Chronic dialysis in children and adolescents: challenges and outcomes

Review

Chronic dialysis in children and adolescents: challenges and outcomes Lesley Rees, Franz Schaefer, Claus Peter Schmitt, Rukshana Shroff, Bradley A Warady

Chronic dialysis is rarely required during childhood. Despite technical advances that have facilitated the treatment of even the youngest children, morbidity and mortality remain higher with chronic dialysis than after renal transplantation. The cost of equipment and skilled personnel to provide the service compromises the availability of such dialysis in parts of the world where financial resources are constrained. This Review describes the incidence and causes of end-stage kidney disease in children on long-term dialysis, and highlights management issues, including dialysis modality selection, complications, and patient outcome data.

Introduction Children and adolescents with such severe chronic kidney disease that they require renal replacement therapy (RRT), which includes dialysis or transplantation, are uncommon. RRT for older children started in the 1970s, and since then developments in general understanding of the management of complications and improvement in technical aspects have facilitated the treatment from birth. These children will spend the rest of their lives dependent on RRT, so strict attention to optimising their care is crucial if they are to experience extended and productive lives. This notion is particularly true for their time on dialysis, which is associated with increased morbidity and mortality compared with transplantation. This Review will focus on the aspects of chronic dialysis therapy that are specific to childhood and adolescence (defined here as 10–21 years of age).

Disease incidence The reported incidence of end-stage kidney disease and the need for RRT in children varies around the globe, with the differences related to genetic and environmental factors, and the economic capacity to treat affected children.1,2 The median incidence of such disease in children younger than 19 years worldwide is nine cases (range four to 18) per million of the age-related population (pmarp), with the prevalence of RRT ranging from 18 to 100 pmarp.3 In the USA, the incidence of RRT was reported as 14·2 per million children (aged <21 years) in 2014, which represented 1398 children.4 In Europe, the incidence of RRT in children younger than 20 years old was estimated to be 8·9 pmarp (for 2007–11), whereas it was 5·5 pmarp (for 2009–11) for children younger than 15 years old.5,6

Disease spectrum Data published from the US Renal Data System revealed the most common disease categories for paediatric patients with end-stage kidney disease in 2010–14 were primary glomerular disease (25·3%), congenital anomalies of the kidney and urinary tract (CAKUT; 24·1%), cystic, hereditary, or congenital disorders (14·3%), and secondary glomerular disease (12·4%; figure 1).4 The North American Pediatric Renal Trials and Collaborative

Studies (NAPRTCS) found that CAKUT represented the largest disease category, accounting for 35% of patients undergoing dialysis. The most common individual diagnoses in NAPRTCS consisted of focal segmental glomerulosclerosis (14·4%), renal aplasia, hypoplasia, or dysplasia (14·2%), and obstructive uropathy (12·6%).7 In Europe, the proportions of children with CAKUT (58–59%) and hereditary nephropathy (15–19%) are slightly higher than in the NAPRTCS database, while glomerulonephritis is lower (5–7%); this discrepancy could be due to the differences in racial distribution.3 For example, focal segmental glomerulosclerosis accounts for 30% of all black patients older than 13 years in the NAPRTCS database, which is in part related to the high

Lancet Child Adolesc Health Published Online July 19, 2017 http://dx.doi.org/10.1016/ S2352-4642(17)30018-4 Renal Office, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK (Prof L Rees MD, R Shroff PhD); Division of Pediatric Nephrology and Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany (Prof F Schaefer MD, C P Schmitt MD); and Division of Pediatric Nephrology, Children’s Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA (Prof B A Warady MD)

Key messages • The global prevalence of children requiring renal replacement therapy is 18–100 per million age-related population. This variability is primarily related to economic differences around the world. • Congenital anomalies of the kidney and urinary tract are the most common cause of end-stage kidney disease in children; prevalence of these anomalies decreases proportinately with age, whereas glomerular disease prevalence increases. • Peritoneal dialysis is used more commonly in infants, in whom vascular access can be difficult. Thereafter, preferences vary around the world. For peritoneal dialysis and haemodialysis, dialysis access sites need to be preserved as children have a lifetime of renal replacement therapy ahead of them. • New developments include new peritoneal dialysis fluids, new programmes allowing better fluid and solute clearances on peritoneal dialysis, remote programming, and monitoring using internet connections. The availability of portable home haemodialysis machines, machines to dialyse premature infants, haemodiafiltration, and extended dialysis programmes should enhance the capacity to provide effective dialysis to all children with end-stage kidney disease. • Chronic kidney disease-mineral bone disorders are a notable complication that not only causes bone pain, fractures, and poor growth, but can also lead to vascular calcification and cardiovascular disease, which is the most common cause of death in patients on dialysis at all ages. • Poor growth is another important complication of chronic kidney disease, with 50% of patients being below the 3rd centile. However, growth outcomes are improving. • 5-year patient survival is around 90%, but is lower for infants. Survival is reduced by the presence of comorbidities, late referral, and low socioeconomic status. • A specially trained multidisciplinary team is needed to provide optimal care of children on dialysis.

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Correspondence to: Prof Lesley Rees, Renal Office, Great Ormond St Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK [email protected]

Other causes CAKUT

CHC diseases Secondary glomerulonephritis Primary glomerulonephritis

100

Percentage of patients (%)

80

60

40

20

0

0–4

5–9

10–13 Age group (years)

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Figure 1: Distribution of primary cause of end-stage renal disease, by age, in incident paediatric dialysis patients reported to USRDS in 2010–144 The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government. USRDS=US Renal Data System. CAKUT=congenital anomalies of the kidney and urinary tract. CHC=cystic, hereditary, and congenital.

prevalence of focal segmental glomerulosclerosis in black patients who possess the high risk APOL1 genotype.8 The distribution of causes also varies substantially with age, with CAKUT being the predominant disorder in younger patients and glom­erulonephritis the leading cause of endstage kidney disease in the adolescent population.

Global access to dialysis Approximately 80% of all paediatric patients who receive RRT live in Europe, North America, or Japan, where virtually all children with end-stage kidney disease have access to RRT. By contrast, RRT is scarce or not available in low-income and middle-income countries where there are few fiscal resources and a lack of trained personnel. Constraints placed on health-care budgets by local health authorities and because the annual cost of dialysis can exceed the gross domestic income per capita of most lowincome and middle-income countries means that dialysis is prohibitively expensive in many such countries.9 For example, in a comprehensive systematic review of publications related to the availability, quality, and outcomes of dialysis treatment for patients with end-stage kidney disease in sub-Saharan Africa, only 61% of children with the disease received one or more dialysis sessions, and only 35% of children remained on dialysis for at least 3 months. This short treatment was probably owing to the families being unable to pay for therapy.10 The mortality of those who required but did not receive dialysis was 95%. The effect of macroeconomic factors on dialysis availability has also been addressed in an analysis of the International Pediatric Dialysis Network (IPDN) registry, which includes information from 33 countries with a wide range of gross national incomes.2 In countries with a low annual 2

per-capita gross national income (
Choice of RRT modality Owing to superior survival and quality of life, transplantation is the primary choice of RRT in children.3 If pre-emptive transplantation is not feasible, two dialysis options are available, peritoneal dialysis and haemo­ dialysis. Peritoneal dialysis is undertaken at home and therefore is the most compatible with children’s schooling and social life. However, the feasibility of this strategy strongly depends on the families’ willingness and capacity to take responsibility for ambulatory medical care. Although haemodialysis has traditionally been conducted in a dialysis centre, home-based treatment is becoming increasingly popular because of the availability of portable machines. There is no difference in morbidity and mortality between peritoneal dialysis and haemodialysis in children and adolescents. Peritoneal dialysis is generally preferred in infants as vascular access for haemodialysis can be difficult to achieve and to maintain, especially in infants, although with skilled personnel, even neonates can be haemodialysed successfully.12 Peritoneal dialysis can be initiated from birth and continued until transplantation when a bodyweight of 8–10 kg is reached (ie, at 1·5–2 years).

Peritoneal dialysis Peritoneal dialysis provides a cost-effective approach to RRT, without the personnel and space required for in-centre haemodialysis. The dialysate is delivered by a Tenckhoff catheter that is surgically positioned in the pelvis via a subcutaneous tunnel. The peritoneal membrane acts as the dialyser. Dialysis exchanges can be done manually or by machine (cycler) delivery. Although manual peritoneal dialysis with 3–4 exchanges of dialysate per day is cheaper than is cycler-based therapy, it provides inadequate solute and fluid removal in children with poor residual renal function and during infancy when their high nutritional requirements are achieved by liquid formulae. Therefore, most children are dialysed using

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cycler machines that deliver dialysate exchanges overnight and allow normal activities during the day. The number of cycles and concentration of the osmotic agent (glucose) within the dialysate can be adjusted according to the requirements for toxin and fluid removal (ultrafiltration). Peritoneal blood vessel density decreases with age, from the highest levels in infancy, thus solute removal rates decrease proportionately.13 This situation also leads to a reduced ultrafiltration capacity because of the increased resorption speed of the osmotic agent, so infants require shorter dialysis cycles than do older children to maintain the osmotic gradient. The volume of dialysate exchanged with each cycle is tailored to the child’s body surface area, specifically 600–800 mL/m² in those younger than 2 years and 1000–1400 mL/m² in older children, to maintain the intraperitoneal pressure at less than 14 cm of water in children older than 2 years and 8–10 cm of water in younger children.14 A high intraperitoneal pressure will prevent ultrafiltration, interfere with food intake, and increase the risk of hernia formation. Removal of fluid is particularly problematic in children, especially if there is anuria, because an infant’s diet is mostly liquid, and compliance with fluid restrictions is not always possible. This problem has led to the development of cyclers that can deliver short small exchanges at the beginning of the night to favour water removal, followed by longer and larger dwells to improve solute removal.15 This approach is termed adapted peritoneal dialysis. Another new development is cyclers that are connected online to the dialysis centre so that programmes can be read and changed remotely by peritoneal dialysis centre staff. This technology facilitates communication between patients or caregivers and physicians or nurses and ensures problems are detected quickly. Although peritoneal dialysis preserves the vascular reserve required for lifelong RRT and allows greater individual freedom compared with haemodialysis, it also has disadvantages. Infection at the exit site, in the subcutaneous tunnel of the catheter, or in the peritoneal cavity are common.16 Ultrafiltration and purification capacity are less efficient than for haemodialysis and can result in inadequately controlled fluid and salt homoeostasis, and bone disease in 50% of children.17 Dialysate bioincompatibility causes sclerosis of the peritoneum with a resultant loss of capacity for fluid and toxin exchange and the potential for encapsulating peritonitis, which is when the peritoneum becomes thickened and fibrosed, affecting intestinal peristalsis and leading to intestinal obstruction and malnutrition.18 Peritoneal dialysis fluids with a neutral pH and low toxic glucose degradation product content have been licensed in Europe for 15 years, but are not used worldwide. These fluids help preserve residual renal function and long-term peritoneal function, and are associated with decreased peritonitis rates.19 However, IPDN data show that 69% of

the 3200 paediatric patients undergoing peritoneal dialysis who were followed up in 43 countries over the past 10 years were treated with the less expensive, acidic fluids containing high amounts of glucose degradation products.

Haemodialysis The proportion of patients on haemodialysis compared with peritoneal dialysis increases with age. Haemodialysis is usually performed in-centre three times per week for 3–5 h per session. To obtain high blood flow rates of 140–200 mL/min per m² body surface area, which are necessary for good clearance in a dialysis session of reasonable duration, high-quality vascular access is crucial. An arteriovenous fistula is superior to a central venous haemodialysis catheter because it allows the insertion of wide bore needles to enable such high blood flows. In children younger than 6–8 years, fistula formation is a technically challenging surgical procedure and psychological preparation is needed for the painful needling. Central venous catheters are still used by most paediatric haemodialysis units. Although the catheters allow for high blood flow rates, they are associated with a much higher risk of infection and dysfunction than is seen with fistulas.20 Part of the preference for catheters is explained by the expectation of timely kidney transplantation in children. However, this expectation is one that should be critically reviewed because waiting times for deceased donor kidney transplantation vary considerably; in Europe the median waiting time is 11 months, ranging from 4 months in Scandinavian countries to more than 3 years in Turkey.21 Dialysers and lines need to be tailored to the size of the child; although the more blood that is processed, the better the clearances, this advantage should be balanced against what is a safe extracorporeal circulation. The lines and haemodialyser are selected on the basis that the child can tolerate 8% (up to a maximum of 10%) of their total blood volume (80 mL/kg estimated optimum weight) in the extracorporeal circuit. However, there are specific problems in infants because the extracorporeal volume can reach a third of total blood volume in neonates. Currently used paediatric dialysers and lines have a fill volume of greater than 70 mL, which exceeds the safe extracorporeal blood volume for the smallest patients. The circuit, which is primed with saline in bigger children, therefore needs to be primed with albumin or red blood cells, or both, in infants and young children. The dangers of recurrent blood primes are that human leucocyte antigen sensitisation can occur, resulting in a reduction in the potential kidney transplant donor pool. Children might also find it difficult to comply with their fluid allowance, particularly if it is low because of oliguria. Adequate fluid removal could then be difficult as ultrafiltration rates exceeding 13 mL/kg per h and 8% of bodyweight per haemodialysis session are usually less tolerated. Furthermore, high rates of ultrafiltration are associated with regional left ventricular wall motion

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For more on the International Pediatric Dialysis Network see www.pedpd.org

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abnormalities, so-called stunning, which can lead to irreversible cardiac damage.22 Such patients, therefore, might need haemodialysis more than three times per week. As with peritoneal dialysis, haemodialysis has improved in recent years. High-flux dialysers have improved clearance rates, especially of larger toxins. New machines combine diffusive and convective solute transport (haemodiafiltration) and generate ultrapure dialysate and infusion fluids online (ie, while in use). In-centre online haemodiafiltration23 and extended dialysis sessions, either as overnight in-centre haemodialysis or haemodia­ filtration,24 frequent home haemodialysis,25 or daily nocturnal home dialysis,26 improve blood pressure and electrolyte homoeostasis despite little or no dietary restrictions, and do not affect health-related quality of life or school attendance. Catch-up growth is also observed with frequent online haemodiafiltration.23 Similar to findings in adult patients undergoing haemodialysis, these observations suggest intensified regimens in children have major advantages. However, implementation into clinical practice remains limited to a few paediatric centres. According to a recent survey within 134 IPDN centres, inadequate funding is a major barrier to implementation. Portable haemodialysis machines are easy to operate and use domestic, sterile-filtered water supplemented with electrolytes and buffer. Although they are licensed for use in individuals weighing more than 30 kg, some centres have adapted them for use in children weighing as little as 10 kg. Combining home haemodialysis systems with telemetric functions for online surveillance by paediatric dialysis centres might promote intensified dialysis regimens on a broader scale and thus potentially improve the outcomes of children without substantially increasing costs. Notably, CARPEDIEM (Bellco, Mirandola, Italy) and NIDUS (Allmed Medical Care, London, UK) haemo­ dialysis machines have been designed for acute and chronic haemodialysis for infants weighing as little as 800 g. These machines use slow motion pumps (5–50 mL/min), highly sensitive precision scales, and miniaturised tubing and filter systems with an extracorporeal priming volume of less than 20 mL.27 They have successfully been used for treatment of acute kidney injury and, in the future, might be applied in infants who are not suitable for chronic peritoneal dialysis.

Psychosocial issues Administration of chronic dialysis care to children is associated with various psychosocial issues that affect the patient and their family, which highlights the importance of having social workers, psychologists, and play therapists as part of the multidisciplinary dialysis team.28 Global health-related quality-of-life scores in children who receive long-term dialysis are lower than are those seen in most other chronic conditions, except for cancer.29 Depression is particularly common and is probably 4

related to the dependence on a machine for survival and the frequent absenteeism from school because of dialysis needs or admission to hospital. Caregivers often find it difficult to fulfil their roles as parents and health-care providers.30 The stress caused by the responsibilities regarding the provision of care, concerns about their potential role in complications experienced by their child, and the trauma associated with watching their child undergo invasive procedures can be accompanied by spousal tension and sibling neglect. Depression has also been well documented in parents caring for children receiving home-based peritoneal dialysis, thus regular screening of their physical and psychosocial wellbeing is required to ensure prompt intervention when necessary.31

Chronic kidney disease–mineral and bone disorder One complication of dialysis that is particularly important in children because of its potential interference with growth and cardiovascular health is chronic kidney disease–mineral and bone disorder (CKD–MBD). The kidneys have an important role in regulating calcium and phosphate homoeostasis. In the early stages of chronic kidney disease, compensatory mechanisms mediated by vitamin D, parathyroid hormone, and fibroblast growth factor 23 maintain calcium and phosphate in the normal range.32,33 However, for children on conventional haemodialysis (three times a week) or peritoneal dialysis (daily), phosphate clearance is inadequate, and dietary phosphate control and oral phosphate binders can be insufficient to prevent hyperphosphataemia. Plasma calcium depends on dietary intake and dialysis clearance, particularly in children with poor urine output, and levels can be high or low. High phosphate levels stimulate excess fibroblast growth factor 23 production and increase parathyroid hormone; together, these changes can promote bone demineralisation and cause vascular calcification.32,34,35 In parallel, reduced production of active vitamin D by the failing kidneys leads to hypocalcaemia. If hypocalcaemia is not corrected, calcium is mobilised from the bone into the circulation via increased parathyroid hormone and fibroblast growth factor 23, leading to bone demineralisation. The mineral dysregulation in endstage kidney disease directly affects bone strength, which is largely influenced by bone mineralisation, and architecture.36 Notably, as calcium is mobilised out of the bone and the bone loses its normal formation-resorption activity, excess calcium and phosphate could deposit in soft tissues, causing vascular calcification (figure 2).34 The growing skeleton is uniquely vulnerable. Children on dialysis develop reduced bone mineral accrual, which causes bone pain, deformities, growth retardation, and fractures. The IPDN noted clinical symptoms or radiological signs of bone disease in 15% of patients, including radiological signs of osteodystrophy or rickets, radiological osteopenia, limb deformities, bone pain, and short stature.17 Abnormal bone micro-architecture and

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Chronic kidney disease

↓1,25-dihydroxyvitamin D3 production

↑Phosphate retention

↓Calcium absorption ↑FGF23 Parathyroid hormone

Phosphate binders

+/– increase calcium burden

Calcium and phosphate release from bone

Chronic kidney disease— mineral and bone disorder

Laboratory abnormalities

Bone abnormalities CVD fractures mortality

Vascular calcification

Figure 2: Mineral and bone disorder in children with chronic kidney disease, and the potential link with vascular calcification CVD=cardiovascular disease. FGF23=fibroblast growth factor 23.

mineralisation defects are common and are associated with calcium status; on bone biopsy more than 90% of children on dialysis had deficient mineralisation33,37 and fracture risk is 2–3-times higher in boys and girls with chronic kidney disease than it is in their healthy peers.38 Low bone mineral density, low serum Ca, and high parathyroid hormone levels are associated with an increased fracture risk in clinical studies and on bone histology.32,33,37 Several studies have shown that children starting dialysis have a high burden of cardiovascular risk factors, many of which are modifiable.34,35,39–41 High calcium, phosphate , and parathyroid hormone levels, and time on dialysis are associated with changes in vessel structure, increased vessel stiffness, and coronary artery calcification.40–42 In young adults (20–30 years) on dialysis, coronary artery calcification score can double within 20 months, and progressive vascular disease has been associated with higher serum calcium-phosphate product, doses of calcium-based phosphate binders,40 and active vitamin D compounds. When vascular smooth muscle cells are exposed to raised calcium and phosphate levels, they undergo apoptosis and differentiate into bone-like cells; this process is active and highly regulated, similar to bone

ossification.39 A process of accelerated ageing also occurs in dialysis vessels; this process is thought to be driven by overexpression of a mutant nuclear protein called prelamin A that causes DNA damage and vascular senescence.34 The management of CKD–MBD remains challenging, with few evidence-based studies to guide clinical practice. Children on dialysis can suffer from either calcium deficiency, potentially causing an increased fracture risk, or excess calcium, which has been linked with vascular calcification. The growing skeleton has a high demand for calcium; in healthy individuals, the calcium content of the skeleton increases from about 25 g at birth to about 1000 g in adults, with about 25% of total skeletal mass accrued during the 2-year interval of peak height velocity.43 Thus, extrapolating practices from adult studies is not appropriate. Current paediatric consensus guidelines recommend keeping serum calcium and phosphate in the age-appropriate normal range, but guidelines on parathyroid hormone vary considerably.44,45 Intensified dialysis, either using prolonged overnight haemodialysis sessions or more frequent haemodialysis (particularly haemodiafiltration) considerably improves phosphate clearance.23–26 The effects of using different phosphate

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0·5 0

Height standard deviation score

−0·5 −1·0 −1·5 −2·0 −2·5 −3·0 −3·5 −4·0

Cz

ec Can h R ad ep a ub Fr lic an Ne C ce w hin Ze a ala Fin nd lan S d Ge pain rm an y So ut U hK K or Gr ea ee Po ce lan d US A Ch ile I Hu taly n Sin ga ga ry po Un re ite d A U Ind ra rug ia bE u m ay ira M tes Co exic Sa lom o ud b i A ia Ar rab ge ia nt i Tu na M rke ala y ys ia Pe ru Ira n

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New Zealand Asia Europe Latin America Middle East North America Turkey

Countries

Figure 3: Mean height standard deviation score for children on dialysis by country (International Pediatric Dialysis Network data) Dotted line shows the mean expected height standard deviation score.

binders to reduce phosphate in bone disease32,43 and of native and active vitamin D analogues in the prevention and treatment of CKD-MBD in children has been demonstrated in multiple association studies.43–45 How­ ever, there are few data for important patient-centred outcomes, such as fracture risk, bone deformities, growth, and cardiovascular health.

Cardiovascular disease Cardiovascular disease is the most common cause of mortality in children on dialysis, accounting for 30% of all deaths.34 Important risk factors include CKD-MBD and chronic fluid overload, which then lead to vascular calcification, progressive vessel stiffness, left ventricular failure, and sudden death.34,35 Chronic fluid overload is common in patients on dialysis, particularly if urine output is poor and leads to left ventricular hypertrophy, because fluid removal is dependent on ultrafiltration during dialysis.35 Further damage to the myocardium occurs with the removal of large volumes of fluid during a haemodialysis session because of excessive intradialytic weight gain, particularly if the rate of fluid removal is high.22 Hypertension is prevalent in patients with chronic kidney disease and increases in children on dialysis; notably, 50–75% of children on peritoneal dialysis or haemodialysis have hypertension.35 Hypertension is the strongest independent predictor of left ventricular hyper­ trophy in children with chronic kidney disease (stages 2–4), whereas other risk factors, such as anaemia and hyperparathyroidism, are associated with left ventricular hypertrophy and myocardial dysfunction in children on dialysis.34,35 There are two distinct geometric patterns of left ventricular hypertrophy, namely concentric, which is 6

primarily mediated by pressure overload caused by hypertension, altered vascular tone, and sympathetic overactivity, and eccentric, which is related to volume overload. In its early stages, left ventricular hypertrophy could be an adaptive response to maintain cardiac function and reduce left ventricular wall stress during conditions of increased afterload and preload. However, paradoxically, this hypertrophic remodelling is associated with a worse outcome in that a substantial proportion of children with left ventricular hypertrophy and stage 2–5 chronic kidney disease have impaired subclinical systolic dysfunction, which is characterised by lower radial and circumferential left ventricular strain paired with mild cardiac systolic dyssynchrony.36,42 Anti-hypertensive treatment is prescribed to patients with chronic kidney disease as necessary, but the most important therapeutic measure is regular counselling about the importance of keeping to a salt-restricted diet and a fluid allowance, based on urine output and the safe volume of fluid that can be removed at the next dialysis session.

Long-term outcomes Outcomes for final height, quality of life, and adaptation to the demands of adulthood are inextricably linked. Each is affected by the primary renal diagnosis, comorbidities, and the resources and care that is available during childhood. Some children with chronic kidney disease are born with incurable conditions that adversely affect their wellbeing throughout childhood and into adult life. The proportion of children that start RRT in infancy that are born prematurely or small for gestational age is as high as 50% and this contributes to growth difficulties. Comorbidities affect 70% of such infants and influence survival, growth, development, and quality of life.46

Growth Optimisation of growth is one of the most important challenges for paediatric nephrologists. Although growth outcomes have improved as our understanding of the best management of these children has increased, in Europe and the USA about 50% of children have a height that is below the normal range when starting RRT, and this situation often becomes worse during dialysis. Males tend to be shorter than females, although the rate of decline is not different.7,47 Figure 3 shows the mean height standard deviation score (HtSDS) of children in 28 countries that reported to the IPDN in 2016. HtSDS varies worldwide from –1·4 to –3·5. The differences are likely to reflect, in part, regional variations in resources.6 Growth at all ages and all stages of chronic kidney disease can be optimised by paying attention to the correction of fluid, electrolyte and acid-base balance, metabolic bone disease, anaemia, nutrition, and growth hormone resistance. The influence of these factors is especially important in the first 2 years of life,

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Proportion of patients (age <18 years) treated with recombinant human growth hormone

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lo M mb ala ia ys i Sa ud Pe a i A ru ra Ur bi ug a u Tu ay rk Ch ey in Ch a ile UK In di a I Ne Ca ran n w a Z d Ar eala a ge nd n P tin Sin olan a ga d Un p ite M ore ex dA ra Fin ico b E la m nd ira Cz te ec h R It s ep aly u So G blic ut ree h K ce or ea Hu US n A Ge gar rm y a Fr ny an Sp ce ain

0

Co

when the rate of growth is particularly vulnerable because it is greater than at any other time and is mostly dependent on nutrition. Adequate nutritional intake can be difficult to maintain in infants because they are prone to anorexia and vomiting. HtSDS can decline by 2–3 SD in the first 6 months of life, and this decrease can have a permanent effect on future height potential. At the start of dialysis, the HtSDS of children younger than 1 year old averages –2·5 SD, and –2 SD in those aged 2–5 years old.48 Some catch-up growth is possible with the early institution of enteral feeds (especially if given via gastrostomy), and the use of physiological pH peritoneal dialysis solutions and recombinant human growth hormone.49 This situation is in contrast to the experience with older children who often have less of a height deficit at the start of RRT, but almost universally grow poorly on dialysis.7 In general, children with the greatest deficiencies of height have more severe chronic kidney disease-related disturbances and are therefore most likely to benefit from correction by dialysis, so much so that children of a height below the normal range improve on dialysis, whereas children of a normal height do not improve as much.7 This outcome is also the case with growth hormone treatment. The rationale for the use of recombinant human growth hormone is that, despite high levels of growth hormone in blood, IGF-1 bioactivity is low because of high IGF binding protein levels in blood and poor growth. Recombinant human growth hormone improves the availability of bioactive IGF-1. Although it benefits children of all ages, it is particularly effective in younger children because the effects diminish with age.47,49 The proportion of patients treated with this therapy varies worldwide. The current distribution, as determined from the IPDN database, is shown in figure 4. The lack of similarity between the use of recombinant human growth hormone and HtSDS in the same population (figures 3, 4) shows that such hormone therapy is not the only factor that improves HtSDS and shows the importance of pretreatment factors, such as age and HtSDS, at the start of therapy. Prompt attention to the correction of nutritional, haematological, and metabolic abnormalities, and the timely use of recombinant human growth hormone when these measures fail, offer the best possible growth outcome. Although there are no clear differences in growth between children on peritoneal dialysis and those who receive in-centre haemodialysis three times a week, intensified regimens such as short daily haemodia­ filtration or slow overnight dialysis show particular promise, with children reaching centiles predicted from parental heights.24 Notably, final height is improving such that in Europe between 1990 and 2011, 55% of patients attained an adult height within the normal range, whereas this figure has risen to 62% for 2006–11.50 This increase is

Countries

Figure 4: Proportion of patients (<18 years) in the International Pediatric Dialysis Network database treated with recombinant human growth hormone by country (International Pediatric Dialysis Network data)

particularly important as poor growth has been linked to worse psychosocial outcomes and increased mortality risk.51

Psychosocial outcomes Young adults who had end-stage kidney disease throughout childhood have delayed autonomy, and psycho­ sexual and social development. Data from 30 years of follow-up showed that, by then, 70% of individuals have a partner, although a large proportion, particularly those on dialysis, are still living with their parents. It is rare for a patient on dialysis to become a parent. However, patients who start RRT in infancy, rather than in later childhood, do not have worse outcomes; 68% of such young adults have an educational level that is similar to that of their parents. Unemployment rates of adults who start RRT in infancy are 17% in the UK, 20% in Holland, and 14% in Germany, and compare favourably with that of the healthy age-matched population. An association between level of educational attainment and RRT modality or total time spent on RRT has not been consistently shown.52

Patient survival All-cause mortality rates are at least 30 times higher for children on dialysis than for the general paediatric population, and are significantly higher than that of the transplant population.53 The overall 5-year survival rate in European children starting dialysis between 2005 and 2010 was 89·5%.53 Data from the Australia and New Zealand Dialysis and Transplant registry showed mortality rates of 4·8 per 100 patient-years for children receiving haemodialysis, 5·9 per 100 patient-years for peritoneal dialysis, and 1·1 per 100 patient-years for

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For the Australia and New Zealand Dialysis and Transplant registry see www.anzdata.org.au/v1

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Death

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Dialysis survival

We searched MEDLINE and relevant specialty journals for articles published between Jan 1, 1980, and Jan 1, 2017, with the terms “incidence”, “epidemiology”, “mortality”, “morbidity”, “CKD-MBD”, “left ventricular hypertrophy”, “bone disease”, “growth”, “psychosocial”, “outcome” and “haemodialysis”, “peritoneal dialysis”, “children” or “infants”. We only searched for articles published in English, or those translated into English.

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Figure 5: Survival after the start of renal replacement therapy, and the probability of getting a transplant Reproduced with permission from van Stralen and colleagues.57

children receiving a functioning transplant, respectively between 1963 and 2002.54 In addition, the US Renal Data System reported that the expected remaining lifetime for males and females (0–14 years old) was only 24·1 and 22·4 years, respectively, for patients undergoing dialysis versus 59·2 and 61·2 years for transplant recipients based on 2013 data.4 Mortality is particularly high in the infant age group, with reported rates in children younger than 5 years of 49·4 deaths per 1000 patient-years in Europe and 83·4 deaths per 1000 patient-years in the USA, compared with 16·5 in Europe and 25·9 in the USA for older individuals.53,55 Data from four registries on 264 patients who started chronic dialysis as neonates showed a 5-year survival rate of 76% (figure 5).56 However, analyses of historical registry data have shown that survival rates of children receiving chronic dialysis are continuously improving, with mortality risk reductions of 20% (in children under 5 years) and 12% (in older children) for each 5 calendar years between 1990 and 2010.55 Mortality risk is highest during the first year of dialysis; late referral to paediatric nephrology care appears to be a risk factor for early mortality, particularly for children in whom haemodialysis is chosen as the initial treatment.53 An increased risk of death on dialysis has also been associated with the diagnosis of glomerulonephritis, the presence of comorbidities, low socioeconomic status, and reduced access to trans­plantation.36,57,58 A study of the European Society of Pediatric Nephrology, European Renal Association-European Dialysis, and Transplant Association Registry also identified the crucial role of macroeconomic factors in the survival of children undergoing RRT.59 In more than 7000 patients younger 8

than 19 years who initiated RRT across 32 European countries between 2000 and 2013, the percentage of GDP spent on health care was inversely associated with mortality risk and explained 67% of the variation in mortality rates between countries. Additionally, whereas mortality risk was independent of dialysis modality in countries with GDP per capita exceeding $35 000, patients in poorer countries were 66% more likely to die when initiating RRT with haemodialysis as compared with peritoneal dialysis.

Conclusions and future directions Optimal management of a child on dialysis requires skilled parents and a multidisciplinary team of nephrologists, transplantation surgeons, radiologists, nurses, dieticians, psychotherapists, social workers, play therapists, and school teachers who are all specially trained in paediatric care. Given the rarity of chronic dialysis in children, only multicentre, multinational registries and studies will be able to answer the many outstanding questions regarding the best treatments and how they affect outcomes. As a paediatric nephrology community, we are on our way to achieving this, although a great deal still needs to be accomplished to deliver a worldwide provision of care for all children with endstage kidney disease. Contributors All authors contributed equally to the writing of this review. LR coordinated the contributions. Declaration of interests We declare no competing interests. Acknowledgments This work was supported by the UK National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. RS holds a Career Development Fellowship with the UK National Institute for Health Research. References 1 Bertram JF, Goldstein SL, Pape L, et al. Kidney disease in children: latest advances and remaining challenges. Nat Rev Nephrol 2016; 12: 182–91. 2 Schaefer F, Borzych-Duzalka D, Azocar M, et al. Impact of global economic disparities on practices and outcomes of chronic peritoneal dialysis in children: insights from the International Pediatric Peritoneal Dialysis Network Registry. Perit Dial Int 2012; 32: 399–409. 3 Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol 2012; 27: 363–73.

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