The influence of hyperparathyroidism on glucose metabolism in uremia.

We studied glucose metabolism in a group of adolescents and young adults with uremia using the hyperglycemic clamp technique. In eight adolescent patients, the glucose metabolic rate correlated negatively with PTH levels and positively with the glomerular filtration rate. Six patients, one adolescent and five adults on regular hemodialysis with severe hyperparathyroidism, had low glucose metabolic rates and reduced insulin sensitivity compared to normal subjects. After parathyroidectomy, the glucose metabolic rate improved by 47%; plasma insulin concentrations during hyperglycemia increased by 37%, and insulin sensitivity did not change significantly. Thus, correction of hyperparathyroidism was associated with normalization of glucose metabolic rates and increased insulin secretion, but insulin resistance did not change.

Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.

Of 104 patients with idiopathic mesangiocapillary glomerulonephritis studied for at least two years, 69 patients had type I disease and 35 had type II. Forty-five patients were children, and 59 were adults. Type II mesangiocapillary glomerulonephritis was more common in children than in adults, but no other clinical feature distinguished the two types at onset. Complement studies revealed that patients with type II had lower serum C3 concentrations and more frequently showed C3-splitting activity (C3 nephritic factor) in the serum. Children had hypertension or a lowered glomerular filtration rate less frequently at onset than did adults, but children had a higher incidence of a hematuric onset; C3 nephritic factor was also more frequent in the children. During a follow-up period of two to 21 years (mean eight years), only seven patients (five with type I and two with type II) showed clinical remission, whereas 38 percent of patients with type I and 49 percent of patients with type II died or required dialysis; a further 23 percent of patients with type I and 16 percent of patients with type II had continuing disease and reduced glomerular filtration rate. Only the presence and persistence of a nephrotic syndrome in type I predicted renal failure. In both types, the presence of sclerosis or crescents in the initial renal biopsy specimen was associated with a poorer prognosis, but no other feature was of major prognostic value.

A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine.

Based on statistical analysis of data in 186 children, a formula was derived which allows accurate estimation of glomerular filtration rate (GFR) from plasma creatinine and body lenght (GFR(ml/min/1.73 sq m) = 0.55 length (cm)/Per (mg/dl). Its application to clearance data in a separate group of 223 children reveals excellent agreement with GFR estimated by the Ccr (r = .935) or Cin (r = .905). This formula should be useful for adjusting dosages of drugs excreted by the kidney and detecting significant changes in renal function.

von Willebrand factor-cleaving protease in childhood diarrhoea-associated haemolytic uraemic syndrome.

A deficiency of von Willebrand factor (vWF)-cleaving protease, either due to a congenital deficiency or to the presence of a protease inhibitor of vWF-cleaving protease has been associated with thrombotic thrombocytopenic purpura (TTP). We have studied vWF-cleaving protease in diarrhoea-associated haemolytic uraemic syndrome (D+ HUS), which shares clinical features with TTP. 29 children with acute D+ HUS and 13 control children were studied. vWF-cleaving protease activity was normal (range 50-150%) in 39 of 42 plasma samples. Levels of protease activity between 25 and 50% were noted in plasma from two D+ HUS patients. One D+HUS patient, who had clinical features of TTP, had a vWF-cleaving protease inhibitor producing a severe deficiency of vWF-cleaving protease. Thus a deficiency of vWF-cleaving protease appears to be atypical in D+HUS. The detection of a vWF-cleaving protease inhibitor in one patient suggests it may be associated with infection such as E. coli O157.

Activation of coagulation and fibrinolysis in childhood diarrhoea-associated haemolytic uraemic syndrome.

Diarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin producing Eschericia coli. We hypothesized that verotoxin binding to glomerular endothelial cells causes localised endothelial cell activation and thus activation of coagulation and reduction of fibrinolytic potential. We also proposed that treatment with fresh frozen plasma or dialysis would not affect these changes. Markers of activation of coagulation and fibrinolysis were measured in 30 children with acute D+ HUS serially, in healthy children and in children on dialysis. In acute D+ HUS, levels of thrombin-antithrombin III complex and prothrombin fragment 1+2 were significantly increased (p <0.001). The source of thrombin generation was unclear. Factor XIIa levels were increased in patients and controls with renal failure. Factor VIIa levels were not significantly raised in children with acute D+ HUS. D-dimers were increased, but fibrinolytic potential as measured by fibrin plate was reduced. Levels of plasminogen activator inhibitor antigen and activity and tissue plasminogen activator antigen were increased. Neither peritoneal dialysis nor administration of blood products, the most common treatments, altered parameters of coagulation or fibrinolysis.

Glucose intolerance in children with chronic renal failure.

Carbohydrate metabolism was studied by the hyperglycemic clamp technique in 14 children with moderate to severe chronic renal failure (CRF) (8 pubertal and 6 prepubertal) and was compared with 5 healthy prepubertal children and 7 healthy young adults. Constant hyperglycemia was maintained for 120 min. Under these conditions, the average glucose infusion rate (M) is an index of glucose metabolic rate, the average insulin response (I) is an index of beta cell responsiveness to hyperglycemia, and the M/I ratio is an index of insulin sensitivity. Children with CRF were glucose intolerant (lower M), hyperinsulinemic (higher I), and insulin resistant (lower M/I) compared with the control children. An age-related difference in glucose tolerance and insulin sensitivity was noted. Pubertal children with CRF had lower M and lower M/I compared with prepubertal children with CRF. The 7 adult controls also had lower M and lower M/I compared with the 5 children controls. M and M/I correlated with glomerular filtration rate (GFR) in the 8 pubertal children, while M/I also correlated with GFR in the 6 prepubertal children with CRF. The hyperglycemic clamp provides a useful tool in studying the pathogenesis of carbohydrate disturbances in children with CRF.

Secondary hyperparathyroidism and glucose intolerance in children with uremia.

Glucose metabolism was studied using the glucose clamp technique in 8 children with CRF (4 pubertal and 4 prepubertal) before and after correction of secondary hyperparathyroidism (HPD) by a regime of phosphate binders and dietary phosphate restriction. Glucose metabolic rate (M) increased by 34%, insulin response (I) increased by 32%, and insulin sensitivity (M/I) did not change. Compared to corresponding normal values, these patients were glucose-intolerant (low M) before treatment and became glucose-tolerant after treatment (normal M). They were insulin-resistant (low M/I) before treatment and remained so after treatment. The 5 uremic children without secondary HPD were treated with the same regime to prevent the secondary HPD. Their M, I, and M/I did not change after treatment. The change in I correlated closely with the change in M in all 13 patients. One pubertal patient with uremia was studied on three occasions. Initially, without secondary HPD, he had a normal M and a low M/I. When he developed secondary HPD, M decreased by 39%, I decreased by 37%, and M/I did not change. Treatment of his secondary HPD restored M and I values back to initial levels, and M/I again did not change. Treatment of secondary HPD by correction of phosphate retention led to an improvement of glucose intolerance with an increase in insulin secretion.

Effect of salt supplementation of newborn premature infants on neurodevelopmental outcome at 10-13 years of age.

BACKGROUND: The nutritional requirements of prematurely born infants are different from those of babies born at term. Inadequate or inappropriate dietary intake in the neonatal period may have long term adverse consequences on neurodevelopmental function. The late effect of neonatal sodium deficiency or repletion in the premature human infant on neurological development and function has not been examined, despite evidence in animals of a serious adverse effect of salt deprivation on growth of the central nervous system. METHODS: Thirty seven of 46 children who had been born prematurely (gestational age of 33 weeks or less) and allocated to diets containing 1-1.5 mmol sodium/day (unsupplemented) or 4-5 mmol sodium/day (supplemented) from the 4th to the 14th postnatal day were recalled at the age of 10-13 years. Detailed studies of neurodevelopmental performance were made, including motor function and assessment of intelligence (IQ), memory and learning, language and executive skills, and behaviour. Sixteen of the children were found to have been in the supplemented group and 21 in the unsupplemented group. RESULTS: Children who had been in the supplemented group performed better in all modalities tested than those from the unsupplemented group. The differences were statistically significant (analysis of variance) for motor function, performance IQ, the general memory index, and behaviour as assessed by the children's parents. The supplemented children outperformed the unsupplemented controls by 10% in all three components of the memory and learning tests (difference not significant but p < 0.1 for each) and in language function (p < 0.05 for object naming) and educational attainment (p < 0.05 for arithmetic age). CONCLUSION: Infants born at or before 33 weeks gestation require a higher sodium intake in the first two weeks of postnatal life than those born at or near term, and failure to provide such an intake (4-5 mmol/day) may predispose to poor neurodevelopmental outcome in the second decade of life.

Quantitative microfocal radiography of children with renal osteodystrophy; comparison with laboratory and histological findings.

High definition microfocal radiography permitted the quantitative assessment of the radiographic features of renal osteodystrophy in the phalanges of 11 children in stable chronic renal failure, treated with phosphate binders for 1 year. The most consistent feature was subperiosteal cortical resorption, expressed as a ratio total length of resorbed subperiosteal bone/total length subperiosteal bone x 100. It was found that the extent of resorbed bone was significantly greater in the middle phalanx and on the ulnar surface of the phalanges. The radiological findings over the duration of the disease were compared with laboratory assessments and bone histomorphometry. The extent of the percentage of subperiosteal resorption at base line and its change during the study period correlated significantly with the level of serum parathyroid hormone levels and its change over the same period. No other significant correlations were found between radiographic features and laboratory assessments or with bone histomorphometry.

The influence of sodium on growth in infancy.

Sodium (Na) is an important growth factor, stimulating cell proliferation and protein synthesis and increasing cell mass. Sodium chloride (NaCl) deprivation inhibits growth, as reflected by reduced body and brain weight, length, muscle and brain protein and RNA content and brain lipid content compared with controls. This is not due to deficiency of other nutrients since control and experimental diets were identical except for NaCl content. Subsequent NaCl supplementation restores growth velocity to control values but does not induce "catch-up" growth. In humans, salt loss causes growth failure and subsequent salt repletion improves growth. Preterm infants < 32 weeks' gestation at birth are renal salt losers in the first 2 weeks of post-natal life and are vulnerable to hyponatraemia. This can be prevented by increasing Na intake, which also produces accelerated weight gain that persists beyond the period of supplementation. Early nutrition in preterm infants can affect subsequent growth and also cognitive function: this is probably multifactorial, but NaCl intake differed substantially between study groups and is likely to be an important factor. The mechanism whereby Na promotes cell growth is not understood, but stimulation of the membrane Na+,H(+)-antiporter with alkalinization of the cell interior is a likely possibility.

A practical approach to evaluating urinary tract infection in children.

All children with urinary tract infections should be investigated by either excretory urography or abdominal X-ray, ultrasonography and technetium 99m - dimercaptosuccinic acid scintigraphy. Patients in the following categories should also have micturating (voiding) cystourethrography to diagnose or exclude vesico-ureteral reflux: infants aged less than 1 year, children with recurrent (second or subsequent) infections, children with clinically diagnosed acute pyelonephritis and those with a family history of reflux or chronic pyelonephritis. Cystography can safely be omitted in children over 1 year of age with unscarred kidneys and none of the additional risk factors listed. They should be followed for 1-2 years following the first infection for evidence of recurrence.

The syndrome of inappropriate secretion of antidiuretic hormone.

The physiology of the release of antidiuretic hormone (ADH) from the posterior pituitary is briefly reviewed. The importance of both osmolar and non-osmolar stimuli is emphasised. Osmolar and non-osmolar factors usually reinforce each other; for example, hydropenia leads to hyperosmolality and hypovolaemia, both promoting ADH release, while hydration has the opposite effect. In disease, osmolar and non-osmolar factors may become dissociated leading to baroreceptor-mediated ADH release in the presence of hyponatraemia and hypo-osmolality. Examples include heart failure, glucocorticoid or thyroxine deficiency, hepatic cirrhosis and nephrotic syndrome with or without the superimposed effect of diuretics, i.e. conditions in which circulatory, and in particular effective arterial, volume is reduced. It is dangerous to label such conditions as 'inappropriate' secretion of ADH since the maintenance of circulating volume is at least as important a physiological requirement as the defence of tonicity. The syndrome of inappropriate secretion of ADH (SIADH) is uncommon in childhood and should only be diagnosed when physiological release of ADH in response to non-osmolar as well as osmolar factors has been excluded. Criteria for the correct identification of SIADH are discussed; the presence of continuing urinary sodium excretion in the presence of hyponatraemia and hypo-osmolality is essential to the diagnosis. SIADH in children is usually due to intracranial disease or injury. The mainstay of treatment is water restriction which reverses all the physiological abnormalities of the condition. Hypertonic saline is rarely indicated for the short-term control of neurological manifestations such as seizures. Drugs have little or no place in the treatment of SIADH in children.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension associated with unilateral renal disease in childhood. Report of two cases and review of the literature.

Two girls are described, aged 7 and 10 years respectively, who presented with arterial hypertension associated with unilateral kidney disease. Both were cured by nephrectomy, according to criteria for cure which are described in the paper. Only 45 similar cases could be found in the literature; these results are summarized and compared with those obtained in adult patients. The cure rate in children was 76%; similar large series including patients of all ages, but consisting predominantly of adults, show cure rates of only about 25%. It is inferred that the age of the patient is an important factor in determining prognosis, and should be considered in the selection of patients for nephrectomy. Methods of investigation of these patients, and possible mechanisms concerned in the pathogenesis of the hypertension, are briefly discussed.

The treatment of glomerulonephritis in children.

The results of treatment of glomerulonephritis (GN) in childhood with oral corticosteroids, immunosuppressive drugs, anticoagulants and the newer regimens of pulsed, high-dose intravenous methylprednisolone and plasma exchange are reviewed and compared with the natural history of the untreated condition. Poststreptococcal GN and the nephritis of Schönlein-Henoch purpura need no specific treatment unless extensive glomerular crescents are present. The progression of mesangiocapillary GN can probably be slowed or even reversed with long-term, alternate-day steroid therapy. As in adults, recovery of renal function in GN due to antibody to glomerular basement membrane can be achieved in some patients using plasma exchange, but only those in whom some renal function is still present when treatment is started. In rapidly progressive (extracapillary) GN with crescents, "traditional" therapy with oral steroids, immunosuppressive drugs and anticoagulants reduces renal mortality from 85%-90% to about 50%, while pulsed methylprednisolone and plasma exchange improve the outcome further, mortality falling to about 25%. It is recommended that children with crescentic GN and deteriorating function be treated initially with pulsed methylprednisolone, followed by plasma exchange in those who fail to respond or who deteriorate following temporary response to pulse therapy. Treatment must be given early in the course of the illness if good results are to be obtained.

Salt and the newborn kidney.

Renal function differs in term infants from that in adults, with lower glomerular filtration rate (GFR) and reduced proximal tubular reabsorption of sodium (Na) and water: nevertheless, it is adequate for their needs. This is not true of very preterm infants in whom hyponatraemia is common. Animal studies have shown that Na+, K(+)-ATPase and the Na+/K+ exchanger are poorly expressed at birth with rapid postnatal rises. Cell receptors for hormones that influence tubular Na transport are less numerous in the premature infant than later in life: intracellular second messenger systems may also be immature. The low GFR is due to vasoconstriction and may be necessary to prevent water and electrolyte wasting due to tubular overload. The hyponatraemia of prematurity could, in principle, be due either to Na loss or water excess and can be prevented either by giving additional Na or by restricting water intake. Na supplementation causes relative volume expansion (VE), water restriction volume contraction (VC); this is demonstrated by the effect of the two approaches on weight gain and on the levels of vasoactive hormones in the blood. We argue that moderate VE is more physiological than VC, both in attempting to simulate intrauterine conditions and in consideration of the infant's nutritional needs. The much less common complication of hypernatraemia is usually due to abnormal water loss and should be prevented by increasing water intake appropriately. The above applies to well, preterm babies: sick preterm infants are much more variable in their Na and water requirements than well infants of comparable gestation and weight and each needs an individually tailored regimen based on frequent clinical assessment and laboratory measurement.