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The prime minister’s commitment to “fighting against the burning injustice that if you’re born poor, you will die on average nine years earlier than others”1 is welcome and achievable. As her government has acknowledged,2 half of this difference in life expectancy is due to the higher rates of smoking among the least affluent, so major improvements can …

Background A growing body of knowledge exists to guide efforts to improve the organisation and delivery of health care, most of which is based on work carried out in hospitals. It is uncertain how transferable this knowledge is to primary care. Aim To understand the enablers and constraints to implementing a large-scale quality improvement programme in general practice, designed to improve care for people with chronic obstructive pulmonary disease. Design and setting A qualitative study of 189 general practices in a socioeconomically and ethnically-mixed, urban area in east London, UK. Method Twelve semi-structured interviews were conducted with people leading the programme and 17 in-depth interviews with those participating in it. Participants were local health system leaders, clinicians, and managers. A theoretical framework derived from evidence-based guidance for improvement programmes was used to interpret the findings. A complex improvement intervention took place with social and technical elements including training and mentorship, guidance, analytical tools, and data feedback. Results Practice staff wanted to participate in and learn from well-designed collaborative improvement projects. Nevertheless, there were limitations in the capacities and capabilities of the workforce to undertake systematic improvement, significant problems with access to and the quality of data, and tensions between the narrative-based generalist orientation of many primary care clinicians and the quantitative single-disease orientation that has characterised much of the quality improvement movement to date. Conclusion Improvement guidance derived largely from hospital-based studies is, for the most part, applicable to improvement efforts in primary care settings, although large-scale change in general practice presents some particular challenges. These need to be better understood and addressed if improvement initiatives are to be effective.

In 1739 Samuel Johnson wrote an essay on the life of Dr Hermann Boerhaave, Professor of Physic at the University of Leiden, who died in 1738. Boerhaave, born 11 years after Harvey's death, could be said to have been influenced by Harvey in that he favoured experimental natural philosophy as the gateway to scientific medicine. He was denied entry into the church because he was accused wrongly of being a follower of the philosopher Baruch Spinoza, regarded as a heretic because he criticised established religious practices; this in spite of strongly supporting the love of God and humanity. Boerhaave decided to become a physician as he was, in Johnson's words, 'equally qualified for a profession, not indeed of equal dignity or importance, but which must undoubtedly claim the second place amongst those which are the greatest benefit to mankind'. It is this claim that I wish to examine. Can we still claim this regard for our profession? Is the medicine we practise, and the way we practise, of the greatest benefit to mankind, and how do we ensure that it is?

BACKGROUND: Nephropathy associated with vesicoureteric reflux (VUR) and urinary tract infection can result in end-stage renal failure, hypertension, or both. Whether long-term VUR contributes to these outcomes is unknown. We compared, in a randomised trial, medical with surgical management of children with bilateral severe VUR and bilateral nephropathy. METHODS: We stratified by age and glomerular filtration rate (GFR) 25 boys and 27 girls aged 1-12 years and randomly assigned them to medical or surgical management. At enrolment and 4 years' follow-up we estimated GFR from the plasma clearance of 51Cr-labelled edetic acid (EDTA), and did intravenous urography. We also did a metastable 99mTc-labelled dimercaptosuccinic acid (DMSA) assay and contrast cystography. The change in GFR at 4 years, expressed as a percentage change between enrolment and 4 years, was available for 26 of 27 patients in the medical and 24 of 25 in the surgical group. We assessed GFR in 48 patients 10 years after enrolment. FINDINGS: Mean GFR at enrolment was 72.4 mL/min per 1.73 m(2) (SD 24.1) in the medical and 71.7 mL/min per 1.73 m(2) (22.6) in the surgical group. The mean percentage change in GFR at 4 years was 2.4% (SE 4.5) versus 4.7% (5.0) in the medical and surgical groups, respectively. The difference in change in GFR at 4 years between the two groups was not significant (7.1%, 95% CI 6.4% to 20.6%). INTERPRETATION: Our data do not lend support to the view that the outcome for renal function is improved by surgical correction of VUR in children with bilateral disease.

This paper emphasises the need for a consistent identifier to be used to share information between agencies for children in the same way as for adults.

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.

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, P0.001) and prepubertal (r = 0.86, P0.02) 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 (p0.01), 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, P0.02) and with the changes in insulin secretion (r = 0.80, P0.01). 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 delayed graft function on renal allograft survival has been studied in a review of 322 renal transplants performed at one pediatric institution. The appearance of the first radionuclide renal scan was used to indicate early function in patients receiving their first cadaveric allograft. Patients whose first radionuclide renal scan showed both good renal perfusion and good function (n = 52) were compared with those whose scans demonstrated good perfusion but no function (n = 32). the actuarial graft survival of those with no function was significantly worse (P.05). The difference in graft survival was not solely due to grafts lost in the early posttransplant period. Analysis of serial serum creatinine estimations suggests a process of continued inexorable nephron loss in some patients whose grafts showed a delay in achieving function.

The European Society for Paediatric Nephrology (ESPN) was founded 25 years ago. The progress of paediatric nephrology in Europe since then has been considerable, but we now face a number of problems. The care of the child with kidney disease is often expensive and more needs to be done to examine the cost effectiveness of the management of the child with kidney disease. International co-operation can also foster clinical research to determine the effectiveness of treatment through the institution of controlled trials and outcome studies. Particular problems are posed by the need to integrate the countries of Eastern Europe that have changed from command to market economies over the last year. In many instances there is no shortage of doctors, nurses and hospital beds but there is a need to change administrative and academic structures and to introduce appropriate technology. It is suggested that this may be assisted by twinning units. The integration of Europe requires that the role of the paediatric nephrologist in different countries needs to be examined, and appropriate training to fulfil these responsibilities needs to be agreed. Different countries obviously have different ways of organising and providing services for children with kidney disease. Kidney failure is rare in childhood and there are economic and academic advantages from close collaboration, both with adult nephrology services and with other paediatric specialities. Where it is intended to integrate children's hospitals into large multidisciplinary university hospitals for economic reasons, it is nonetheless necessary to make sure that the requirements of children are properly recognised and the requirements of the European Charter for children in hospital are met.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 13 children subjected to elective tonsillectomy, 6 of whom (study patients) received supplemental intravenous isotonic saline during and after operation, and 7 of whom (controls) did not. Clinical and biochemical evidence of hypovolaemia was present in the control but not in the study patients. Plasma antidiuretic hormone (ADH) and urine osmolality were higher in controls (p less than 0.005 and p less than 0.05 respectively). Plasma sodium concentration and osmolality were similar in the two groups. We conclude that hypovolaemia is the principal stimulus to ADH release following surgery and that, in addition to replacement of observed losses of blood and other fluids by fluids of appropriate composition, hypovolaemia should be prevented by the administration of maintenance quantities of isotonic fluid, rather than exacerbated by fluid restriction, in patients in whom oral fluid intake is interrupted for more than a brief period. Hypotonic and sodium free fluids should be avoided because of the risk of hyponatraemia.

Six children (aged 3 years 11 months to 15 years 9 months) with end-stage renal failure and anaemia (mean haemoglobin 7.1 g/dl, range 6.3-7.7 g/dl) on thrice-weekly haemodialysis were treated with recombinant human erythropoietin (rHuEPO), given as an intravenous bolus in an escalating dose regime after dialysis. All responded with an increase in reticulocyte count and haemoglobin concentration in a mean time of 11 weeks (range 9-13 weeks) and at a dose of 100 or 150 units/kg thrice weekly. The dose of rHuEPO was then adjusted to maintain the haemoglobin concentration within the lower half of the normal range for the child's age and sex. The mean haemoglobin after 12 weeks treatment was 10.9 g/dl (range 8.5-12.1 g/dl) and after 24 weeks, 10.5 g/dl (range 7.9-13.3 g/dl). Four children had no further need for blood transfusion and are thus no longer at risk of blood-borne infection, iron overload and sensitisation to HLA histocompatibility antigens. Serum ferritin fell in the three patients with evidence of iron overload; the three with low or normal iron stores at the onset of treatment maintained erythropoiesis with oral iron supplementation. HLA antibodies decreased in all patients. The only serious complication encountered was thrombosis of vascular access in one child. No child became seriously hypertensive or developed cerebral symptoms. The benefits of rHuEPO therapy for children with end-stage renal failure are potentially considerable and with careful monitoring, the risks low.

SOCIETY FLIES BLIND WHEN IT COMES TO HEALTH CARE. The value of treatments to patients, in particular with respect to health gain, is not routinely measured. As a result, reforms focus less on improving health and value to patients and more on cost minimization; consequently, such reforms are led by administrators, not physicians. Physicians are disgruntled and disenfranchised, and perversities result such as, in the United States, cost shifting and other forms of dysfunctional competition. The way forward is for physicians to seize the initiative, take as their goal improved value of care to patients, organize medical practice around medical conditions and care cycles, and measure riskadjusted outcomes and costs, all within a competitive health system. Positive-sum competition for value to patients will result that only physicians can deliver. Tinkering with financial incentives in the system will never be enough. In a reduced form, this is the main argument advanced by Porter and Teisberg for reforming and improving the US health care system. However, there are important similarities in England’s National Health Service (NHS). While reducing overall cost growth is not a problem due to the (relatively) large real-term increases in the global fixed budget over the last 7 years, health reforms in England have been in the main led by politicians and implemented by managers, with the physician community largely on the sidelines, antagonized or marginalized. Measuring risk-adjusted clinical outcomes is not widely implemented, prompted by public outrage (for example, following well-publicized failures in cardiac surgery) as much as by professional leadership. The financial bottom line, rather than health gain, tends to drive local reconfigurations in service. To improve the health care system, physicians should take a firm lead: a large portion of the activities most likely to have an impact on improving outcomes and quality are embedded in the care setting provided by physicians interacting directly with patients. However, it is unlikely that physicians will rise to the leadership needed, at least in the NHS, and some of the “false solutions” rejected by Porter and Teisberg are necessary and worthwhile candidates for future reforms. In this Commentary, we explain why, and describe how some of these “false solutions” are being used to reform the NHS to achieve better value for patients.

THE RECURRENCE OF SEVERE ACUTE RESPIRATORY SYNdrome (SARS) in China during 2004 has highlighted the continuing threat to human health from infectious disease outbreaks. A zoonosis caused by a novel coronavirus, SARS first emerged among humans in the southern Chinese province of Guangdong during November 2002. By March 2003, SARS had spread to neighboring Hong Kong and from there to Toronto, Ontario, and many other areas in a matter of days. The World Health Organization (WHO) has reported that by July 2003 when the epidemic had waned, in Hong Kong there were 1755 probable cases of SARS with 300 deaths (17%) and in Canada there were 251 probable cases with 43 deaths (17%). Most Canadian cases and all deaths were in the Toronto area. Both areas had serious difficulties managing the outbreak, and several inquiries into public health and epidemic management have since been performed. We led the panels that first reported on SARS and public health in each jurisdiction. Both panels worked through the summer of 2003 and issued their reports within a week of one another in early October 2003. Herein, we compare our findings, highlight common conclusions, and suggest some general lessons that may be applicable to other areas.

Information about a patient's health is recorded in order to provide for that patient's care. Most patients will not think about the other uses for their data and many assume that the information they provide will go no further than the health care professionals who have been caring for them. Information collected about patients is essential for developments in our understanding of health and health care. Most patients will be happy to allow their data to be used for these purposes, once this has been explained. Health care professionals have an obligation to ensure that patients know when identifiable data about them are to be used and to get their agreement about making disclosures. We know that this is not easily achieved; doctors, nurses and others providing care are already over-stretched. Patients may be anxious about their condition and treatment. They may not, for a variety of reasons, read leaflets or letters sent or given to them. This does not mean our obligations to respect patients by keeping them informed and seeking their agreement can be ignored. Openness about how health care professionals work and partnership with patients are essential to the continued trust of the public in the professions. The challenge is not to answer the question whether we need consent but rather how we can best obtain it.

At present, NHS managers are highly constrained, suffering excessive regulation and central control. More autonomy for trusts would mean fewer directives and less performance management. Giving trusts a new organisational form, such as a public interest company or foundation hospital, might be reinvigorating and would not involve further reorganisation. These new freedoms should be accompanied by new accountabilities, not solely to politicians but to independent NHS regulators, local communities and patients. Devolved power and greater patient choice could produce a more responsive NHS. Its potential needs to be explored through experimentation and evaluation.

Red cell morphology was examined by light microscopy in 122 urine specimens from 99 patients with haematuria in an attempt to define the site of origin. Altogether 84% of glomerular bleeding and 91% of non-glomerular bleeding was correctly assigned according to diagnoses determined by renal biopsy in 51 patients and clinically in 48. The test should be interpreted with caution as both false positive and false negative results were observed, some in the same individual with unchanged pathology at different times. No advantage of phase contrast over bright field microscopy was apparent even when examining uncentrifuged urines.

Eleven boys, mean age 15.3 years (range 13.2-17.5), with pubertal delay in association with steroid therapy for steroid-sensitive nephrotic syndrome and following renal transplantation were treated with oxandrolone 2.5 mg daily for a mean of 0.50 years (range 0.34-0.61). Mean growth velocity increased from 3.9 cm/year (range 1.1-6.3) to 6.1 cm/year (range 2.0-14.4) and was maintained at 6.1 cm/year (range 0.4-10.2) (P less than 0.05). However, there was no significant difference in growth between the treated boys and age- and puberty-matched controls. Elevation of blood cyclosporin A and creatinine levels occurred in the transplant patients. Oxandrolone may initiate a pubertal growth spurt in patients taking steroid therapy for renal disease, but should be used with extreme caution because of potential side-effects.

This paper summarises a symposium concerned with the provision of care for children with kidney disease in developing countries. Better organisation of services is required to prevent waste of resources, with the emphasis on team work between professionals, shared care with local health care personnel remote from the paediatric nephrology unit and good communications. Families need to be educated and provided with appropriate information so that they can care for their child at home. Technology should be simple and robust and the staff using it should be fully trained to maintain it in use. Therapies should be definitive where possible, because long-term supervision of treatment is often difficult. Effective but inexpensive medications should be used where possible. Twinning of developing and richer countries is valuable to transfer technology, help with training and assist in care through the development of personal contacts.

We studied 40 children with a history of vesicoureteric reflux (VUR) without evidence of renal scarring, 93 children with a history of VUR and renal scarring and 10 children with previous urinary tract infections in whom the urinary tract was radiologically normal. Urine retinol-binding protein (RBP), albumin and N-acetyl-beta-D-glucosaminidase (NAG) were measured in each child. All were free from infection at the time of the analysis. Urinary RBP and NAG levels were significantly elevated (P0.001) in the group of children with renal scarring. Elevated RBP levels were detected in 51% of children with bilateral renal scarring compared with 7% of children with unilateral scarring. Urine RBP excretion increased progressively according to the type of scarring, best determined by the type of scarring of the less affected kidney. In children with renal scarring, elevated NAG levels were seen mostly in the 65 children with bilateral scarring and severe reflux. Urine albumin excretion was elevated in 10 children, 9 with bilateral scarring, all of whom had elevated RBP excretion. Urine protein excretion was unaffected by the presence or absence of persisting VUR. There was a strong negative correlation between glomerular filtration rate and RBP excretion (r = -0.69). We conclude that evidence of tubular dysfunction is common in children with bilateral renal scarring and usually precedes any glomerular protein leak. Tubular dysfunction may be the consequence of relative nephron hyperperfusion in the presence of bilateral scarring.

Although red cell morphology has been used to localise the site of haematuria in the urinary tract, the cause of red cell deformity is still speculative. We have conducted experiments in vitro using venous red cells which indicate that hypochromia depends mainly upon sodium concentration and occurs when this falls below 75 mmol/l. We simulated the passage of red cells through the renal tubule by sequentially treating them with fluids of composition similar to those in different tubular segments, and produced anisocytosis and hypochromia but not the typical "bizarre deformity"--the hallmark of glomerular haematuria. We conclude that dual injury is required to produce the "typical" dysmorphic red cells in glomerular haematuria. First, mechanical damage caused by passage of red blood cells through the glomerular basement membrane followed by a second, osmotic, injury sustained by red cells during passage through the hypotonic tubular segment.

A study of long-term outcome of 78 subjects who had had Henoch-Schonlein nephritis during childhood (at a mean of 23.4 years after onset) shows that severity of clinical presentation and initial findings on renal biopsy correlate well with outcome but have poor predictive value in individuals. 44% of patients who had nephritic, nephrotic, or nephritic/nephrotic syndromes at onset have hypertension or impaired renal function, whereas 82% of those who presented with haematuria (with or without proteinuria) are normal. 17 patients deteriorated clinically from an initial assessment in 1971; 7 of these had apparently completely recovered in 1976. 16 of 44 full-term pregnancies were complicated by proteinuria and/or hypertension, even in the absence of active renal disease. These findings indicate that childhood Henoch-Schonlein nephritis requires long-term follow-up, especially during pregnancy.

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.

Long-term steroid therapy has a depressant effect on hypothalamo-pituitary pulsatile secretion of growth hormone (GH), and this results in an attenuated pubertal growth spurt. Oxandrolone and recombinant human GH improve growth rates in children taking long-term steroid therapy for renal disease, but there are potential side effects. Treatment with recombinant human erythropoietin improved the growth of three prepubertal, but not three pubertal haemodialysis patients.

Enzyme-linked immunosorbent assays (ELISA) have been developed for the measurement of beta 2-microglobulin (B2M), retinol-binding protein (RBP), alpha 1-microglobulin (A1M) and urine protein 1 (UP1) in children. Results from random urine samples in 43 children (31 for B2M) are, when corrected for urine creatinine (geometric mean (range)): B2M 9.8 (6.0-40.7) micrograms/mmol, RBP 8.1 (less than 1-24.5) micrograms/mmol, A1M 0.4 (0.1-2.2) mg/mmol and UP1 17.8 (less than 2-309.4) micrograms/mmol. Fractional excretions (FE) in 23 children (14 for B2M) are (geometric mean (range)): FEB2M 0.04% (0.02-0.10%) and FEUP1 0.10% (0.01-1.21%). Results in overnight urine collections are also presented. Our results extend existing data for normal ranges in adults to include children and provide data on UP1 concentrations.

We measured the excretion rate of endogenous creatinine in 84 24-hour urine collections obtained from 60 term and preterm newborn infants between the 3rd and the 68th postnatal day, at postconceptional ages 28-42 weeks. The rate was positively correlated with weight, height, and postconceptional age but not with postnatal age; the strongest correlation was that with weight. When the rate was factored by weight it was constant across the range of values studied, with a median and logarithmic mean value of 90 mumol/kg/day (10 mg/kg/day) and a range (2 log SD) of 45-180 mumol/kg/day (5-20 mg/kg/day).

During 1971-5, 72 episodes of acute renal failure were treated in 70 children aged up to 16 years. The commonest causes were renal hypoperfusion (31 cases), haemolytic-uraemic syndrome (12), glomerulonephritis (9), septicaemia (5), and congenital abnormalities (6). Though referral from other hospitals was generally prompt, 10 out of 51 patients had been observed for up to seven days before transfer. Dailysis was used in 44 cases, the most common complications of which were peritonitis in those treated with peritoneal dialysis and acute changes in fluid balance in those treated with haemodialysis. Altogether 37 patients fully recovered, 10 were discharged with chronically impaired renal function, 17 died, and six entered the dialysis and transplantation programme. The mortality fell from 33% in 1972 to 20% in later years, which was due solely to maintenance dialysis being available. Though all patients with irrevocable kidney failure who were suitable entered the dialysis and transplantation programme, with current financial restrictions we doubt whether we shall be able to find places for all such patients in the future.

Eight boys aged 9.5 to 17 years, on regular hemodialysis for chronic renal failure, were treated for 0.4 to 1.3 years with the anabolic steroid oxandrolone. The effects on linear growth, skeletal maturation, cell mass, and the fasting levels and response to intravenous glucose of BG, IRI, NEFA, BCAA, and IRG were measured. Following treatment there was a significant increase in mean growth velocity, growth velocity standard deviation score related to bone age, and cell mass. Overall skeletal maturation was not accelerated, and only a small advance in pubertal status was seen. There was a descrease in fasting levels of BG and NEFA; fasting BCAA and IRG were increased. The response to intravenous glucose was altered; there was a decrease in peak BG response, an increase in peak IRI response, and a more marked fall in plasma NEFA and BCAA levels. Fasting IRG levels correlated with fasting BG levels, and fell significantly following intravenous glucose both before and after treatment. Hepatotoxicity, which was reversible, was seen in a ninth boy who did not complete the study. The only other side effect, salt and water retention, was controlled by a reduction in oxandrolone dosage. These preliminary results suggest that anabolic steroids may be useful to stimulate anabolism and growth in uremic children, and that their effect is mediated by an increase in insulin secretion and/or an improvement in tissue sensitivity to insulin. Further studies with careful monitoring are required to substantiate the effect on final height and the risks involved.

Fourteen patients with familial juvenile nephronophthisis are described, eight of whom displayed one or more additional disorders. One boy with short limbed dwarfism and an abnormal chest was considered to have Jeune's syndrome; review of the published reports supports the view that nephronophthisis is the principal cause of renal failure in this disorder. Another patient with renal failure and retinitis pigmentosa at presentation developed progressive neurological and neuromuscular impairment leading to the discovery of ragged red fibre disease (mitochondrial cytopathy). Cardiomyopathy was present in this and one other patient. Tapeto-retinal degeneration, hepatic fibrosis, cerebellar ataxia, and oculomotor apraxia were among the other disorders encountered. Three patients presented in extremis with acute heart failure and irreversible oligo-anuria and this complication developed in another child who was already known to have nephronophthisis. Awareness of this disease and its associations is important for early diagnosis and appropriate management.

Hyponatraemia implies water retention in excess of sodium with or without increased loss of sodium from the body; extracellular fluid volume may be increased, normal or reduced. It has many causes which are briefly reviewed. Among these is the rare syndrome of inappropriate secretion of antidiuretic hormone (SIADH). It is suggested that SIADH is often diagnosed incorrectly because the raised ADH levels are appropriate for the volume status of the child. Precision in the diagnosis is important because whilst water restriction is necessary for the treatment of SIADH, other measures including the administration of extra fluid are often required if the raised ADH is appropriate. Hyponatraemia in the newborn may be caused by prerenal failure, renal failure or renal sodium wasting which is common in premature infants. Careful control of sodium intake as well as water intake is vital in this age group. Surgery is associated with water retention, but recent studies suggest that ADH levels are raised post-operatively because of volume depletion and that present recommendations for fluid therapy during and following surgery are inadequate. The use of electrolyte-free dextrose solutions should be abandoned and more liberal use of physiological saline or colloid is recommended.

Fifty-eight children with minimal-change nephrotic lesions who relapsed repeatedly and showed toxic side effects from corticosteroids were treated with cyclophosphamide for an average of 12 weeks. The initial dose was 5 mg/kg/day. Four to seven years (mean 5.8 years) later 20 remained in remission, 34 were still relapsing, and 4 had died (two during relapses, one of measles after cyclophosphamide, and one of a brain-stem astrocytoma). The half time for the relapse-free period after treatment was 2.8 years. There was no relationship between the length of treatment with cyclophosphamide and the stability of remission within the limits studied.

A 4-yr-old boy with hypertension and hypokalaemic alkalosis had low plasma aldosterone levels and renin activity. The hypertension and hypokalemia responded to spironolactone and triamterene therapy. A partial response to dexamethasone was observed. Analysis of urinary steroid metabolites by gas chromatography-mass spectrometry showed that the excretion of metabolites of deoxycorticosterone and aldosterone was subnormal, and there was no evidence for sizeable excretion of unusual steroids with potential mineralocorticoid activity. The cortisol excretion rate, however, was subnormal, and the relative excretions of individual metabolites of this hormone were not typical. In particular, the excretion of tetrahydrocortisone was markedly reduced, and the excretions of allotetrahydrocortisol and free cortisol and metabolites were elevated. These findings suggest that modified or deficient metabolism of adrenal steroids could give rise to elevated blood pressure. It is not known whether the inappropriate production of unusual cortisol metabolites were responsbile for the high blood pressure or whether the altered metabolism is indicative of similar abnormality in the metabolism of other adrenal steroids, resulting in hyperproduction or extended half-life of minor but highly active mineralocorticoids of unknown structures.

Children grow most during the first 2 years of life; growth retardation at this time has a major effect on the height of a child. Dietary therapy to maximize growth during the first few years before dialysis and transplantation are generally recommended as important. Energy and protein requirements for children in relation to their body weights are greater than for adults. In addition, the metabolic rate may be increased in uremia. Malnutrition and the metabolic disturbances of uremia appear to be more severe in prepubertal children than in adults and growth in such children is generally poor. This may be related to the lower anabolic drive of the prepuberal child; anabolic steroids may improve growth. Severely limited protein diets are difficult to achieve in children without reducing energy intake. It may be easier to give babies diets high in energy and low in protein with essential amino acid supplements to ensure an adequate essential amino acid intake. Fat intake should be increased to provide sufficient energy without causing hypertriglyceridemia. It is hoped that ketoacids may allow sufficient protein to be consumed as that an adequate energy intake is ensured while reducing nitrogen toxicity.

The assessment of growth in children with kidney disease includes measurements of stature, nutritional status, skeletal maturity, and sexual development. The purposes of these assessments in general are described in the preceding paper (Roche, this issue). For the child with kidney disease, the number of variables affecting growth make it difficult to project adult stature. When a specific variable is dominant, data is accumulating that make this projection possible. Elsewhere (Potter and Greifer; Travis et al, this issue) is summarized experience in children with various types of renal insufficiency and in children after renal transplantation. Growth rate can be improved but not sufficiently so that stature and development are normal. By contrast, children with uncomplicated renal tubular acidosis (RTA) when treated adequately from an early age may exhibit catch-up growth and attain normal stature (McSherry, this issue). Growth assessment in the individual child with kidney disease is helpful to physician and patient in understanding the course of his disease, the effect of therapy, and in gaining some projection of growth potential. Serial growth assessment of a group of children is helpful toward defining the variables of disease most affecting growth. From such data the natural history of disease can be defined in relation to its effect upon ultimate stature and development. Response of growth to therapy to evaluate the potential efficacy of therapy is a third reason for assessing growth. Stature is the index of growth of most concern to children. How tall they are, how fast they are growing, and how tall they are going to be are the important questions. Measuring stature serially is the first requisite. Nutritional status, skeletal maturation, and sexual development, however, all influence statural growth and remaining growth potential. These variables also are important in themselves in evaluating the course of the disease and in planning therapy. Judging from past experience, there is a need to develop guidelines for presenting data on growth assessment of children with kidney disease. The recommendations in this report are presented as a step towards fulfilling that need. Drawing from the previous paper (Roche, this issue), we recommend the following measurements to be made at intervals suitable for the purposes of the investigator. Some recommendations about frequency of measurement, method of recording, and data reduction for individual and statistical treatment are also included. The Combined Report on regular dialysis and transplantation of children in Europe [1] is a useful additional reference.

Fifteen patients with rapidly progressive glomerulonephritis (R.P.G.N.) were treated with quadruple chemotherapy—i.e., prednisolone, azathioprine or cyclophosphamide, dipyridamole, and heparin followed by warfarin. In addition, one patient was treated with anticoagulants and dipyridamole only. The diagnosis of R.P.G.N. was based on a clinical course with rapidly deteriorating renal function in patients in whom occluding extra-capillary crescents were present in more than 60 of glomeruli in an adequate renal-biopsy specimen Of these sixteen patients, six had idiopathic R.P.G.N. (of whom three had mesangiocapillary glomerulonephritis), four had systemic lupus erythematosus, two had polyarteritis nodosa, two had Henoch-Schonlein purpura, one had relapsing polychrondritis, and one had post-streptococcal glomerulonephritis. These patients were treated for periods of 1 to 34 months. Six had oligo-anuria at the start of therapy and the remaining ten had glomerular-filtration rates between 3·2 and 21·6 ml. per minute. None of those who were oligo-anuric responded to this form of therapy, but renal function improved in all those with progressive renal failure, irrespective of the clinicopathological diagnosis. Two patients had moderate gastrointestinal bleeding and heparin was stopped; in one bonemarrow activity was suppressed by azathioprine. There were no serious consequences in any of these patients.

The most common causes of end stage renal failure in 46 children (mean age 11 years, range 4-14) treated between January 1972 and June 1977 were: reflux nephropathy (n = 12), cystinosis (n = 7), focal and segmental glomerulosclerosis (n = 6), and Schönlein-Henoch disease (n = 5). The quality of life, degree of renal function, and height attainment of the 31 survivors were assessed in June 1985, when their mean age was 22 years (range 14-27), using hospital records and a questionnaire designed to highlight social and psychological problems. Twenty six patients had a functioning transplanted kidney. Average growth during treatment for all survivors was normal, but most were disappointed with their 'final height'. Though five patients had some form of disabling bone disease, all 31 could walk and 27 could run. Sixteen (67%) were in full or part time employment and nine were living independently. A group of 32 patients with juvenile onset diabetes treated at this hospital for at least five years were also asked to complete the questionnaire and of these, 17 responded. On average, their data could usefully be compared with those of cases of end stage renal failure. More of the diabetics had jobs, but most sexually mature patients with renal disease were concerned about their physical appearance and had not achieved any stable long term sexual relationships. We suggest that a poor body image resulting in low self esteem may be responsible for the deficiency and believe that further study in this group is warranted.

Six children with chronic renal failure were treated with dietary protein restriction and essential amino acid and keto acid supplements for 6 months. Dietary protein and phosphate intake decreased, dietary calcium increased, and dietary carbohydrate and energy did not change. Plasma urea and urea to creatinine ratio decreased significantly during treatment. Glucose metabolism was studied before and after 6 months of treatment using the hyperglycemic clamp technique. Fasting hyperglycemia, glucose intolerance, and insulin resistance improved during treatment, while fasting insulin and insulin levels during hyperglycemia did not change. These metabolic changes were not related to hyperparathyroidism and were probably due to reduction in nitrogen toxicity.

The effects on growth, nitrogen balance, and body composition of a protein-restricted diet supplemented with oral essential amino acids (EAA) were studied in seven children with advanced chronic renal failure. The diet was designed to provide minimum protein requirements for height-age, half in unselected form and half as an EAA supplement. Energy from carbohydrate and fat were increased to give a protein/energy ratio of 1.25 G:100 kcal. Nitrogen balance, studied in five children before and after 6 to 8 months of EAA treatment, was improved in each case. intracellular water (total body water minus bromide space) increased in four children but fell in three children during treatment. No significant improvement in growth, expressed as height or height velocity standard deviation scores in relation to bone age, was observed. Serum urea and urea/creatinine ratio fell after institution of EAA treatment, but the fall was not sustained. Although the EAA preparation proved acceptable to the children, dietary assessments indicated that the desired dietary aims were rarely achieved. It is concluded that, in this pediatric age group, the long-term application of a protein restricted diet with EAA supplements is of limited value.

Between 1962 and 1970, 36 children with acute biopsy-proven poststreptococcal glomerulonephritis (PSGN) entered a prospective long-term follow-up study. The initial biopsies were scored into four histological grades using criteria based on endocapillary proliferation, leucocyte infiltration, epithelial "hump" and crescent formation; 5 patients had grade-1 (least severe), 14 grade-2, 15 grade-3 and 2 grade-4 biopsies. Two children died from rapidly progressive glomerulonephritis; both had grade-4 biopsies. Early repeat biopsy in 12 patients showed improvement in all but one patient who progressed from grade 2 to type 2 mesangiocapillary glomerulonephritis (MCGN). The initial biopsy grade correlated significantly with heavy proteinuria (chi2 = 9.73, P less than 0.01) but not with hypertension, haematuria or renal functional impairment. Follow-up observations were made after mean periods of 9.5 years (range 5.4-12.4 years; 32 subjects) and 19.0 years (range 14.6-22 years; 30 subjects). None of the survivors had an abnormal plasma creatinine. Only one patient (grade-3 biopsy), a female with a subsequent history of recurrent pyelonephritis, was hypertensive. Isolated microscopic haematuria persisted in 1 grade-2 and 2 grade-3 subjects. One grade-2 subject had proteinuria secondary to MCGN and one grade-3 subject had mild proteinuria and borderline hypertension. Although 20% of subjects had urinary abnormalities, we conclude that the long-term outcome of PSGN in children is excellent.

Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. The effects on growth, body composition, and metabolism of a protein-restriced diet supplemented with essential aminoacids, the calcium-ketoacids of valine, leucine, isoleucine, and phenylalanine, and the calcium-hydroxyacid of methionine, were investigated in seven growth-retarded children with chronic renal failure. During 0.4 to 1.0 years of treatment there were significant increases in growth velocity and upper arm circumferenceSD scores, body cell mass (intracellular water calculated as tritium space minus corrected sodium bromide space) and serum transferrin. Blood urea and urea:creatinine ratio fell in all children. Renal function assessed from plasma creatinine and 51 Cr EDTA clearance did not change significantly. During treatment there was an increase in plasma calcium, high levels necessitating brief interruption of therapy in two children, and a decrease in plasma phosphate. Levels of serum parathormone fell in all children, and were correlated inversely with plasma calcium and positively with plasma phosphate. Abnormalities compared to control children in blood aminoacid and branched-chain ketoacid levels were unaffected by treatment. These results suggest that a protein-restricted diet supplemented with essential aminoacids and calcium-keto and hydroxyacids may be useful to improve linear growth and nutritional status in children with chronic renal failure, and that a reduction in hyperparathyroidism may be partly responsible for some of the beneficial effects observed. Supplementation orale en acides-amines essentiels et en cetoacides chez des enfants atteints d'insuffisance renale chronique. Les effets sur la croissance, la composition corporelle, et le metabolisme d'un regime restreint en proteines, supplemente avec des acides amines essentiels et les cetoacides calciques de la valine, la leucine, l'isoleucine et la phenylalanine et l'hydroxyacide calcique de la methionine ont ete etudies chez sept enfants atteints de retard de croissance et d'insuffisance renale chronique. Pendant 0.4 a 1.0 an de traitement, il y avait des augmentations significatives des index deSD de la vitesse de croissance et de la circonference de la partie superieure du bras, de la masse cellulaire corporelle (l'eau intracellulaire calculee comme etant l'espace tritium diminue de l'espace bromure de sodium corrige), et de la transferrine serique. L'uree sanguine et la rapport uree sur creatine a diminue chez tous les enfants. La fonction renale mesuree par la creatinine plasmatique et la clearence du 51 Cr EDTA n'a pas change significativement. Pendant le traitement il y avait une augmentation du calcium plasmatique, des valeurs elevees necessitant une breve interruption du traitement chez deux enfants et une diminution de la phosphatemie. Les concentrations de parathormone serique ont diminue chez tous les enfants, et etaient correlees inversement avec la calcemie et positivement avec la phosphatemie. Par rapport aux enfants controles, les anomalies des concentrations d'aminoacides plasmatiques et de cetoacides a chaines branchees etaient inchangees par le traitement. Ces resultats suggerent qu'un regime restreint en proteines supplemente avec des aminoacides essentiels et des ceto et hydroxyacides calciques peut etre utile pour ameliorer la croissance lineaire et l'etat nutritionnel d'enfants atteints d'insuffisance renale chronique et qu'une reduction de l'hyperparathyroidisme peut etre partiellement responsable de quelques uns des effets benefiques observes.

Inulin clearance (C In ) has long been accepted as the standard method for measurement of glomerular filtration rate (GFR) in normal subjects [1–3]. In renal transplant recipients and donors, however, Rosenbaum et al [4] showed a significant decrease in standard C In relative to the standard clearances of other markers of GFR such as iothalamate (C Io ) and creatinine (C Cr ). This phenomenon was seen within a week of transplantation and persisted in one patient up to 14 years. Heller, Horacek, and Hollyova [5] reported a similar discrepancy in transplanted dogs but only as a transient phenomenon. At 6 months after transplantation C In and C Cr in these dogs were identical. To our knowledge, there is no corresponding information in children.

As part of a larger study of serial complement profiles in glomerulonephritis plasma C3 and C4 concentrations were measured using commercially available immunodiffusion plates. A total of 303 samples were obtained from 128 patients suffering from forms of nephritis associated with hypocomplementaemia-namely, lupus nephritis, mesangiocapillary glomerulonephritis (M.C.G.N.), and acute glomerulonephritis.These simple measurements of C3 and C4 gave clinically useful information. In lupus nephritis C3 and C4 generally correlated and C4 concentrations were more often and more profoundly depressed than C3 concentrations. Neither C3 nor C4 concentrations alone correlated well with the antinuclear factor titre.In both acute glomerulonephritis and M.C.G.N. the C3 concentrations were frequently lower than 20% of normal (which was never the case in patients with lupus), while the C4 concentration was usually normal and was almost never depressed in the absence of C3 depression. This suggests activation of complement at the C3 level by the "bypass" pathway in acute nephritis as well as in M.C.G.N., though both may be operating in some patients. In acute glomerulonephritis but not in M.C.G.N. C3 concentrations returned to normal within eight to 12 weeks.The two varieties of M.C.G.N. identified by the site of the deposits in the capillary glomerular walls differed in their C3 levels. In 10 patients with intramembranous dense linear deposits the C3 was always low over very long periods of time, rising in three out of four patients only after transplantation and immunosuppression. Other patients with M.C.G.N., in contrast, often showed normal C3 concentrations. Concentrations of C4 did not differ in either group, being normal in 80% of samples from all types.