Early hemodynamic and renal effects of tumor necrosis factor alpha: role of thromboxane.

TNF alpha is an early mediator of endotoxemic shock. Its acute effect on renal hemodynamics is not known. In this study, the early hemodynamic and renal effects of TNF alpha were investigated in a rabbit model of shock, in which the measurement of the aortic blood flow before the bifurcation of the renal arteries allows one to differentiate between prerenal factors and hemodynamic renal response. Six groups of rabbits were studied, receiving either: (1) endotoxin, (2) endotoxin + thromboxane inhibitor Dazmegrel, (3) TNF alpha, (4) TNF alpha + Dazmegrel, (5) TNF alpha+indomethacin, or (6) placebo. Between 60 min and 3 hr after the injection, endotoxin induced a mean fall in arterial pressure of 32% (P < 0.01) and TNF alpha of 16% (P < 0.01). After endotoxin, the aortic blood flow decreased by 27% (P < 0.01) and after TNF alpha by 18% (P < 0.001). Both specific thromboxane inhibition and indomethacin abolished the TNF alpha central hemodynamic effect. The renal blood flow (-53%), the renal fraction of the aortic blood flow (-38%), and the glomerular filtration rate (-47%, P < 0.05) decreased 1 hr after endotoxin injection. In contrast, TNF alpha induced only a slight fall of the renal fraction of the aortic blood flow (-19%) after 2.5 hr. Glomerular filtration was not modified after TNF alpha injection most likely because of a 17% mean increase of filtration fraction in this group (P < 0.001). These data indicate that TNF alpha is implicated in the early hemodynamic changes of endotoxemic shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of magnesium on phosphorus and calcium metabolism.

Magnesium is an element that occurs ubiquitously in nature. Magnesium and calcium metabolism are closely related. The intestinal absorption and the renal excretion of the two ions are interdependent. The relationship between phosphorus and magnesium metabolism is more difficult to demonstrate. The most frequent causes of hypomagnesemia in children are reduced intake, impaired intestinal absorption, renal loss and genetic diseases. Hypomagnesemia is reflected clinically in the nervous system, and there are neurophysiological and metabolic changes. Severe hypomagnesemia induces secondary hypocalcemia in most experimental animals except rats. Furthermore, severe hypomagnesemia induces functional hypoparathyroidism. In vitro studies have demonstrated that magnesium can modulate parathyroid hormone (PTH) secretion in a similar way to calcium. An acute decrease in magnesium concentration stimulates PTH secretion, and an acute increase in concentration decreases secretion. Magnesium is likely to play an important role in vitamin D metabolism. Some patients with hypocalcemia and magnesium deficiency are resistant to pharmacological doses of vitamin D or may have a form of magnesium-dependent vitamin D-resistant rickets. Phosphate depletion has been observed to be accompanied by an increase in urinary magnesium and calcium. In pediatrics the syndrome of phosphate depletion is observed particularly often in premature babies, who often receive a low-P diet. Magnesium is involved in many of the biochemical reactions that take place in the cell, and particularly in processes involving the formation and utilization of ATP. Thus, at the cellular level, magnesium plays a key role in ionic transport processes.

Serum and intracellular magnesium during normal pregnancy and in patients with pre-eclampsia.

OBJECTIVE: To determine the serum and lymphocyte magnesium concentrations during normal pregnancy and to compare the magnesium status in the third trimester of pregnancy between women with normal pregnancy and those with gestational hypertension (GH) or pre-eclampsia (PE). DESIGN: A prospective cross-sectional study followed by a prospective comparative study. SETTING: Department of Obstetrics and Gynecology, Department of Pediatrics and Genetics, Hôpital Cantonal Universitaire Genève, Switzerland. SUBJECTS: Seventy-one healthy pregnant women, with normal pregnancies between 6 and 38 weeks gestation. The second part included 43 women in the third trimester of pregnancy, 11 had GH, 11 had PE and 21 formed the comparison group of healthy normotensive women. MAIN OUTCOME MEASURES: Total serum and intralymphocytic Mg concentrations and urinary Mg excretion. RESULTS: There was a progressive reduction in total serum magnesium concentrations during normal pregnancy, thought to be partly due to haemodilution, because the decline in concentration of serum proteins paralleled that of Mg (P less than 0.001). In the three groups studied in the third trimester the serum Mg concentration was very similar in the GH and the comparison groups, but it was significantly higher in the PE group (P less than 0.01). The intralymphocytic Mg concentrations and the urinary Mg excretion were similar in all three groups. In five patients treated with MgSO4 there was a large increase in the serum Mg concentration and in the urinary Mg excretion. The intralymphocytic Mg concentration remained remarkably stable. CONCLUSIONS: Our data does not support the conclusion that Mg deficiency is the primary cause of pre-eclampsia.

Atrial natriuretic factor after heart operations in children. Relation to hemodynamic and renal parameters.

The purpose of this study was to measure changes in serum atrial natriuretic factor concentrations immediately after heart operations in children under baseline conditions and in response to continuous infusion of dopamine (2.5 and 5.0 micrograms/kg/min). During control periods, levels of atrial natriuretic factor were elevated at 190 +/- 24 and 199 +/- 36 pg/ml. The cardiac index was 2.6 L/min/m2 and the renal plasma flow was decreased to 269 +/- 41 ml/min/1.73 m2, indicating a state of renal vasoconstriction (mean renal fraction of cardiac index of 10.0% +/- 1.0%). The mean sodium fractional reabsorption was 99.0% +/- 0.2%. During dopamine infusion, atrial natriuretic factor concentrations increased to 259 +/- 57 pg/ml and to 280 +/- 56 pg/ml, with dopamine 2.5 and 5.0 micrograms/kg/min, respectively (p = not significant), whereas left atrial pressure decreased from 11.7 +/- 0.9 mm Hg during the control period to 10.1 +/- 0.9 and to 9.9 +/- 1.0 mm Hg (p less than 0.05). No correlation was found between changes in left atrial pressure and atrial natriuretic factor levels. Dopamine at 5 micrograms/kg/min increased the cardiac index to 3.0 +/- 0.2 L/min/m2 (p less than 0.001) and the renal plasma flow to 406 +/- 61 ml/min 1.73 m2 (p less than 0.001), alleviating the renal vasoconstriction. The mean urinary sodium excretion increased to 0.33 +/- 0.08 mmol/kg/hr (p less than 0.01). The atrial natriuretic factor plasma concentrations were not related to the urinary sodium excretion, renal plasma flow, or glomerular filtration rate during the control period or during dopamine treatment. These data indicate that after heart operations in children, low urinary sodium excretion occurs despite high circulating atrial natriuretic factor levels. Atrial natriuretic factor concentrations were related neither to left atrial pressures nor to the renal changes induced by dopamine.

Pyridoxine-dependent seizures, clinical and therapeutic aspects.

Pyridoxine-dependency is a rare autosomal recessive disorder causing a severe seizure disorder of prenatal or neonatal onset, psychomotor retardation and death in untreated patients. Treatment requires life-long supplementation with pyridoxine (vitamin B6). The underlying defect is unknown, and there is no biological marker for the disease. Clinical diagnosis is often delayed and severe neurological sequelae are common. This article summarizes both clinical and therapeutic aspects.

Anti-liver-kidney microsome antibody-positive autoimmune hepatitis associated with alopecia.

A 14-year-old girl presented with anti-liver-kidney microsome autoimmune hepatitis preceded by alopecia 3 years earlier. Both pathologies were greatly improved by immunosuppressive therapy. Alopecia is a newly reported extrahepatic manifestation of type 2 autoimmune hepatitis. Its appearance could alert the clinician to an increased risk of autoimmune hepatitis in children.

Serum tumour necrosis factor in newborns at risk for infections.

Tumour necrosis factor-alpha (TNF-alpha) is an important mediator in the pathogenesis of Gram-negative shock. In order to assess the role of TNF-alpha as a marker of the severity of infections in the neonates, serum TNF-alpha concentrations were determined at the time of septic work-up in 69 newborns (gestational age: 28-40 weeks). Nine patients had systemic infection (group A), four of them with signs of circulatory failure. Eleven patients had positive cultures of gastric aspiration or placental smears (group B) and 49 patients had completely negative septic work-up. Patients of group A had significantly more elevated serum TNF-alpha levels than patients of group B and C. Within group A, patients with circulatory failure had mean serum TNF-alpha concentration of 2165 +/- 817 pg/ml versus 27 +/- 8 pg/ml in newborns without shock. Serum TNF-alpha concentrations of more than 15 pg/ml detected systemic infections in eight out of nine patients. The specificity was 98% (1 elevated TNF-alpha concentration out of 60 non infected patients). These data indicate that premature neonates and term newborns are able to produce TNF-alpha when they are infected. Highly elevated TNF-alpha concentrations are found in severe systemic infections causing cardiovascular impairment.

Chronic renal magnesium loss, hypocalciuria and mild hypokalaemic metabolic alkalosis after cisplatin.

Renotubular handling of sodium, potassium (K) calcium (Ca), phosphate, hydrogen ions and glucose, and urinary concentrating ability were studied in three children (aged 8, 8.5, 11 years) with renal magnesium (Mg) loss, persisting for more than 2 years after discontinuation of cisplatin treatment for neuroblastoma. A group of healthy children served as controls. Besides renal Mg wasting, a clear-cut tendency towards reduced calciuria associated with normal or slightly elevated plasma Ca was observed. Plasma K tended to be low (3.4-3.7 mmol/l), and plasma chloride was normal. Plasma bicarbonate (HCO3) ranged from 24.9 to 27.8 mmol/l, and urinary pH was always less than 6.0, indicating a renal HCO3 threshold exceeding 24 mmol/l. Plasma creatinine levels, glucosuria and phosphaturia, and urinary concentrating capacity were adequate. Comparable features were found in three children (aged 4.5, 9, 13 years) with primary renotubular hypomagnesaemia-hypokalaemia and hypocalciuria. This study complements the picture of chronic cisplatin tubulopathy in childhood demonstrating that, apart from Mg wasting, a reduced Ca excretion, and a tendency to hypokalaemia and metabolic alkalosis exist. Thus cisplatin may induce renal functional damage identical to that found in primary renotubular hypomagnesaemia--hypokalaemia with hypocalciuria.

Atrial natriuretic factor in patients with congenital heart disease: correlation with hemodynamic variables.

To investigate the alpha-atrial natriuretic factor in congenital cardiac malformations, three groups of children, aged 7 months to 16 years, with different hemodynamic situations were studied during routine cardiac catheterization. Twenty-one (group I) had tetralogy of Fallot, 24 (group II) had a left to right shunt with pulmonary hypertension and 12 (control group) had a minor cardiac lesion. Alpha-atrial natriuretic factor levels were determined by a radioimmunoassay on blood samples from the inferior vena cava, right atrium, pulmonary artery, left atrium and aorta. To evaluate the effect of an acute volume load, measurements of hormone and pressures were repeated after right ventriculography. Alpha-atrial natriuretic factor levels varied over a wide range in all groups and in all chambers investigated. Nevertheless, children with pulmonary hypertension had significantly higher levels of the hormone (p less than 0.01) and were well separated from the control group, but less well from those with tetralogy of Fallot. A 50% increase of alpha-atrial natriuretic factor from the inferior vena cava to the right atrium occurred in patients with shunt lesions with pulmonary hypertension and in patients with tetralogy of Fallot (p less than 0.001) and a further 30% increase from the right atrium to the pulmonary artery (p less than 0.05). After right ventriculography, a 100% to 200% increase of alpha-atrial natriuretic factor was observed in the total sample (p less than 0.001). A positive correlation was observed between right atrial mean pressure and right atrial alpha-atrial natriuretic factor (r = 0.63) and between pulmonary artery mean pressure and pulmonary artery alpha-atrial natriuretic factor (r = 0.61).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of low dose dopamine on hemodynamic and renal function in children.

The purpose of the study was to investigate the effect of low doses of dopamine in children. Fourteen cases were studied after open heart surgery. Cardiac output and renal parameters were determined under baseline conditions and under continuous infusion of dopamine 2.5 and 5 micrograms/kg/min. During the control period cardiac index was 2.62 +/- 0.19 L/min/m2, renal plasma flow was decreased at 269 +/- 41 mL/min/1.73 m2, GFR was 86.6 +/- 9.2 mL/min/1.73 m2, and filtration fraction was elevated at 37.1 +/- 1.9%. Plasma concentration of aldosterone correlated with the filtration fraction. At 5 micrograms/kg/min dopamine increased significantly cardiac output, renal plasma flow, and to a lesser extent GFR, thus decreasing the filtration fraction. At 2.5 micrograms/kg/min dopamine, increased renal plasma flow only in patients older than 5 y and had no effect on the other parameters. The increase of cardiac output in response to dopamine was abolished by propranolol pretreatment. By contrast, the hemodynamic renal response to dopamine was not altered by beta-blockade. These results indicate that 5 micrograms/kg/min of dopamine could prevent renal failure after open heart surgery in children by increasing renal blood flow and attenuating renal compensatory mechanisms.

[Osteogenesis imperfecta and localized involvement of the spine: a peculiar form? Apropos of a familial case]. / Osteogenesis imperfecta et atteinte localisée au rachis: forme particulière? A propos de l'observation d'une famille.

The authors report a particular type of Osteogenesis Imperfecta (O.I.), where the symptoms of bony fragility affected only the spine in three members of the same family, a father and his two daughters. This type of O.I. represents a type IA variety according to the classification of D. Silence. The authors while underlining the wide variety of this condition think that it is very likely that non recognition of the condition is in part due to the mild symptoms attributable to this lesion in the spine. This diagnosis has to be considered for all symptomatic osteoporosis of the vertebrae in children and adults. After eliminating other osteopenic conditions, diagnosis may be established on the basis of clinical signs and family history. Although this condition is related to a collagen metabolism deficiency particularly in type I, for the present condition there was no specific biochemical test available.

Metabolic studies in primary tubular hypomagnesaemia-hypokalaemia.

13 1/2 year old boy with short stature and pubertal delay had infrequent episodes of tetany. Biochemical determinations demonstrated low plasma and high urinary magnesium and potassium levels, hypocalciuria, slightly increased plasma bicarbonate, slightly reduced fractional distal reabsorption of chloride and sodium, high plasma renin activity and high urinary excretion of prostaglandins (E2, F2 alpha). The other parameters of renal functions were normal. Endocrine evaluation of short stature and pubertal delay was normal. Intracellular magnesium and potassium levels in lymphocytes and erythrocytes were within normal limits. Cyclooxygenase blockade with Indomethacin 2.5 mg/kg daily during 4 weeks normalized urinary excretion of prostaglandins and corrected in part low plasma and high urinary potassium levels, but had no effect on magnesium, calcium, sodium and chloride handling. These data raise the possibility that tubular hypomagnesaemia-hypokalaemia could be solely explained by a low renal threshold for magnesium.

Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721.

In chronic renal failure (CRF), secondary hyperparathyroidism (sHPT) plays a major role in skeletal lesions and also probably in the deterioration of renal functions consecutive to nephrocalcinosis. In this study we tested whether WR-2721 [S-,2-(3-aminopropylamino)-ethylphosphorothioic acid], an inhibitor of parathyroid hormone (PTH) secretion, could prevent the deleterious effects of sHPT at both the bone and kidney level in an animal model of CRF. Rats were either subtotally nephrectomized (NX) or sham-operated (SHAM). They were then pairfed a high phosphorus (1.4%), middle Ca (0.6%) diet. This regimen accelerated the deterioration of renal function in NX rats which displayed signs of severe sHPT in bone (three- to fourfold increase in osteoclast number and resorption surfaces) and kidney (sixfold increase in Ca content) after four weeks. Chronic administration of WR-2721 (20 mg = 0.093 mmol/kg s.c. twice daily) during four weeks completely prevented the progressive elevation of both plasma urea and inorganic phosphate, and the fall of plasma Ca. It also prevented kidney Ca accumulation to the same extent as parathyroidectomy. However, WR-2721 given at this dose only partially prevented the histomorphometric indices of increased bone resorption and formation. This discrepant response suggests that WR-2721 could exert an additional protective effect at the kidney level that might be related to its property of acting as a free radical scavenger. In conclusion, this study suggests that WR-2721 might be a useful compound in CRF, not only because it inhibits PTH secretion, but also because it could protect against the deleterious effect of secondary hyperparathyroidism on kidney functions.

Interference of WR-2721 with magnesium metabolism: mechanism of action.

Recently, a radio-, and chemoprotective drug, WR-2721 (S-2-[3-aminopropylamino]-,ethylphosphorothioic acid) proved to be a potent inhibitor of parathyroid hormone (PTH) secretion. In human subjects, it not only decreased plasma Ca, but also induced a significant fall in the plasma magnesium level. In the present study in rats we investigated the mechanism(s) of this hypomagnesemic effect. In intact rats WR-2721 (0.7 mmol/kg s.c.) decreased plasma Mg from 0.96 +/- 0.03 to 0.67 +/- 0.02 mmol/l (p less than 0.001) within 2 h. In thyroparathyroidectomized (TPTX) animals plasma Mg fell from 0.93 +/- 0.03 to 0.72 +/- 0.03 mmol/l (p less than 0.001) 2 h after the same dose of WR-2721. In both intact and TPTX animals renal clearance experiments revealed that the WR-2721-induced hypomagnesemia was associated with an increase in urinary Mg excretion. This renal effect was not accompanied by a significant elevation in urinary sodium excretion, contrasting strikingly with the magnesuric action of furosemide. In bilaterally nephrectomized rats the hypomagnesemic effect of WR-2721 was abolished. Finally, the intracellular and/or tissue Mg contents of circulating lymphocytes, red blood cells, skeletal muscle, liver, bone and salivary glands were not significantly influenced by hypomagnesemic doses of WR-2721. In conclusion, these results indicate that the effects of WR-2721 on Mg metabolism cannot be ascribed to alterations in PTH and calcitonin secretion. Furthermore, they strongly suggest that the WR-2721-induced hypomagnesemia is mainly due to an inhibition of tubular Mg reabsorption.

"High-dose" calcitriol for control of renal osteodystrophy in children on CAPD.

High doses of calcitriol were used prospectively for 11 to 29 months to raise serum calcium levels in an effort to control renal osteodystrophy in 16 children undergoing CAPD. Serum Ca, P, iPTH and alkaline phosphatase were measured monthly; hand radiographs were obtained every six months, and a semiquantitative score of bone abnormalities was evaluated by two independent observers. During the study, serum Ca increased from 9.9 +/- 0.9 to 11.0 +/- 0.6 mg/dl (P less than 0.001); serum iPTH decreased by 113 +/- 131 microliter Eq/ml (P less than 0.005); serum P was unchanged; and serum alkaline phosphatase fell by 33 +/- 46% (P less than 0.02), 530 +/- 397 to 204 +/- 551 IU/liter. The radiographic score fell from 4.8 +/- 4.6 to 0.9 +/- 1.2 (P less than 0.005). The average and maximal doses of calcitriol were 0.61 +/- 0.37 and 0.95 +/- 0.56 microgram/day or 28 +/- 18 and 46 +/- 28 ng/kg body wt/day, respectively. Transient and asymptomatic hypercalcemia occurred in nine patients and two patients had reversible conjunctivitis in association with the hypercalcemia. Thus, "high dose" calcitriol prevented or controlled progression of hyperparathyroid bone disease in most pediatric CAPD patients. The failure to suppress PTH or reverse secondary hyperparathyroidism until the serum Ca rose to 10.5 to 11.0 mg/dl could reflect an increase in the "set point" for PTH suppression by serum calcium in many uremic children.

Transient hyperphosphatasemia of infancy.

Six patients with transient hyperphosphatasemia of infancy (THI) are described and compared to similar cases reported in the literature. THI appears to be more common than usually thought and may occur in healthy children as well as in patients with various clinical disorders. The evolution of such children seems uniformly normal. Invasive diagnostic procedures should therefore be avoided in this benign condition.

Familial Bartter's syndrome: report of a case with early manifestations and persistent hypercalciuria.

A case of familial Bartter's syndrome is reported. The child had early and severe clinical and biochemical manifestations. Indomethacin treatment effectively controlled the increased prostaglandin excretion but corrected only partially the potassium and the calcium losses. The child developed during treatment high serum calcium levels which were associated with high parathyroid hormone and calcitriol serum levels.

Failure of dehydroepiandrosterone enanthate to promote growth.

Adrenal androgens may promote pubertal growth. To assess this possibility, we administered dehydroepiandrosterone (DHEA) enanthate in monthly im injections in a dose of 70 mg/m2 for 1 yr to five boys with constitutional short stature (aged 11-13 4/12 yr) and one boy (aged 13 4/12 yr) with panhypopituitarism (coincidentally receiving T4 and human GH). All had bone age delay of at least 3 yr and subnormal levels of DHEA and DHEA sulfate (DHEA-S) for their chronological age. Pretreatment growth velocity ranged from 3-5 cm/yr. After DHEA enanthate injection, plasma DHEA levels were increased 10-fold after 8 days, 2.6-fold after 15 days, and 1.8-fold after 22 days. At the same times, plasma DHEA-S concentrations were 14-, 6-, and 4-fold increased, respectively. There was no rise in plasma testosterone and delta 4-androstenedione, which remained at prepubertal levels. During the year of therapy and for 1 yr after therapy, there was no significant change in growth velocity, and the rate of skeletal maturation assessed by x-ray was not affected. Three of the five boys with constitutional short stature entered puberty within 1 yr after discontinuation of therapy. These results demonstrate that this long-acting form of DHEA administered for 1 yr did not raise plasma testosterone above prepubertal levels and did not accelerate either growth or skeletal maturation. These findings do not support the possibility that DHEA plays a role in normal growth.

Relationship between magnesium, potassium and sodium concentrations in lymphocytes and erythrocytes from normal subjects.

Mg, K and Na were measured in erythrocytes, lymphocytes and serum obtained from 20 normal subjects. The cells of 20 ml of blood were separated in Ficoll gradient, washed with a choline buffer and digested with H2SO4. The cations were measured by atomic absorption photometry, protein was determined by the Lowry method and the results were expressed as nmol/mg of protein. Intracellular lymphocyte concentrations (mean +/- SD, n = 20) were: Mg: 57.6 +/- 5.1, Na: 30.0 +/- 7.9, K: 614.3 +/- 69. In the red cells, ion concentrations were: Mg: 7.97 +/- 0.8, Na: 20.9 +/- 4.8, K: 343.0 +/- 42.0. There was a highly significant correlation between Mg and K concentration in erythrocytes (p less than 0.001) and lymphocytes (p less than 0.001). A negative correlation (p less than 0.05) was also found between lymphocyte and erythrocyte K concentration and K serum concentration.