distinguishes proximal tubular acidosis (low TmHCO3) from distal tubular acidosis (normal or high TmHCO3). In the latter case, the presence of hypokalemia suggests a distal tubular acidosis either due to deficiency of the H(+)-ATPase pumps (absence of increased urinary pCO2 after oral loading dose of NaHCO3) or to the inability of the kidney to maintain a normal H+ gradient (normal increase of urinary pCO2. The presence of hyperkalemia suggests diseases associated with hypoaldosteronism (low or inappropriate serum aldosterone concentrations), abnormal transepithelial voltages or with a pseudo-hypoaldosteronism syndrome (high plasma aldosterone concentration). The prevalence of distal tubular acidosis with hyperkalemia is on the increase whilst tubular acidosis with hypokalemia remains rare.

[Hypocalcemia in adults and their treatment]. / Hypocalcémies de l'adulte et leur traitement.

The first thing to do is to confirm that the number of circulating calcium ions has really decreased. This is achieved either by correction of the total blood calcium level, taking into account possible variations in albuminaemia and pH, or by direct measurement of plasma calcium ions, using a special electrode. The aetiological diagnosis may be easy in some clinical situations, but it often demands a systematic approach, which implies a specialized and brief exploration, feasible in out-patients, with simultaneous measurement, under basal conditions, not only of plasma calcium ions, but also of plasma magnesium, intact 1-84 parathyroid hormone (PTH), nephrogenic cyclic AMP and 25 (OH) D. Rationally, hypocalcaemias may be divided into two groups : (1) extraparathyroid, where hyperparathyroidism is constant and hypocalcaemia is due either to calcium intake reduction, vitamin deficiency of high bone accretion, or to a primary renal calcium leakage; (2) parathyroid, by impaired secretion of PTH or alteration of PTH receptors, which means hypoparathyroidism or pseudohypoparathyroidism. The diagnostic and therapeutic possibilities in both groups are discussed.

Determinants of parathormone secretion in primary hyperparathyroidism.

We studied the effects of acute modifications in plasma calcium on parathormone (PTH) secretion in 23 patients with primary hyperparathyroidism (PHPT). In 12 patients, PTH hypersecretion was autonomous, and basal plasma calcium concentration was positively correlated with maximal serum PTH(1-84) reached during Na2EDTA infusions. In 11 patients, PTH hypersecretion remained suppressible, but with elevated set point value, and basal plasma calcium concentration was positively correlated with set point. Thus, the degree of hypercalcemia seems mainly determined by the magnitude of maximal PTH secretion and set point error in autonomous and suppressible PHPT, respectively. We have previously suggested that high serum calcitriol levels might chronically inhibit PTH hypersecretion in PHPT. We showed that hyperparathyroid patients with renal stone presentation exhibited an abnormally high value of circulating calcitriol and a moderately elevated PTH activity, while patients with severe bone disease presentation displayed a low to normal calcitriol value and a dramatically increased PTH activity. The hypothesis was supported by a recent study from our Unit in one hyperparathyroid patient with severe bone disease and normal serum calcitriol level. Increment of serum calcitriol after daily intravenous Rocaltrol for 5 days directly suppressed PTH hypersecretion without change in plasma ionized calcium.

Marked direct suppression of primary hyperparathyroidism with osteitis fibrosa cystica by intravenous administration of 1,25-dihydroxycholecalciferol.

A marked direct suppression of primary hyperparathyroidism with osteitis fibrosa cystica has been achieved by the intravenous administration of 1,25-dihydroxycholecalciferol [1,25(OH)2D]. In a recent survey of 306 patients with primary hyperparathyroidism (PHPT), we hypothesized that the far higher degree of parathyroid hormone (PTH) hypersecretion in PHPT with osteitis fibrosa cystica than in PHPT without overt bone disease might be due to the absence of suppression of hormonal hypersecretion by the low-to-normal circulating 1,25(OH)2D reflecting a relative vitamin D deficiency. To test this hypothesis, a patient having hypercalcemic PHPT with florid osteitis fibrosa cystica and normal serum 1,25(OH)2D was given increasing daily doses of intravenous calcitriol (0.5-2 micrograms) for several days. Doubling the level of circulating 1,25(OH)2D from 48 to 100-114 pg/ml was accompanied by a marked decline (46%) in serum iPTH(1-84), without a change in the serum calcium concentration. A lowered set point of parathyroid cells for calcium, and a diminished maximum secretory rate of PTH, may contribute to the marked suppression of PHPT.

Effects of citrate on urinary calcium excretion.

Thyroparathyroidectomized rats were studied during control, citrate infusion, and recovery periods to analyze the effects of citrate on urinary calcium excretion. The rats were infused with human PTH-(1-34) at a constant rate throughout the experiments that produced physiologic circulating PTH activity. Ultrafiltrable calcium was measured with a micropartition system while maintaining constant the pH and PCO2 of the sample. The plasma acid-base status, filtered load of calcium, and urinary sodium excretion rate did not vary during citrate infusion. The urinary calcium excretion rate increased from 71 +/- 9 nmol/min/g kidney during control period to 122 +/- 22 nmol/min/g kidney (p less than 0.05) during citrate infusion, and then returned below control levels during recovery period. A strong positive linear relationship was observed between the urinary excretion rates of calcium and citrate (r = 0.88; p less than 0.001). We conclude that tubular fluid citrate inhibits renal calcium reabsorption probably by forming calcium-citrate complexes.

[Primary hyperparathyroidism seen in rheumatology. Clinical symptoms and the relation between bone histologic signs and biological parameters]. / Hyperparathyroïdie primitive vue en rhumatologie. Signes cliniques et relations entre les signes histologiques osseux et les paramètres biologiques.

We report the clinical and biological picture of 34 primary hyperparathyroidism (PHT) cases, diagnosed in rheumatology. It concerned 25 women and 9 men, aged 61 + 11 years. The PHT was often asymptomatic (47 p. cent of cases) at the time of diagnosis. The clinical manifestations were dominated by asthenia (50 p. cent) and renal lithiasis (47 p. cent). We found a chondrocalcinosis in 29 p. cent of patients. No patient presented any bony manifestations of cystic osteitis; 7 out of 34 patients (including 6 women between 57 and 74 years) presented vertebral compression. The mean calcemia was 117 +/- 9 mg/l. There were no hypercalcemic attack. The dosage of PTH and cyclic AMP were elevated in 29 out of 32 and 28 out of 31 patients respectively. In all patients, the level of either of these two tests was increased. The chloremia/phosphoremia ratio was also extremely predictive of HBP, since it was increased, exceeding 3.3 in 33 out of 34 patients. The 25-hydroxyvitamin D levels (25 (OH) D) were normal. The levels of 1,25 (OH) 2D were markedly spread (37 +/- 16 pg/ml) and not significantly different from the reference group. Patients with lithiasis did not present a higher level of 1,25 (OH) 2D. A bone histomorphometry carried out in 15 patients showed a bone trabecular volume similar to that of the reference with the same age. The osteoclastic resorption was increased in all cases and was not correlated with the PTH level, but was significantly correlated with the level of 1,25 (OH) 2D (r = 0.79 p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Factors associated with early remission of type I diabetes in children treated with cyclosporine.

To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.

Maximal PTH secretory rate and set point for calcium in normal subjects and patients with primary hyperparathyroidism. In vivo studies.

The characteristics of PTH secretion, which have been extensively studied in vitro with dispersed cells of normal and abnormal parathyroid glands, remain poorly studied in vivo. We performed ethylenediamine tetraacetate (EDTA) intravenous infusions in 12 normal subjects and 5 patients with hypercalcemia (serum ionized calcium between 2.72 and 2.89 mEq/l) and surgically proven primary hyperparathyroidism (PHPT) to establish the relationship between nephrogenous cyclic AMP (NcAMP) used as an index of PTH secretion and serum ionized calcium. We determined the maximal NcAMP taken as an index of maximal secretory rate for PTH, the set point and sensitivity of parathyroid cells for calcium. In normal subjects, mean values (+/- SD) were 4.04 +/- 0.47 nmol/dl glomerular filtrate (GF) for maximal NcAMP, 2.23 +/- 0.04 mEq/l for set point, and -250 +/- 58 for sensitivity when NcAMP was expressed in percent of maximal value and serum calcium in mEq/l. In patients with PHPT, the differences between maximal and basal values of NcAMP represented 50% or more of maximal NcAMP, indicating that PTH secretion was suppressible. Sensitivity values were within normal limits in all patients. Calculated set point values were abnormally elevated (between 2.64 and 2.83 mEq/l) in all patients. Maximal NcAMP values ranged from low to normal (2.77 nmol/dl GF) to abnormally high (6.64 nmol/dl GF), and a positive linear correlation was observed with parathyroid cell mass. Basal serum calcium concentrations were not correlated with either parathyroid cell mass or maximal NcAMP values, and were close to calculated set point values for each patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal mass and reserve of vitamin D: determinants in primary hyperparathyroidism.

We studied circulating 1,25(OH)2D3 and its determinants in 102 patients with primary hyperparathyroidism (PHPT), 33 of them with recurrent renal stones, 60 with non-specific symptoms, and nine with overt bone disease. Means for serum 1,25(OH)2D3 and intestinal absorption of calcium were abnormally high in the renal stone group, slightly elevated in the non-specific group, and low-normal in the bone disease group. In the whole population of patients, we found a positive correlation between circulating 1,25(OH)2D3 and creatinine clearance (taken as an index of the functional renal mass). Negative correlations were observed between 1,25(OH)2D3 and age, and between creatinine clearance and age, the latter being not different from that observed in a normal large population. In the renal stone group, means for the determinants of the renal 1 alpha hydroxylase activity, that is, PTH activity expressed as nephrogenous cyclic AMP (NcAMP), serum phosphate and calcium were identical to those of the group with non-specific symptoms. However means for age were lower and functional renal mass significantly higher in the renal stone group, which may account for the higher value of circulating 1,25(OH)2D3. In the bone disease group, means for age, renal mass and serum calcium were identical to those of the group with non-specific symptoms, and NcAMP was far higher and hypophosphatemia more marked, which may not account for the lower value of circulating 1,25(OH)2D3. However, in the bone disease group, serum 25(OH)D was abnormally low, which may limit the renal production of 1,25(OH)2D3 and explain the low-normal circulating values.(ABSTRACT TRUNCATED AT 250 WORDS)

[Multiple hypersecreting lesions of the parathyroid glands during treatment with lithium]. / Lésions hypersécrétantes multiples des parathyroïdes au cours d'un traitement par le lithium.

A 64 year old woman had been on lithium carbonate for 12 years for manico-depressive psychosis. Mild asthenia leads to the diagnosis of primary hyperparathyroidism based on the findings of hypercalcemia up to 2.85 mmol/l inappropriate levels of parathormone and a non-suppressive rise of nephrogenic cyclic AMP. These symptoms were not relieved by removal of a chief cell adenoma of the left inferior parathyroid; surgical reexploration leads to the removal of an adenoma in a high, ectopic situation. Further venous samplings were collected during cervico mediastinal phlebography because of persistent hypercalcemia: parathormone levels were high in a thymic vein and a new cervicotomy revealed a fifth gland with an adenoma in the high mediastinum. After removal of the third adenoma, the patient became hypocalcemic. Lithium was not discontinued according to the patient's wishes. Eighteen months later she was well and normocalcemic on alfacalcidol therapy. Multiple adenomas of the parathyroids are rare (1.7 p. 100 to 5 p. 100) and the recurrence of an adenoma on a supernumerary gland is exceptional. Eighteen clinical cases of primary hyperparathyroidism under lithium therapy have been reported, but mild asymptomatic hypercalcemia with inappropriate increased parathormone levels seems to be more common. Duration of treatment is very variable: 1 day to 12 years, and serum calcium levels or up to 3.9 mmol have been observed. Ten patients underwent cervicotomy with removal of an adenoma 6 of them remaining under treatment, with 2 recurrences in our case. Five of the 8 non-operated patients remained on lithium therapy and showed mild hypercalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Pseudohypoaldosteronism type II: proximal renal tubular acidosis and dDAVP-sensitive renal hyperkalemia.

The mechanisms of metabolic acidosis and hyperkalemia were investigated in a patient with chronic mineralocorticoid-resistant renal hyperkalemia (5.3-6.9 mmol/l), metabolic acidosis (arterial blood pH 7.27, total CO2 17 mmol/l), arterial hypertension, undetectable plasma renin activity (less than 0.10 ng/ml/h), high plasma aldosterone level (32-100 ng/dl), and normal glomerular filtration rate (131 ml/min/1.73 m2). During the hyperkalemic period, urine was highly acidic (pH 4.6-5.0), urinary NH4 excretion (10-13 microEq/min) and urinary net acid excretion (19-24 microEq/min) were not supernormal as expected from a chronic acid load. During NaHCO3 infusion, the maximal tubular HCO3 reabsorption was markedly diminished (19.8 mmol/l glomerular filtrate), and the fractional excretion of HCO3 (FE HCO3) when plasma HCO3 was normalized was 20%. Urine minus blood PCO2 increased normally during NaHCO3 infusion (31 mm Hg), and the urinary pH remained maximally low (less than 5.3) when the buffer urinary excretion sharply increased after NH4Cl load. When serum K was returned toward normal limits, metabolic acidosis disappeared, urinary NH4 excretion rose normally after short NH4Cl loading while the urinary pH remained maximally low (4.9-5.2), the maximal tubular HCO3 reabsorption returned to normal values (24.8 mmol/l glomerular filtrate), and FE HCO3 at normal plasma HCO3 was 1%. Nasal insufflation of 1-desamino-8-D-Arginine Vasopressin (dDAVP) resulted in an acute normalization of the renal handling of K and in an increase in net urinary acid excretion. We conclude that: the effect of dDAVP on renal handling of K may be explained by the reversal of the distal chloride shunt and/or an increase in luminal membrane conductance to K; the distal acidification seems to be normal which in the event of distal chloride shunt impairing distal hydrogen secretion might be explained by the presence of systemic acidosis which is a potent stimulus of hydrogen secretion, and metabolic acidosis in the steady state was accounted for by the diminution of bicarbonate reabsorption and ammonia production in the proximal tubule secondary to chronic hyperkalemia.