A super-agonist of growth hormone–releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease

Niemczyk, Stanisław; Sikorska, Hanna; Wiȩcek, Andrzej; Żukowska-Szczechowska, E; Załęcka, Klaudia; Gorczyńska, Joanna; Kubik, Małgorzata; Czerwieńska, Beata; Gosek, Katarzyna; Veldhuis, Johannes D.; Wagner, David; Gaudreau, Pierrette; Hakonen, Tiina; Kay, Sam Wai Kit; Jouhikainen, T.; Schaefer, Franz

doi:10.1038/ki.2009.480

Cited by 22 publications

(17 citation statements)

References 30 publications

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“…The use of recombinant human GH (rhGH) and rhIGF-1 in CKD patients is an obvious choice with some potential to improve muscle protein turnover and nitrogen retention. In children with CKD and growth retardation use of GH and IGF-1 has demonstrated to have positive effects on growth and outcome [70] and recently a newer GH releasing hormone ‘super-agonist’ has been utilised in stage 4/5 CKD patients showing significant positive effects on anabolism and LBM [77]. …”

Section: The Gh-igf-1 Axismentioning

confidence: 99%

Exploring metabolic dysfunction in chronic kidney disease

Slee

2012

Nutr Metab (Lond)

105

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Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies.

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Section: The Gh-igf-1 Axismentioning

confidence: 99%

Exploring metabolic dysfunction in chronic kidney disease

Slee

2012

Nutr Metab (Lond)

105

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“…Whilst pharmacologically correct, such an approach can be cumbersome and draw focus away from the endogenous agonist. This has led to some commentators to coin the term 'super agonism' to describe situations A c c e p t e d M a n u s c r i p t 14 where synthetic orthosteric ligands that share an overlapping binding site with the endogenous ligand(s) have been demonstrated to activate the receptor with higher efficacy than the endogenous agonist (Niemczyk et al, 2010, Tan et al, 2002.…”

Section: Efficacy and Super Agonismmentioning

confidence: 99%

When simple agonism is not enough: Emerging modalities of GPCR ligands

Smith¹,

Bennett²,

Milligan³

2011

Molecular and Cellular Endocrinology

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Recent advances in G protein-coupled receptors have challenged traditional definitions of agonism, antagonism, affinity and efficacy. The discovery of agonist functional selectivity and receptor allosterism has meant researchers have an expanded canvas for designing and discovering novel drugs. Here we describe modes of agonism emerging from the discovery of functional selectivity and allosterism. We discuss the concept of ago-allosterism, where ligands can initiate signaling by themselves and influence the actions of another ligand at the same receptor. We introduce the concept of dualsteric ligands that consist of distinct elements which bind to each of the orthosteric and an allosteric domain on a single receptor to enhance subtype selectivity. Finally, the concept that efficacy should be defined by the activity of an endogenous ligand will be challenged by the discovery that some ligands act as 'super-agonists' in specific pathways or at certain receptor mutations.

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“…In renal failure phosphorylation of JAK2 and the downstream signaling molecules STAT5, STAT3 and STAT1 are impaired as is the nuclear levels of phosphorylated STAT proteins. It showed very promising results with rapid improvement of nutritional status in these patients [86]. studies would seem to be of major importance.…”

Section: Important Clinical Studies Of the Effects Of Treatment With mentioning

confidence: 91%