Derangements of the somatotropic hormone axis in chronic renal failure

Abstract

Recent evidence indicates that disturbances of the somatotropic hormone axis play an important pathogenic role for growth retardation and catabolism in children with chronic renal failure (CRF). Whereas the growth hormone (GH) secretion rate in CRF is variable between patients and studies, a prolonged half-life of GH as a result of a reduced renal metabolic clearance rate is a consistent finding. Accordingly, the serum GH levels in children with CRF are normal or elevated depending on the extent of renal failure. The apparent discrepancy between normal or elevated GH levels and diminished longitudinal growth in CRF has led to the concept of GH insensitivity, which is caused by multiple alterations in the distal components of the somatotropic hormone axis. Serum insulin-like growth factor (IGF)-I and IGF-II levels are normal in preterminal CRF, while in end-stage renal disease (ESRD) IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated growth hormone levels in ESRD, these serum IGF-I levels appear as inadequately low. Indeed, there is both clinical and experimental evidence for a decreased hepatic IGF-I production rate in CRF. This hepatic insensitivity to the action of GH may be partially the consequence of a reduced GH receptor expression in liver tissue. The action and metabolism of IGFs are modulated by specific high-affinity IGF binding proteins (IGFBPs), which bind approximately 99% of circulating IGF. IGFBP-1, IGFBP-2, and low molecular weight IGFBP-3 fragments are increased in CRF serum in relation to the degree of renal dysfunction. Both decreased renal filtration, in particular of low molecular weight IGFBP-3 fragments, and increased hepatic production of IGFBP-1 and -2 contribute to high IGFBP serum levels. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action on target tissues by competition with the type 1 IGF receptor for IGF binding.