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.

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.

Markers of endothelial cell activation and injury in childhood haemolytic uraemic syndrome.

Diarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin-producing Escherichia coli. Histology shows endothelial swelling with localised thrombus. Activation of coagulation and fibrinolysis also occurs. These facts, combined with the knowledge that recovery usually follows within weeks, led us to hypothesise that verotoxin causes localised endothelial cell activation but not injury. Markers of endothelial cell activation and injury were measured serially in 30 children with acute D+ HUS, healthy children, and children receiving chronic dialysis. Interpretation of markers was complicated by the renal dysfunction characteristic of D+ HUS. Nevertheless there was no evidence for endothelial cell injury, as soluble tissue factor levels were not increased and soluble thrombomodulin levels were lower than dialysed controls (P<0.001). In the acute phase, soluble vascular cell adhesion molecule levels were raised above normal (P<0.001), but were lower than dialysed controls (P<0.001), and soluble E-selectin levels were not significantly increased compared with normal controls (P=0.2). Hence, there was no evidence for endothelial cell damage or endothelial cell activation by the time children reached hospital; but this study did not exclude the possibility that endothelial cell activation occurred prior to hospital admission.

Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children.

We studied 34 apparently healthy children and 2 propositi from kindreds with familial juvenile hyperuricaemic nephropathy (FJHN) - a disorder characterised by early onset, hyperuricaemia, gout, familial renal disease and a similarly low urate clearance relative to glomerular filtration rate (GFR) [fractional excretion of uric acid (FEur) 5.1+/-1.6%] in young men and women. In addition to the propositi, 17 asymptomatic children were hyperuricaemic -- mean plasma urate (368+/-30 micromol/l), twice that of controls (154+/-41 micromol/l). Eight of them had a normal GFR ( > 80 ml/min per 1.73 m2), and 11 renal dysfunction, which was severe in 5. The FEur in the 14 hyperuricaemic children with a GFR > 50 ml/min was 5.0+/-0.5% and in the 5 with a GFR < or =50 ml/min was still low (11.5+/-0.2%) compared with controls (18.4+/-5.1%). The 17 normouricaemic children (185+/-37 micromol/l) had a normal GFR (>80 ml/min) and FEur (14.0+/-5.3%). The results highlight the dominant inheritance, absence of the usual child/adult difference in FEur in FJHN and presence of hyperuricaemia without renal disease in 42% of affected children, but not vice versa. Since early allopurinol treatment may retard progression to end-stage renal failure, screening of all relatives in FJHN kindreds is essential.

Low molecular weight protein excretion in glomerular disease: a comparative analysis.

We studied 23 children with steroid-sensitive nephrotic syndrome (SSNS), 21 children with steroid-resistant types of nephrotic syndrome and 32 children with other types of nephritis. Our controls were 43 apparently healthy children. We measured the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and the low molecular weight (LMW) protein beta 2-microglobulin (B2M), retinol-binding protein (RBP), alpha 1-microglobulin (A1M) and urine protein 1 (UP1). Results for B2M were considered only for a urine pH greater than 6.0. Comparisons were made with urine albumin excretion, glomerular filtration rate (GFR) and tubular abnormalities in selected renal biopsy samples. We found that abnormalities of LMW protein excretion occurred in between 50% (B2M) and 88% (UP1) of all subjects. In children with SSNS, A1M (r = 0.73), UP1 (r = 0.65) and NAG (r = 0.54) excretion were significantly correlated with albumin excretion, but not RBP or B2M excretion. Increased fractional excretion of A1M, B2M and UP1 and increased plasma A1M were demonstrated in 9 children with SSNS, suggesting competition for tubular reabsorption with albumin, most marked for UP1. In the steroid-resistant nephrotic and nephritic syndromes, correlation with albumin was found for all proteins. In these subjects, RBP (r = 0.37), B2M (r = 0.42) and A1M (r = 0.28) were inversely correlated with GFR, but not UP1, NAG or albumin. We found that RBP excretion was significantly greater in the presence of severe tubular abnormalities in 11 children with recent renal biopsies, but not A1M, UP1 or NAG. We conclude that LMW proteinuria is common in children with glomerular disease, and does not necessarily imply a poor prognosis. Factors other than histologically proven tubular abnormality may account for elevated LMW protein excretion. RBP is the LMW protein most closely associated with structural abnormality and least affected by increasing albuminuria.

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.

Mid-aortic syndrome presenting in childhood.

Mid-aortic syndrome (MAS) is an uncommon condition characterized by segmental narrowing of the proximal abdominal aorta and ostial stenosis of its major branches. It is usually diagnosed in young adults, but may present in childhood as a challenging problem. Over the past 20 years 13 patients with MAS have presented to this institution. All had hypertension, four had associated neurofibromatosis, three persistent eosinophilia and three had Williams syndrome. In all cases arteriography showed a smooth segmental narrowing of the abdominal aorta with concomitant stenosis at the origins of the renal arteries. Six children were successfully treated with antihypertensive medication alone. Percutaneous transluminal angioplasty was attempted in two cases with poor result. Surgery was indicated in seven children with refractory hypertension and progressive renal impairment. Techniques used to revascularize the kidneys included thoracoabdominal to infrarenal aortic bypass with renal artery reimplantation, splenorenal bypass, gastroduodenal to renal bypass, aortorenal bypass and autotransplantation.

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)

Improved survival in lupus nephritis in the modern era (1979 - 1989).

We analysed outcome retrospectively in relation to treatment and disease stage in patients with systemic lupus erythematosus and glomerulonephritis, and compared these with similar patients referred to us during 1969 - 78, and other published series from the same period. Eighty two patients with lupus nephritis were referred during 1979 - 89. Of these, 73 were followed up for a mean of 58.1 (SD 34.5) months. The histological pattern in renal biopsies was WHO Class IV (diffuse proliferative glomerulonephritis) in 59% of patients. In the acute phase 43 patients received intravenous nethyl-prednisolone IG daily, for three days, in 25 accompanied by daily 4 litre plasma exchanges on 5 to 10 days. Twelve patients received induction therapy using oral cyclophosphamide during the acute phase, for 8 - 12 weeks only. Maintenance therapy was with oral prednisolone in all patients, accompanied by azathioprine in 84% of cases. Long- term cyclophosphamide was never used, neither intravenously nor orally. At 10 years actuarially calculated patient survival was 87% and survival of renal function 86% compared with 57% and 65% respectively in 1970 - 78 ([P < 0.01]). Survival was no different in patients with renal biopsies classified into the various WHO classes. In patients with Class IV biopsies, survival in those treated with prednisolone and azathioprine only was the same as that in those given intravenous methylprednisolone and/or plasma exchange as well. However, patients treated with methylprednisolone or plasma exchange tended to have more severe disease. At last followup, 24/82 patients were in complete remission, 23 had normal plasma creatinine concentrations but abnormal urine, ie proteinuria, haematuria, or both, 16 had abnormal urine and elevated plasma creatinine concentrations, and 9 had started renal replacement therapy. Eight patients had died. The survival of patients with lupus nephritis has improved in the past decade in patients with comparable severity of disease, and renal failure is no longer the principle cause of death. Results of maintenance treatment using azathioprine as adjunct to oral prednisolone in patients with severe nephritis are as good as those in series published elsewhere describing regular intravenous cyclophosphamide. No clear advantage was evident from the additional use of intravenous methylprednisolone and/or plasma exchange in the acute phase, in patients with WHO Class IV severe diffuse proliferative glomerulonephritis.

Improved survival in lupus nephritis in the modern era (1979 - 1989) using only oral corticosteroids and azathioprine as maintenance

The authors analysed outcome retrospectively in relation to treatment and disease stage in patients with systemic lupus erythematosus and glomerulonephritis; and compared these with similar patients referred to us during 1969 - 78; and other published series from the same period. Eighty two patients with lupus nephritis were referred during 1979 - 89. Of these; 73 were followed up for a mean of 58.1 (SD 34.5) months. The histological pattern in renal biopsies was WHO Class IV (diffuse proliferative glomerulonephritis) in 59 per cent of patients. In the acute phase 43 patients received intravenous nethyl-prednisolone IG daily; for three days; in 25 accompanied by daily 4 liter plasma exchanges on 5 to 10 days. Twelve patients received induction therapy using oral cyclophosphamide during the acute phase; for 8 - 12 weeks only. Maintenance therapy was with oral prednisolone in all patients; accompanied by azathioprine in 84 per cent of cases. Long term cyclophosphamide was never used; neither intravenously nor orally. At 10 years actuarially calculated patient survival was 87 per cent; and survival of renal function 86 per cent; compared with 57 per cent and 65 per cent respectively in 1970 - 78 (p less than 0.01). Survival was no different in patients with renal biopsies classified into the various WHO classes. In patients with Class IV biopsies; survival in those treated with prednisolone and azathioprine only was the same as that in those given intravenous methylprednisolone and/or plasma exchange as well. However; patients treated with methylprednisolone or plasma exchange tended to have more severe disease. At last followup; 24/82 patients were in complete remission; 23 had normal plasma creatinine concentrations but abnormal urine; ie proteinuria; heaematuria; or both; 16 had abnormal urine and elevated plasma creatinine concentrations; and 9 had started renal replacement therapy. Eight patients had died. The survival of patients with lupus nephritis has improved in the past decade in patients with comparable severity of disease; and renal failure is no longer the principle cause of death. Results of maintenance treatment using azathioprine as adjunct to oral prednisolone in patients with severe nephritis are as good as those in series published elsewhere describing regular intravenous cyclophosphamide. No clear advantage was evident from the additional use of intravenous methylprednisolone and/or plasma exchange in the acute phase; in patients with WHO Class IV severe diffuse proliferative glomerulonephritis

Insulin and growth in chronic renal failure.

We studied glucose metabolism using the hyperglycemic technique in a cross-section of 23 children (15 pubertal, 8 prepubertal) with stable chronic renal failure as a possible cause of their poor growth. Linear growth was expressed as growth velocity standard deviation score (GVSDS). GVSDS correlated with glucose disposal rate but not with insulin sensitivity index in the pubertal (r = 0.87, P < 0.001) and prepubertal (r = 0.86, P < 0.02) children with chronic renal failure. Thirteen children were followed longitudinally during medical suppression of hyperparathyroidism with dietary phosphate restriction and high-dose phosphate binders. Following significant suppression of serum parathyroid hormone (PTH) levels back to the normal range (932 +/- 240 ng/l to 199 +/- 50 ng/l), GVSDS, glucose disposal rate and insulin secretion all increased significantly (p < 0.01), with no change in insulin sensitivity index and renal function. The changes in GVSDS correlated with the changes in glucose disposal rate (r = 0.86, P < 0.02) and with the changes in insulin secretion (r = 0.80, P < 0.01). However, the changes in GVSDS did not correlate with the changes in PTH. The hypothesis that insulin may be more important than PTH in the pathogenesis of growth failure in chronic renal disease deserves further investigation.

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.

Acute renal failure complicating diabetic ketoacidosis.

Two previously healthy children, aged 13 and 14 years, respectively, presented with diabetic ketoacidosis. Both children developed acute renal failure, a rare complication of diabetic ketoacidosis and required dialysis.

Middle aortic syndrome: clinical and radiological findings.

Eight patients with the middle aortic syndrome are described. They were aged 2 months to 14 years at diagnosis; follow up was one to 11 years. Clinical presentations included asymptomatic hypertension (n = 5), severe headache, nose bleed, and chest pain (n = 1), and cardiac failure (n = 1). All had severe hypertension requiring multiple drug treatment. Diminished peripheral pulses were not helpful in the diagnosis, which is made on aortography. Associated clinical findings were Williams' syndrome (n = 3) and appreciable eosinophilia (n = 3). The differential diagnosis includes Takayasu's arteritis, fibromuscular dysplasia, and neurofibromatosis. Blood pressure was adequately controlled by medical treatment in six patients. Surgical angioplasty was performed in two. One patient remained normotensive without drug treatment 21 months after operation; the other died of sepsis and uncontrollable haemorrhage in the postoperative period. Medical treatment is satisfactory in most cases: surgery should be reserved for those in whom blood pressure cannot be controlled without unacceptable side effects of drug treatment. Although rare, the middle aortic syndrome should be considered in the differential diagnosis of hypertension when commoner causes have been excluded. Aortography is necessary for diagnosis.

Effects of oral phosphocysteamine and rectal cysteamine in cystinosis.

Diurnal variation in leucocyte cystine and the effects of equimolar single doses of oral phosphocysteamine and rectal cysteamine were studied in eight patients with cystinosis, aged 1.8-16.5 years. No significant diurnal variation in leucocyte cystine was found. Absorption of cysteamine was reduced after rectal administration compared with the oral dose: mean (SD) peak concentration 17.2 (6.3) mumol/l v 36.4 (5.5) mumol/l at 40 min and mean (SD) area under the curve 22.3 (14.3) v 59.4 (33.1) mumol/h/l. Oral phosphocysteamine significantly reduced the mean (SD) leucocyte cystine from 8.09 (0.47) to 3.26 (1.48) nmol 1/2 cystine/mg protein at three hours. At 12 hours the mean leucocyte cystine was significantly lower than the pretreatment concentration. Rectal cysteamine did not significantly reduce the mean leucocyte cystine concentration. In conclusion, phosphocysteamine suspension may be administered every 12 hours. Rectal cysteamine administration is feasible but higher doses are required before efficacy can be judged.

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.

Treatment of hyperkalaemia with intravenous salbutamol.

Thirteen children with hyperkalaemia were treated by intravenous infusions of salbutamol, 4 micrograms/kg over 20 minutes. Reductions in the mean (SD) plasma potassium concentrations, of 1.48 (0.5) and 1.64 (0.5) mmol/l were obtained at 40 and 120 minutes, respectively, after completion of the infusions. No side effects were noted.