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. 2021 Aug;36(8):2511-2530.
doi: 10.1007/s00467-021-05097-6. Epub 2021 Jun 18.

Renal effects of growth hormone in health and in kidney disease

Dieter Haffner  1   2 , Andrea Grund  3   4 , Maren Leifheit-Nestler  3   4
Affiliations

Renal effects of growth hormone in health and in kidney disease

Dieter Haffner et al. Pediatr Nephrol. 2021 Aug.

Abstract

Growth hormone (GH) and its mediator insulin-like growth factor-1 (IGF-1) have manifold effects on the kidneys. GH and IGF receptors are abundantly expressed in the kidney, including the glomerular and tubular cells. GH can act either directly on the kidneys or via circulating or paracrine-synthesized IGF-1. The GH/IGF-1 system regulates glomerular hemodynamics, renal gluconeogenesis, tubular sodium and water, phosphate, and calcium handling, as well as renal synthesis of 1,25 (OH)2 vitamin D3 and the antiaging hormone Klotho. The latter also acts as a coreceptor of the phosphaturic hormone fibroblast-growth factor 23 in the proximal tubule. Recombinant human GH (rhGH) is widely used in the treatment of short stature in children, including those with chronic kidney disease (CKD). Animal studies and observations in acromegalic patients demonstrate that GH-excess can have deleterious effects on kidney health, including glomerular hyperfiltration, renal hypertrophy, and glomerulosclerosis. In addition, elevated GH in patients with poorly controlled type 1 diabetes mellitus was thought to induce podocyte injury and thereby contribute to the development of diabetic nephropathy. This manuscript gives an overview of the physiological actions of GH/IGF-1 on the kidneys and the multiple alterations of the GH/IGF-1 system and its consequences in patients with acromegaly, CKD, nephrotic syndrome, and type 1 diabetes mellitus. Finally, the impact of short- and long-term treatment with rhGH/rhIGF-1 on kidney function in patients with kidney diseases will be discussed.

Keywords: Children; Chronic kidney disease; Diabetic nephropathy; Growth hormone; Hypertrophy; IGF-1; Klotho; Nephrotic syndrome.

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Figures

Fig. 1
Fig. 1
Physiological and pathophysiological actions of growth hormone and its mediator insulin-like growth factor-1 (IGF-1) on the kidneys: GH and IGF-1 receptors (GHR/IGF-1R) are widely expressed in the glomerular and tubular cells. GH can act on the kidneys, either directly via activation of the GHR/Janus kinase-2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) and ERK1/2 pathways, or indirectly via circulating or paracrine-synthesized IGF-1 by activating IGF-1R. Most of the glomerular and tubular effects of GH are mediated by IGF-1 and include the following: (1) dilation of the afferent and efferent arterioles via increased synthesis of the endogenous vasodilator nitric oxide (NO), resulting in enhanced glomerular filtration rate and renal plasma flow; (2) stimulation of phosphate (Pi) reabsorption in the proximal tubules via up-regulation of the sodium-phosphate transporters (Na-Pi2a/2c; (3) stimulation of sodium (Na+) and water (H2O) reabsorption in the distal nephron via up-regulation of the epithelial sodium channel (ENaC); and (4) stimulation of the 1α-hydroxylase and thereby, calcitriol synthesis in the proximal tubule, with subsequent increases in calcium (Ca+) absorption via up-regulation of the epithelial calcium channels TRPV6 and TRPV5 in the intestine and distal renal tubule, respectively. Some GH effects may also be mediated by IGF-1, including stimulation of (1) net acid secretion via increased ammonia (NH4+) production in the proximal tubule and a Na+-dependent mechanism in the distal tubule and (2) renal Klotho synthesis in the distal renal tubule. GH was shown to directly enhance renal gluconeogenesis in proximal tubular cells. In states of GH excess, GH can directly induce glomerulosclerosis and podocyte injury, characterized by podocyte hypertrophy, apoptosis, dedifferentiation of podocytes (epithelial–mesenchymal transition, EMT), and/or cross-linking of the basement membrane resulting in increased podocyte permeability to albumin and detachment of podocytes from the glomerular basement membrane. By contrast, IGF-1 excess results in tubular hypertrophy only. The kidneys of patients with chronic kidney disease (CKD) are protected from the potentially negative effects of long-term GH-treatment on the glomerulus, likely due to the CKD-associated GH insensitivity of the kidneys and/or the much lower GH exposure in GH-treated patients, compared to those with the abovementioned conditions.
Fig. 2
Fig. 2
Changes in estimated glomerular filtration rate (eGFR) during the 5-year longitudinal follow-up. eGFR decline within 5 years was not significantly different between recombinant human growth hormone (rhGH)-treated (KIGS register) and non-rhGH-treated (ESCAPE trial) patients. Data is given as the mean± standard error of the mean (SEM). *Significant differences between groups, #significant difference from baseline. Figure reproduced with permission from Mehls et al. [173].
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