Eurasian J Med 2015; 47: 62-5 Review

Growth Hormone Therapy in Children with Chronic Renal Failure Kronik Böbrek Yetmezliği olan Çocuklarda Büyüme Hormonu Tedavisi Atilla Cayir1, Celalettin Kosan2 1Department of Pediatric Endocrinology, Regional Training and Research Hospital, Erzurum, Turkey 2Department of Pediatric Nephrology, Ataturk University Faculty of Medicine, Erzurum, Turkey

Abstract Özet Growth is impaired in a chronic renal failure. Anemia, acidosis, re- Kronik böbrek yetersizliğinde büyüme bozulmaktadır. Anemi, asidoz, duced intake of calories and protein, decreased synthesis of vitamin kalori ve protein alımının azalması, azalmış vitamin D sentezi ve artmış D and increased parathyroid hormone levels, hyperphosphatemia, parathormon düzeyi, hiperfosfatemi, renal osteodistrofi ve büyüme renal osteodystrophy and changes in growth hormone-insulin-like hormonu, insülin benzeri growth faktör ile gonadotropin- gonadal growth factor and the gonadotropin-gonadal axis are implicated in akstaki değişiklikler büyümenin yetersiz olmasından sorumlu tutul- this study. Growth is adversely affected by immunosuppressives and maktadır. Böbrek transplantasyonundan sonra ise immunosupressifler corticosteroids after kidney transplantation. Treating metabolic dis- ve kortikosteroidlerin etkileri ile büyüme olumsuz olarak etkilenmek- orders using the recombinant human growth hormone is an effective tedir. Metabolik bozuklukların düzeltilmesine rağmen büyüme hızı option for patients with inadequate growth rates. yetersiz olan olgularda rekombinant insan büyüme hormonu iyi bir Keywords: Child, chronic renal failure, growth hormone, therapy tedavi seçeneğidir. Anahtar Kelimeler: Çocuk, kronik böbrek yetersizliği, büyüme hor- monu, tedavi

Introduction mone takes place with glomerular filtration and breakdown in the proximal tubules. In CRF, a decrease in the rate of glo- Inadequate growth is a widespread problem in children merular filtration leads to impairment of the metabolic clear- with chronic renal failure (CRF). Inadequate growth appears ance of the growth hormone and to an increase in half-life. in chronic kidney disease under the influence of various fac- An increase in growth hormone releasing hormone (GHRH) tors, such as poor or insufficient nutrition, metabolic acidosis, and a decrease in somatostatin levels is also seen in CRF. anemia, renal osteodystrophy, changes in the gonadotropin- This change in GHRH and somatostatin levels arises from a gonadal axis and insensitivity to growth hormone [1-3]. decrease in the negative feedback effect of the insulin-like Corticosteroids and immunosuppressives used after kidney growth factor (IGF), growth hormone and insulin. Growth transplantation may also have an adverse effect on growth. hormone secretion in CRF is normal or elevated in the Supportive measures and kidney transplantation are used in growth hormone stimulation tests. Elevation in the growth order to prevent and correct growth disorder in CRF. However, hormone peak values during growth hormone stimulation a great many children with CRF, including those undergone tests and in sleep stems from these changes in the growth kidney transplantation, continue to experience growth prob- hormone clearance and secretion in CRF. lems despite these measures. Recombinant human growth After the secretion by the pituitary gland, growth hor- hormone (rhGH) is an effective and well-tolerable therapeutic mone is transported by binding to GHBP in plasma. Since approach in children with permanent growth disorder [4-11]. GH bound to GHBP is too large to be expelled from the This paper reviews the doses, efficacy and indications of kidney, this complex prevents the expulsion of the growth rhGH used in children with CRF in the light of the current hormone from the kidney. In patients with CRF, a decrease literature. from the normal levels of 40-80% is seen in both GHBP and in growth hormone’s capacity to bind to GHBP. Therefore, in Growth Hormone and Chronic Renal Failure CRF, growth hormone is at higher levels compared to those Kidney plays an important role in the metabolism of pep- in healthy individuals. Tissue insensitivity has been recorded tide hormones. Most metabolic clearance of the growth hor- with a decrease in the growth hormone in tissue receptors.

Received: August 23, 2013 / Accepted: March 30, 2014 / Available Online Date: December 5, 2014 Correspondence to: Atilla Cayir, Department of Pediatric Endocrinology, Regional Training and Research Hospital, Erzurum, Turkey Phone: +90 442 232 53 65 e-mail: [email protected] ©Copyright 2015 by the Atatürk University School of Medicine - Available online at www.eajm.org DOI:10.5152/eajm.2014.57 Eurasian J Med 2015; 47: 62-5 Cayir and Kosan Growth Hormone and Chronic Renal Failure 63

The inadequate growth in CRF, despite the high growth Resistance to growth hormone develops in CRF. Growth hormone levels, is due to this tissue insensitivity to growth hormone in pharmacological doses raises the levels of IGF-I hormone. in the circulation. Experimental and clinical studies show Most of the growth-inducing effects of the growth hor- that resistance developing against growth hormone in CRF mone take place with IGF (particularly type 1). Although the can be overcome with the administration of growth hor- liver is the main source of IGFs, physiologically significant mone in greater than physiological doses. Growth hormone levels are also produced in non-hepatic tissues. These bind should therefore be used in higher doses in children with to their own binding protein (IGFBP) in the blood and tissues. CRF. The rhGH dose should be 0.045-0.05 mg/kg per day or IGFBPs prolong the half-life of IGFs, regulate the passage of 4 IU/m2 per day. Growth hormone is administered daily in IGFs to the extravascular space, restrict the bioefficacy of the form of subcutaneous injections. In children undergoing free IGFs by affecting IGF receptors, prevent the hypogly- peritoneal dialysis who reject subcutaneous injection, rhGH cemic effects of IGFs and affect the cells by binding directly can be given within a dialysis fluid. Intraperitoneal adminis- to their own receptors. IGFBPs are broken down by prote- tration of rhGH provides sufficient absorption. However, the ases. Proteolysis of IGFBPs in the circulation allows IGFs to growth is lower compared to subcutaneous administration. freely enter the circulation, and IGF enters the extravascular In addition, intraperitoneal rhGH can increase the risk of peri- space. In CRF, the levels of free IGFs decrease in line with the tonitis. Due to these uncertainties, subcutaneous injection is decrease in GH tissue receptors. It has been suggested that the preferred mode of administration in children undergoing IGFBP-3 levels rise in CRF, and that, with its greater affinity for peritoneal dialysis [1, 2, 15-19]. IGFs, IGFBP is responsible for the inhibition of IGF bioactivity [2, 5, 12-15]. Side-Effects and Observation in GH Therapy In conclusion, high growth hormone levels, IGF levels Patients starting growth hormone therapy must be declining in line with the growth hormone levels, decreased observed at 3-4-month intervals to monitor the growth the growth hormone receptors, increased IGFBPs and and development of any side-effects. Height, weight and, in decreased the proteolysis activity, and the presence of post- patients aged under 3, head circumference, must be mea- receptor defects in the IGF receptors are responsible for the sured at every session in order to assess the growth, and a Z impaired growth in CRF. score must be calculated for rate of growth. In the event of a decrease in growth rate, the dose of growth hormone must Indications for the Growth Hormone Therapy in CRF be readjusted, bearing the weight gain in mind. and the Treatment Protocol While observing a child with CRF started on growth The rate of growth in the proximal tibia has been shown hormone to increase at histological analysis performed after the - Nutritional status, treatment with growth hormone in animal models with the - Stage of puberty, induced CRF. Randomized control studies have shown that - Serum glucose, electrolyte, creatinine, calcium phos- recombinant human growth hormone (rhGH) has a positive phorus and parathyroid hormone levels from labora- effect on growth and is reliable in children with CRF under- tory examinations, going renal replacement therapy, dialysis or post-renal - Bone age in years, transplantation. The highest growth potential has been - Fundus examination and observed in the pre-pubertal period (defined as Tanner - Knee and hip imaging if necessary must all be evalu- stages 1 and 2). ated. The indications for the growth hormone therapy in CRF No adverse affects of long-term growth hormone thera- are set out below: py have been identified. No difference has been observed in • Continuing growth retardation despite the correction the studies assessing the effects of growth hormone therapy of insufficient nutrition, metabolic acidosis, fluid and in terms of kidney functions, lipid profile, glucose intolerance electrolyte disorders, anemia and renal osteodystrophy or development of diabetes mellitus or a rise in the incidence • Glomerular filtration rate less than 75 mL/min per 1.73 of acute rejection in allograft recipients compared to control m2 groups. However, children treated with rhGH have been • Being below the 3rd percentile for age and gender observed to be under greater risk of developing idiopathic (-1.88 standard deviation score) or a standard deviation intracranial hypertension (pseudotumor cerebri). Routine score below -2 for age and gender. fundus examination is therefore recommended in order to Subjects with activity malignity should be excluded from identify the changes that may occur in the optic disk in chil- the treatment. dren with CRF receiving the growth hormone therapy. 64 Cayir and Kosan Growth Hormone and Chronic Renal Failure Eurasian J Med 2015; 47: 62-5

Displacement of the upper femoral epiphysis and wors- Conclusion ening of the existing scoliosis in association with rapid growth may be seen in the patients started on RhGH. Growth assessments should be performed with great care Therefore, before starting rhGH therapy, bone radiograms in the children with CRF. rhGH therapy should be started at should be taken from all patients, and detailed assessments an early age and stage of CRF. Follow-up should be based on should be performed at follow-ups with repeated images in the effects and side-effects of the growth hormone therapy. symptomatic patients. Every patient started on growth hormone therapy should Peer-review: Externally peer-reviewed. be monitored for the development of glucose intolerance, Author Contributions: Concept - A.C., C.K.; Design - A.C.; Supervision and those receiving glucocorticoid therapy and patients - C.K.; Literature Review - A.C., C.K.; Writing - A.C.; Critical Review - with additional risk factors, such as type 2 diabetes, must be C.K.; Other - A.C. monitored even more closely. Conflict of Interest: No conflict of interest was declared by the Existing clinical data have shown that rhGH therapy does authors. not accelerate the residual renal function loss in patients with CRF. However, individual rises in the plasma creatinine Financial Disclosure: The authors declared that this study has concentrations have been observed. In the absence of any received no financial support. other reason for a decrease in renal functions, rhGH therapy should be revised. 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