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Table 2 Table to summarise the potential and probable effects of specific mediators on kidney function, the alterations observed in human CKD; and effects on the modulation of nutritional, metabolic and haemodynamic factors and outcome

From: Exploring metabolic dysfunction in chronic kidney disease

Hormonal, inflammatory or nutritional mediator Effects of mediator on kidney function in normal state Altered during CKD (levels/activities) Potential or probable effects of alterations in mediators in human CKD on the following;
Proinflammatory Cytokines ↑?
GH-IGF-1 ? ? ↑? ↑?
Angiotensin II ↑? ? ?
Aldosterone ↑? ? ?
Leptin ? ↑? ↑?
Adiponectin ↑? ↑? ? ? ↓↑? ? ↑? ↑?
Ghrelin ? ↑↓? ↑? ↑? ? ? ? ?
Vitamin D ↑? ? ↑? ↑? ↑?
Glucocorticoids ↑ short-term ↓chronic ↑? ↑?
  1. Key: W/CX = wasting/cachexia; AX = anorexia; IR = insulin resistance; HYP = hypertension; DYSL = dyslipidemia; CVDR&M = cardiovascular disease risk & mortality.
  2. Table 2 summarises the possible and potential effects of different mediators discussed in the CKD state. In humans and in vivo it is difficult to establish direct and indirect causal evidence for certain effects and many are by association only. The proinflammatory cytokines appear central within many chronic disease states by supporting inflammatory processes, increasing oxidative stress and antagonising normal anabolic pathways. In progressive CKD this inflammatory response may be damaging and relate to dysfunction of different systems and pathways described. Further, as has been discussed there are many complex ‘paradoxes’ that appear to function within CKD and probably only after many long term clinical studies will these factors become clearer. For example, the levels and activities of different mediators are difficult to interpret as renal clearance maybe reduced for some peptides and/or inactive forms being synthesised. There is also the possibility of resistance locally such as in GH-IGF-1 resistance. Further, differentiating between normal, deficient and supraphysiological levels such as in the example of GH therapy in CKD requires investigation. E.g. in the healthy physiological state normal GH-IGF-1 levels would likely promote an increase in kidney function by maintaining normal cell growth, turnover and homeostasis. However, supraphysiological levels may have adverse effects. In CKD the GH-IGF-1 axis becomes dysregulated with relative GH resistance and a drop in IGF-1. The drop in IGF-1 can be related to both GH resistance and progressive general malnutrition in CKD, e.g. anorexia, reduced caloric intake and reduced protein intake (both therapeutically and involuntarily). Angiotensin II, ANGII in the healthy state has the physiological role of maintaining blood pressure and potentially other pathways such as oxidative stress and cell cycle factors. In CKD over-activation of the RAAS system may take place, which is similarly related to possible hyperaldosteronism in CKD. Much of the human research in CKD has been using renin angiotension system, RAS blockade studies using angiotensin-receptor blockers, ARBs and angiotensin-converting enzyme inhibitors, ACEIs., and more recently mineralcorticoid receptor, MR blockers. Leptin in the normal state plays a major role in “switching off” appetite and increasing energy expenditure. In CKD, hyperleptinemia and hyperactivation of anorexigenic pathways may contribute to the development of the anorexia-cachexia syndrome. Other roles are suggestible, such as effects on inflammation and potential in-direct effects on hypertension via activation of the sympathetic nervous system. In human CKD data is scarce on other direct effects. Adiponectin may have a beneficial effect on different pathways and insulin sensitivity. In CKD, adiponectin levels increase systemically but the relevance of this effect is unknown. Different variants of the peptide and/or adiponectin resistance may be implicated in the dysfunctional state and effects on metabolism; e.g. dysregulation of oxidative stress/inflammatory and/or insulin sensitivity factors. Ghrelin levels rise in CKD, however, there has been some debate in the literature as to whether the peptide is a dysfunctional variant (i.e. des-acyl ghrelin) and/or there is some level of ghrelin resistance within tissues, e.g. centrally in the hypothalamus. Vitamin D; studies show that prevalence of vitamin D deficiency/insufficiency is high and correlates with CVD and outcome/survival. Other new research suggests it may have multiple functions within skeletal muscle and in immune function, for example. Glucocorticoids; are implicated in disease pathology and stress-mediated effects; the true implications of glucocorticoid function in CKD and metabolic dysfunction has not been fully evaluated.