Tönshoff B, Blum W F, Mehls O
Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Germany.
Kidney Int Suppl. 1997 Mar;58:S106-13.
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.
近期证据表明，生长激素轴紊乱在慢性肾衰竭（CRF）患儿的生长发育迟缓及分解代谢中起重要致病作用。尽管CRF患者的生长激素（GH）分泌率在不同患者及研究中存在差异，但由于肾脏代谢清除率降低导致GH半衰期延长是一致的发现。因此，CRF患儿的血清GH水平根据肾衰竭程度正常或升高。CRF患者GH水平正常或升高与纵向生长受限之间明显的差异导致了GH不敏感的概念，这是由生长激素轴远端成分的多种改变引起的。在终末期前的CRF患者中，血清胰岛素样生长因子（IGF）-I和IGF-II水平正常，而在终末期肾病（ESRD）中，IGF-I水平略有下降，IGF-II水平略有升高。鉴于ESRD中普遍存在的生长激素水平升高，这些血清IGF-I水平显得过低。事实上，有临床和实验证据表明CRF患者肝脏IGF-I产生率降低。肝脏对GH作用的不敏感可能部分是由于肝组织中GH受体表达减少所致。IGF的作用和代谢受特定的高亲和力IGF结合蛋白（IGFBPs）调节，这些蛋白结合约99%的循环IGF。与肾功能不全程度相关，CRF患者血清中IGFBP-1、IGFBP-2和低分子量IGFBP-3片段增加。肾脏滤过减少，特别是低分子量IGFBP-3片段的滤过减少，以及肝脏IGFBP-1和-2产生增加，均导致血清IGFBP水平升高。实验和临床证据表明，CRF患者血清中这些过量的高亲和力IGFBPs通过与1型IGF受体竞争IGF结合来抑制IGF对靶组织的作用。
