REVIEW URRENT C OPINION
Growth in children with chronic kidney disease: role of nutrition, growth hormone, dialysis, and steroids Elizabeth G. Ingulli and Robert H. Mak
Purpose of review Children with chronic kidney disease (CKD) have impaired growth that leads to short stature in adulthood. The problem persists even with successful transplantation and steroid withdrawal protocols. The aim of this review is to provide an overview of the pressing issues related to growth failure in children with CKD both before and after transplantation. Recent findings Although great strides have been made in dialysis and transplantation, the incidence of abnormal adult height in children growing up with CKD remains as high as 45–60%. The lack of catch-up growth and resultant short stature is a critical issue for self-esteem and quality of life in many children with CKD. Aggressive daily dialysis, improved nutrition, treatment of metabolic bone disease, and the use of recombinant human growth hormone provide some hope for catch-up growth in select patients. Summary The causes of growth failure in the setting of CKD are multifactorial. Attention to all the details by optimizing nutritional, bone and mineral metabolism, correcting metabolic acidosis and anemia, achieving excellent blood pressure control, reversing cardiovascular complications such as left ventricular hypertrophy, and minimizing the use of corticosteroids is the current standard of care. Aggressive daily dialysis can reverse many of the uremic derangements. For patients not yet on dialysis or for those after renal transplant, early institution of recombinant human growth hormone can promote growth. Improved understanding of the mechanisms of hormone resistance may offer novel targets or measurements of treatment effectiveness. Keywords cachexia, chronic kidney disease, growth failure, nutrition, pediatrics, quality of life, recombinant human growth hormone, renal transplantation
INTRODUCTION Growth failure is a major complication observed in children with chronic kidney disease (CKD) and does not always resolve after successful transplantation. The association of kidney disease and short stature was first reported in 1897 [1]. Despite many advances in the care of children with CKD, including optimizing nutrition, aggressive dialysis, recombinant human growth hormone (rhGH) therapy, and renal transplantation, the number of short adults with CKD is staggering with estimations as high as 30–60% [2,3,4 ]. Short stature is defined as a height of two standard deviation scores below the mean for age and sex. This corresponds to a height below the 2.5 percentile. The degree of renal dysfunction correlates with &&
the degree of growth failure and children with endstage renal disease (ESRD) on chronic dialysis have the most profound growth losses [5]. It is estimated that one quarter to one third of children on dialysis are well below the normal range for height. In addition, registry studies have shown that children with CKD have progressive growth failure over time Division of Pediatric Nephrology, Rady Children’s Hospital San Diego, University of California, San Diego, La Jolla, California, USA Correspondence to Robert H. Mak, MD, PhD, Division of Pediatric Nephrology, University of California, San Diego, 9500 Gilman Drive, MC0634, La Jolla, CA 92093, USA. Tel: +1 858 822 6717; e-mail: [email protected] Curr Opin Pediatr 2014, 26:187–192 DOI:10.1097/MOP.0000000000000070
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KEY POINTS Growth remains a serious comorbidity for children with CKD; many children developed significant height deficits upon reaching adulthood. The lack of catch-up growth and resultant short stature is a critical issue for self-esteem and quality of life in many children with CKD. Aggressive daily dialysis, improved nutrition, treatment of metabolic bone disease, and the use of rhGH provide some hope for catch-up growth in select patients. Steroid avoidance or steroid-free immunosuppressive protocols have been employed as a successful strategy to improve growth after transplant in short-term studies; long-term follow-up on these patients will reveal whether these gains persist to impact final adult height.
independent of renal function. The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 2006 annual report states that the heights of children are 1.64 SDS below the mean at the time chronic dialysis is initiated, 1.71 SDS after 1 year of dialysis, and 1.84 SDS after 2 years on dialysis [6]. Infants born with CKD demonstrate more profound height deficits than those children who acquire CKD later in childhood [7]. The recent report published by the ESPN/ERA-EDTA registry found that 45% of children with ESRD who started dialysis before 19 years of age had a final adult height that was less than the third percentile for normal age-matched and sex-matched controls [4 ]. &&
THE SIGNIFICANCE OF GROWTH FAILURE IN CHRONIC KIDNEY DISEASE Growth failure in CKD has been associated with both increased morbidity and mortality [8]. For every decrease in height SDS, mortality has been reported to increase by 14% [9] and the more profound the deficit, the higher the mortality [10]. Children with growth failure at the time of initiation of dialysis have had increased hospitalizations and missed days of school [9,11]. Taller stature has been associated with better health, better income, more social opportunities, and fewer behavioral problems in adults [12,13]. Children with short stature have poorer school performance, lower self-esteem, difficulties with adaptation, teasing in school, and juvenilization [14,15]. The Chronic Kidney Disease in Children (CKiD) study recently examined short stature in children 188
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with CKD and found that children who gained height had better perceptions of health-related quality of life. Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and growth hormone use on parent-proxy reports of child physical functioning and social functioning. Older children with CKD had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children. The finding that height gains and growth hormone use were associated with increases in physical and social functioning by parent report provided additional support for interventions to improve height in children with CKD [16 ]. &&
IMPACT OF BIRTH HISTORY ON GROWTH IN CHRONIC KIDNEY DISEASE Birth history influences linear growth and ultimately adult height. Infants born small for gestational age (SGA) catch up for lost growth within the first 6 months of life, whereas premature infants can take up to 2 years to catch up. Greenbaum et al. [17] investigated the effect of disrupted birth history on linear growth in 426 children with CKD using the CKiD Study database. They found that there was a higher incidence of low birth weight (LBW) infants and infants who were SGA among CKD children than the general population and that these children were shorter than children with CKD who were not LBW or SGA. These authors identified LBW and SGA as risk factors of short stature in children with CKD independent of renal function. As growth in the first 2 years of life is crucial for achieving full adult potential, an aggressive approach to normalizing and promoting catch-up growth is essential in this population. A recent study by Franke et al. [18 ] confirms that birth parameters can predict poor growth with a sensitivity of 72.7% and a specificity of 63.2% in children with moderate-to-severe CKD. In that study, 28% of children with CKD were SGA and less than 33% of them demonstrated catch-up growth. Thus, CKD in infancy will delay growth and blunt achievement of full adult height. &&
CACHEXIA AND GROWTH FAILURE IN CHILDREN WITH CHRONIC KIDNEY DISEASE Children with CKD are at risk for cachexia or protein-energy wasting. These terms describe a pathophysiologic process resulting in the loss of muscle, with or without loss of fat, and involving maladaptive responses, including anorexia and elevated Volume 26 Number 2 April 2014
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metabolic rate [19]. Cachexia/protein-energy wasting has been defined specifically in relation to adults with CKD. Mortality risk, which is at least 10-fold higher in patients with ESRD than in the general population, is strongly correlated with the components of cachexia/protein-energy wasting. Although cachexia/protein-energy wasting defined using adult diagnostic criteria increases with declining renal function in children, it does not predict incident hospitalizations, whereas growth failure does. The inclusion of growth failure may augment the definition of cachexia and improve risk discrimination in children with CKD [20].
ADVANCES IN NUTRITION HAVE IMPROVED GROWTH IN CHILDREN WITH CHRONIC KIDNEY DISEASE Poor nutrition is a key factor in the cause of growth failure in children with CKD. Optimal nutrition can improve growth in children at any age up to adulthood [21]. In older children with CKD, oral intake of less than 80% of the recommended daily allowance is associated with delayed growth. Anorexia and emesis are prominent contributors to poor intake. Poor appetite results from an altered taste, restrictive diets, need for multiple medications, protein losing states, and polydipsia. Multiple episodes of infections, chronic inflammation, and the uremic state degrade protein stores and slow growth rates as well. Optimizing caloric intake with nutritional supplements or appetite stimulants in children with CKD can improve growth; however, in many cases, catchup growth is not achieved by optimizing nutrition alone. The International Pediatric Peritoneal Dialysis Network (IPPN) reported on 153 children less than 2 years of age from 18 different countries on chronic peritoneal dialysis and found that improvements in linear growth occurred with aggressive enteral feeding, biocompatible dialysate solutions, and growth hormone therapy [22]. Children on chronic peritoneal dialysis are plagued with protein losses in dialysate, gastroesophageal reflux, emesis, delayed gastric emptying, and increased intraabdominal pressure. Nutrition in this population is recognized to be the most important factor to influence growth. Although it was well recognized worldwide, the methods of enteral feeds varied regionally in the IPPN study with the longest-lived improvements achieved in Europe. Infants receiving nasogastric and gastrostomy tube feeds achieved improved growth over those children who were fed on demand. Despite these improvements in nutrition, sometimes leading to obesity, growth retardation still occurred in these children on peritoneal dialysis.
OPTIMIZING THE DIALYSIS PRESCRIPTION CAN IMPROVE GROWTH Mean height SDS at the time of transplant over the past 20 years has improved from 2.4 in 1987 to 1.4 in 2007 [23]. One factor that has played a role in this improvement in growth was advanced dialysis therapy. The use of biocompatible peritoneal dialysis fluids low in toxic glucose degradation products was associated with improved growth in the IPPN study [22]. Recent studies have focused on more intensive daily dialysis regimens to improve patient outcomes and nutritional status. In children with ESRD, dialysis dose has been shown to improve growth in children. In 2006, Fischbach et al. [24] reported that long, nocturnal, in-center daily hemodialysis improved growth in five children with ESRD compared with children on conventional hemodialysis. They recommended that 18 h of hemodiafiltration per week resulting in a Kt/V of 8.4, high middle-molecule clearance by a large convective mass transport component, and use of ultrapure dialysate that minimized activation of inflammatory processes, improved blood pressure, sodium levels, fluid and acid/base balance, and eliminated dietary restrictions and the need for phosphate binders. There was also reduced resistance to rhGH therapy. There was a mean change in height SDS of þ1.84/year in children on daily dialysis while the conventional hemodialysis counterparts lost height SDS 0.64 over the same period of time. In a follow-up study [25], the authors found that catch-up growth continued in the daily dialysis group, which would allow the children to eventually reach their targeted mid-parental height. De Camargo et al. [26 ] conducted a prospective study on 50 children comparing daily dialysis with conventional hemodialysis and found that 33% of patients demonstrated catch-up growth in the daily dialysis group compared with 8% in the conventional hemodialysis group. In addition, daily dialysis promoted adequate caloric intake, whereas conventional hemodialysis did not. Zaritsky et al. [27 ] also studied the utility of short-term daily dialysis to improve growth in children with ESRD. They found that levels of fibroblastic growth factor (FGF) 23 were higher in patients on conventional hemodialysis three times per week than those patients on daily dialysis. Levels of FGF-23, an important regulator of vitamin D and phosphate metabolism, were known to increase progressively as the stage of CKD increased. Increased FGF-23 levels are associated with mortality, left ventricular hypertrophy, endothelial dysfunction, and progression of CKD. FGF-23 is emerging as a novel biomarker that may help identify which CKD
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patients might benefit most from aggressive management of disordered phosphorus metabolism, which can be achieved with daily dialysis.
RECOMBINANT HUMAN GROWTH HORMONE CAN REVERSE THE OBSERVED GROWTH HORMONE RESISTANCE IN CHRONIC KIDNEY DISEASE AND AFTER TRANSPLANTATION Growth hormone stimulates linear growth, increases muscle mass, and improves bone density. Perturbations in the growth hormone axis in uremic children can have profound negative effects on linear growth and muscle wasting. Serum growth hormone levels are normal or even elevated in children with CKD and growth hormone receptor (GHR) levels are elevated on targeted organs in rats with CKD, suggesting there is an acquired end-organ resistance to growth hormone effects [28,29]. Insensitivity to growth hormone in patients with CKD has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway, resulting in reduced transcription of insulin-like growth factor-I (IGF-I). Recurrent or chronic inflammation is common in CKD patients. Children on chronic dialysis are at risk for bacterial infections due to indwelling catheters. Release of endotoxin induces an increased catabolic state and protein degradation. Endotoxin has been shown to impair STAT5b signaling and IGF-I production, thereby contributing to the growth hormone resistance. In addition, with impaired renal clearance, there is an increase in circulating IGF-I binding proteins, resulting in less bioavailable IGF-I. IGF-I mediates growth by stimulating proliferation [30] and differentiation [31] of growth plate chondrocytes and preventing their apoptotic death. At the same time, SOCS2 expression is increased and provides a negative feedback loop of GHR signaling in CKD [32 ,33 ]. Troib et al. [34 ] studied the effects of impaired growth hormone signaling on the epiphyseal growth plates of rats with CKD. The epiphyseal growth plate is a cartilage plate in the metaphysis of each end of a long bone, where linear bone growth occurs by chondrocyte proliferation and subsequent development into bone. They found that decreased vascularization of the growth plate in CKD was associated with decreased JAK2, decreased STAT5 phosphorylation, and decreased growth plate levels of IGF-I and vascular endothelial growth factor (VEGF) levels. In addition, they found increased expression of suppressor of cytokine signaling (SOCS)-2, an inhibitor of growth hormone signaling and specifically a known inhibitor of STAT5. These abnormalities in signal transduction in rats &
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with CKD were independent of nutrition. Thus, impaired GHR signaling in growth plates of long bone can, in part, explain the effects of CKD on linear growth. Supraphysiologic doses of rhGH have been successful in overcoming the resistance to growth hormone observed in children with CKD. However, it is used in the minority of patients [22] and the beneficial effects can be short-lived. The improvement in linear growth in response to GH therapy was often significantly decreased in the second and subsequent years of therapy [35,36]. Recently, it has been suggested that IGF-I generation tests can be used to tailor growth hormone therapy and optimize its effectiveness in children with CKD and growth failure [37 ]. These studies demonstrated a brisk response in circulating IGF-I levels after rhGH administration in patients, which demonstrated, improved growth velocities. However, the IGF-I response to growth hormone in CKD patients did not reliably predict the subsequent linear growth responses. The NAPRTCS 2006 report showed a mean height SDS of 1.5 at the time of transplant with the majority of children not able to catch up for lost growth, resulting in 32–77% of patients 2 SDS or greater below the mean for final height [6]. After transplantation, children less than 6 years of age experienced the best catch-up growth, especially with the administration of rhGH. Widespread use of rhGH after transplantation is impeded by fears of growth hormone inducing rejection episodes. Previous studies have tried to address this question [38–41], but the data have failed to convince the community at large that rhGH is safe and effective after transplant. A recent meta-analysis [42 ] of five randomized controlled trials in children using rhGH after transplantation showed significant improvements in growth in those with poor growth without increases in rejection rates after 1 year of use. The Cochran Review analysis [43 ] confirmed the effectiveness and safety of rhGH in pediatric transplant recipients. Steroid avoidance or steroid-free immunosuppressive protocols [44 ,45] have been employed as a strategy to improve growth after transplant. Without question these strategies have promoted catch-up growth, especially in the youngest patients. Long-term follow-up on these patients will reveal whether these gains persist to impact final adult height. Alterations in bone metabolism are linked to growth, cardiovascular disease, and decreased life expectancy. Peak bone mass is achieved within the first two decades of life. Children with CKD would, therefore, be at risk for less bone reserve heading &
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Growth in children with chronic kidney disease Ingulli and Mak
into adulthood in addition to the risk for renal osteodystrophy and a dynamic bone disease. Renal transplant recipients receiving rhGH despite steroids demonstrate improved bone health [46]. Decreased renal function leads to increases in FGF-23 [47] and increased levels of FGF-23 after transplantation have been associated with acute rejection episodes [48]. Hyperparathyroidism can persist in patients after transplantation and is usually associated with 25-OH vitamin D deficiency [49–52]. Normalizing calcium, phosphorus, and vitamin D levels after transplantation will optimize growth potential and responsiveness to rhGH therapy.
CONCLUSION Failure to achieve full genetic potential for growth is the hallmark of CKD in children. Although there are consistent improvements in reducing the height deficit over the last two decades, 45% of children with CKD remain significantly short in adulthood. The causes of growth failure in CKD are complex and therapies focus on correcting the multiple metabolic derangements that lead to a chronically catabolic inflammatory state as well as resistance to growth hormone. Adequate nutrition and rhGH administration can overcome some losses in growth, but the biggest improvement appears to be correcting the uremic milieu with aggressive daily hemodiafiltration with or without the addition of rhGH. rhGH appears to be safe and effective in children with CKD with growth failure before and after renal transplantation. Acknowledgements None. Conflicts of interest R.H.M. is supported by grants from NIH U01 DK-03012, NIH R24HD050837, Cystinosis Research Foundation, and AbbVie Inc. The authors have no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Guthrie LG. Chronic interstitial nephritis in childhood. Lancet 1897; 149:585. 2. Mehls O, Lindberg A, Nissel R, et al. Predicting the response to growth hormone treatment in short children with chronic kidney disease. J Clin Endocrinol Metab 2010; 95:686–692. 3. Nissel R, Brazda I, Feneberg R, et al. Effect of renal transplantation in childhood on longitudinal growth and adult height. Kidney Int 2004; 66:792–800. 4. Harambat J, Bonthuis M, van Stralen KJ, et al. for the ESPN/ERA-EDTA Registry. && Adult height in patients with advanced CKD requiring renal replacement therapy during childhood. Clin J Am Soc Nephrol 2014; 9:92–99. This study reported a 45% incidence of growth failure in 1620 adults with CKD, who initiated chronic dialysis before the age of 19 years, from 20 European countries.
5. Norman LJ, Coleman JE, Macdonald IA, et al. Nutrition and growth in relation to severity of renal disease in children. Pediatr Nephrol 2000; 15:259–265. 6. North American Pediatric Renal Trials and Collaborative Studies (2006) Annual Report. https://web.emmes.com/study/ped/annlrept/annlrept.html. Accessed 4 January 2007. 7. Mekahli D, Shaw V, Ledermann SE, Rees L. Long-term outcome of infants with severe chronic kidney disease. Clin J Am Soc Nephrol 2010; 5:10–17. 8. Furth SL, Hwang W, Yang C, et al. Growth failure, risk of hospitalization and death for children with end-stage renal disease. Pediatr Nephrol 2002; 17:450–455. 9. Wong CS, Gipson DS, Gillen DL, et al. Anthropometric measures and risk of death in children with end-stage renal disease. Am J Kidney Dis 2000; 36:811–819. 10. Furth SL, Stablein D, Fine RN, et al. Adverse clinical outcomes associated with short stature at dialysis initiation: a report of the North American Pediatric Renal Transplant Cooperative study. Pediatrics 2002; 109:909–913. 11. Fine RN, Martz K, Stablein D. What have 20 years of data from the North American Pediatric Renal Transplant Cooperative Study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr Nephrol 2010; 25:739–746. 12. Judge TA, Cable DM. The effect of physical height on workplace success and income: preliminary test of a theoretical model. J Appl Psychol 2004; 89:428–441. 13. Stabler B, Siegel PT, Clopper RR, et al. Behavior change after growth hormone treatment of children with short stature. J Pediatr 1998; 133:366–373. 14. Sandberg DE, MacGillivray MH, Clopper RR, et al. Quality of life among formerly treated childhood-onset growth hormone-deficient adults: a comparison with unaffected siblings. J Clin Endocrinol Metab 1998; 83:1134–1142. 15. Zimet GD, Cutler M, Litvene M, et al. Psychological adjustment of children evaluated for short stature: a preliminary report. 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Poor growth was observed in 55% of patients, who were more likely to be preterm or SGA. 19. Mak RH, Cheung WW, Zhen JY, et al. Cachexia and protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol 2012; 27:173–181. 20. Abraham AG, Mak RH, Mitsnefes M, et al. Protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol (in press). 21. Rees L, Mak RH. Nutrition and growth in children with chronic kidney disease. Nat Rev Nephrol 2011; 7:615–623. 22. Rees L, Azocar M, Borzych D, et al., for the International Pediatric Peritoneal Dialysis Network (IPPN) registry. Growth in very young children undergoing chronic peritoneal dialysis. J Am Soc Nephrol 2011; 22:2303–2312. 23. Fine RN, Martz K, Stablein D. What have 20 years of data from the North American Pediatric Renal Transplant Cooperative Study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr Nephrol 2010; 25:739–746. 24. Fischbach M, Terzic J, Menouer S, et al. Intensified and daily hemodialysis in children might improve statural growth. Pediatr Nephrol 2006; 21:1746– 1752. 25. Fischbach M, Terzic J, Menouer S, et al. Daily online haemodiafiltration promotes catch-up growth in children on chronic dialysis. Nephrol Dial Transplant 2010; 25:867–873. 26. de Camargo MF, Henriques CL, Vieira S, et al. Growth of children with end&& stage renal disease undergoing daily hemodialysis. Pediatr Nephrol 2013; Nov 20. [Epub ahead of print]. This study found catch-up growth and improved caloric intake, without rhGH therapy, in 24 children undergoing daily hemodialysis compared with 26 children treated with conventional hemodialysis. 27. Zaritsky J, Rastogi A, Fischmann G, et al. Short daily hemodialysis is && associated with lower plasma FGF23 levels when compared with conventional hemodialysis. Nephrol Dial Transplant 2013; Sep 5. [Epub ahead of print] This study found lower FGF-23 levels in 24 adults undergoing short daily hemodialysis compared with 54 patients treated with conventional hemodialysis. 28. Mak RH, Cheung WW, Roberts CT Jr. The growth hormone-insulin-like growth factor-I axis in chronic kidney disease. Growth Horm IGF Res 2008; 18:17–25. 29. Sun DF, Zheng Z, Tummala P, et al. Chronic uremia attenuates growth hormone-induced signal transduction in skeletal muscle. J Am Soc Nephrol 2004; 15:2630–2636.
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Nephrology 30. Nilsson O, Marino R, De Luca F, et al. Endocrine regulation of the growth plate. Horm Res 2005; 64:157–165. 31. Gat-Yablonski G, Yackobovitch-Gavan M, Phillip M. Nutrition and bone growth in pediatrics. Pediatr Clin North Am 2011; 58:1117–1140. 32. Farquharson C, Ahmed SF. Inflammation and linear bone growth: the inhibi& tory role of SOCS2 on GH/IGF-1 signaling. Pediatr Nephrol 2013; 28:547– 556. This is a comprehensive review on the inhibitory signaling involved in linear bone growth. 33. Pass C, MacRae VE, Huesa C, et al. SOCS2 is the critical regulator of GH & action in murine growth plate chondrogenesis. J Bone Miner Res 2012; 27:1055–1066. The authors use the SOCS2(–/–) mouse to better understand the mechanism of how SOCS2 signaling mediated the local effects of growth hormone on epiphyseal chondrocytes and bone growth. 34. Troib A, Landau D, Kachko L, et al. Epiphyseal growth plate growth hormone & receptor signaling is decreased in chronic kidney disease-related growth retardation. Kidney Int 2013; 84:940–949. The study determined that STAT5 phosphorylation was decreased and SOCS2 signaling was increased in growth plates of rats with CKD. 35. Fine RN. Growth hormone treatment of children with chronic renal insufficiency, end-stage renal disease and following renal transplantation: update 1997. J Pediatr Endocrinol Metab 1997; 10:361–370. 36. Haffner D, Wu¨hl E, Schaefer F, et al. Factors predictive of the short- and longterm efficacy of growth hormone treatment in prepubertal children with chronic renal failure. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. J Am Soc Nephrol 1998; 9:1899–1907. 37. Al-Uzri A, Swinford RD, Nguyen T, et al. The utility of the IGF-I generation test & in children with chronic kidney disease. Pediatr Nephrol 2013; 28:2323– 2333. This study looked at whether IGF-I levels, after administration of low-dose and highdose rhGH, predicted growth responses in children with CKD. 38. Guest G, Be´rard E, Crosnier H, et al. Effects of growth hormone in short children after renal transplantation. French Society of Pediatric Nephrology. Pediatr Nephrol 1998; 12:437–446. 39. Johansson G, Sietnieks A, Janssens F, et al. Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants: an interim report on five European studies. Acta Paediatr Scand Suppl 1990; 370:36–42; discussion 43. 40. Maxwell H, Rees L. Randomised controlled trial of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients. British Association for Pediatric Nephrology. Arch Dis Child 1998; 79:481–487.
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41. Fine RN, Stablein D, Cohen AH, et al. Recombinant human growth hormone postrenal transplantation in children: a randomized controlled study of the NAPRTCS. Kidney Int 2002; 62:688–696. 42. Wu Y, Cheng W, Yang XD, Xiang B. Growth hormone improves growth in && pediatric renal transplant recipients: a systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol 2013; 28:129–133. This is a systemic review and meta-analysis study assessing the safety and effectiveness of rhGH administration in pediatric transplant recipients. 43. Hodson EM, Willis NS, Craig JC. Growth hormone for children with chronic && kidney disease. Cochrane Database Syst Rev 2012; CD003264. This study identified randomized controlled trials from the Cochrane Renal Group’s Specialized Registry to evaluate the effectiveness of rhGH in achieving final adult height in pediatric renal transplant recipients. 44. Sarwal MM, Ettenger RB, Dharnidharka V, et al. Complete steroid avoidance && is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant 2012; 12:2719–2729. This study reported on the 3-year follow-up results on using a steroid avoidance protocol from 12 different pediatric renal transplant centers. 45. Ho¨cker B, Weber LT, Feneberg R, et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 2010; 25:617–624. 46. Sanchez CP, Kuizon BD, Goodman WG, et al. Growth hormone and the skeleton in pediatric renal allograft recipients. Pediatr Nephrol 2002; 17:322–328. 47. Gutie´rrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359:584–592. 48. Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011; 22:956–966. 49. Monier-Faugere MC, Mawad H, Qi Q, et al. High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000; 11:1093–1099. 50. Carlini RG, Rojas E, Weisinger JR, et al. Bone disease in patients with longterm renal transplantation and normal renal function. Am J Kidney Dis 2000; 36:160–166. 51. Roe SD, Porter CJ, Godber IM, et al. Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism. Osteoporos Int 2005; 16:142–148. 52. Ewers B, Gasbjerg A, Moelgaard C, et al. Vitamin D status in kidney transplant patients: need for intensified routine supplementation. Am J Clin Nutr 2008; 87:431–437.
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Growth in children with chronic kidney disease: role of nutrition, growth hormone, dialysis, and steroids Elizabeth G. Ingulli and Robert H. Mak
Purpose of review Children with chronic kidney disease (CKD) have impaired growth that leads to short stature in adulthood. The problem persists even with successful transplantation and steroid withdrawal protocols. The aim of this review is to provide an overview of the pressing issues related to growth failure in children with CKD both before and after transplantation. Recent findings Although great strides have been made in dialysis and transplantation, the incidence of abnormal adult height in children growing up with CKD remains as high as 45–60%. The lack of catch-up growth and resultant short stature is a critical issue for self-esteem and quality of life in many children with CKD. Aggressive daily dialysis, improved nutrition, treatment of metabolic bone disease, and the use of recombinant human growth hormone provide some hope for catch-up growth in select patients. Summary The causes of growth failure in the setting of CKD are multifactorial. Attention to all the details by optimizing nutritional, bone and mineral metabolism, correcting metabolic acidosis and anemia, achieving excellent blood pressure control, reversing cardiovascular complications such as left ventricular hypertrophy, and minimizing the use of corticosteroids is the current standard of care. Aggressive daily dialysis can reverse many of the uremic derangements. For patients not yet on dialysis or for those after renal transplant, early institution of recombinant human growth hormone can promote growth. Improved understanding of the mechanisms of hormone resistance may offer novel targets or measurements of treatment effectiveness. Keywords cachexia, chronic kidney disease, growth failure, nutrition, pediatrics, quality of life, recombinant human growth hormone, renal transplantation
INTRODUCTION Growth failure is a major complication observed in children with chronic kidney disease (CKD) and does not always resolve after successful transplantation. The association of kidney disease and short stature was first reported in 1897 [1]. Despite many advances in the care of children with CKD, including optimizing nutrition, aggressive dialysis, recombinant human growth hormone (rhGH) therapy, and renal transplantation, the number of short adults with CKD is staggering with estimations as high as 30–60% [2,3,4 ]. Short stature is defined as a height of two standard deviation scores below the mean for age and sex. This corresponds to a height below the 2.5 percentile. The degree of renal dysfunction correlates with &&
the degree of growth failure and children with endstage renal disease (ESRD) on chronic dialysis have the most profound growth losses [5]. It is estimated that one quarter to one third of children on dialysis are well below the normal range for height. In addition, registry studies have shown that children with CKD have progressive growth failure over time Division of Pediatric Nephrology, Rady Children’s Hospital San Diego, University of California, San Diego, La Jolla, California, USA Correspondence to Robert H. Mak, MD, PhD, Division of Pediatric Nephrology, University of California, San Diego, 9500 Gilman Drive, MC0634, La Jolla, CA 92093, USA. Tel: +1 858 822 6717; e-mail: [email protected] Curr Opin Pediatr 2014, 26:187–192 DOI:10.1097/MOP.0000000000000070
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KEY POINTS Growth remains a serious comorbidity for children with CKD; many children developed significant height deficits upon reaching adulthood. The lack of catch-up growth and resultant short stature is a critical issue for self-esteem and quality of life in many children with CKD. Aggressive daily dialysis, improved nutrition, treatment of metabolic bone disease, and the use of rhGH provide some hope for catch-up growth in select patients. Steroid avoidance or steroid-free immunosuppressive protocols have been employed as a successful strategy to improve growth after transplant in short-term studies; long-term follow-up on these patients will reveal whether these gains persist to impact final adult height.
independent of renal function. The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 2006 annual report states that the heights of children are 1.64 SDS below the mean at the time chronic dialysis is initiated, 1.71 SDS after 1 year of dialysis, and 1.84 SDS after 2 years on dialysis [6]. Infants born with CKD demonstrate more profound height deficits than those children who acquire CKD later in childhood [7]. The recent report published by the ESPN/ERA-EDTA registry found that 45% of children with ESRD who started dialysis before 19 years of age had a final adult height that was less than the third percentile for normal age-matched and sex-matched controls [4 ]. &&
THE SIGNIFICANCE OF GROWTH FAILURE IN CHRONIC KIDNEY DISEASE Growth failure in CKD has been associated with both increased morbidity and mortality [8]. For every decrease in height SDS, mortality has been reported to increase by 14% [9] and the more profound the deficit, the higher the mortality [10]. Children with growth failure at the time of initiation of dialysis have had increased hospitalizations and missed days of school [9,11]. Taller stature has been associated with better health, better income, more social opportunities, and fewer behavioral problems in adults [12,13]. Children with short stature have poorer school performance, lower self-esteem, difficulties with adaptation, teasing in school, and juvenilization [14,15]. The Chronic Kidney Disease in Children (CKiD) study recently examined short stature in children 188
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with CKD and found that children who gained height had better perceptions of health-related quality of life. Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and growth hormone use on parent-proxy reports of child physical functioning and social functioning. Older children with CKD had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children. The finding that height gains and growth hormone use were associated with increases in physical and social functioning by parent report provided additional support for interventions to improve height in children with CKD [16 ]. &&
IMPACT OF BIRTH HISTORY ON GROWTH IN CHRONIC KIDNEY DISEASE Birth history influences linear growth and ultimately adult height. Infants born small for gestational age (SGA) catch up for lost growth within the first 6 months of life, whereas premature infants can take up to 2 years to catch up. Greenbaum et al. [17] investigated the effect of disrupted birth history on linear growth in 426 children with CKD using the CKiD Study database. They found that there was a higher incidence of low birth weight (LBW) infants and infants who were SGA among CKD children than the general population and that these children were shorter than children with CKD who were not LBW or SGA. These authors identified LBW and SGA as risk factors of short stature in children with CKD independent of renal function. As growth in the first 2 years of life is crucial for achieving full adult potential, an aggressive approach to normalizing and promoting catch-up growth is essential in this population. A recent study by Franke et al. [18 ] confirms that birth parameters can predict poor growth with a sensitivity of 72.7% and a specificity of 63.2% in children with moderate-to-severe CKD. In that study, 28% of children with CKD were SGA and less than 33% of them demonstrated catch-up growth. Thus, CKD in infancy will delay growth and blunt achievement of full adult height. &&
CACHEXIA AND GROWTH FAILURE IN CHILDREN WITH CHRONIC KIDNEY DISEASE Children with CKD are at risk for cachexia or protein-energy wasting. These terms describe a pathophysiologic process resulting in the loss of muscle, with or without loss of fat, and involving maladaptive responses, including anorexia and elevated Volume 26 Number 2 April 2014
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metabolic rate [19]. Cachexia/protein-energy wasting has been defined specifically in relation to adults with CKD. Mortality risk, which is at least 10-fold higher in patients with ESRD than in the general population, is strongly correlated with the components of cachexia/protein-energy wasting. Although cachexia/protein-energy wasting defined using adult diagnostic criteria increases with declining renal function in children, it does not predict incident hospitalizations, whereas growth failure does. The inclusion of growth failure may augment the definition of cachexia and improve risk discrimination in children with CKD [20].
ADVANCES IN NUTRITION HAVE IMPROVED GROWTH IN CHILDREN WITH CHRONIC KIDNEY DISEASE Poor nutrition is a key factor in the cause of growth failure in children with CKD. Optimal nutrition can improve growth in children at any age up to adulthood [21]. In older children with CKD, oral intake of less than 80% of the recommended daily allowance is associated with delayed growth. Anorexia and emesis are prominent contributors to poor intake. Poor appetite results from an altered taste, restrictive diets, need for multiple medications, protein losing states, and polydipsia. Multiple episodes of infections, chronic inflammation, and the uremic state degrade protein stores and slow growth rates as well. Optimizing caloric intake with nutritional supplements or appetite stimulants in children with CKD can improve growth; however, in many cases, catchup growth is not achieved by optimizing nutrition alone. The International Pediatric Peritoneal Dialysis Network (IPPN) reported on 153 children less than 2 years of age from 18 different countries on chronic peritoneal dialysis and found that improvements in linear growth occurred with aggressive enteral feeding, biocompatible dialysate solutions, and growth hormone therapy [22]. Children on chronic peritoneal dialysis are plagued with protein losses in dialysate, gastroesophageal reflux, emesis, delayed gastric emptying, and increased intraabdominal pressure. Nutrition in this population is recognized to be the most important factor to influence growth. Although it was well recognized worldwide, the methods of enteral feeds varied regionally in the IPPN study with the longest-lived improvements achieved in Europe. Infants receiving nasogastric and gastrostomy tube feeds achieved improved growth over those children who were fed on demand. Despite these improvements in nutrition, sometimes leading to obesity, growth retardation still occurred in these children on peritoneal dialysis.
OPTIMIZING THE DIALYSIS PRESCRIPTION CAN IMPROVE GROWTH Mean height SDS at the time of transplant over the past 20 years has improved from 2.4 in 1987 to 1.4 in 2007 [23]. One factor that has played a role in this improvement in growth was advanced dialysis therapy. The use of biocompatible peritoneal dialysis fluids low in toxic glucose degradation products was associated with improved growth in the IPPN study [22]. Recent studies have focused on more intensive daily dialysis regimens to improve patient outcomes and nutritional status. In children with ESRD, dialysis dose has been shown to improve growth in children. In 2006, Fischbach et al. [24] reported that long, nocturnal, in-center daily hemodialysis improved growth in five children with ESRD compared with children on conventional hemodialysis. They recommended that 18 h of hemodiafiltration per week resulting in a Kt/V of 8.4, high middle-molecule clearance by a large convective mass transport component, and use of ultrapure dialysate that minimized activation of inflammatory processes, improved blood pressure, sodium levels, fluid and acid/base balance, and eliminated dietary restrictions and the need for phosphate binders. There was also reduced resistance to rhGH therapy. There was a mean change in height SDS of þ1.84/year in children on daily dialysis while the conventional hemodialysis counterparts lost height SDS 0.64 over the same period of time. In a follow-up study [25], the authors found that catch-up growth continued in the daily dialysis group, which would allow the children to eventually reach their targeted mid-parental height. De Camargo et al. [26 ] conducted a prospective study on 50 children comparing daily dialysis with conventional hemodialysis and found that 33% of patients demonstrated catch-up growth in the daily dialysis group compared with 8% in the conventional hemodialysis group. In addition, daily dialysis promoted adequate caloric intake, whereas conventional hemodialysis did not. Zaritsky et al. [27 ] also studied the utility of short-term daily dialysis to improve growth in children with ESRD. They found that levels of fibroblastic growth factor (FGF) 23 were higher in patients on conventional hemodialysis three times per week than those patients on daily dialysis. Levels of FGF-23, an important regulator of vitamin D and phosphate metabolism, were known to increase progressively as the stage of CKD increased. Increased FGF-23 levels are associated with mortality, left ventricular hypertrophy, endothelial dysfunction, and progression of CKD. FGF-23 is emerging as a novel biomarker that may help identify which CKD
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patients might benefit most from aggressive management of disordered phosphorus metabolism, which can be achieved with daily dialysis.
RECOMBINANT HUMAN GROWTH HORMONE CAN REVERSE THE OBSERVED GROWTH HORMONE RESISTANCE IN CHRONIC KIDNEY DISEASE AND AFTER TRANSPLANTATION Growth hormone stimulates linear growth, increases muscle mass, and improves bone density. Perturbations in the growth hormone axis in uremic children can have profound negative effects on linear growth and muscle wasting. Serum growth hormone levels are normal or even elevated in children with CKD and growth hormone receptor (GHR) levels are elevated on targeted organs in rats with CKD, suggesting there is an acquired end-organ resistance to growth hormone effects [28,29]. Insensitivity to growth hormone in patients with CKD has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway, resulting in reduced transcription of insulin-like growth factor-I (IGF-I). Recurrent or chronic inflammation is common in CKD patients. Children on chronic dialysis are at risk for bacterial infections due to indwelling catheters. Release of endotoxin induces an increased catabolic state and protein degradation. Endotoxin has been shown to impair STAT5b signaling and IGF-I production, thereby contributing to the growth hormone resistance. In addition, with impaired renal clearance, there is an increase in circulating IGF-I binding proteins, resulting in less bioavailable IGF-I. IGF-I mediates growth by stimulating proliferation [30] and differentiation [31] of growth plate chondrocytes and preventing their apoptotic death. At the same time, SOCS2 expression is increased and provides a negative feedback loop of GHR signaling in CKD [32 ,33 ]. Troib et al. [34 ] studied the effects of impaired growth hormone signaling on the epiphyseal growth plates of rats with CKD. The epiphyseal growth plate is a cartilage plate in the metaphysis of each end of a long bone, where linear bone growth occurs by chondrocyte proliferation and subsequent development into bone. They found that decreased vascularization of the growth plate in CKD was associated with decreased JAK2, decreased STAT5 phosphorylation, and decreased growth plate levels of IGF-I and vascular endothelial growth factor (VEGF) levels. In addition, they found increased expression of suppressor of cytokine signaling (SOCS)-2, an inhibitor of growth hormone signaling and specifically a known inhibitor of STAT5. These abnormalities in signal transduction in rats &
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with CKD were independent of nutrition. Thus, impaired GHR signaling in growth plates of long bone can, in part, explain the effects of CKD on linear growth. Supraphysiologic doses of rhGH have been successful in overcoming the resistance to growth hormone observed in children with CKD. However, it is used in the minority of patients [22] and the beneficial effects can be short-lived. The improvement in linear growth in response to GH therapy was often significantly decreased in the second and subsequent years of therapy [35,36]. Recently, it has been suggested that IGF-I generation tests can be used to tailor growth hormone therapy and optimize its effectiveness in children with CKD and growth failure [37 ]. These studies demonstrated a brisk response in circulating IGF-I levels after rhGH administration in patients, which demonstrated, improved growth velocities. However, the IGF-I response to growth hormone in CKD patients did not reliably predict the subsequent linear growth responses. The NAPRTCS 2006 report showed a mean height SDS of 1.5 at the time of transplant with the majority of children not able to catch up for lost growth, resulting in 32–77% of patients 2 SDS or greater below the mean for final height [6]. After transplantation, children less than 6 years of age experienced the best catch-up growth, especially with the administration of rhGH. Widespread use of rhGH after transplantation is impeded by fears of growth hormone inducing rejection episodes. Previous studies have tried to address this question [38–41], but the data have failed to convince the community at large that rhGH is safe and effective after transplant. A recent meta-analysis [42 ] of five randomized controlled trials in children using rhGH after transplantation showed significant improvements in growth in those with poor growth without increases in rejection rates after 1 year of use. The Cochran Review analysis [43 ] confirmed the effectiveness and safety of rhGH in pediatric transplant recipients. Steroid avoidance or steroid-free immunosuppressive protocols [44 ,45] have been employed as a strategy to improve growth after transplant. Without question these strategies have promoted catch-up growth, especially in the youngest patients. Long-term follow-up on these patients will reveal whether these gains persist to impact final adult height. Alterations in bone metabolism are linked to growth, cardiovascular disease, and decreased life expectancy. Peak bone mass is achieved within the first two decades of life. Children with CKD would, therefore, be at risk for less bone reserve heading &
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Growth in children with chronic kidney disease Ingulli and Mak
into adulthood in addition to the risk for renal osteodystrophy and a dynamic bone disease. Renal transplant recipients receiving rhGH despite steroids demonstrate improved bone health [46]. Decreased renal function leads to increases in FGF-23 [47] and increased levels of FGF-23 after transplantation have been associated with acute rejection episodes [48]. Hyperparathyroidism can persist in patients after transplantation and is usually associated with 25-OH vitamin D deficiency [49–52]. Normalizing calcium, phosphorus, and vitamin D levels after transplantation will optimize growth potential and responsiveness to rhGH therapy.
CONCLUSION Failure to achieve full genetic potential for growth is the hallmark of CKD in children. Although there are consistent improvements in reducing the height deficit over the last two decades, 45% of children with CKD remain significantly short in adulthood. The causes of growth failure in CKD are complex and therapies focus on correcting the multiple metabolic derangements that lead to a chronically catabolic inflammatory state as well as resistance to growth hormone. Adequate nutrition and rhGH administration can overcome some losses in growth, but the biggest improvement appears to be correcting the uremic milieu with aggressive daily hemodiafiltration with or without the addition of rhGH. rhGH appears to be safe and effective in children with CKD with growth failure before and after renal transplantation. Acknowledgements None. Conflicts of interest R.H.M. is supported by grants from NIH U01 DK-03012, NIH R24HD050837, Cystinosis Research Foundation, and AbbVie Inc. The authors have no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Guthrie LG. Chronic interstitial nephritis in childhood. Lancet 1897; 149:585. 2. Mehls O, Lindberg A, Nissel R, et al. Predicting the response to growth hormone treatment in short children with chronic kidney disease. J Clin Endocrinol Metab 2010; 95:686–692. 3. Nissel R, Brazda I, Feneberg R, et al. Effect of renal transplantation in childhood on longitudinal growth and adult height. Kidney Int 2004; 66:792–800. 4. Harambat J, Bonthuis M, van Stralen KJ, et al. for the ESPN/ERA-EDTA Registry. && Adult height in patients with advanced CKD requiring renal replacement therapy during childhood. Clin J Am Soc Nephrol 2014; 9:92–99. This study reported a 45% incidence of growth failure in 1620 adults with CKD, who initiated chronic dialysis before the age of 19 years, from 20 European countries.
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41. Fine RN, Stablein D, Cohen AH, et al. Recombinant human growth hormone postrenal transplantation in children: a randomized controlled study of the NAPRTCS. Kidney Int 2002; 62:688–696. 42. Wu Y, Cheng W, Yang XD, Xiang B. Growth hormone improves growth in && pediatric renal transplant recipients: a systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol 2013; 28:129–133. This is a systemic review and meta-analysis study assessing the safety and effectiveness of rhGH administration in pediatric transplant recipients. 43. Hodson EM, Willis NS, Craig JC. Growth hormone for children with chronic && kidney disease. Cochrane Database Syst Rev 2012; CD003264. This study identified randomized controlled trials from the Cochrane Renal Group’s Specialized Registry to evaluate the effectiveness of rhGH in achieving final adult height in pediatric renal transplant recipients. 44. Sarwal MM, Ettenger RB, Dharnidharka V, et al. Complete steroid avoidance && is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant 2012; 12:2719–2729. This study reported on the 3-year follow-up results on using a steroid avoidance protocol from 12 different pediatric renal transplant centers. 45. Ho¨cker B, Weber LT, Feneberg R, et al. Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 2010; 25:617–624. 46. Sanchez CP, Kuizon BD, Goodman WG, et al. Growth hormone and the skeleton in pediatric renal allograft recipients. Pediatr Nephrol 2002; 17:322–328. 47. Gutie´rrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359:584–592. 48. Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011; 22:956–966. 49. Monier-Faugere MC, Mawad H, Qi Q, et al. High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000; 11:1093–1099. 50. Carlini RG, Rojas E, Weisinger JR, et al. Bone disease in patients with longterm renal transplantation and normal renal function. Am J Kidney Dis 2000; 36:160–166. 51. Roe SD, Porter CJ, Godber IM, et al. Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism. Osteoporos Int 2005; 16:142–148. 52. Ewers B, Gasbjerg A, Moelgaard C, et al. Vitamin D status in kidney transplant patients: need for intensified routine supplementation. Am J Clin Nutr 2008; 87:431–437.
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