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Growth failure in children with chronic kidney disease: Treatment with growth hormone

Growth failure in children with chronic kidney disease: Treatment with growth hormone
Literature review current through: Jan 2024.
This topic last updated: Apr 12, 2023.

INTRODUCTION — Growth impairment is a common problem in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality [1,2]. Several factors may contribute, including inadequate nutrition, metabolic acidosis, renal osteodystrophy, and insensitivity to the action of growth hormone (GH) [3-7].

Management to prevent and correct growth impairment due to CKD includes supportive measures that correct amenable complications of CKD (eg, poor nutrition and metabolic acidosis) and kidney replacement therapy (KRT), particularly kidney transplantation. However, despite these interventions, poor growth persists in a significant proportion of children with CKD, including kidney allograft recipients. In children who have persistent growth impairment, recombinant human growth hormone therapy (rhGH) is an effective and well-tolerated intervention that improves growth.

The use of rhGH in children with CKD, including efficacy, indications, and dosing will be reviewed here. The pathogenesis, risk factors, evaluation, and overall management of growth impairment in children with CKD are discussed separately. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis" and "Growth failure in children with chronic kidney disease: Prevention and management".)

DEFINITIONS

Height Z-score – The growth measurement Z-score for height is a conversion of height/length that represents the number of standard deviations from the mean height for age. A child with a height Z-score <-1.88 (<3rd percentile) has short stature. The following calculators can be used to determine height Z-scores for males ≥2 years old (calculator 1), females ≥2 years old (calculator 2), and infants (calculator 3). (See "Measurement of growth in children", section on 'Use of Z-scores'.)

Growth or height velocity – Growth or height velocity, the change in growth over time, is a more sensitive index of growth than is a single measurement. Current height/length measures are compared with previous growth points to determine the interval growth/height velocity (figure 1A and figure 1B).

rhGH THERAPY

Mechanism of action — Experimental and clinical evidence demonstrate that growth hormone (GH) insensitivity associated with CKD can be overcome by supraphysiologic doses of exogenous GH [8-11]. The administration of exogenous pharmacologic doses of GH results in increased circulating levels of total and free insulin-like growth factor-1 (IGF-1) as the relative increase in IGF-1 production is greater than the increase in inhibitory IGF-binding proteins, which raises the rate of longitudinal growth.

In a uremic animal model, histologic analyses showed increased growth of the proximal tibia in animals treated with GH [8].

Limited data from patients with CKD also suggest that GH therapy improved bone metabolism. In a small study of 10 prepubertal patients with CKD, recombinant human growth hormone (rhGH) therapy administered for one year produced a significant increase in lumbar spine and total body bone mineral content and bone mineral density [12].

Goals of therapy — The goal of recombinant human growth hormone (rhGH) therapy in children with CKD is "normalization" of final height. There is some debate concerning how this goal is defined. The most commonly used definitions are either:

Attainment of the patient's individual target height (ie, above the lower end of the patient's midparental height range (calculator 4)), or

Attainment of a normal population-related final height (ie, >3rd percentile or a Z-score >-1.88)

Although the former goal is certainly desirable for the individual patient, the latter approach may be economically more acceptable in view of the high cost of rhGH therapy. In our practice, the minimal therapeutic goal is a height greater than the third percentile of the general population.

It is important to monitor the growth of all children with CKD. When there is a reduction of growth velocity below normal values based on age and sex, an evaluation should be performed to identify and correct any amenable risk factors that contribute to growth impairment, such as inadequate nutrition or metabolic acidosis [2]. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Further evaluation to identify underlying risk factors' and "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Overview'.)

Criteria for initiating rhGH — Expert panels of pediatric nephrologists and endocrinologists developed the following criteria for initiation of rhGH therapy, which are generally consistent with the approach used in our center [2,13,14]. We generally initiate rhGH therapy if all of the following criteria are met:

Persistent growth impairment – This is generally defined as growth delay that persists for >3 months in infants and >6 months in older children. As discussed below, different thresholds are used to define growth impairment for this criterion. We generally prefer early initiation of therapy (ie, when the child's height for age is between the 3rd and 10th percentiles or height velocity is <25th percentile for age) rather than waiting until the child meets stricter criteria for growth failure. (See 'Timing' below.)

Other contributing factors have been addressed – Other factors that contribute to growth impairment should be addressed prior to starting rhGH. Other modifiable factors include [15]:

Inadequate nutrition

Metabolic acidosis

Fluid and electrolyte abnormalities

Anemia

Renal osteodystrophy

These issues are discussed separately. (See "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Supportive measures'.)

Child has significant kidney impairment – This includes any of the following:

Stage 3 to 5 CKD (see "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Staging: Risk stratification')

On dialysis (see 'Patients on dialysis' below)

Kidney transplant recipients who do not have spontaneous catch-up growth by one year post-transplantation (see 'Kidney transplant recipients' below)

Child has growth potential – Based on clinical assessment and presence of open epiphyses on radiographic bone age.

No active malignancy – Children with active malignancies should not receive rhGH therapy.

Timing — The optimal timing for starting rhGH therapy is uncertain. In particular, there is debate as to whether therapy should be started at an early stage when the child first shows signs of growth delay or if it should be used only once the child meets strict criteria for growth failure. In general, beginning treatment at a younger age (before six years of age) and early in the course of CKD leads to a better response to rhGH, which is more likely to result in normal or near-normal adult height.

We generally prefer a liberal approach, initiating rhGH when the child’s height for age is between the 3rd and 10th percentiles or height velocity is <25th percentile for age, provided that the growth delay persists for >3 to 6 months [13].

Other experts use stricter criteria, initiating rhGH only if the child meets the formal definitions of short stature or growth failure (ie, height Z-score <-1.88 or height velocity for age <3rd percentile that persists for ≥3 months) [2]. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Diagnosis of growth failure'.)

We and other experts advocate for starting treatment early because a persistently reduced growth rate will ultimately result in short stature [13]. In addition, there is some evidence that the practice of starting rhGH at an earlier stage might be more cost-effective than initiating rhGH therapy at an older age, when growth failure has become evident and higher absolute rhGH doses are required to account for the higher body weight [13]. Support for this approach is based on data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) and clinical trials that demonstrated children who meet the definition of growth failure (height Z-score <-1.88) before starting rhGH did not achieve sufficient catch-up growth to obtain normal adult height [16].

Pretreatment evaluation — The following baseline assessments should be performed prior to starting rhGH therapy:

Laboratory tests, including:

Blood glucose

Serum creatinine

Serum calcium and phosphate levels

Parathyroid hormone (PTH) level

Fundoscopic examination

Bone age

Determining pubertal status (ie, Tanner stage) (see "Normal puberty", section on 'Sexual maturity rating (Tanner stages)')

Pretreatment counseling — Although it might be assumed that most children with CKD who are shorter than their peers wish to be taller, the advantages and disadvantages of rhGH therapy must be discussed with the patient and their family/caregivers. In addition to reviewing the benefits and potential side effects of rhGH as outlined in this topic, counseling should include a frank discussion of the burdens of receiving daily subcutaneous injections for many years. These considerations are of particular importance for immobilized patients and those with syndromic kidney diseases [13].

Dosing — The recommended dose of rhGH for children with CKD is 0.045 to 0.05 mg/kg body weight per day given once daily (typically in the evening) via subcutaneous injection. This corresponds to a daily dose of approximately 4 international units (IU) per m2 body surface area. The injection site should be changed daily to avoid lipoatrophy [13].

In a meta-analysis of three clinical trials (150 children), a rhGH dose of 4 IU per m2 per day resulted in better growth velocity compared with a lower dose of 2 IU per m2 per day (mean difference of 1.18 cm per year) [17].

The dose of rhGH used for treating children with CKD-related growth failure is greater than what is typically used for treating children with GH deficiency. This is consistent with the current understanding that CKD causes GH insensitivity. As a result, children with CKD require a higher therapeutic dose rather than simply replacement dosing as is used in children with GH deficiency. (See "Treatment of growth hormone deficiency in children".)

Adverse effects — Long-term rhGH therapy is generally safe and well tolerated in children with CKD [17,18].

Reported side effects associated with rhGH treatment in children include (see "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'):

Headaches, usually mild

Idiopathic intracranial hypertension (pseudotumor cerebri)

Increased intraocular pressure

Slipped capital femoral epiphysis

Worsening of existing scoliosis

Insulin resistance/glucose intolerance/type 2 diabetes

In addition, concerns have been raised about a possible increased risk of malignancy in patients receiving long-term rhGH therapy. This is discussed in detail separately. (See "Treatment of growth hormone deficiency in children", section on 'Long-term risks'.)

Based on the available data, treatment-associated adverse events are rare in children with CKD receiving rhGH therapy.

In a study from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, the frequency of rhGH-related adverse events over a 6.5-year period was evaluated in 2333 patients who had current or prior use of rhGH therapy compared with 8533 patients who never received rhGH [18]. There were no differences between the two groups in the incidence of malignancy, slipped capital femoral epiphysis, avascular necrosis, glucose intolerance, pancreatitis, progressive deterioration of kidney function, acute allograft rejection, or fluid retention. The incidence of idiopathic intracranial hypertension was similar in both groups (0.2 versus 0.1 percent).

In an observational study of 1670 children with a variety of kidney diseases, there were 15 cases (0.9 percent) of intracranial hypertension [19]. However, all 15 children were using other medications that could predispose to intracranial hypertension.

In a retrospective subsequent study from NAPRTCS, there did not appear to be an increased risk of post-transplant lymphoproliferative disease in children who received rhGH during dialysis or post-transplant [20].

Monitoring

Monitoring for toxicity — We suggest the following monitoring for patients with CKD treated long-term with rhGH [2]:

Screening for type 2 diabetes mellitus (T2DM) – We suggest monitoring for T2DM with hemoglobin A1c and/or fasting blood glucose at least annually. This is particularly important in patients with additional risk factors (eg, concomitant glucocorticoid treatment, family history of type 2 diabetes). (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Screening'.)

Most patients treated with rhGH therapy maintain normal glucose tolerance; however, there are rare reports of development of T2DM in children with CKD that appeared to be temporally related to starting rhGH therapy [21,22]. In all cases, the abnormalities resolved after discontinuation of rhGH therapy.

Although insulin secretion increases during the first year of rhGH treatment and hyperinsulinemia persists during long-term therapy, normal glucose tolerance is preserved during up to five years of rhGH administration in CKD patients [23]. Hyperinsulinemia is most pronounced in transplanted patients on concomitant glucocorticoid therapy. Hyperinsulinemia may, at least in theory, contribute to the development of atherosclerosis or induce diabetes mellitus by exhaustion of beta cells. However, this has not been observed in CKD patients receiving rhGH [18].

Kidney function – The available clinical data indicate that rhGH therapy does not accelerate the loss of residual kidney function in children with CKD stages 2 to 4 [17,18,24-26]. However, because increases in the plasma creatinine concentration have been observed in individual patients, kidney function (serum creatinine) should be monitored, and rhGH therapy should be reconsidered if there is an otherwise unexplained decrease in kidney function.

Eye examination – Children receiving rhGH therapy should have routine fundoscopic examinations to assess for signs of papilledema suggestive of idiopathic intracranial hypertension (pseudotumor cerebri). Examinations are performed every three to four months initially, and then annually if there are no concerns. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Papilledema'.)

However, as discussed above, it is uncertain whether pediatric patients with CKD who are treated with rhGH are at increased risk for pseudotumor cerebri. (See 'Adverse effects' above.)

Monitoring for CKD-mineral bone disorder (CKD-MBD) and orthopedic complications – Monitoring for CKD-MBD while on rhGH includes:

Serum calcium, phosphate, and PTH levels, measured every three to four months initially

Hip and knee radiographs if the patient develops symptoms concerning for slipped capital femoral epiphysis (see "Evaluation and management of slipped capital femoral epiphysis (SCFE)")

CKD-MBD should be adequately treated before starting rhGH therapy. rhGH therapy should be withheld in patients with persistent severe secondary hyperparathyroidism (PTH >500 pg/mL) and can be reinstituted when PTH levels return to the desired target range [27-29]. There is not an associated deterioration of renal osteodystrophy, but rapid growth acceleration may contribute to an increased risk of slipped capital femoral epiphysis. As a result, it is advisable to obtain bone radiographs prior to initiating rhGH and to repeat the studies if symptoms occur.

Response to treatment — The response to treatment is assessed with the following:

Measuring the growth velocity

Monitoring pubertal stage

Radiographic bone age, assessed annually

An adequate growth response to rhGH is defined as a growth velocity that is ≥2 cm/year over the baseline prior to starting therapy.

Growth should be assessed every three to four months with measurements of height, weight, and, in children younger than three years of age, occipitofrontal circumference. Growth velocity and Z-score for height should be calculated. The following calculators can be used to determine height Z-scores for males ≥2 years old (calculator 1), females ≥2 years old (calculator 2), and infants (calculator 3). (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Diagnosis of growth failure'.)

Monitoring the response to rhGH therapy in children with CKD differs from the approach used in children with GH deficiency. Specifically, insulin-like growth factor 1 (IGF-1) levels are not routinely monitored in the CKD population whereas IGF-1 levels are routinely used for guiding dose adjustments in children with primary GH deficiency. (See "Treatment of growth hormone deficiency in children", section on 'Dose adjustment based on IGF-1 response'.)

Measurement of total IGF-I levels is not informative in children with CKD because free IGF-1 levels decrease with decreasing glomerular filtration rate (GFR). This issue is discussed in greater detail separately. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Pathogenesis: Disturbance of growth hormone/IGF-1 axis'.)

Treatment failure — For patients who do not adequately respond to rhGH therapy (ie, growth velocity <2 cm/year over the baseline prior to rhGH therapy), the following evaluation should be performed:

Assess patient compliance by taking a focused history since nonadherence is an important contributor to poor treatment response [30].

Confirm the weight-based rhGH dose is correct, and if necessary, readjust the dose for weight gain.

Assess whether other nutritional or metabolic factors for poor growth are present, and if so, initiate a corrective treatment plan.

Patients with persistently poor growth despite correction of these issues may require referral to a pediatric endocrinologist for further evaluation of other possible causes of growth failure [2].

Duration of therapy — The optimal duration of rhGH remains uncertain. Although clinical studies have shown that the growth response is greatest in the first two years of therapy, growth velocity is persistently greater than baseline in years three through five of therapy. Dosing needs to be readjusted every three to four months to account for weight gain.

In our practice, we continue rhGH therapy so long as growth velocity remains ≥2 cm/year above the baseline pretreatment growth rate. Treatment is discontinued if any of the following occur [2]:

Closed epiphyses on bone radiograph

Development of an active malignancy

Hypersensitivity to rhGH or components of its formulation

Increased intracranial pressure

Noncompliance that cannot be adequately addressed

Severe hyperparathyroidism based on CKD stage – PTH level >400 pg/mL for patients with CKD stage 2 through 4 and >900 pg/mL for patients with CKD stage 5

In addition, a dose reduction (eg, 50 percent of the usual dose) may be considered when the height goal is achieved based on midparental height.

EFFICACY

General efficacy — The efficacy of rhGH is supported by randomized clinical trials and observational studies showing that rhGH improves growth parameters in children with CKD [11,16,24,31-35].

In a meta-analysis of seven trials including 287 children with CKD, rhGH therapy improved height velocity compared with placebo (mean difference +3.9 cm over first year, 95% CI 3.3-4.4 cm) [17]. The small size of these trials did not allow for subgroup analysis to assess the relative efficacy of rhGH in different subpopulations (ie, patients with CKD not requiring kidney replacement therapy [KRT] versus patients on dialysis versus allograft recipients).

Observational studies have also demonstrated improved growth velocity in children with CKD treated with rhGH [16,31,35].

Catch0up growth – Based on the available data, rhGH appears to be associated with catch-up growth in children with CKD in all three subcategories, including patients who have not initiated KRT, those on dialysis, and kidney transplant recipients [16,31,35]. However, better kidney function at start of treatment is associated with better response. (See 'Predictors of response to rhGH' below.)

In a report from North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), that included nearly 1500 children with CKD without current or previous KRT who were treated with rhGH, 27 percent achieved catch-up growth [16]. In the same report, of the nearly 1700 children on dialysis who received rhGH therapy, 11 percent achieved catch-up growth. Of the 134 allograft recipients who received rhGH therapy, 25 percent achieved catch-up growth. In all groups, the highest catch-up growth was seen in patients who were prepubertal (defined as Tanner stage I or II) prior to initiating treatment.

The use of rhGH in patients on dialysis and in transplant recipients is discussed below. (See 'Patients on dialysis' below and 'Kidney transplant recipients' below.)

Growth during puberty – Data are limited on the effect of rhGH during puberty in patients with CKD. Addressing this question is challenging since several factors impact the pubertal growth spurt in patients with CKD. In general, the pubertal growth spurt occurs later and is considerably shorter in patients with CKD compared with children without CKD [36]. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Puberty'.)

Some studies have suggested improved height gain during puberty in rhGH-treated patients compared with historically matched controls [37,38]. In addition, an analysis of the Pfizer International Growth (KIGS) database demonstrated catch-up growth in patients with CKD who were either in early (Tanner stage II or III) or late (Tanner stage IV or V) puberty when rhGH therapy was initiated (cumulative increase in mean height Z-scores of 1.3 and 1.0, respectively) [39].

Predictors of response to rhGH — Independent predictors of the response to rhGH in the first and second year of treatment include [39,40]:

Age (younger age is associated with better response)

Pretreatment kidney function (better kidney function is associated with better response)

Target height (ie, midparental height; taller midparental height is associated with better response)

Prior growth rates (higher pretreatment growth rates correlate with better response)

Factors that impact final adult stature include [36,39,40]:

Height Z-score at initiation of therapy

Age at the start of rhGH

Duration of rhGH therapy

Time on dialysis

Age at puberty

These data suggest that earlier intervention at a younger age (before six years of age) and early in the course of CKD leads to a better response to rhGH and is more likely to result in achieving the goal of a normal adult height. (See 'Timing' above and 'Infants' below.)

Special populations

Patients on dialysis — Although the response to rhGH is reduced compared with that seen in children with CKD that do not require KRT, rhGH still is beneficial in patients undergoing dialysis treatment [39,41,42]. Responsiveness can be markedly improved when dialytic clearance is augmented by daily hemodiafiltration [43]. rhGH therapy improves height in dialysis patients irrespective of the underlying bone histologic features, and bone formation rates are higher in rhGH recipients compared with controls [44]. (See "Hemodialysis for children with chronic kidney disease" and "Alternative kidney replacement therapies in end-stage kidney disease", section on 'Hemofiltration and hemodiafiltration'.)

Observational studies of children undergoing dialysis reported a mean increase of growth velocity of 2.6 to 3.5 cm per year during the first year of administration of rhGH over the baseline rate before the initiation of therapy [45,46]. Although the growth rate decreased in subsequent years, it remained above the baseline rate.

Kidney transplant recipients — Successful kidney transplantation reverses the uremic milieu and should theoretically permit normal growth hormone (GH) secretion and function [47]. Persistent growth failure in this setting is primarily a result of reduced graft function and glucocorticoid therapy. If catch-up growth cannot be achieved by using a glucocorticoid-sparing regimen, we suggest initiating rhGH therapy, particularly in children with suboptimal graft function (GFR <50 mL/min per 1.73 m2), in whom spontaneous catch-up growth is unlikely to occur [48,49]. rhGH is usually prescribed only after the first year post-transplant, because spontaneous growth should be monitored for at least 12 months after kidney transplantation. Of note, rhGH is not approved for use in pediatric kidney allograft recipients by European or North American drug regulatory agencies.

In a meta-analysis of five randomized controlled trials including 401 pediatric kidney transplant recipients, children receiving rhGH therapy had higher growth velocity compared with the control group after one year (mean standardized height difference of 0.68, 95% CI 0.25-1.11) [50]. The mean difference in growth expressed as change in height Z-score between the rhGH and control groups was 0.52 (95% CI 0.37-0.68). There was no apparent between-group difference in rates of rejection rate between the two groups (17 versus 10 percent, risk ratio 1.56, 95% CI 0.97-2.53). The study did not detect a difference in GFR between the two groups.

Additional evidence supporting the benefit of rhGH in growth-delayed kidney allograft recipients was provided by a retrospective NAPRTCS study that compared the outcome of 513 pediatric kidney allograft recipients who received rhGH with 2263 transplant patients who were not treated with rhGH [51]. The rhGH-treated group had improved growth with a mean cumulative increase in height of 3.6 cm over five years compared with controls, which resulted in higher mean final adult height Z-scores (-1.8 versus -2.6).

Although there had been concerns about a possible link between rhGH and an increase in the risk of acute rejection [32], subsequent data have shown no association between rhGH and acute rejection [17,33,51].

An important limitation of the available data is that most studies were conducted in an earlier era when transplant recipients commonly received immunosuppressive regimens that included glucocorticoids. Thus, the findings in these studies may not be generalizable to the contemporary era wherein glucocorticoid-sparing regimens are generally preferred for posttransplant immunosuppression. (See "Kidney transplantation in children: Immunosuppression", section on 'Glucocorticoid-sparing regimen'.)

Taken together, these data suggest that rhGH is effective and safe for use in growth-delayed pediatric kidney allograft recipients despite the lack of approval by drug regulatory agencies in this population.

Infants — In infants, correction of nutritional status is the primary measure to restore normal growth and this intervention is often sufficient. However, there is evidence from observational studies and clinical trials that rhGH may be beneficial in infants with CKD who have growth failure despite adequate caloric intake [11,52,53]. Early rhGH therapy may improve weight gain and growth in such infants, allowing them to reach the body size required for kidney transplantation and avoid delays in transplantation.

The following data support the use of rhGH in infants:

The Genentech Cooperative Study Group (GCSG) trial was a two-year placebo-controlled randomized trial evaluating rhGH in children with CKD. In a subgroup analysis of patients <2.5 years old (mean age 1.4 years) enrolled in the GCSG trial, those in the rhGH group had greater growth rates compared with the placebo group both in the first year (14.1 versus 9.3 cm) and second year (8.6 versus 6.9 cm) [52].

In a multicenter trial of infants with a mean age of 12 months and a GFR ≤60 mL/min per 1.73 m2, patients assigned to rhGH therapy had a greater increase in length over one year compared with controls (14.5 versus 9.5 cm) [11]. All patients had adequate nutritional intake and good metabolic control.

These results suggest that early initiation of rhGH therapy in this phase of rapid growth might reverse or prevent the otherwise common irreversible loss of growth potential in infancy. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Infancy'.)

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

Rationale for treatment – Growth impairment is a common problem in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality. Although the mechanisms underlying growth impairment 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) play key roles. (See 'Introduction' above and "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis".)

Goals of therapy – The primary goal of recombinant human growth hormone (rhGH) therapy is to attain normal or near-normal adult height as expected for the child's genetic height potential (based on midparental height). The minimal therapeutic aim should be a height >3rd percentile of the general population. (See 'Goals of therapy' above.)

Criteria for starting therapy – We recommend rhGH in children with CKD who meet all of the following criteria (Grade 1B):

The child has persistent growth impairment (ie, persisting for >3 months in infants and >6 months in older children). Different thresholds are used to define growth impairment for this criterion, as discussed below.

All other modifiable factors for growth impairment have been addressed, including inadequate nutrition, metabolic acidosis, fluid and electrolyte abnormalities, anemia, and osteodystrophy. (See "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Supportive measures'.)

The child has stage 3 to 5 CKD, is on dialysis, or has undergone kidney transplantation.

The child has growth potential based on the presence of open epiphyses on radiographic bone age.

The child does not have an active malignancy.

Timing – We suggest starting rhGH at an early stage (ie, when the child’s height for age is between the 3rd and 10th percentiles or height velocity is <25th percentile) rather than waiting until the child meets formal definitions of short stature or growth failure (ie, height or height velocity for age <3rd percentile) (Grade 2C). In general, intervention at a younger age (before six years of age) and early in the course of CKD leads to a better response to rhGH, which is more likely to result in a normal or near-normal adult height. (See 'Timing' above.)

Dosing – For treatment of CKD-related growth impairment, rhGH therapy is given at an initial daily dose of 0.045 to 0.05 mg/kg via subcutaneous injection once daily, typically in the evening. The dose should be readjusted every three to four months to account for weight gain. (See 'Dosing' above.)

Monitoring – Children treated with rhGH should be routinely monitored for potential adverse effects and to ensure adequate response to therapy. This includes (see 'Monitoring' above):

Assessing growth by measuring height, weight, and, in children <3 years old, occipitofrontal circumference. Growth velocity (figure 1A-B) and Z-score for height should be calculated. The following calculators can be used to determine height Z-scores for males ≥2 years old (calculator 1), females ≥2 years old (calculator 2), and infants (calculator 3).

Assessing nutritional status regularly.

Regular fundoscopic examinations to assess for papilledema.

Assessing pubertal stage.

Laboratory tests including hemoglobin A1c and/or fasting blood glucose, serum electrolytes, creatinine, calcium, phosphate, and parathyroid hormone (PTH) levels. These are measured every three to four months initially.

Bone age, annually.

Hip and knee radiographs if there are symptoms concerning for slipped capital femoral epiphysis. (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)".)

Treatment response – An adequate growth response is defined as a growth velocity that is >2 cm/year over the baseline rate prior to rhGH therapy. In patients who fail to have an adequate response, evaluation consists of assessments of patient compliance, correct dosing, and whether there are contributing factors to growth impairment. (See 'Response to treatment' above and 'Treatment failure' above.)

Duration of treatment – We generally continue rhGH for as long as growth velocity remains ≥2 cm/year above the baseline pretreatment growth rate. Treatment is discontinued if any of the following occur (see 'Duration of therapy' above):

Closed epiphyses on bone radiograph

Development of an active malignancy

Hypersensitivity to rhGH or components of its formulation

Increased intracranial pressure

Noncompliance that cannot be adequately addressed

Severe hyperparathyroidism based on CKD stage: PTH level >400 pg/mL for patients with CKD stage 2 through 4 and >900 pg/mL for patients with CKD stage 5

In addition, we reduce the dose by 50 percent once the of the target height is achieved based on midparental height.

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Topic 6140 Version 30.0

References

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