Growth hormone axis in chronic kidney disease

Abstract

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH-IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD.

Fig. 1

GH/IGF-1 axis in CKD: deranged somatotropic axis in chronic renal failure. The GH/IGF-I axis in CRF is changed markedly, compared with the normal axis shown here. In CRF the total concentrations of the hormones in the GH/IGF-I axis are not reduced, but there is reduced effectiveness of endogenous GH and IGF-I, which probably plays a major role in reducing linear bone growth. The reduced effectiveness of endogenous IGF-I likely is due to decreased levels of free, bioactive IGF-I as levels of circulating inhibitory IGF-binding proteins (IGFBPs) are increased. In addition, less IGF-I is circulating in the complex with acid labile subunit (ALS) and IGFBP-3 as a result of increased proteolysis of IGFBP-3. Together, these lead to decreased IGF-I receptor activation and a decreased feedback to the hypothalamus and pituitary. Low free IGF-I and high IGFBP-1 and IGFBP-2 levels probably contribute to reduced renal function and lead to reduced stature. The direct effects of GH on bone, which are poorly understood, also are blunted. Reprinted from [8] with permission

Fig. 2

Growth hormone-mediated JAK/STAT signal transduction. GH activates several signaling pathways via JAK2, including the JAK/STAT pathway [22, 23]. Binding of GH to its receptor (GHR) activates JAK2, which then self-phosphorylates. This is followed by phosphorylation of the GHR and, subsequently, STAT 1a, STAT 3, STAT 5a, and STAT 5b, members of a larger family of cytoplasmic transcription factors. These phosphorylated STATs form dimers that enter the nucleus, where they bind to specific DNA sequences and activate their target genes, IGF-1 and some suppressors of cytokine signaling (SOCS). Deletion of STAT5 expression leads to retarded body growth, and STAT5b is required for GH-mediated IGF-1 gene expression. In renal failure phosphorylation of JAK2 and the downstream signaling molecules STAT5, STAT3, and STAT1 is impaired, as are the nuclear levels of phosphorylated STAT proteins. This important cause of uremic GH resistance may result, in part, from up-regulation of SOCS2 and SOCS3 expression with suppressed GH signaling and also from increased protein tyrosine phosphatase activity, with enhanced dephosphorylation and deactivation of the signaling proteins. Reprinted from [14] with permission

Fig. 3

Growth hormone treatment in chronic kidney disease: change from initially predicted adult height at baseline in 38 children (32 boys and six girls) with chronic renal failure who received growth hormone treatment compared with 50 control children with chronic renal failure who did not receive growth hormone, according to gender. Values are means ± SD. Asterisks indicate significant differences from the previous period (P < 0.001) and daggers indicate significant differences from the children who were not treated with growth hormone (P < 0.001). Reprinted from [1] with permission