Growth failure in children with chronic kidney disease: Prevention and management

INTRODUCTION — Growth failure is a major complication of children with chronic kidney disease (CKD). Poor growth is a marker of disease severity and is associated with significant morbidity and mortality [1,2].

The prevention and management of growth failure in children with CKD and after kidney transplantation will be reviewed here. The impact, risk factors, evaluation, and diagnosis of growth failure in children with CKD are discussed separately. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis".)

DEFINITIONS

Chronic kidney disease — Classification schema for CKD in children is based upon the level of kidney function (defined by glomerular filtration rate [GFR]) as follows (table 1) [3]:

●G1 – Normal GFR (≥90 mL/min per 1.73 m²)

●G2 – GFR between 60 and 89 mL/min per 1.73 m²

●G3a – GFR between 45 and 59 mL/min per 1.73 m²

●G3b – GFR between 30 and 44 mL/min per 1.73 m²

●G4 – GFR between 15 and 29 mL/min per 1.73 m²

●G5 – GFR of less than 15 mL/min per 1.73 m² (kidney failure)

Growth measurement

●Z-score (also called standard deviation score [SDS]) for height (or length) represents the number of standard deviations (SD) from the mean height values for age. (See "Measurement of growth in children", section on 'Use of Z-scores'.)

●Growth velocity (or height velocity) is the change in growth over time. It is a more sensitive index of growth compared with a single measurement. It is determined by comparing current height/length measurements with previous growth points (figure 1 and figure 2).

OVERVIEW — The prevention and management of growth impairment in children with CKD are based on addressing the following factors that contribute to poor growth (see "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Contributing factors'):

●Inadequate nutrition

●Fluid and electrolyte abnormalities including metabolic acidosis

●Renal osteodystrophy

●Disturbances of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis

The management approach consists of a combination of the following interventions:

●Supportive measures are directed toward preventing or correcting amenable complications of CKD, including malnutrition, metabolic acidosis, fluid and electrolyte abnormalities, and renal osteodystrophy. (See 'Supportive measures' below.)

●Kidney replacement therapy (KRT; ie, dialysis and/or kidney transplantation) is generally initiated in children with stage 5 CKD and who have uremic symptoms and/or metabolic abnormalities that are refractory to medical management. KRT facilitates fluid management and ensures adequate nutrition. Kidney transplantation is the optimal KRT modality to prevent and correct growth failure. (See "Overview of kidney replacement therapy for children with chronic kidney disease" and "Kidney transplantation in children: Outcomes", section on 'Growth after kidney transplantation'.)

●In children requiring immunosuppression for management of kidney disease (eg, nephrotic syndrome, post-transplant), glucocorticoid-sparing agents are used when possible since glucocorticoid therapy is a major contributor to poor growth. (See 'Reducing glucocorticoid exposure' below.)

●Recombinant human growth hormone (rhGH) therapy to address GH/IGF-1 abnormalities. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

SUPPORTIVE MEASURES — Supportive care should be provided to all children with CKD. This includes correcting and preventing any of the amenable contributing factors for growth failure.

Nutrition — Early referral to a pediatric nephrology center followed by careful nutritional and metabolic management is vital in the prevention of growth retardation. Sufficient nutritional support including energy and protein intake is essential for normal growth, particularly for infants in whom growth is most sensitive to energy intake. Successful nutritional management requires a multidisciplinary team that includes clinicians, skilled nurses, and dieticians.

●Energy requirements – Energy intake should be 100 percent of the Dietary Reference Intake (DRI) based on age and sex (table 2).

●Protein requirements – Protein intake depends on the stage of CKD:

•For children with stages 3a and 3b CKD, protein intake should be between 100 to 140 percent of DRI based on age and sex (table 3).

•For children with CKD stages 4 and 5 CKD, protein intake should be between 100 and 120 percent of DRI based upon age and sex (table 3).

•For children undergoing chronic peritoneal dialysis (CPD), protein intake should be increased to compensate for protein losses in the dialysate. The aim is to maintain a normal serum albumin and a urea <20 mmol/L, if possible.

For children with polyuric salt-wasting CKD who are unable to adequately concentrate their urine or conserve salt, supplementation with formulas containing additional sodium at high volumes appears to improve growth [4].

Enteral feeding is indicated in children with CKD when spontaneous calorie intake is insufficient to maintain growth. Routes for enteral feeding include gastrostomy and nasogastric tubes. In an observational study of 153 young children (less than 24 months) who commenced peritoneal dialysis (PD), gastrostomy feeding compared with either nasogastric tube feeding or demand feeding was associated with improved linear growth [5]. This finding may be due to decreased episodes of vomiting associated with gastrostomies compared with nasogastric tubes.

With early initiation of intensive nutritional and medical care including enteral feedings, severe growth failure in infants with CKD can be prevented with catch-up growth [5,6]. In a study from a single center of 101 infants with CKD, intensive nutrition (approximately 90 percent were fed enterally) and early kidney transplantation resulted in a mean normal adult height in patients without comorbidities [6].

However, even optimal nutritional management may not be able to prevent growth failure in many patients, particularly older children with advanced stages of CKD. Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database showed that catch-up growth without recombinant human growth hormone (rhGH) therapy was only observed in children <5 years old [7]. These results demonstrate that other factors such as disturbances of growth hormone (GH) metabolism and its primary mediator, insulin-like growth hormone-1 (GH/IGF-1 axis), are important contributors to impaired growth in children with CKD, which optimal nutrition alone cannot overcome. As a result, rhGH therapy has been a beneficial intervention in these patients. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Pathogenesis: Disturbance of growth hormone/IGF-1 axis' and "Growth failure in children with chronic kidney disease: Treatment with growth hormone", section on 'Efficacy'.)

Other supportive measures — Other supportive measures include preventing or correcting the following risk factors that contribute to growth impairment in children with CKD :

●Metabolic acidosis – Prevention and correction of metabolic acidosis with administration of oral bicarbonate preparations. (See "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis'.)

●Electrolyte and fluid loss – Replacement of increased kidney losses of fluids and electrolytes. Supplementation of sodium chloride is important in young children on PD, since significant amounts of sodium chloride (ie, 2 to 5 mmol/kg of body weight) may be lost via ultrafiltration of the peritoneal fluid. (See "Chronic kidney disease in children: Complications", section on 'Fluid and electrolyte abnormalities'.)

●Renal osteodystrophy – Monitoring mineral and bone status with routine measurements of serum calcium, phosphate, parathyroid hormone (PTH) levels, and, if appropriate, 25-hydroxyvitamin D levels. Interventions are initiated depending on laboratory results and include phosphate restriction, calcium and vitamin D supplementation, and the use of phosphate binders. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Management'.)

●Anemia – Anemia is corrected with the administration of erythropoiesis stimulating agents (eg, recombinant human erythropoietin and its longer-acting analog darbepoetin). (See "Chronic kidney disease in children: Complications", section on 'Erythropoiesis-stimulating agents'.)

However, apart from nutritional support in early infancy, true catch-up growth can rarely be obtained by any of these therapeutic interventions. At most, a growth pattern parallel to the growth percentiles is observed in response to optimization of nutritional support and medical treatment in children with CKD beyond infancy.

KIDNEY REPLACEMENT THERAPY (KRT) — Once children have reached end-stage kidney disease (ESKD; ie, stage 5 CKD), growth rates generally continue to deteriorate. In particular, patients who receive chronic dialysis are at risk for growth failure. Although dialysis attenuates the uremic state, longitudinal growth is not usually improved and long-term peritoneal dialysis (PD) or hemodialysis are associated with a gradual loss of standardized height in children and adolescents, which can be a loss of one standard deviation (SD) of height per year in infants [8,9]. Children on dialysis who maintain some residual kidney function have the best growth; indeed, residual kidney function may be a better predictor of longitudinal growth than dialytic clearance [10,11]. Even children who undergo kidney transplantation and theoretically should have normal growth, and potentially catch-up growth in prepubertal patients, still are at risk for growth impairment, particularly as a result of glucocorticoid therapy. (See "Diagnostic approach to children and adolescents with short stature", section on 'Is the child short?'.)

Hemodialysis — Children who undergo long-term conventional hemodialysis (ie, three treatments per week) generally have further deterioration of their growth (figure 3) [12]. This was illustrated by one case series of 51 children who underwent conventional hemodialysis for 12 to 111 months that reported a 0.4 SD annual loss of mean relative height [13]. In this study, one-third of the patients grew along the growth percentile attained at initiation of dialysis, one-third had slightly retarded growth, and one-third had severely retarded growth.

With increased intensity of nutrition and hemodialysis (eg, hemodiafiltration six times per week or nocturnal hemodialysis), single-center studies have reported that the growth rate of children on maintenance hemodialysis improved significantly [14,15]. In an observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution hemodiafiltration (HDF) in children, height SD score slightly increased in HDF but remained static in HD [16]. A possible mechanism behind this finding is that intensified dialysis improves clearance of solutes, middle molecules, and inflammatory cytokines, and reverses the abnormalities of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis secondary to CKD. (See "Hemodialysis for children with chronic kidney disease", section on 'Type, length, and frequency of dialysis sessions' and "Hemodialysis for children with chronic kidney disease", section on 'Growth'.)

Continuous peritoneal dialysis — Growth appears to be better after the start of continuous peritoneal dialysis (PD) in children, especially in those below six years of age after conservative treatment or compared with hemodialysis (figure 4) [12,17]. This relative improvement in growth compared with hemodialysis has been partially attributed to the better nutritional status of patients as a consequence of their peritoneal glucose uptake [18]. PD is usually more effective in solute and fluid removal than conventional hemodialysis, and improved growth and nutritional status are correlated with increased solute and volume clearance [18]. However, a gradual decline of relative height is frequently observed in children who have undergone long-term PD, indicating that the impact of the dialysis modality on growth diminishes with time [19,20]. These data temper the initial enthusiasm that PD would result in a significant beneficial sustained impact on growth. At best, parallel growth along the child's growth percentile is achieved by PD, but not persistent catch-up growth. (See "Chronic peritoneal dialysis in children".)

Transplantation — Kidney transplantation is the optimal KRT modality to prevent and correct growth failure, as a well-functioning allograft restores the physiological conditions required for normal growth. However, growth rates after kidney transplantation in children are highly variable and often do not fulfill the expectations of true catch-up growth, which generally is only observed in children less than five years of age [21]. The main contributing factors to continued growth depression in pediatric kidney allograft recipients are glucocorticoid treatment for immunosuppression, reduced graft function and administration of growth hormone pretransplantation [22]. The final height also depends on the age of the child and the severity of the growth failure at time of transplantation (figure 5). (See "Kidney transplantation in children: Outcomes", section on 'Growth after kidney transplantation'.)

REDUCING GLUCOCORTICOID EXPOSURE — Daily glucocorticoid therapy following kidney transplantation or to treat glomerular disease has historically been an important contributor to poor growth in children. Strategies to reduce the cumulative effects of glucocorticoid therapy include late or early glucocorticoid withdrawal and use of alternative immunosuppressive agents.

●Kidney transplant – The introduction of other immunosuppressive agents, particularly calcineurin inhibitors (ie, cyclosporine and tacrolimus) and the antimetabolite, mycophenolate mofetil (MMF), has greatly reduced the need for glucocorticoid therapy in pediatric kidney transplant recipients. Clinical trials and observational studies have demonstrated that steroid-sparing regimens are associated with improved growth following transplantation [23]. Additional details of glucocorticoid-sparing immunosuppressive regimens post-transplant are provided separately. (See "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen'.)

●Nephrotic syndrome – The use of glucocorticoid-sparing therapy in children with nephrotic syndrome is discussed separately. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Alternative treatments for patients with steroid toxicity'.)

RECOMBINANT HUMAN GROWTH HORMONE THERAPY — Recombinant human growth hormone (rhGH) therapy is safe and effective in improving growth in children with CKD, including allograft recipients. The European Society for Paediatric Nephrology (ESPN) CKD-Mineral and Bone Disorder (MBD), Dialysis and Transplantation working groups developed clinical practice recommendations for the use of rhGH in children with CKD on dialysis and after kidney transplantation [24]. The indications, dosing, efficacy, and side effects of rhGH are discussed in greater detail separately. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in children".)

SUMMARY AND RECOMMENDATIONS

●Importance – Growth retardation is a major complication of children with chronic kidney disease (CKD). Poor growth is a marker of disease severity and is associated with significant morbidity and mortality. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Impact of poor growth'.)

●Supportive care – Supportive care for children with CKD aims to correct and prevent amenable contributing factors for growth impairment. This includes (see 'Supportive measures' above):

•Optimal nutrition – Nutritional support focuses on ensuring adequate energy and protein intake (table 2 and table 3). If spontaneous calorie intake is insufficient to maintain growth, initiation of enteral feeding via gastrostomy or nasogastric tube may be required. (See 'Nutrition' above.)

•Other supportive measures – Interventions for other complications of CKD include the following, each of which is discussed separately (see 'Other supportive measures' above):

-Bicarbonate therapy to treat metabolic acidosis (see "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis')

-Correction of electrolyte and fluid abnormalities (see "Chronic kidney disease in children: Complications", section on 'Fluid and electrolyte abnormalities')

-Vitamin D and calcium supplementation and phosphate restriction to treat renal osteodystrophy (see "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Management')

-Erythropoiesis stimulating agents for anemia (see "Chronic kidney disease in children: Complications", section on 'Erythropoiesis-stimulating agents')

●Kidney replacement therapy (KRT) – Once children have reached end-stage kidney disease (ESKD, stage 5 CKD), growth rates generally deteriorate. Kidney replacement therapy (KRT; ie, dialysis and/or kidney transplantation) is generally initiated in children with ESKD and those who have uremic symptoms and/or metabolic abnormalities that are refractory to medical management. Kidney transplantation is the optimal KRT modality to prevent and correct growth failure. This is discussed in greater detail separately. (See "Overview of kidney replacement therapy for children with chronic kidney disease" and "Kidney transplantation in children: Outcomes", section on 'Growth after kidney transplantation'.)

●Reducing glucocorticoid exposure – Glucocorticoid therapy following kidney transplantation or to treat glomerular disease has historically been an important contributor to poor growth in children with CKD. The introduction of other immunosuppressive agents (eg, calcineurin inhibitors [cyclosporine, tacrolimus]) and mycophenolate mofetil [MMF]), has greatly reduced the need for glucocorticoid therapy in pediatric kidney transplant recipients. Details regarding use of glucocorticoid-sparing immunosuppressive therapy in kidney transplant recipients and in children with nephrotic syndrome are provided separately. (See "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Alternative treatments for patients with steroid toxicity'.)

●Recombinant human growth hormone (RhGH) – RhGH is a safe therapeutic intervention that promotes growth in children with CKD, including in those who are pediatric kidney allograft recipients. Use of RhGH in children with CKD is discussed separately. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)