NKF KDOQI GUIDELINES
Growth failure and linear height deficit are the most visible complications of CKD in children and are associated with serious medical and psychological comorbidities.
Early nutritional intervention and the prevention and treatment of metabolic deficits are key components in the preservation of growth in a child with CKD. In children who demonstrate poor growth despite these measures, the addition of rhGH therapy can be beneficial.
2.1 Identification and treatment of existing nutritional deficiencies and metabolic abnormalities should be aggressively pursued in children with CKD stages 2 to 5 and 5D, short stature (height SDS < −1.88 or height-for-age < 3rd percentile), and potential for linear growth. (A)
2.2 Serum bicarbonate level should be corrected to at least the lower limit of normal (22 mmol/L) in children with CKD stages 2 to 5 and 5D. (B)
2.3 Recombinant human growth hormone (rhGH) therapy should be considered in children with CKD stages 2 to 5 and 5D, short stature (height SDS < −1.88 or height-for-age < 3rd percentile), and potential for linear growth if growth failure (height velocity-for-age SDS < −1.88 or height velocity-for-age < 3rd percentile) persists beyond 3 months despite treatment of nutritional deficiencies and metabolic abnormalities. (B)
2.1: Identification and treatment of existing nutritional deficiencies and metabolic abnormalities should be aggressively pursued in children with CKD stages 2 to 5 and 5D, short stature (height SDS < −1.88 or height-for-age < 3rd percentile), and potential for linear growth. (A)
A variety of factors can contribute to the poor growth seen in children with CKD.112 Interventions to normalize inadequate protein and calorie intake, water and electrolyte losses in those with polyuric and salt-wasting conditions, metabolic acidosis (see Recommendation 2.2), renal osteodystrophy, and resistance to hormones mediating growth must be aggressively managed.
Caloric deficiency and abnormal protein metabolism may have an important role in growth impairment, particularly in infants and younger children.113 Reduced caloric intake may be a result of anorexia, emotional distress, altered taste sensation, or nausea and vomiting. Prior studies provided evidence that energy intake significantly correlated with growth velocity in children with CKD that developed during infancy, such that normal growth occurred if energy intake exceeded 80% of recommended values, whereas it would be expected to cease if intake decreased to less than 40%.114 Early nutritional interventions, including tube feeding in infants, and prevention and treatment of metabolic deficits of CKD are fundamental measures for preventing severe stunting in the first 2 years of life.111,115 Studies also have shown that nutritional supplementation in malnourished children with CKD can result in improved growth.18,111,116 Finally, there is recent evidence that frequent (daily) HD is associated with enhanced nutrition and a normal height velocity.117
Infants with renal dysplasia typically exhibit the most severe height deficits, which may reflect the age at onset of kidney disease, degree of tubular abnormality inherent in the condition, and the resultant loss of sodium and other substances important for growth.118 Thus, salt supplementation for a polyuric infant with CKD who is growing poorly may be therapeutic.111,119,120
Growth can be adversely affected by renal osteodystrophy. Renal osteodystrophy represents a range of disorders, from secondary hyperparathyroidism and high-turnover bone disease to low-turnover osteomalacia and adynamic bone disease.118 Secondary hyperparathyroidism may cause growth failure by modulating genes involved in endochondral bone formation and altering the architecture of the growth plate. A key component of the management of high-turnover bone disease is control of serum phosphorus level. Dietary and medication therapy are designed to target a normal serum phosphorus level for age. The prevention/correction of adynamic bone disease requires close monitoring of dietary calcium intake and vitamin D therapy with a goal of maintaining serum calcium level in the normal range.121
The use of corticosteroids can lead to suppression of growth in children with CKD by their effect on the integrity of the somatotropic hormone axis.122 The action of corticosteroids is at various levels of the axis and involves suppression of pituitary growth hormone release by stimulating hypothalamic somatostatin tone, downregulation of hepatic growth hormone receptors, inhibition of insulin-like growth factor (IGF) bioactivity, alteration of the IGF-binding protein serum profile, and a direct suppressive effect on local growth factor and tissue matrix production.123 Discontinuing or modifying the dose of corticosteroids is in turn desirable from the perspective of growth as long as the patient's medical condition that prompted the use of the corticosteroids is not exacerbated.
2.2: Serum bicarbonate level should be corrected to at least the lower limit of normal (22 mmol/L) in children with CKD stages 2 to 5 and 5D. (B)
CKD-induced acidosis impedes statural growth through a variety of mechanisms, which lead to both endogenous growth hormone and rhGH resistance. Optimal growth in children with CKD will be achieved with acid-base status normalization.
Metabolic acidosis develops in adult patients with CKD stages 4 to 5.25,26 Metabolic acidosis may impede statural growth through a number of growth factor–specific mechanisms, including reduction in thyroid hormone levels and blunting of IGF response to rhGH, which has been demonstrated in healthy adult patients after long-term acid loading.124,125Animal data also suggest an acidosis-induced human growth hormone–IGF-1 axis impairment118by decreasing pulsatile growth hormone secretion,126 hepatic IGF-1 and growth hormone receptor messenger RNA (mRNA) production,127 and IGF-1 expression at the level of the chondrocyte.128 Metabolic acidosis also can impede growth through mechanisms not specific to growth factor impairment, such as increased protein catabolism,129,130 increased calcium efflux from bone,131,132 and decreased albumin synthesis.133
No data exist to evaluate the efficacy of isolated acidosis correction on growth failure in children with CKD, likely because growth retardation in children with CKD is multifactorial.112 However, data show a profound growth improvement in children with isolated renal tubular acidosis treated with alkali therapy.134,135 Because these studies showed that maximal height was inversely related to the duration of acidosis before therapy, oral alkali therapy should be initiated when persistent acidosis is observed in children with CKD. Oral alkali can be prescribed in the form of sodium bicarbonate or sodium citrate preparations, but citrate preparations should not be prescribed to patients receiving aluminum-based phosphorus binders because citrate enhances enteral aluminum absorption.
In children on dialysis therapy who have persistent acidosis, a trial of increased dialysis dose and/or a higher bicarbonate bath concentration can be considered to correct acidosis. Although no studies evaluated the effect of increasing dialysis dose in patients with persistent acidosis, 1 pediatric study demonstrated better growth rates in children receiving continuous ambulatory PD (CAPD) versus continuous cycler-assisted PD (CCPD) versus HD that may have been explained partially by better uremic control and acidosis correction by using CAPD.136
2.3: rhGH therapy should be considered in children with CKD stages 2 to 5 and 5D, short stature (height SDS < −1.88 or height-for-age < 3rd percentile), and potential for linear growth if growth failure (height velocity-for-age SDS < −1.88 or height velocity-for-age < 3rd percentile) persists beyond 3 months despite treatment of nutritional deficiencies and metabolic abnormalities. (B)
The growth hormone–IGF-1 axis is an important regulator of growth and metabolism, and substantial abnormalities in the axis have been identified in children with CKD, all of which result in growth hormone resistance. These abnormalities include decreased expression of the growth hormone receptor, impaired signal transduction of the growth hormone receptor, decreased production of IGF-1, and decreased activity of IGF by inhibitory IGF-binding proteins.112,123,137 Despite the presence of these inhibitory factors, the use of rhGH regularly results in improved height velocity in children with CKD.112,137-141
Clinical trials have demonstrated the safety and efficacy of rhGH therapy in promoting linear growth in children with CKD.112,142 Fifteen randomized clinical trials examining rhGH versus placebo have demonstrated improvement in height SDS, height velocity, and height velocity SDS, with the most dramatic response occurring in the first year of treatment followed by a progressively reduced effect thereafter. The target height deficit at the initiation of therapy and duration of treatment are the most important predictors of cumulative height gain.143 Long-term rhGH therapy in children with CKD has been shown to result in catch-up growth, and many patients achieve a final height within the normal range.32,143-146
Hokken-Koelega et al145 found that treatment during puberty was associated with a sustained improvement in height SDS without deleterious effects on GFR and bone maturation. Treatment showed no significant increase in the incidence of malignancy, slipped capital femoral epiphysis, avascular necrosis, glucose intolerance, pancreatitis, progressive deterioration in renal function, fluid retention, or incidence of benign intracranial hypertension.112 In a recent analysis of data contained in an international growth database of children with CKD, Nissel et al143 revealed that the increment in height SDS during the first year of rhGH treatment was greatest in patients who were prepubertal and experienced a normal onset of puberty and those who had early puberty.
Clinical studies support the efficacy of rhGH therapy in patients requiring kidney replacement therapy. Whereas children receiving dialysis experience an increase in growth with rhGH therapy, the response is less than that of patients with earlier stages of CKD, thus emphasizing the need to initiate rhGH therapy at a young age and/or early in the evolution of CKD to maximize the achievement of growth potential.32,143,144
Poor growth outcomes after kidney transplantation are associated with corticosteroid use, persistent CKD, and abnormalities of the growth hormone–IGF-1 axis. The use of rhGH after transplantation does lead to catch-up growth, and Fine et al147 demonstrated that final height was superior in rhGH-treated kidney transplant patients compared with controls, with no adverse effect on allograft function. In most cases, initiation of rhGH therapy has been delayed until 1 year or more after kidney transplantation.147
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