By Bradley Warady, MD Progressive growth retardation is an all too frequent characteristic of children on dialysis and children who receive a kidney transplant. The result is a substantial percentage of patients (as many as 60 percent in one study) who develop end-stage renal disease (ESRD) during childhood, develop marked short stature and attain a final adult height at or below the third percentile on a standard growth chart. Although a variety of factors play a role in the varying degrees of growth impairment seen in children with renal disease, the patient’s age at the onset of renal insufficiency can have a significant impact. It is well recognized the younger the age of the child at the onset of renal disease, the more severe the growth impairment tends to be. While complications such as malnutrition, renal osteodystrophy (bone disease) and acidosis may also contribute to the poor growth rates and need to be treated aggressively in all patients, abnormalities related to the function of growth hormone and related substances exert their influence during mid-childhood (age three to puberty) and have the most profound influence on growth delay in this population. Growth hormone (GH) is synthesized in the pituitary gland and indirectly promotes the growth of a child by stimulating the production of insulin-like growth factor 1 (IGF-1). IGF-1, which directly promotes cell growth, is produced in the liver, growth cartilage and many other tissues. Its production is in part dependent on an adequate dietary protein and calorie intake in addition to the presence of GH. Paradoxically, many children with renal disease and growth retardation have normal or elevated levels of GH in their blood. In contrast, the levels of IGF-1 that are needed to stimulate growth are low. The low levels appear to be due to the presence of proteins in the blood that are normally removed from the body in urine, but accumulate in kidney failure. These proteins bind to and reduce the function of IGF-1 which results in the suboptimal height velocity characteristic of children with impaired kidney function. The initial trials using man-made or recombinant human growth hormone (rHuGH) therapy to increase the growth rate of children with renal insufficiency occurred just 10 years ago. Subsequent studies conducted over the past five years have provided indisputable evidence that infants and children with renal disease and growth retardation who receive daily r-HuGH, typically by subcutaneous (under the skin) injection, grow faster than children with similar kidney function who do not receive r-HuGH therapy. In most studies and in clinical practice, the indication for starting r-HuGH therapy has been growth retardation as defined by a height less that the third percentile, although very poor growth rate has been the stimulus for starting treatment in some centers. Recombinant human growth hormone appears to work by increasing the availability of IGF-1 to directly stimulate growth and is only administered to children with “growth potential” as evidenced by open bone growth plates on X-ray evaluation. The use of this therapy has allowed some recipients to experience a faster rate of growth than their peers, or so-called “catch up growth.” Because of the growth inhibiting effects of uremia, in association with the need for dialysis and steroids following transplantation, (see paragraph to follow) the provision of r-HuGH during the pre-ESRD period is likely the optimal approach to take when the goal is to prevent or correct the growth retardation that occurs in these children. Where as r-HuGH has been used by a substantial number of children with chronic renal failure (CRF), the use of this therapy in the pediatric dialysis and transplant population has been more limited. As in the case of patients with CRF, the use of r-HuGH by children on dialysis has resulted in enhanced growth rates during the first year of treatment, although at a lower rate than seen in association with pre-ESRD therapy. Whether or not an increased dose of r-HuGH might further enhance the growth rate of these patients without the development of treatment related complications is currently being studied. Adequate nutrition and control of renal osteodystrophy are prerequisites for a successful response and all dialysis patients who receive r-HuGH should have their bone disease monitored closely with repeated physical examinations and assessments of their intact parathyroid hormone (PTH) level. In children who receive a kidney transplant at more than six years of age, spontaneous “catch-up growth” is unlikely, even with a properly functioning transplant. Here too, preliminary studies have provided evidence that r-HuGH usage can increase the growth rates of these patients. However, the possibility does exist that r-HuGH might also increase the risk of transplant rejection. This issue is of concern to some transplant physicians and has been a major reason there is hesitancy to use the therapy in this setting. A multi-center study addressing the safety and efficacy of r-HuGH in the transplant population will be completed within the next one or two years and clinicians anxiously await the results of this important investigation. To date, many children who are growth retarded and who have kidney failure do not receive r-HuGH because of an apparent lack of substantial patient, parent and physician concern about the short stature when the patient is young. Unfortunately, many of these same children later desire the therapy when there is little time available for growth. According to strategies designed to prevent this life-long complication of renal insufficiency must include educational programs designed for patients and parents that address the following: 1) the natural history of growth retardation associated with CRF and ESRD, 2) the limited “window of opportunity” children have for growth and 3) the results of studies and clinical experiences with r-HuGH therapy in children with renal insufficiency. Only in this manner is it likely that a substantial percentage of the children deserving of this effective therapy will benefit from its use. Bradley Warady, MD is Director, Dialysis and Transplantation and Chief, Section of Pediatric Nephrology for Children’s Mercy Hospital in Kansas City, MO. |