11.1 Children should have hip X-rays and a wrist bone age performed prior to initiation of GH therapy. Children with active rickets or a slipped capital femoral epiphysis should not begin GH therapy until these problems have been resolved. (EVIDENCE)
11.2 Growth hormone therapy should not be initiated until the PTH level is no greater than 2X the target upper limit for CKD Stages 2-4 or 1.5X (450pg/mL) the target upper limit in CKD Stage 5 (dialysis) (see Guideline 1). (OPINION)
11.3 Growth hormone therapy should not be initiated until the phosphorus is no greater than 1.5X the upper limit for age (see Guideline 4). (OPINION)
11.4 Children receiving GH therapy in Stages 2-4 CKD should have calcium, phosphorus, PTH, and alkaline phosphatase monitored at least every 3 months during the first year of therapy. Children receiving GH therapy in CKD Stage 5 should have calcium, phosphorus, PTH, and alkaline phosphatase monitored at least every month during the first 6 months of therapy. Thereafter, interval measurements should be made according to stage of CKD (see Guideline 1). (OPINION)
11.5 Children receiving GH therapy should have a wrist bone age performed yearly. Hip X-rays should be performed when clinically indicated.
11.6 Growth hormone therapy should be stopped temporarily:
11.6.a CKD Stages 2-4: If the patient has a PTH level >400 pg/mL; GH should not be restarted until the PTH level is ≤200 pg/mL (EVIDENCE AND OPINION)
11.6.b CKD Stage 5: If the patient has a PTH level >900 pg/mL; GH should not be restarted until the PTH level is ≤50 pg/mL (EVIDENCE AND OPINION)
11.6.c In all stages of CKD, if the patient develops a slipped capital femoral epiphysis or symptomatic high-turnover renal osteodystrophy (EVIDENCE)
11.7 Growth hormone therapy should be stopped permanently when the epiphyses are closed.
Growth retardation is common in children with CKD, and frequently leads to decreased adult height. Metabolic acidosis, inadequate nutritional intake, and osteodystrophy may all contribute to this complication. In healthy children, GH acts by stimulating the production of insulin-like growth factor I (IGF-I), which is the primary stimulus for linear growth. In contrast, children with CKD have an inadequate response despite normal or elevated levels of GH, reflecting a state of apparent GH resistance. Possible mechanisms include: reduced GH-receptor expression especially in the liver, which decreases production of IGF-I; increased IGF-I-binding protein levels, which reduces the levels of free IGF-I; and decreased IGF-I receptor signaling.
Pharmacological doses of rhGH improve linear growth in children with CKD, although the efficacy appears to be less in children who are receiving dialysis.405,406 The recommended dose of rhGH, which is given as a daily subcutaneous injection, is 0.05 mg/kg/day or 30 IU/m 2/week. While the response to rhGH therapy tends to decrease after the first year of treatment, there does appear to be a positive effect of the therapy on final adult height.405,407
For some children with CKD, an improvement in growth will occur with optimization of nutritional management and correction of metabolic acidosis.408 Malnutrition and metabolic acidosis should be corrected prior to initiating rhGH. Inadequate nutrition and metabolic acidosis diminish the effectiveness of rhGH therapy.157
There are complex interactions between growth, growth hormone, and bone metabolism. The use of rhGH is regularly associated with enhanced height velocity in children with CKD and poor growth, but may lead to complications, especially without careful attention to bone metabolism.
The skeletal complications of CKD in children include rickets, avascular necrosis of the femoral head,54,63 and slipped capital femoral epiphysis.49,58,409 Recombinant growth hormone therapy in children without CKD may cause slipped capital femoral epiphysis, perhaps due to an acceleration of growth.410 In children with CKD, the inherent predisposition to these skeletal complications makes it necessary to screen for complications such as slipped capital femoral epiphysis,405 avascular necrosis of the femoral head,63,411,412 and active rickets, prior to the initiation of rhGH therapy.
Recombinant human GH may have beneficial effects on the BMD of children with CKD, although the long-term clinical consequences are not known.413-415 However, clinical reports suggest that rhGH therapy can have deleterious effects on bone metabolism through the worsening of 2° HPT.416-418 Hence, 2° HPT should be controlled prior to the initiation of rhGH therapy, and monitoring for this complication is necessary throughout the course of therapy. The risk of this complication is likely greatest during the first 6-12 months of rhGH therapy, and more vigilant monitoring is indicated during this period of time. Control of 2° HPT after the initiation of rhGH may require increased use of an active vitamin D sterol417 in addition to the prevention of hyperphosphatemia. Therapy may need to be stopped until 2° HPT resolves. An increased alkaline phosphatase level secondary to new bone formation is expected with rhGH therapy, although a continued increase may be indicative of worsening 2° HPT.
The effectiveness of rhGH in improving linear growth in children with CKD and impaired height velocity has been demonstrated in a placebo-controlled study.405 The clinical evidence for an interaction between rhGH therapy and bone metabolism has not been extensively studied in a prospective manner in CKD patients.
In children with CKD, there is insufficient clinical research on rhGH therapy and bone disease. Guidelines for monitoring PTH, calcium, phosphorus, alkaline phosphatase, and X-rays are based on expert opinion, not firm clinical evidence. There is also an absence of firm clinical data supporting the levels of PTH upon which cessation and reinitiation of GH are based.
These guidelines recommend close monitoring of mineral metabolism during rhGH therapy in children with CKD. A patient who has poorly controlled 2° HPT, active rickets, or a slipped capital femoral epiphysis may be at increased risk for more severe bone disease if rhGH therapy is continued. Given this potential, it is prudent not to use rhGH in children with poorly controlled osteodystrophy.
Along with appropriate monitoring of bone disease, optimal response to rhGH requires correction of malnutrition and metabolic acidosis.
The mechanism for the variable response to GH in some children with CKD is unknown. There is little information on optimal dosing of GH in children with CKD, especially during puberty or while receiving dialysis. More information is needed on the relationship between GH and clinical outcomes beyond linear growth.