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 (CKD): Risk factors, evaluation, and diagnosis" and "Growth failure in children with chronic kidney disease: Prevention and management".)
DEFINITION
Z-height score — The growth measurement Z-score for height is a conversion of height/length that represents the number of standard deviations (SD) from the mean height for age. A child with a height Z-score <-1.88 has short stature. (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 1 and figure 2).
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 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].
EFFICACY — There is strong evidence from clinical trials and observational data from large registries that recombinant human growth hormone (rhGH) therapy improves growth in children with CKD.
Clinical trials — Randomized clinical trials have shown that rhGH stimulates growth in children with CKD [11,13-16].
This was best illustrated in a meta-analysis of clinical trials that included 809 children with CKD [17]. In this review, some analyses included patients in all clinical settings for CKD: those who never received kidney replacement therapy (KRT), were on dialysis, or had received a kidney transplantation. The following findings were noted:
●Children who were randomly assigned to rhGH (dose 28 international units [IU]/m2 per week) had a greater increase in mean height velocity (+3.9 cm) than patients who received either no treatment or placebo after one year.
●There was no evidence of adverse effect on kidney function. In six trials of children postkidney transplantation, there was no difference in the risk of acute rejection; however, in one trial, there were more episodes of acute rejection in children who received rhGH.
●There was no evidence that rhGH advanced the pubertal growth spurt, sped up the normal growth process, or that it advanced bone age.
●Data from patients followed until they achieved final height demonstrated an improved mean Z-score for final height for the rhGH group compared with the control group (-1.6 versus -2.1).
This review was limited as it only was able to study the effects of growth for a maximum of two years. In addition, the relative small number of patients did not allow for subgroup analysis based on the clinical status (ie, CKD without KRT, CKD with dialysis, or allograft recipient).
Observational data — The benefit of rhGH in promoting growth in all three clinical settings of pediatric CKD has been supported by observational data.
A report from North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) demonstrated the extent of use of rhGH therapy and its benefit in all three clinical settings [18]:
●Of the 6505 children with CKD without current or previous KRT, 22 percent received rhGH. Hormonal therapy was associated with catch-up growth in 27 percent of treated patients.
●Of the 5122 children on dialysis, 33 percent received rhGH. Hormonal therapy was associated with catch-up growth in 11 percent of treated patients.
●Of the 4478 children who received a kidney allograft, 3 percent received rhGH. Hormonal therapy was associated with catch-up growth in 25 percent of treated patients.
●In all groups, the highest catch-up growth was seen in patients who were prepubertal (defined as Tanner stage I or II).
Specific populations — As discussed above, the use of rhGH is beneficial in children with CKD in all three settings of CKD: without KRT, dialysis, and postkidney transplantation. Although most studies have primarily been comprised of prepubertal children, there is also good evidence to support the use of rhGH in infants. It remains uncertain whether rhGH can significantly improve growth in pubertal children, as data in this group of patients are limited.
Prepubertal patients
●CKD without KRT — Several clinical trials of children with CKD without KRT, which were included in the meta-analysis discussed above, showed that patients who received rhGH therapy had an increased growth velocity compared with controls who received placebo therapy [15-17].
In the Genentech Cooperative Study Group trial of 125 children with CKD (mean age six years), the mean growth rate was increased in the rhGH versus the placebo group in both the first year (10.7 versus 6.5 cm/year) and second year (7.8 versus 5.5 cm/year) of the study [16]. Continued treatment for a total of five years showed the maximum increase in height occurred during the first two treatment years; however, changes in mean height Z-scores continued to be greater in the rhGH group in subsequent years [19].
Observational data from the NAPRTCS CKD registry also show the beneficial effect of rhGH in children with CKD who are not receiving KRT. In a case-control study of patients enrolled in the CKD registry (never underwent dialysis or kidney transplantation), patients who were treated with rhGH had a better mean height Z-score than matched control patients who did not receive rhGH (-1.46 versus -2.02) after two years [20]. Controls were matched by age, gender, base-line height, and length of time on the registry, but the estimated glomerular filtration rate (GFR) of the treated group was less than that of the control group (37.5 versus 42.3 mL/min per 1.73 m2). However, the lower GFR would be expected to reduce the height gain in the rhGH group.
●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 [21-23]. Responsiveness can be markedly improved when dialytic clearance is augmented by daily hemodiafiltration [24]. 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 [25]. (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/year during the first year of administration of rhGH over the baseline rate before the initiation of therapy [26,27]. Although the growth rate decreased in subsequent years, it remained above the baseline rate.
In the 2011 NAPRTCS dialysis report, children treated with rhGH compared with untreated patients were more likely to be growth impaired at the initiation of dialysis [28]. However, after 12 months on dialysis, children who received rhGH had a greater change in height Z-score with the greatest improvement in children less than six years of age.
•For children less than six years of age, the rhGH group had a mean change in height Z-score of +0.63 versus +0.01 for the untreated group.
•For children six years and older, the mean height Z-scores were +0.26 versus -0.1 for the rhGH and untreated groups, respectively.
●Kidney transplantation — Successful kidney transplantation reverses the uremic milieu and should theoretically permit normal growth hormone (GH) secretion and function [29]. 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 an alternate-day glucocorticoid regimen, and if discontinuation of glucocorticoids is not possible because of unstable graft function, rhGH therapy should be initiated, particularly in children with suboptimal graft function (GFR below 50 mL/min per 1.73 m2), in whom spontaneous catch-up growth is unlikely to occur [30,31]. 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, the use of rhGH in pediatric kidney allograft recipients is not approved by European or North American drug regulatory agencies.
Exogenous GH reverses the catabolic and growth-depressing effects of glucocorticoids in both experimental and clinical settings [32]. In particular, rhGH can counteract the interference of pharmacological doses of glucocorticoids with the integrity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis.
Clinical trials, which were included in the previously mentioned meta-analysis [17], have shown the benefit of rhGH in growth-retarded pediatric kidney allograft recipients, as illustrated by the following [13,14,33]:
●In a French trial, patients assigned to rhGH therapy had a higher growth velocity than control patients in the first year of the study (7.7 versus 4.6 cm per year) [13]. Subsequently, a decrease in growth velocity was noted, with growth of 5.9, 5.5, and 5.2 cm occurring at two, three, and four years, respectively. These data indicate that GH therapy clearly induces catch-up growth, but the effect becomes limited with time.
●In a second randomized controlled trial of growth-retarded patients performed by the NAPRTCS, patients assigned to rhGH had a higher mean change in height Z-score than control patients after one year (+0.49 versus -0.1) [14].
Additional evidence supporting the benefit of rhGH in growth-retarded 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 patients who were not treated with rhGH [34]. 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 [13], subsequent data have shown no association between rhGH and acute rejection [14,17,34].
A systemic review and meta-analysis of randomized controlled trials on rhGH therapy in pediatric kidney transplant recipients reported the following [35]:
•One year after randomization, children receiving rhGH therapy had a higher growth velocity than the control group (mean standardized height difference of 0.68, 95% CI 0.25-1.11). The mean difference in growth expressed as delta height Z-score between the rhGH and control groups was 0.52 (95% CI 0.37-0.68).
•There was no statistical difference in the rejection rate between the two groups. In the rhGH group, there were 35 rejection episodes in 205 patients compared with 19 in 185 patients (17 versus 10 percent, risk ratio 1.56, 95% CI 0.97-2.53).
•The mean difference in glomerular filtration rate between the two groups was 3.27 mL/min per 1.73 m² but this difference was not statistically significant (95% CI -3.54-10.09).
Based upon the above discussion and data, it appears that rhGH is effective and safe for use in growth-retarded pediatric kidney allograft recipients despite the lack of approval by European or North American drug regulatory agencies.
Infants — In infants, correction of nutritional status is the primary and often sufficient measure to restore normal growth. However, particularly in infants with growth failure despite adequate caloric intake, there is evidence from observational studies and clinical trials that rhGH may be beneficial in infants with CKD [11,36,37]. Early rhGH therapy may accelerate length and weight gain in such infants, allowing adequate growth to reach the body size required for kidney transplantation without delay. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines for nutritional management in children with CKD suggest that rhGH should be initiated promptly if nutritional management has not induced catch-up growth within three months [38].
The following data support the use of rhGH in infants:
●A subanalysis of the Genentech Cooperative Study Group clinical trial demonstrated that infants and young children (less than 2.5 years of age, mean age 1.4 years) who were randomly assigned to rhGH therapy had greater growth rates in both the first year (14.1 versus 9.3 cm) and second year (8.6 versus 6.9 cm) of the study than patients who receive placebo treatment [36].
●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 compared with controls (14.5 versus 9.5 cm). All patients had adequate nutritional intake and good metabolic control [11].
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 (CKD): Risk factors, evaluation, and diagnosis", section on 'Infancy'.)
Pubertal children — Data are limited on the effect of rhGH in pubertal patients with CKD. Assessment of growth is also challenging, as the pubertal growth spurt is usually delayed and shortened in patients with CKD. As a result, an adequate evaluation of the effect of rhGH on pubertal growth requires an analysis of the degree and duration of the entire pubertal growth spurt. (See "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Puberty'.)
In one report that followed initially prepubertal patients (mean age 10.4 years at start of the study) treated long term with rhGH (mean duration of treatment 5.3 years), total pubertal height gain was similar in control and GH-treated children with kidney failure [39]. The gain was 65 percent of that observed in normal children because of a shorter (by 1.6 years) pubertal growth spurt.
In contrast, studies in short pubertal children treated with rhGH after transplantation reported higher mean gain in height compared with historically matched controls [40,41]. 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 with a cumulative increase in mean height Z-scores of 1.3 and 1 [23].
Final adult height — Based on observational data, adult or near-adult height was greater in patients who received rhGH for at least 2 years as children compared with matched historical control groups [42]. The median absolute increase in rhGH-treated patients was 7.4 cm (range, 1.4 to 10.8 cm) in boys and 7 cm (range, 1.3 to 10.1 cm) in girls.
The efficacy of rhGH to improve final height is mainly affected by the following factors [23,39,43]:
●The total duration of rhGH therapy.
●The kidney failure treatment modality, as end-stage kidney disease (ESKD) treated by dialysis adversely affects the long-term efficacy of rhGH.
●Age at puberty onset and age of start of rhGH are negatively associated with final height.
INITIATION OF rhGH THERAPY
Goal — 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 therapeutic end point could either be attainment of the patient's individual target height (ie, the 50th percentile of midparental height) or of a normal population-related final height (ie, greater than the third 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 (approximately USD $30,000 per patient per year). 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 gender, 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 (CKD): 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'.)
Timing and indications — The timing of initiation of rhGH is based on optimizing the response to therapy when the indications for therapy are met. Because a persistently reduced growth rate will ultimately result in short stature, the clinical practice recommendations for growth hormone treatment in children with chronic kidney disease suggest that rhGH therapy is considered in children with height between the 3rd and 10th percentiles who have low height velocity (below the 25th percentile) that persists beyond three months in infants and beyond six months in children with growth potential provided that other potentially treatable risk factors for growth failure have been adequately addressed [42].
Whether a height velocity below the 25th percentile is an indication to start GH even before height drops below the 3rd percentile is unclear. Such early, preventive therapy might be more cost-effective than initiating rhGH therapy at an older age, when growth retardation has become evident and higher absolute rhGH doses are required to account for the higher body weight [42]. 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 were already growth-retarded (height Z-score <-1.88) before rhGH was started did not have sufficient catch-up growth to obtain normal population-related final height. As a result, early initiation of therapy is advocated for patients who meet the criteria for rhGH therapy.
Although it might be assumed that short children with CKD wish to be taller, the pros and cons of rhGH therapy, including the burden of receiving daily subcutaneous injections for many years, must be discussed with the patient and their family. These considerations are of particular importance for immobilized patients and those with syndromic kidney diseases [42].
Predictors for growth response to rhGH — In the first and second year of treatment, age, glomerular filtration rate (GFR), target height (ie, midparental height), and prior growth rates are independent predictors of the response to rhGH [23,43]. Height velocity negatively correlates with increasing age and positively correlates with higher kidney function and target height. Factors that positively impact final adult stature include height Z-score at initiation of therapy and duration of rhGH therapy, and those with adverse effects include increasing time on dialysis, delayed puberty, and the age at the start of rhGH.
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 more robust response to rhGH and is more likely to result in achieving the goal of a normal final height. In particular, the use of rhGH appears to be most beneficial in infants who are most likely to achieve successful catch-up growth. (See 'Infants' above.)
Indications — Indications for initiation of rhGH therapy in children with CKD are based on limited data and clinical experience. An algorithm was developed by a consensus group of pediatric nephrologists to target the population of children with CKD who would most benefit from rhGH therapy. The following indications were proposed for initiation of therapy, which are consistent to the approach used in our center [2]:
●All other amenable factors that contribute to growth impairment have been adequately addressed. These include insufficient nutrition, metabolic acidosis, fluid and electrolyte abnormalities, anemia, and renal osteodystrophy. This is in agreement with the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) pediatric nutrition guidelines that recommend correction of existing nutritional deficiencies and metabolic abnormalities prior to consideration of rhGH therapy for growth failure [44]. Management of these factors is discussed separately. (See "Growth failure in children with chronic kidney disease: Prevention and management", section on 'Supportive measures'.)
●Estimated GFR is less than 75 mL/min per 1.73 m2.
●There is evidence of growth impairment, defined as height velocity Z-score <-1.88 or a height velocity for age <3rd percentile that persists beyond three months (figure 1 and figure 2). Z-scores represent the number of standard deviations from the mean values for age and gender based on data for the general population. The following calculators can be used to determine the Z-score for height for boys, girls, and infants (calculator 1 and calculator 2 and calculator 3). (See "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Diagnosis of growth failure'.)
●Children with active malignancies should be excluded from rhGH therapy.
●Baseline assessments should be performed that will be used in monitoring rhGH response and potential adverse effects. These include laboratory testing (ie, glucose, serum creatinine, calcium, phosphorus, and parathyroid hormone [PTH]), funduscopic examination, bone age, and determining pubertal status (ie, Tanner stage).
Dose of rhGH — The recommended dose of rhGH currently used in Europe and the United States for children with CKD is 0.045 to 0.05 mg/kg body weight per day, which corresponds to approximately a daily dose of 4 international units (IU) per m2 body surface area. This is given daily by subcutaneous injection. Although data are limited, the previously discussed meta-analysis showed that this dose (defined as a cumulative weekly amount of 28 IU/week per m2 body surface area in the systematic review) resulted in a higher growth velocity than a lower dose of 14 IU/week per m2 body surface area (mean difference of 1.18 cm per year) [17].
The amount of rhGH given to children with CKD is greater than what is normally given to growth hormone (GH)-deficient children. This is consistent with the current understanding that CKD causes GH insensitivity; as a result, pharmacologic rather than replacement dosing is required in treating children with CKD.
Frequency and mode of administration — In children with CKD, daily administration of rhGH is more effective in stimulating growth than injections given three times weekly. To mimic the physiological circadian rhythm of endogenous rhGH secretion, evening injections are recommended. The injection side should be changed daily to avoid lipoatrophy [42].
MONITORING RESPONSE AND FOR ADVERSE EFFECTS
Response to rhGH — Ongoing monitoring evaluates the response to recombinant human growth hormone (rhGH) and detects any potential adverse effects. An adequate growth response is defined as a growth velocity that is greater than 2 cm/year over the baseline prior to rhGH therapy.
●Every three to four months:
•Assess growth with measurements of height, weight, and, in children younger than three years of age, occipitofrontal circumference, and calculate growth velocity and Z-score for height. If growth velocity decreases, readjustment of the dose might be needed with an increase in weight.
•Nutritional status.
•Funduscopic examination.
•Pubertal stage.
•Laboratory tests including serum glucose, electrolytes, creatinine, calcium, phosphorus, and parathyroid hormone (PTH) level.
●Yearly: Bone age
●If symptomatic, hip and knee radiographs
Adverse effects — Prolonged rhGH therapy does not appear to be associated with any major adverse effects, as illustrated by the following [17,45]:
●In the previously mentioned systematic review, although the number of adverse events was small, the frequency of side effects was similar between the rhGH and control groups [17]. In particular, there were no differences in the risk of kidney function deterioration, lipid profile abnormalities, glucose intolerance, or diabetes mellitus, and in pediatric allograft recipients, the incidence of acute rejection.
●In a study from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry, the frequency of GH-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 [45]. 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. There was also no significant increase in the incidence of benign intracranial hypertension.
●In a subsequent study from NAPRTCS, retrospective data demonstrated there was no increased risk of post-transplant lymphoproliferative disease in children who received rhGH during dialysis or post-transplant.
However, overall data in all children treated with rhGH suggest that there may be a slightly higher risk of developing idiopathic intracranial hypertension (pseudotumor cerebri), slipped capital femoral epiphysis, and worsening of existing scoliosis. Whether these are true side effects of rhGH itself or related to rapid growth due to rhGH is unknown. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)
In the above reports of children with CKD, the overall number of adverse events is small, and it is possible that rhGH could be associated with a small increased incidence of adverse effects. However, if there is such a risk, it does not appear to be significant and should not limit the use of rhGH in children who might benefit.
Nevertheless, we suggest the following follow-up care of patients with CKD treated long term with rhGH [2]:
●Glucose metabolism – Although rhGH therapy does not alter glucose tolerance in the vast majority of patients, there are two reported individual cases of the development of diabetes mellitus in children with CKD that are temporally related to the initiation of rhGH therapy [46,47]. In both cases, diabetes mellitus was reversible after discontinuation of rhGH therapy. In the NAPRTCS report, eight patients in the control group and no patients in the rhGH developed diabetes.
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 [48]. 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, up to now this has not been observed in CKD patients receiving rhGH [45].
Based on this limited data, we suggest monitoring of glucose homeostasis, particularly in those patients with additional risk factors, such as concomitant glucocorticoid treatment and familial type 2 diabetes.
●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 [16,17,19,45,49]. 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.
●Benign intracranial hypertension – It is uncertain whether pediatric patients treated with rhGH are at increased risk for benign intracranial hypertension. In one large observational study of 1670 children with a variety of kidney disease, 15 cases (0.9 percent) of intracranial hypertension were reported [50]. However, all of the 15 children were using other medications, which could predispose them to intracranial hypertension. In the systematic review, there was report of one patient each in the rhGH treatment and control groups [17], and in the NAPRTCS study, there was not a difference in the risk of intracranial hypertension between the two groups (0.2 versus 0.1 percent) [45].
Based on these results, we suggest that follow-up care include routine funduscopic examination to detect any change in optic disc suggestive of intracranial hypertension. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Papilledema'.)
●Orthopedic complications – CKD-mineral bone disorder (CKD-MBD) should be adequately treated before initiation of 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 [51-53]. 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. (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)".)
Failure of response — For patients who do not adequately respond to rhGH therapy (ie, growth velocity is less than 2 cm/year over the baseline prior to rhGH therapy), the following evaluation should be performed:
●Assess patient compliance as nonadherence results in poor growth velocity [54]
●Assess if the weight-based rhGH dose is correct, and if necessary, readjust the dose.
●Assess whether other nutritional or metabolic factors for poor growth are present, and if so, initiate a corrective treatment plan.
Patients with persistent poor growth despite correction of these issues may require referral to a pediatric endocrinologist for further evaluation of other possible causes for inadequate growth [2].
Doubling the dose appears to be a reasonable therapeutic approach in patients who fail to respond to one year of the initial rhGH regimen. We have observed individual patients in whom such an increase in dose induced sustained catch-up growth over time [55]. However, this procedure may present hazards because a higher dose increases the potential risk of side effects.
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 based on the weight of the patient.
In our practice, we continue rhGH therapy if the growth velocity remains greater than 2 cm/year above the baseline pretreatment growth rate. Treatment is discontinued if one of the following circumstances occurs [2]:
●Closed epiphyses
●Development of an active neoplastic disorder
●Hypersensitivity to rhGH or components of its formulation
●Increased intracranial pressure
●Noncompliance
●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
●A dose reduction (eg, 50 percent of the recommended dose) may be considered when the height goal is achieved based on midparental height
Cost–benefit ratio of rhGH therapy — As discussed above, the expected increase in adult height after two to five years of rhGH treatment is approximately 7.2 cm (7.4 cm in boys and 7 cm in girls) [42]. A cost analysis by members of the European Society for Paediatric Nephrology (ESPN) reported a lower incremental cost per centimeter gained in adult height for a patient aged 5 years at the start of treatment (range €1,800 to €5,300) compared with the cost for a patient at 12 years at the start of treatment (range €3,800 to €11,100). The range of cost was dependent on the length of treatment and required daily amount of rhGH, which is related to body weight. Earlier initiation of rhGH therapy in a young patient would be more cost-effective if long-term dialysis is prevented by early kidney transplantation. Finally, early initiation of rhGH treatment in a small child may substantially shorten the time taken to achieve the body size required for kidney transplantation [42].
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 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), are the primary pathogenetic mechanisms for poor growth in children with CKD. (See "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Pathogenesis: Disturbance of GH/IGF-1 axis'.)
●Both clinical trials and observational data from a large registry have shown that recombinant human growth hormone (rhGH) therapy improves growth in children with CKD in all clinical settings: patients with CKD without kidney replacement therapy (KRT), patients undergoing dialysis therapy, and patients with a functioning kidney allograft. (See 'Efficacy' above.)
●The goal of rhGH therapy is for children with CKD to attain normal final height. The minimal therapeutic aim should be a height greater than the third percentile of the general population. (See 'Goal' above.)
●We recommend rhGH be initiated in children with CKD when the following criteria have been met (Grade 1B):
•All other amenable risk factors for growth impairment have been addressed. These include 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'.)
•Estimated glomerular filtration rate (GFR) is less than 75 mL/min per 1.73 m2.
•There is evidence of growth impairment; defined as height velocity Z-score <-1.88 or a height velocity for age <3rd percentile that persists beyond three months (figure 1 and figure 2). The following calculators can be used to determine the Z-score for height for boys, girls, and infants (calculator 1 and calculator 2 and calculator 3). (See "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Diagnosis of growth failure'.)
•There is no evidence of active malignancies.
●In general, earlier intervention at a younger age (before six years of age) and early in the course of CKD leads to a more robust response to rhGH, which is more likely to result in achieving the goal of a normal final height. (See 'Indications' above.)
●When rhGH therapy is given to children with CKD, we recommend an initial daily dose of 0.045 to 0.05 mg/kg body weight (corresponds to a daily dose of 4 international units (IU) per m2 body surface area) given by subcutaneous injection (Grade 1B). The dose of rhGH is greater than what is normally given to GH-deficient children, as children with CKD require pharmacologic rather than replacement dosing. (See 'Dose of rhGH' above.)
●An adequate growth response is defined as a growth velocity that is greater than 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 rhGH' above and 'Failure of response' above.)
●Although prolonged rhGH therapy does not appear to be associated with any major adverse effects, we suggest that patients treated long term with rhGH be monitored for glucose metabolic abnormalities (serum glucose), increased intracranial pressure (funduscopic examination), kidney function (serum creatinine), and, if symptomatic, hip radiographs to detect slipped capital femoral epiphysis (Grade 2B). (See 'Adverse effects' above.)
