INTRODUCTION — 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 [1,2].

The prevention and management of growth impairment in children with CKD and after renal transplantation will be reviewed here. The impact, risk factors, and underlying pathogenesis of growth impairment in children with CKD are discussed separately. (See "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease".)

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 for growth is a conversion of height/length that 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'.)

OVERVIEW — The prevention and management of growth impairment in children with CKD are based on avoiding and correcting the following factors that contribute to poor growth (see "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease", section on 'Pathogenesis: Disturbance of GH/IGF-1 axis' and "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease", section on 'Risk factors that contribute to impaired growth'):

●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.

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

●In children with renal allografts or those with nephrotic syndrome (NS), glucocorticoid-sparing agents are used to minimize or avoid glucocorticoid therapy, a major contributor to poor growth. (See 'Corticosteroid therapy' below.)

●Recombinant human growth hormone (rhGH) therapy to address GH/IGF-1 abnormalities.

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

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.

The energy intake should be 100 percent of the Dietary Reference Intake (DRI) based on age and gender (table 2). Protein intake should be between 100 to 140 percent of DRI based on age and gender for children with CKD stages 3a and 3b and between 100 and 120 percent for those with CKD stages 4 and 5 (table 3). In patients 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 below 20 mmol/L as far as possible. A more detailed discussion on energy and protein intake requirements in children with CKD is discussed separately. (See "Chronic kidney disease in children: Complications".)

Supplementation with formulas containing high-volume and additional sodium supplementation has shown to substantially improve growth in children who are unable to adequately concentrate their urine or conserve salt [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 renal 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 aged younger than five years [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 "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease", section on 'Pathogenesis: Disturbance of GH/IGF-1 axis' and "Growth hormone treatment in children with chronic kidney disease and postkidney transplantation", 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 (see "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease", section on 'Risk factors that contribute to impaired growth'):

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

●Electrolyte and fluid loss – Replacement of increased renal 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.

●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 recombinant human erythropoietin. (See "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis'.)

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.

RENAL REPLACEMENT THERAPY — Once children have reached end-stage renal disease (ESRD; 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 renal function have the best growth; indeed, residual renal function may be a better predictor of longitudinal growth than dialytic clearance [10,11]. Even children who undergo renal 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 1) [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 'Length of dialysis and frequency of 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 2) [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.

Transplantation — Renal transplantation is the optimal renal replacement therapy (RRT) modality to prevent and correct growth failure, as a well-functioning allograft restores the physiological conditions required for normal growth. However, growth rates after renal 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 renal 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 3). (See "Overview of kidney replacement therapy (KKT) for children with chronic kidney disease", section on 'Timing of RRT' and "Overview of kidney replacement therapy (KKT) for children with chronic kidney disease", section on 'KRT options' and "Kidney transplantation in children: Outcomes", section on 'Growth after kidney transplantation'.)

Corticosteroid therapy — Daily glucocorticoid therapy following renal transplantation or to treat glomerular disease is an important contributor to poor growth in children. Strategies to reduce the cumulative effects of glucocorticoid therapy include the use of alternate-day glucocorticoids, late or early glucocorticoid withdrawal, and immunosuppressive regimens that avoid glucocorticoid therapy.

Efforts to reduce or eliminate glucocorticoid therapy for children with renal allografts are reviewed below. 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'.)

Alternate-day corticosteroid — An alternate-day glucocorticoid regimen has a less inhibitory effect on growth velocity compared with daily administration, and does not adversely affect graft survival or long-term graft function, as illustrated by the following studies [23-25]:

●In a report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry of 2001 children with functioning allografts 12 months after transplantation, approximately 17 percent of patients (n = 337) were maintained on immunosuppressive therapy that included an alternate-day regimen of glucocorticoids [24]. Patients who received alternate-day glucocorticoids had a greater increase in relative height compared with those maintained on a daily glucocorticoid regimen (mean height Z-score difference of +0.5). There was no difference in graft survival or function between the two groups.

●In another study of 30 children below the age of five years at the time of kidney transplantation, maintenance immunosuppression consisted of cyclosporine A, azathioprine, and alternate-day glucocorticoid treatment [25]. Catch-up growth without recombinant human growth hormone (rhGH) therapy was observed initially in 24 patients. However, in subsequent years (five to seven years after transplantation), only 10 children showed significantly improved longitudinal growth. As noted above, catch-up growth is usually only observed in children less than five years of age [21].

Corticosteroid withdrawal or avoidance — The introduction of other immunosuppressive agents, particularly calcineurin inhibitors (ie, cyclosporine and tacrolimus) and the antimetabolite, mycophenolate mofetil (MMF), has permitted the reduction, and in some centers withdrawal or avoidance, of glucocorticoid therapy.

Immunosuppressive regimens for children undergoing renal transplantation that avoid or discontinue glucocorticoid therapy are discussed separately. (See "Kidney transplantation in children: Immunosuppression", section on 'Our approach' and "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen'.)

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 growth hormone in children with CKD on dialysis and after renal transplantation [26]. The benefits, indications, dosing, and side effects of rhGH are discussed in greater detail separately. (See "Growth hormone treatment in children with chronic kidney disease and postkidney transplantation".)

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 — Growth retardation is a major complication of children with chronic kidney disease (CKD).

The management approach to prevent and correct growth impairment combines supportive measures that focus on amenable complications of CKD, renal replacement therapy (RRT), particularly renal transplantation, reduction and avoidance of glucocorticoid therapy, and the administration of recombinant human growth hormone (rhGH) therapy.

●We recommend that supportive care be provided to all children with CKD that corrects and prevents amenable contributing factors for growth impairment (Grade 1B). This includes early initiation of optimal nutrition for all children with CKD, which may require enteral feeding (eg, gastrostomy and nasogastric feeding) to ensure both adequate energy and protein intake (table 2 and table 3). Other risk factors and their interventions include metabolic acidosis (bicarbonate therapy), electrolyte and fluid abnormalities (replacement of excessive renal losses), renal osteodystrophy (vitamin D and calcium supplementation and phosphate restriction), and anemia (recombinant human erythropoietin). (See 'Supportive measures' above.)

●Once children have reached end-stage renal disease (ESRD, stage 5 CKD), growth rates generally deteriorate. In children with ESRD, we recommend renal transplantation as the preferred RRT that promotes growth and overall quality of life (Grade 1A). If transplantation is not an option, modest initial gains in relative height can be achieved with intensive nutritional intervention in children who are treated with peritoneal dialysis (PD) or intensive hemodialysis. (See 'Renal replacement therapy' above and "Overview of kidney replacement therapy (KKT) for children with chronic kidney disease".)

●Although renal transplantation is the preferred RRT, growth may be impaired, especially in children who receive daily glucocorticoid treatment for immunosuppression or have an allograft with reduced function. In addition, the final height is dependent on age of the child and the severity of the growth failure at time of transplantation. (See 'Transplantation' above and "Kidney transplantation in children: Outcomes", section on 'Growth after kidney transplantation'.)

The introduction of new therapeutic agents has permitted the use of immunosuppressive regimens that reduce or eliminate glucocorticoid therapy, which has improved growth in pediatric renal allograft recipients. Ongoing studies are focused on determining the optimal regimen for long-term patient and graft survival, improved growth, and quality of life. (See "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen' and "Kidney transplantation in children: Immunosuppression", section on 'Our approach'.)

●RhGH is a safe therapeutic intervention that promotes growth in children with CKD, including in those who are pediatric renal allograft recipients. (See "Growth hormone treatment in children with chronic kidney disease and postkidney transplantation".)