Phenotypic variability in Bartter syndrome type I.

Limited phenotypic variability has been reported in patients with Bartter syndrome type I, with mutations in the Na-K-2Cl cotransporter gene (BSC). The diagnosis of this hereditary renal tubular disorder is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis. Among nine children with hypercalciuria and nephrocalcinosis, we identified new mutations consistent with a loss of function of the mutant allele of the BSC gene in five. Three of the five cases with BSC gene mutations were unusual due to the absence of hypokalemia and metabolic alkalosis in the first years of life. The diagnosis of incomplete distal renal tubular acidosis was considered before molecular evaluation. Three additional patients with hypokalemia and hypercalciuria, but without nephrocalcinosis in the first two and with metabolic acidosis instead of alkalosis in the third, were studied. Two demonstrated the same missense mutation A555T in the BSC gene as one patient of the previous group, suggesting a single common ancestor. The third patient presented with severe hypernatremia and hyperchloremia for about 2 months, and a diagnosis of nephrogenic diabetes insipidus was hypothesized until the diagnosis of Bartter syndrome type I was established by molecular evaluation. We conclude that in some patients with Bartter syndrome type I, hypokalemia and/or metabolic alkalosis may be absent in the first years of life and persistent metabolic acidosis or hypernatremia and hyperchloremia may also be present. Molecular evaluation can definitely establish the diagnosis of atypical cases of this complex hereditary tubular disorder, which, in our experience, may exhibit phenotypic variability.

Feeding dysfunction in infants with severe chronic renal failure after long-term nasogastric tube feeding.

Nasogastric tube feeding (NGTF) is frequently necessary to overcome the inadequate caloric intake of children with severe chronic renal failure (CRF). In a multicenter retrospective study, we evaluated feeding dysfunction after tube feeding withdrawal in children with severe CRF who started long-term enteral nutrition early in childhood. We considered, almost exclusively, infants who had started NGTF very early and continued to be tube fed for at least 9 months. Twelve patients were included in the study: 8 showed significant and persistent eating difficulties, with difficulties in chewing and swallowing in 7 and food refusal in 6. For 2 patients "panic attacks" from swallowing were repeatedly reported. These problems persisted for more than year in 5 patients and between 1 and 6 months in 4. The possible feeding difficulties that may follow NTGF must be carefully evaluated. A possible means of overcoming these difficulties might include: encouraging the use of a pacifier, proposing water for spontaneous assumption, leaving the child the possibility of eating food spontaneously during the daytime, and increased support for the parents during weaning. These need prospective study.

Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes.

Clinical or biochemical findings were reevaluated in 34 pediatric patients with primary renal tubular hypokalemic metabolic alkalosis. The patients were subdivided into two groups. Bartter syndrome (primary renal tubular hypokalemic metabolic alkalosis with normocalciuria or hypercalciuria) was diagnosed in 18 patients with molar urinary calcium/creatinine ratios greater than 0.20, and Gitelman syndrome (primary renal tubular hypokalemic metabolic alkalosis with magnesium deficiency and hypocalciuria) was diagnosed in 16 patients with molar urinary calcium/creatinine ratios less than or equal to 0.20 and plasma magnesium levels less than 0.75 mmol/L. Some clinically important differences between the groups were observed. Patients with Bartter syndrome were often born after pregnancies complicated by polyhydramnios (8/18) or premature delivery (7/18) and had short stature (11/18) or polyuria, polydipsia, and a tendency to dehydration (16/18) during infancy (12/18) or before school age (18/18). Patients with Gitelman syndrome had tetanic episodes (12/16) or short stature (3/16) at school age (14/16). We conclude that the Bartter and Gitelman syndromes represent two distinct variants of primary renal tubular hypokalemic metabolic alkalosis and are easily distinguished on the basis of urinary calcium levels.

Severe nephropathy in three adolescents with cystic fibrosis.

Renal involvement has rarely been reported in patients with cystic fibrosis. We describe severe nephropathy with a rapidly fatal outcome in three adolescents with cystic fibrosis, and evaluate the important repercussions that the nephrotic syndrome had on the precarious clinical situation of these patients.

Acute effects of calcitriol and phosphate salts on mineral metabolism in children with hypophosphatemic rickets.

We investigated the acute effects of oral administration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) and phosphate on the major mineral metabolism indexes in six children with vitamin D-resistant rickets treated with a long-term regimen of phosphate and calcitriol. Two acute tests were performed in which plasma calcium, phosphate, immunoreactive parathyroid hormone (iPTH) (intact molecule), 25-hydroxyvitamin D (25-OHD), and 1,25-(OH)2D levels were measured: the first after an oral phosphate load (20 mg/kg) was administered after calcitriol had been discontinued for 10 days, and the second after a calcitriol load (0.03 microgram/kg) plus the same phosphate load but with the children receiving the usual combination treatment. There were no significant differences in basal levels of calcium, phosphate, iPTH, 25-OHD, or 1,25-(OH)2D between the two tests, nor were delta percent calcium and 25-OHD values significantly different. The delta percent plasma phosphate concentration at 60 minutes was significantly higher during test 2 than during test 1 (p less than 0.01) and delta percent iPTH concentration at 60 minutes was significantly higher during test 1 than during test 2 (p less than 0.01). In test 2 the iPTH level returned to baseline at 180 minutes. Higher delta percent 1,25-(OH)2D values at 60 minutes were observed in test 2 than in test 1 (p less than 0.01). Furthermore, the delta percent 1,25-(OH)2D levels were still higher at 180 minutes in test 2 than during test 1 (p less than 0.01). Our study indicates that oral calcitriol has an inhibitory effect on iPTH secretion in the hours immediately after oral phosphate administration in children with vitamin D-resistant rickets.

Sodium excretion and hyperfiltration during glucose infusion in man.

The relations between renal hemodynamics (Inutest, CPAH) and sodium excretion were studied in 7 nondiabetics in whom a similar expansion was induced (1) with a 3-hour 5% glucose infusion and (2) with a 0.9% saline load. With both infusions the body weight increased, hematocrit fell, and the plasma renin activity was suppressed. During glucose infusion, blood glucose rose from 3.9 mmol/l to a plateau of around 13 mmol/l; glycosuria was absent during the 1st h, then appeared and stabilized during the following 2h. Glucose infusion caused a progressive increase in glomerular filtration rate and in renal blood flow in both absence and presence of glycosuria, without significant changes in sodium excretion despite volume expansion and increase of filtered sodium load. When saline was infused, there was a sustained increase of fractional sodium excretion, and no hemodynamic modifications were observed. We suggest that a primary glucose-induced metabolic stimulation of sodium reabsorption may play a role in the genesis of glucose-induced hyperfiltration.

Persistent tubular resistance to aldosterone in infants with congenital hydronephrosis corrected neonatally.

Renal function of 18 infants who had undergone surgery in the neonatal period because of severe congenital hydronephrosis was followed up for 5 to 36 months (mean +/- SD 21 +/- 10 months). In all cases the diagnosis was made prenatally by sonography and confirmed at birth by intravenous urography. Creatinine clearance developed normally in all the children. Eight had a reduction in maximal urinary concentrating ability after intranasal DDAVP; this defect was transient and resolved after 4 to 5 months in all but one child, in whom it persisted. However, other tubular abnormalities were present. Throughout the observation period, patient serum potassium concentrations were significantly higher than normal, paralleled by a significant increase in plasma aldosterone concentration but with normal excretion fraction of sodium and potassium. There were no disturbances of acid-base balance. These findings may be accounted for by a persistent partial reduced sensitivity of the distal tubule to the action of aldosterone despite normal renal function. This alteration is usually mild, but may constitute a persistent metabolic risk despite successful surgical intervention.

Haemolytic uraemic syndrome: therapeutic effect of plasma infusion.

The therapeutic effect of plasma infusion was evaluated in 10 children and seven adults with haemolytic uraemic syndrome. All but one patient responded to this treatment with rapid disappearance of haematological abnormalities. The patient who apparently failed to respond to plasma infusion obtained complete remission of the disease after plasmapheresis. Although 15 of the 17 patients were anuric or oliguric on admission, renal function recovered completely in eight children and two adults. Seven patients showed residual chronic renal failure and two required long-term maintenance haemodialysis. Treatment with plasma was also successful in patients with relapses or recurrent episodes. Plasma infusion is a promising therapeutic approach for the haemolytic uraemic syndrome and deserves further study in clinical trials.

Effect on nephrotic syndrome on absorption and disposition of prednisolone in children.

The pharmacokinetics and bioavailability of prednisolone and prednisone after doses of 60 mg/m2 oral prednisone and 50 mg/m2 intravenous prednisolone were determined in six children receiving corticosteroids for treatment of nephrotic syndrome during active disease and in remission. Pharmacokinetic parameters were compared with values previously obtained from asthmatic children who received similar intravenous doses. In nephrotic children the area under the curve of prednisolone (AUCPn) was higher (by 134 +/- 42%) after oral doses of prednisone when compared to the intravenous prednisolone doses. This indicates that acute nephrotic syndrome does not produce impaired absorption and conversion of prednisone to prednisolone. A larger steady-state volume of distribution (Vss = 3.4 vs. 1.2 l/kg) was observed in active disease than in remission, suggesting greater availability of the steroid to tissues. Apparent prednisolone clearance in both stages of nephrotic syndrome were greater than those obtained in asthmatic children, possibly due to decreased protein binding of prednisolone in nephrotics. The increased tissue distribution and clearance of prednisolone which occur in children with active nephrotic syndrome decreases as their disease improves. The mean renal clearance and urinary excretion of prednisone and prednisolone in nephrotic syndrome are normal and suggest that glomerular leakage of protein bound drug is not significant.

Disposition of pulse dose methylprednisolone in adult and paediatric patients with the nephrotic syndrome.

The disposition of a large pulse-dose of methylprednisolone was examined in paediatric and adult patients with the nephrotic syndrome. Plasma concentrations and urinary excretion rates were measured by high performance liquid chromatography. Most of the dose was metabolized, as indicated by urinary recovery of less than 10 percent of the dose. There was only slight age-dependence of the plasma clearance and volume of distribution of the steroid, although the T1/2 and mean transit time were shorter in younger patients. The pharmacokinetic parameters of the large doses (12-20 mg/kg) were similar to low dose (0.5-1 mg/kg) data from asthmatic patients. The limited variability of the pharmacokinetics of methylprednisolone suggests that tissue sensitivity may be a more important indicator of drug dosage needs in nephrotic syndrome.

[Treatment of inappropriate ADH secretion syndrome with demethylchlortetracycline]. / Traitement du syndrome de sécrétion inappropriée d'hormone antidiurétique par la déméthylchlortetracycline.

A sixteen month girl with inappropriate ADH secretion was treated with demethylchlortetracycline. On a dose of 20 mgs/kg/day the disorder resolved completely. Treatment was continued with a maintenance dose of 15 mgs/kg/day. No side effects were observed.