Department of Nephrourology, Great Ormond Street Hospital for Children NHS Trust, London, UK
Keywords: dialysis; end-stage renal failure; infant; outcome
Introduction
One of the greatest challenges for the paediatric nephrologist is the successful management of the infant with end-stage renal failure (ESRF). At no other time are there so many emotional and ethical dilemmas, both for the family and the medical team. The birth of such an infant may have been preceded by months of parental anxiety, as termination of pregnancy may have been discussed, or foetal interventions undergone. Parents are fearful for the outcome of their baby, which can only be successful if there is full commitment from themselves and a highly skilled and resourced medical team. It is at this time of vulnerability that families and the medical team must discuss together the multiple factors affecting the management and potential outcome for their child, before making the decision to embark on long-term renal replacement therapy.
The scope of the problem
Although the acceptance of infants onto ESRF programmes has become increasingly common over the last 15 years, numbers remain small. In the UK, there were 18 children under 2 years of age, who were either on dialysis or had transplants in 1999, and 13 at a single time point in 2001 [1]. This represents 0.3 per million population per year, and is comparable with data from the USA of six new patients per million of the same age [2]. It is not known how many pregnancies are terminated because of renal anomalies, or the number of infants who are born with severe co-morbid conditions but not referred for ESRF management.
Although infants are only 12% of the paediatric ESRF population, they represent a disproportionately greater workload, as care of these infants is extremely labour intensive, both for the medical team and the families.
Diagnoses
The commonest diagnosis is renal dysplasia, with or without obstruction or reflux, of which two-thirds are boys with posterior urethral valves. Congenital nephrotic syndrome is the next most common diagnosis. Then, there are smaller numbers of other diagnoses, such as cortical necrosis usually due to birth asphyxia, autosomal recessive polycystic disease and other assorted causes [3]. Unlike any adult programme, the incidence of glomerulonephritis is very low. There is a preponderence of boys, which persists even when the posterior urethral valves are excluded, and is due to the higher incidence of renal dysplasia in males [1]. Approximately one-third of babies are diagnosed antenatally [3].
Prognostic indicators
Until recently, the prognosis for infants with ESRF was considered to be gloomy and paediatric nephrologists were undecided as to whether ESRF management is appropriate. Indeed, an international survey of paediatric nephrology units in 1998 showed that only 50% would offer dialysis to those under one year of age and 40% to those less than 1 month of age [4]. The number of studies on which to base discussions with families is small and long-term data are limited. However, what is available suggests that the mortality and outcome for growth, development and subsequent transplantation justifies such intensive treatment [3,5,6].
In our centre, survival between 1986 and 1998 for those presenting in the first 18 months of life with a glomerular filtration rate (GFR) of less than 20 ml/min/1.73 m2 was 87% at 1 year and 78% at 5 years. The most important influence on mortality was the presence of co-morbidity. Of the 12 deaths in the first 2 years of life in those who were actively treated, five had severe co-morbid conditions [3]. This has also been reported by Ellis et al. [7], although the mortality in this study of 21 infants was higher, at 43% within the first year of life. This study also identified that infants with oliguria fared worst, with 7 deaths out of 11 in this group. Pulmonary hypoplasia, which occurs in infants with abdominal distension due to enlarged kidneys, and in infants with oligohydramnios, is also an important adverse influence on outcome. The infant with congenital nephrotic syndrome has its own particular problems, which have been well described by the Finnish group [8]. However, even if survival extends past infancy, it cannot be expected that such children will have a normal life expectancy, and, as yet, there are no details of long-term survival rates.
What are the treatment options?
Options are palliative care; supportive care to monitor the effect of time on renal function before embarking on ESRF management; or an intensive policy of feeding and dialysis to ensure maximum brain and somatic growth to enable early transplantation.
Palliative and supportive care
There may be circumstances when the family believes that the pain and suffering that may be inflicted on their infant cannot be justified. This is particularly likely with infants with co-morbid conditions. Data shows that such infants do have a significantly increased mortality over children who are otherwise normal. In our series of 101 infants with ESRF, 13 were not actively managed, 10 of whom died in the first year of life. Three were otherwise normal, but 10 had severe co-morbidity such as Jeunes and Downs syndromes, cystic fibrosis, blindness and developmental delay. This increased mortality in children with other handicaps extended to those who were actively managed [3]. Parents of infants with co-morbid conditions must be counselled appropriately.
However, it may be difficult to predict with certainty the infant's renal prognosis. Over the first year of life there is a spontaneous improvement in GFR (ml/min/1.73 m2) in the normal infant, from 5 at 28 weeks gestation to 20 at term, to the adult value of 80 to 120 at 1 year. An improvement in renal function can also be seen in infants with chronic renal failure (CRF). Indeed, occasionally infants are able to come off dialysis. One study of 11 infants with renal dysplasia showed that only those with a calculated GFR of <15 ml/min/1.73 m2 at 6 months of age did not show an improvement in their renal function [9]. We found that the creatinine (mean (range) µmol/l) in children with renal dysplasia requiring dialysis or transplantation before the age of 5 years was surprisingly high, at 283 (159404) at 6 months of age and 358 (173776) at 1 year of age [3]. Furthermore, ESRF can persist for an unpredictable length of time, possibly many months, because approximately two-thirds of infants have polyuric CRF with large daily losses of water and electrolytes so that hypertension and hyperkalaemia are rare.
It is true that the decision to focus on palliative care rather than treatment aimed to cure or prolong life often evolves gradually. Different members of staff and family may be working towards the decision at different rates, and time and discussion are essential. However, without dietary supplementation and correction of electrolyte disturbances, intake is rarely adequate, and linear growth, which is maximal in the first 18 months, and brain growth, which is maximal in the first 3 to 6 months, is likely to be severely affected. During the period of waiting, therefore, not only is it likely that irreparable harm will occur, but also the family is likely to bond with the infant. This can sometimes lead to a reversal of the decision for palliative care.
Intensive management
Intensive management of infants is undertaken with a view to optimizing growth so that transplantation can take place at the earliest opportunity. The input from medical, nursing and dietetic staff, as well as from the family itself, is crucial to success. Carers must be made aware of the input that will be required of them. Overnight home dialysis frees them from three times weekly hospital visits for haemodialysis, but increases the burden at home. Most infants will require overnight feeds delivered via a pump. Unbroken sleep is rare due to machine alarms. Hospital visits for readjustment of feeds and the dialysis prescription are frequent. Complications of dialysis or surgery for the original disease or other complications often necessitate hospital admissions. This is undertaken with the constant knowledge that death may be the outcome. The stresses on the family, which are financial as well as emotional, cannot be overestimated.
Peritoneal dialysis
Overnight cycling peritoneal dialysis is the preferred option for dialysis in early life. Twelve to 14 hours of dialysis are usually prescribed, in order to provide adequate solute and volume removal for the infant diet. Catheter complications are common: an analysis of 20 infants dialysed in our centre for up to 6 years found that 12 required at least one catheter replacement. Peritonitis occurred at a rate of 1.1 episodes per patient-year. Four children died: one from pulmonary hypoplasia; one each from cerebral and bowel infarction; and one from an unknown cause. However, 15 children were successfully transplanted [5].
Haemodialysis
Haemodialysis is technically possible, but morbidity and mortality are high. In a retrospective review of 10 patients with ESRF weighing <10 kg dialysed in one centre over a period of 14 years, three died before 5 months of age. Clotting and infection of venous access occurred frequently, and adequate dialysis was difficult to achieve. Anaemia was common despite the use of erythropoietin, as the haemodialysis lines require blood priming and blood losses in the lines are high [10]. This places the child at risk of HLA sensitization and may preclude later transplantation.
Clinical management
The key to successful medical management is frequent review of the patients. This is because the rapid growth and high calorie requirement, particularly in the first year of life, mean that without regular increases in the dietary and dialysis prescriptions, the infant will quickly become inadequately dialysed and underfed. For example, an infant weighing 3.5 kg may have a peritoneal dialysis fill volume of 140 ml, and a feed of 525 ml. The expected weight gain would be 200 g per week, so that by 2 weeks, with a weight of 3.9 kg, the fill volume would require an increase from 140 to 160 ml and the feed should increase from 525 to 585 ml. Prevention of bone disease is particularly difficult in these infants and requires frequent adjustments of phosphate binders and activated vitamin D.
Dietary management
Spontaneous dietary intake is rarely adequate in infants with ESRF, who feed very poorly and have a high incidence of gastro-oesophageal reflux and vomiting. Calorie and protein requirements are as high as 150 calories/kg and 3 g protein/kg in infants on peritoneal dialysis, and even higher, at up to 180 calories/kg and 4 g protein/kg in premature infants [11]. Many infants with structural renal abnormalities have tubular losses of bicarbonate and sodium, and require supplementation. The majority requires enteral feeding in order to deliver these requirements and optimize growth. In our unit, 80% of infants are enterally fed. Over half have a gastrostomy, which is placed percutaneously in those with CRF, and created by an open procedure in children already established on peritoneal dialysis [12]. Nissen fundoplication is necessary in approximately half of these infants because of persistent vomiting [3].
Renal transplantation
Successful renal transplantation offers the best prognosis for growth and cognitive development in young children with ESRF, and removes the burden of chronic dialysis. Although early studies suggested an increased mortality and risk of graft loss in very young children, selected recent reports show results that are similar to those in older children [13,14]. One of the most important factors leading to improved outcome has been the recognition that young donor age increases the risk of transplant venous thrombosis, which is the principal cause of graft loss in small children. Results from parental donation are particularly good, but recipient age less than 2 years remains a significant risk factor for cadaveric graft loss [14]. In centres where there is surgical and medical expertise, and where there is a parental donor, there is, therefore, no reason to withhold transplantation until a particular age or size is reached. In our centre, we prefer to undertake all childhood vaccinations before transplantation, and this is rarely achievable before 18 months of age.
Growth
The concept that CRF presenting in the first 2 years of life may have a long-standing adverse effect on height prognosis is well known [15]. Growth at this time is principally dependent on nutrition rather than growth hormone (GH): as many as 150 calories per day are stored in new tissue and the rate of growth is as high as 1.5 cm per month in the first 6 months of life. Without strict attention to dietary intake, growth rates rapidly become subnormal, so that by 3 months of age the height standard deviation score (Ht SDS) may fall by 1 SD [16]. However, considerable catch-up growth in both length and head circumference can occur with aggressive nutritional therapy [3,5]. Mean Ht SDS and head circumference SDS increased over 1 year from -1.8 to -1.1 and -1.9 to -0.9, respectively, in 20 infants on peritoneal dialysis in our centre [5]. Another treatment option for infants with CRF is recombinant human GH, which gives results similar to those seen with intensive nutrition, and should be reserved, therefore, for infants that have not responded to enteral feeding [3,16].
Long-term emotional and developmental outcome
The small number of studies that are available have demonstrated good outcomes for up to 15 years for infants with ESRF. In the study from our unit, 14 of the 16 survivors have normal development [5]. Warady et al. [17] found that of 28 survivors of 34 infants who began dialysis before 3 months of age, only one was developmentally delayed, and all but one attended mainstream school.
Conclusions
The management of infants with ESRF is challenging for families and the medical team. Survival in otherwise normal infants is similar to older children and, with aggressive medical intervention, the prognosis for growth and development is good. However, the long-term outcome remains unknown.
Notes
Correspondence and offprint requests to: Dr Lesley Rees MD FRCP FRCPCH, Consultant Paediatric Nephrologist, Renal Office, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK. Email: Reesl{at}gosh.nhs.uk
References