Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis

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 impact, pathogenesis, risk factors, evaluation, and diagnosis of growth failure in children with CKD will be reviewed here. The management of growth failure in this population is discussed separately. (See "Growth failure in children with chronic kidney disease: Prevention and management" and "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

DEFINITIONS

Chronic kidney disease — The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for Evaluation and Management of Chronic Kidney Disease revised the 2002 classification of pediatric CKD by the Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for Chronic Kidney Disease [3,4]. (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Definitions and diagnosis'.)

The KDIGO guideline also includes CKD staging for children older than two years of age, and stratifies the risk for progression of CKD and its complications based on glomerular filtration rate (GFR). This classification is used to guide management, including what therapeutic interventions should be initiated and when (table 1):

●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) 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).

IMPACT OF POOR GROWTH

Childhood morbidity and mortality — Poor growth in children with CKD, which is a marker of disease severity, is associated with significant morbidity and mortality. This is illustrated by the following studies:

●In the first study using data from the United States Renal Data System (USRDS) of 1949 children starting chronic dialysis therapy, multivariate analysis showed the risk of death increased by 14 percent for each unit of decrease of height Z-score [5].

●In a second study using USRDS data of 1112 children undergoing chronic dialysis or who received a kidney transplant from 1990 through 1995, the risk of death increased with growth failure, with a threefold increase in patients with severe growth failure (incremental growth <-3 standard deviation [SD]) and a twofold increase in patients with moderate growth failure (>-3 and <-2 SD) [6]. The hospitalization rate was also greater in patients with moderate and severe growth failure.

●Similar results were reported in a study from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) of 2306 children initiated on chronic dialysis between 1992 and 2000 [7]. Multivariate analysis showed the risk of death was twofold higher in patients with heights <1^st percentile for age compared with patients with heights ≥1^st percentile. Children with short stature also had decreased school attendance and a greater number of days of hospitalization.

Short stature also affects the psychological development of the patient. Short children are often treated as being younger than they are, and particularly in the additional context of chronic illness, may be overprotected and have low expectations set for them [8]. Short stature is associated with poorer school performance, physical functioning, social rehabilitation, and quality of life, as well as lower levels of employment and marital status [1,2,9-11]. Survey data based on parental reports also showed that catch-up growth and the use of growth hormone therapy were associated with higher physical and social functioning [10].

Final height — Poor growth during childhood results in adult short stature. Prior to the use of recombinant human growth hormone (rhGH), almost one-half of patients with childhood-onset end-stage kidney disease (ESKD) achieved adult heights below the 3^rd percentile [2]. The reported final adult height for patients with CKD during childhood is significantly lower than for the normal adult population, with heights for women ranging from 148 to 158 cm (2^nd percentile 151 cm) and for men between 162 to 168 cm (2^nd percentile 163 cm) [12]. Final height is most compromised in patients with severe congenital kidney disorders, such as nephropathic cystinosis [13]. Short stature in adulthood contributes to a lower perceived quality of life and self-esteem [8,14].

Important determinants of final height are older age at start of KRT and kidney transplantation, cumulative time with a functioning graft, and greater standardized height at KRT initiation and kidney transplantation [6,15]. In addition, post-transplant catch-up growth is restricted to the youngest patients (<6 years at kidney transplantation) [16,17].

Improvement in final height has been observed over time with advancements in the management of pediatric CKD [3]. This was illustrated by an analysis from the European Registry for Children on Renal Replacement Therapy, European Renal Association, and European Dialysis and Transplantation Association registry that showed height increased significantly from -1.93 SD in children who started kidney replacement therapy (KRT) before 1990, to -1.78 SD in children from 1990 to 1999, and to -1.61 SD in those starting KRT after 1999 [16]. Poorest growth outcomes were associated with earlier start and longer duration of dialysis or a diagnosis of a metabolic disorder such as cystinosis and hyperoxaluria. Patients with the best adult final heights were those with a longer time spent with a kidney transplant and who received rhGH therapy. In the United States, final height SD's among over 2500 patients who underwent transplant and reached 19 years of age improved from -1.93 in the period from 1987 to 1991, to -0.89 in the 2007 to 2013 period [17].

PREVALENCE — Growth failure is a common problem in children with CKD stages 2 through 5, as illustrated by the following data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry.

●In the 2008 NAPRTCS report, more than 35 percent of children at the time of enrollment in the CKD registry had impaired growth defined as a height less than the 3^rd percentile for age and sex (Z-score for height below -1.88) [18]. Overall, the mean Z-score for height was -1.44.

•In this cohort, the risk of growth failure was greatest in infants (<1 year of age, 58 percent) and lowest in older children (>12 years of age, 22 percent).

•The risk for poor growth increased with decreasing kidney function, although even children with mild kidney impairment (glomerular filtration rate [GFR] >60 mL/min per 1.73 m²) were at risk for poor growth (figure 3).

●Growth failure was greater in patients who had been on dialysis for two years with a mean height Z-score of -1.6 [19].

●In an analysis of 2000 recipients enrolled in the transplant NAPRTCS registry who were >19 years of age, one-fourth had significant short stature with a height Z-score less than -2.3, and 10 percent had severe growth failure with a height Z-score less than -3.3 [18].

As noted above, final adult height has improved with advancements in the medical and technical management of CKD including kidney replacement therapy (KRT) [16,20-22]. For example, in Germany, the overall mean standardized height in children on KRT has increased from -3.0 standard deviations (SD) in 1988 to -1.8 SD in 2007 [20]. However, in other parts of the world, particularly in those with inadequate local resources, height prognosis remains poor [16,23].

PATHOGENESIS: DISTURBANCE OF GROWTH HORMONE/IGF-1 AXIS — Although the mechanisms underlying growth failure are not completely understood, clinical and experimental evidence demonstrate that disturbances of growth hormone (GH) metabolism and its main mediator, insulin-like growth factor-1 (IGF-1), are the primary contributing factors for poor growth in children with CKD. Poor nutrition, metabolic acidosis, fluid and electrolyte abnormalities, CKD-related osteodystrophy, and, to a lesser extent, anemia are also important risk factors for growth failure in these children. However, it is only partially known whether and how these factors affect GH/IGF-1 metabolism. (See "Physiology of growth hormone" and "Physiology of insulin-like growth factor 1" and 'Contributing factors' below.)

In children with CKD, the following evidence illustrates the primary pathogenetic mechanisms of GH insensitivity and the decreased bioavailability of IGF-1 resulting in growth failure. These data indicate that growth failure in children with CKD is mainly due to functional IGF-1 deficiency [24].

●In patients with CKD, fasting normal or elevated serum GH levels are disproportionately high for the observed diminished longitudinal growth, which suggests GH insensitivity [24-27]. Data from a uremic rat model that demonstrated a diminished growth response to supraphysiological doses of recombinant growth hormone provide additional supportive evidence of GH insensitivity in CKD [28].

●IGF-1 is generally synthesized in the liver under the control of GH. Although IGF-1 serum levels in CKD vary from normal (CKD stages 2 through 4) to slightly decreased (CKD stage 5), these levels are inadequately low in the face of elevated circulating GH levels. Experimental animal data demonstrate lower than expected hepatic IGF-1 messenger ribonucleic acid (mRNA) expression in CKD [29]. This hepatic insensitivity to the action of GH appears to be due to reduced GH receptor expression in liver tissue and disturbed GH receptor signalling [30-32].

●While total immunoreactive IGF-1 levels in serum from children with CKD stages 4 and 5 are normal or slightly decreased, the free IGF-1 (bioactive form) is reduced, and levels correlate with decreasing glomerular filtration rate (GFR) [33-35]. The reduction of bioactive free IGF-1 is due to the increased presence of inhibitory IGF-binding proteins (IGFBP), whose levels inversely correlate with decreasing GFR [36,37]. In patients with CKD, elevated levels of IGFBP are due to a decrease in kidney clearance and increased hepatic production [29,37].

●In CKD, experimental and clinical evidence suggests that the accumulation of high-affinity IGFBPs inhibit IGF action in growth plate chondrocytes by competing with the type 1 IGF receptor in the growth cartilage for binding free IGF [38,39].

In addition to the decrease in bioactive free IGF-1 due to inhibitory IGFBPs, there are experimental animal data that suggest a postreceptor defect of IGF-1 signaling contributes to poor growth [40,41].

CONTRIBUTING FACTORS — In children with CKD, risk factors that contribute to poor growth include anorexia leading to malnutrition [4], fluid and electrolyte abnormalities, metabolic acidosis, CKD-related osteodystrophy, and chronic inflammation (table 2) [42]. However, because children with increasing severity of CKD often have multiple risk factors, it is difficult to ascertain the individual contributions of each of these factors, with the possible exception of inadequate nutrition.

Severity of chronic kidney disease — The degree of growth failure increases as kidney function deteriorates (figure 3) [18]. Patients with end-stage kidney disease (ESKD; stage 5 CKD) are at the greatest risk for poor growth, as they are the most likely to develop the complications of CKD that contribute to impaired growth, which are discussed in the following sections.

Inadequate nutrition — In children with CKD, inadequate nutritional intake due to anorexia and vomiting is one of the most frequent and important factors contributing to growth failure [12,43].

In these patients, anorexia may be due to the following causes [12]:

●Reduced taste sensation that begins early in the course of CKD and worsens as CKD progresses [44].

●Reduced appetite – Leptin, which acts as an afferent satiety signal, is elevated in children with CKD, presumably due to reduced kidney clearance [45]. There is an inverse linear correlation of plasma leptin levels normalized for body fat mass with spontaneous energy intake in pediatric patients with CKD, suggesting that leptin accumulation contributes to uremic anorexia. In a uremic mice model, elevations in hormonal and inflammatory cytokines including leptin, tumor necrosis factor alpha, interleukin (IL)-1, and IL-6 disrupt signaling pathways within the hypothalamus, which are thought to adversely affect appetite, resulting in a decrease in caloric consumption [42].

●Other factors that may compete with nutritional intake include the need to take multiple medications and, in children with polyuria, the preference of water over food.

In children with CKD, vomiting is common and is likely due to dysfunctional gastrointestinal motor function, resulting in gastroesophageal reflux and delayed gastric emptying [43,46]. In patients who undergo peritoneal dialysis, the increase in intra-abdominal pressure may also cause vomiting and anorexia.

Insufficient dietary intake may also result from episodes of fasting surrounding surgical procedures and episodes of sepsis [46].

Disturbances of water and electrolyte metabolism — Many congenital kidney diseases may be associated with fluid and electrolyte abnormalities due to kidney tubular dysfunction that results in polyuria (leading to hypovolemia), and hyponatremia and hypokalemia from excessive loss of sodium and potassium. (See "Chronic kidney disease in children: Complications", section on 'Fluid and electrolyte abnormalities'.)

Although it is difficult to determine the extent to which disturbances in water and electrolyte metabolism contribute to growth failure in individual patients with CKD, these abnormalities can be significant contributors to growth failure. In children with CKD and tubular dysfunction, who have polyuria and salt-wasting, sodium and water supplementation may maintain or improve growth, and potentially delay kidney replacement therapy (KRT) [47]. Additional support is provided by the observation of impaired growth in children with nephronophthisis and fluid and electrolyte abnormalities prior to the development of renal insufficiency. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Renal disease'.)

Experimental data also demonstrate the effect of electrolyte disturbances on growth. In a rat model, sodium deficiency decreases protein synthesis and growth, which is only partially reversible by sodium repletion [48]. Depletion of chloride also causes growth retardation and diminishes muscle protein synthesis [49].

Metabolic acidosis — Metabolic acidosis is almost inevitably observed in CKD stages 3 through 5. This acidosis is primarily due to the kidney's reduced ability to excrete ammonia. The severity of the acidosis can be aggravated by nutritional protein and acid load, catabolism, and kidney tubular dysfunction. (See "Chronic kidney disease in children: Complications", section on 'Metabolic acidosis'.)

Experimental data in uremic animal models demonstrate the effects of metabolic acidosis on the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis as it is associated with down-regulation of spontaneous GH secretion [50], decreased expression of GH receptor and IGF-I messenger ribonucleic acid (mRNA) [51], and a reduction in both baseline and GH-stimulated serum IGF-I concentrations [52]. In addition, metabolic acidosis is associated with increased glucocorticoid production and protein degradation [53-56].

In an observational study of 1082 children with CKD, metabolic acidosis was associated with a lower height Z-score over time, whereas alkali therapy use was associated with better height Z-scores [5].

Additional support is provided by the almost universal finding of growth failure in children with metabolic acidosis due to renal tubular acidosis [6]. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children".)

Anemia — Children with CKD develop increasing anemia as a result of erythropoietin deficiency. It is not certain if, or to what extent, chronic anemia leads to growth failure. Theoretically, anemia may interfere with growth via various mechanisms, such as poor appetite, intercurrent infections, cardiac complications, and poor oxygenation of cartilage cells in the growth plate. Evidence for anemia as a contributor to growth failure is supported by the observation that transfusion regimens that maintain a near normal hematocrit improve growth in children with growth retardation due to chronic anemia (eg, thalassemia major) [57]. Additionally, hemoglobin decline is associated with growth impairment over time in children with mild to moderate nonglomerular CKD, even before hemoglobin levels reach the cutoffs that are currently used to define anemia in this population [6].

However, it is less clear that anemia in children with CKD is a significant contributor to growth failure, as correction of anemia with recombinant human erythropoietin has not been shown to improve the growth of children with CKD [58]. (See "Chronic kidney disease in children: Complications", section on 'Treatment of anemia'.)

Chronic kidney disease-mineral and bone disorder — CKD-mineral and bone disorder (CKD-MBD) and osteodystrophy are caused by dysfunctional vitamin D metabolism and by secondary hyperparathyroidism. CKD-related osteodystrophy is manifested clinically as skeletal deformities, muscular hypotension, and, occasionally, slipped capital femoral epiphyses. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

In children with CKD, the growth plate is vulnerable to injury with disruption of the connection between the epiphyseal plate and the metaphysis. Although gross skeletal deformities can contribute to the retardation of a child's growth, the appearance of osteodystrophy is not paralleled by alterations in the epiphyseal growth of the long bones. Growth is only arrested completely when secondary hyperparathyroidism results in severe destruction of the metaphyseal bone architecture.

The extent to which secondary hyperparathyroidism contributes to growth failure is unclear [59]. Low bone turnover induced by relatively low parathyroid hormone (PTH) levels may contribute to growth failure [60]. At the other end of the spectrum, excessive secretion of PTH can lead to the destruction of growth plate architecture, epiphyseal displacement, and metaphyseal fractures [60]. However, treatment of children with CKD with vitamin D or 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) does not stimulate longitudinal growth [61]. Serum PTH levels should be kept within the recommended CKD stage-dependent target range for children [62-64]. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Management'.)

Serum concentrations of total 25-hydroxyvitamin D3 should be kept at above 30 ng/mL in all stages of CKD [65].

Prenatal factors — There is an association between poor growth in children with CKD and an abnormal birth history. This was illustrated in a study of 426 children from the Chronic Kidney Disease in Children Study (CKiD) that demonstrated the overall risk of low birth weight (LBW), small for gestational age (SGA), and prematurity was 17, 14, and 12 percent, respectively [66]. A multivariate analysis showed an inverse correlation between current height and weight, and LBW or SGA.

Age at onset of chronic kidney disease — In general, the younger the age of onset of CKD, the greater is the potential magnitude of growth retardation. This is illustrated by data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) CKD registry that measured height when children were initially enrolled [18]. The percentage of children with significant growth retardation (Z-score for height less than -1.88) increased with decreasing age as follows:

●0 to 1 year of age – 58 percent

●2 to 5 years of age – 41 percent

●6 to 12 years of age – 33 percent

●>12 years of age – 22 percent

Infancy — Because one-third of total growth occurs in the first two years of life, infants with CKD are at risk for severe growth retardation, which may result in irreversible loss of growth potential [12,18]. In a study of 73 children with onset of CKD before six months of age, the mean Z-height score was -3 at three years of age as a consequence of prenatal factors and poor postnatal growth [67]. In this cohort, approximately one-third of height reduction occurred during fetal life, one-third during the first postnatal months, and the last third between 0.75 and 1.5 years of age.

The main contributing factor of growth failure for this age group appears to be inadequate nutrition due to anorexia and recurrent vomiting. Supporting data for the influence of nutrition on growth during infancy and early childhood are based on the following:

●In one study, Z-height scores correlated with body cell mass, and serum transferrin and albumin levels (markers of nutritional status) [68].

●In a study from a single tertiary center, intensive nutritional intervention in 101 children with stage 4 or 5 CKD who presented before two years of age improved the mean Z-height score from -2.18 at six months of age to -1.74 and -1.51 at one and two years of age, respectively [69].

Other contributors to poor growth during infancy include water and electrolyte abnormalities, metabolic acidosis, and catabolic episodes during acute illnesses (eg, infection).

However, despite correction or prevention of these conditions and inadequate nutrition, deterioration of growth in infancy may still occur, indicating that the insensitivity to the action of GH is already operative during this period of growth [12]. (See 'Pathogenesis: Disturbance of growth hormone/IGF-1 axis' above.)

Congenital abnormalities — Some infants may have syndromic or congenital causes of CKD with concomitant non-kidney abnormalities that affect growth, such as infantile nephropathic cystinosis.

Mid-childhood — Patients who develop CKD after the second year of life lose relative height early in the course of the disease and subsequently follow this lower growth percentile after stabilization of the disease process. In this group of patients, the impact of the severity of kidney disease is particularly evident. This was illustrated in a prospective study of children with CKD due to kidney hypoplasia/dysplasia followed from birth to 10 years of age that showed a slightly but continuously lower annual growth rate in patients with a glomerular filtration rate (GFR) below 25 mL/min per 1.73 m² compared with patients with a higher GFR [70]. This difference accumulated into a mean height difference of 6 cm between these two groups at the age of 10 years. Multiple variate analysis demonstrated that decreasing GFR was a significant contributor to poor growth.

Other factors such as inadequate nutrition appear to be less important for poor growth in this age group compared with infancy. In addition, catch-up growth appears to be suppressed in a uremic milieu. It has been proposed that this percentile-parallel growth pattern during the mid-childhood period reflects a net balance between the growth suppressive effect of uremia and the inherent tendency for catch-up growth [70].

Puberty — The onset of puberty is usually delayed in adolescents with CKD by an average of 2 to 2.5 years, and approximately two-thirds of adolescents with CKD stage 5 enter puberty beyond the normal age range [71]. As a result, the pubertal growth spurt is also delayed by 2.5 years and the degree of delay correlates with the duration and severity of CKD [71].

Although there is a distinct acceleration of growth during puberty, the total pubertal height gain is reduced in both sexes to approximately 50 percent of normal late-maturing children. This reduction in height gain is due to a marked suppression of the late pre-spurt height velocity, a subnormal peak height velocity, and a shortening of the pubertal growth period by one year in boys and 1.5 years in girls [71]. Notably, the prolonged prepubertal growth phase, resulting from the delayed onset of the pubertal growth spurt, permits the patients to grow to an almost normal immediate pre-spurt height. However, relative height is subsequently lost during the shortened and less robust pubertal growth spurt, resulting in an average postpubertal Z-height score of -2.9 standard deviations (SD) in males and -2.3 SD in females with CKD stage 5.

In subsequent studies with advances in CKD management, most children requiring KRT before puberty have normal or only slightly delayed pubertal onset. In two studies, mean age at pubertal onset as well as age at menarche did not differ between children on KRT and healthy children, and serum levels of pubertal reproductive hormones were normal in the great majority of patients with CKD [20,72]. In particular, early kidney transplantation before the onset of puberty prevents delay in pubertal development and improves adult height [72].

Bone maturation — Bone maturation continues to be delayed by approximately 1.4 years compared with healthy children, although this does not negatively impact pubertal development [20]. However, alterations of bone maturation may result in loss of height gain during the pubertal growth spurt. In patients undergoing dialysis, bone maturation is increasingly retarded before the start of puberty; however, it accelerates dramatically with the onset of puberty [73,74]. This observation, and the fact that uremic boys respond to exogenous application of testosterone esters by an exaggerated increase in skeletal maturation [74], suggest that the sensitivity of the growth plate to sex steroids is conserved. However, because proliferation (ie, growth) cannot keep pace with differentiation (ie, bone maturation), growth potential is irreversibly lost during puberty in advanced CKD.

In contrast, in many patients after kidney transplantation, an apparent standstill of bone maturation is observed, even when the patient is growing and puberty is progressing. This phenomenon is thought to be related to direct interference of glucocorticoids with the differentiation of the growth plate. Despite the delayed bone age, late growth is usually not observed [71,75]. In fact, the successive stages of the pubertal growth spurt seem to occur at increasingly earlier bone ages than would be assumed in a normal population [71].

Glucocorticoid therapy — Glucocorticoid therapy, particularly daily glucocorticoid therapy, was historically used as immunosuppressive therapy following kidney transplantation. Glucocorticoids are also used in a variety of kidney disease, such as idiopathic nephrotic syndrome (NS). Growth failure is a known major adverse effect of glucocorticoid therapy and is discussed separately. (See "Causes of short stature", section on 'Glucocorticoid therapy'.)

EVALUATION OF GROWTH — In all children with CKD, routine measurements of growth should be obtained that measure the growth velocity in children as it is a more sensitive index of growth than is a single measurement of length/height (figure 1 and figure 2). Normal growth velocity varies with age (figure 4). (See "Normal growth patterns in infants and prepubertal children", section on 'Growth velocity'.)

As for any child with a potentially growth-limiting chronic disease, length (before two years of age) and height (from two years of age) should be assessed regularly by trained personnel using standardized techniques with calibrated equipment, which is compared with sex- and age-specific reference charts for healthy children. Gestational age is taken into account when assessing length of infants born preterm.

●For infants or for children when assessment of standing height is not feasible, supine length is measured using a validated length board or mat up to a length of 80 cm.

●For older children, standing height is measured using a wall-mounted stadiometer.

Z-scores of height/length measurement or growth velocity is a conversion that represents the number of standard deviations from the mean values for age and sex based on data for the general population. The Z-score for length/height or growth velocity is commonly used to assess growth in children with CKD. The following calculators are used to determine the Z-score for height for boys and girls, and length in infants (calculator 1 and calculator 2 and calculator 3). (See "Measurement of growth in children", section on 'Use of Z-scores'.)

In a 2009 revision of the nutritional guidelines for children with CKD, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommended that the frequency of growth measurements and nutritional assessment be based on the age of the patient and the CKD stage (table 3 and table 1) [76]. In general, assessment is performed at least twice as frequently as would be performed in a healthy child of the same age.

DIAGNOSIS OF GROWTH FAILURE — The diagnoses of short stature and growth failure in children with CKD are based upon the following definitions [76]:

●Short stature is defined as a length/height Z-score <-1.88 or a length/height for age <3^rd percentile.

●Growth failure is defined as height velocity Z-score <-1.88 or a height velocity for age <3^rd percentile that persists beyond three months.

FURTHER EVALUATION TO IDENTIFY UNDERLYING RISK FACTORS — Further evaluation is undertaken to detect any of the following risk factors for growth failure, which are amenable to treatment (see 'Contributing factors' above and "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Supportive measures') [1]:

●Nutritional assessment to determine if there is adequate energy intake (table 4).

●Serum electrolytes and venous blood gas to evaluate pH, carbon dioxide (PaCO₂), and the bicarbonate to detect any electrolyte abnormality or metabolic acidosis.

●Complete blood count to detect anemia.

●Calculation of glomerular filtration rate (GFR) using serum creatinine and height to assess kidney function [77].

●Serum calcium, phosphorus and parathyroid hormone level, and if appropriate, 25-hydroxyvitamin D levels to assess bone mineral metabolism and detect secondary hyperparathyroidism. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

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 failure is a major complication of children with chronic kidney disease (CKD). Poor growth in children with CKD is associated with increased morbidity (eg, increased hospitalization rate, decreased school attendance, and poorer physical function) and increased mortality. Growth failure results in adult short stature, which contributes to a lower perceived quality of life and self-esteem. (See 'Impact of poor growth' above.)

●Prevalence – Approximately one-third of children with CKD have evidence of short stature (ie, height <3^rd percentile for age and sex). The risk for poor growth increases with decreasing kidney function (figure 3). (See 'Prevalence' above and 'Severity of chronic kidney disease' above.)

●Contributing factors – Important factors that contribute to growth failure in children with CKD include (see 'Contributing factors' above):

•Severity and age of onset of CKD – The degree of growth failure increases as kidney function deteriorates (figure 3). Patients with end-stage kidney disease (ESKD; stage 5 CKD) are at the greatest risk for poor growth. In general, the younger the age at onset of CKD, the greater is the potential impact on growth retardation. As a result, patients who present with CKD in infancy are at higher risk for growth failure compared with older children. (See 'Severity of chronic kidney disease' above and 'Age at onset of chronic kidney disease' above.)

•Other factors – Other important contributing factors include:

-Inadequate nutrition (see 'Inadequate nutrition' above)

-Metabolic acidosis (see 'Metabolic acidosis' above)

-Fluid and electrolyte abnormalities (see 'Disturbances of water and electrolyte metabolism' above)

-Chronic anemia (see 'Anemia' above)

-CKD-related osteodystrophy (see 'Chronic kidney disease-mineral and bone disorder' above)

-Glucocorticoid therapy (see 'Glucocorticoid therapy' above)

●Evaluation of growth – For each child with CKD, ongoing assessment of growth is based on determining the growth velocity between visits. These measurements can be converted to Z-scores of height/length measurement or growth velocity that represent the number of standard deviations from the mean values for age and sex based on data for the general population (figure 1 and figure 2 and figure 4). (See 'Evaluation of growth' above.)

The following calculators can be used to determine the Z-score for height:

•For infants (calculator 3)

•For boys (calculator 1)

•For girls (calculator 2)

The frequency of growth assessment is based on the age of the patient and the severity of their kidney disease (ie, CKD staging) (table 3 and table 1). (See 'Evaluation of growth' above.)

●Diagnosis – The diagnoses of short stature and growth failure in children with CKD are based upon the following definitions. (See 'Diagnosis of growth failure' above.)

•Short stature is defined as a length/height Z-score <-1.88 or a length/height for age <3^rd percentile.

•Growth failure is defined as height velocity Z-score <-1.88 or a height velocity for age <3^rd percentile that persists beyond three months.

●Further evaluation – Further evaluation is focused on detecting risk factors for growth failure that are amenable to treatment. This consists of nutritional assessment and laboratory tests, including complete blood count, serum electrolytes, venous blood gas (to assess pH, carbon dioxide [PaCO₂], and bicarbonate levels), creatinine, calcium, phosphorus, and parathyroid hormone (PTH) levels. (See 'Further evaluation to identify underlying risk factors' above.)