Therapies for Chronic Kidney Disease-Related Protein Energy Wasting: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Giacomo Garibotto.

Protein energy wasting (PEW) is a common complication both in chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Of note, PEW is one of the stronger predictors of morbidity and mortality in this patient population. The pathogenesis of PEW involves several mechanisms, including anorexia, insulin resistance, acidosis and low-grade inflammation. In addition, “sterile” muscle inflammation contributes to PEW at an advanced CKD stage. Both immune and resident muscle cells can activate innate immunity; thus, they have critical roles in triggering “sterile” tissue inflammation. Toll-like receptor 4 (TLR4) can detect endogenous danger-associated molecular patterns generated or retained in blood in uremia and induce a sterile muscle inflammatory response via NF-κB in myocytes. In addition, TLR4, though the activation of the NLRP3 inflammasome, links the sensing of metabolic uremic stress in muscle to the activation of pro-inflammatory cascades, which lead to the production of IL-1β and IL-18. Finally, uremia-induced accelerated cell senescence is associated with a secretory phenotype that favors fibrosis in muscle.

  • innate immunity
  • muscle
  • CKD
  • protein metabolism
  • amino acids

1. Introduction

Decreasing the production or removing circulating damage-associated molecular patterns (DAMPs) in uremia and anti-inflammatory treatments that target the NLRP3 to IL-1 to IL-6 pathway of innate immunity may offer a new paradigm to treat CKDchronic kidney disease (CKD)-related PEW and CVD. Besides the measure of circulating cytokines, the detection of serum levels of growth factors, such as VEGF-A, TGF-β1, FGF-21 and -23, proteases of MMP-2, -3, -9 and natural tissue inhibitors of TIMP-1 and -2, ox-LDL and isoprostane-8 and -15, has the potential to offer both early diagnosis and a follow up of target treatments.

2. Healthy Diets and Modulation of the Microbiome

Diets rich in vegetables, legumes, whole grains and fruits, with the avoidance of sugar-sweetened beverages, processed foods and trans-fats are recommended in prevention guidelines. The Mediterranean diet and plant-based diets can prevent the onset of age-related disorders, and has been associated with a long life [65][1]. Extra-virgin olive oil, which is contained in the Mediterranean diet, contains bioactive polyphenolic compounds that are known for their anti-oxidant and anti-inflammatory properties [66][2].
Toxins generated by the intestinal microbiome represent a potential therapeutic target. Small RCTs have shown that dietary fiber, sevelamer, syn-biotics, pre-biotics and anti-biotics may decrease blood levels of uremic toxins, including indoxyl sulfate, p-cresyl sulfate and p-cresol, as well as change the composition of some intestinal microbial species among patients with CKD and patients with end-stage kidney disease (ESKD). However, these effects are variable and results not consistent [67][3]. In animal CKD models, an oral adsorbent, AST-120, reduced inflammation and serum levels of indoxyl sulfate, and slowed CKD progression [68][4]. However, a large randomized, placebo-controlled trial in patients with CKD4 showed no significant effect of AST-120 on disease progression or death [69][5]. These conflicting results likely express the current gap in the understanding of the microbiome and its relationship to clinical outcomes. Nevertheless, the modulation of the microbiome with specific treatments or dietary interventions represents a promising research topic.
A decrease in circulating inflammatory biomarkers can also be obtained through smoking cessation, dietary interventions and physical exercise. In one study, weight loss in obese subjects decreased hsCRP by a similar magnitude, regardless of dietary composition [70][6]. In another study, dietary patterns with a high pro-inflammatory potential (processed meats, refined carbohydrates and sweetened beverages) were associated with higher CVD risk [71][7], which suggests that reducing the inflammatory potential of the diet may potentially provide an effective strategy for CVD prevention. In the PREDIMED study [72][8] involving persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts was associated with a lower incidence of major cardiovascular events than a reduced-fat diet.

3. Physical Exercise

Cardiovascular risk factors, cardiac autonomic control and left ventricular systolic function are ameliorated by physical exercise in ESKD patients [73,74][9][10]. Moreover, physical exercise has beneficial effects on chronic inflammation, muscle and bone strength in adults with CKD; improvements in inflammatory biomarkers can be accounted for through exercise-mediated shifts towards a less inflammatory immune cell profile, increased nitric oxide release and reduced monocyte infiltration into adipose tissue (see Ref. [75][11] for review). Among the treatment options for preventing the loss of muscle mass and function in ESKD patients, endurance or resistance exercises appeared to be the most useful. Additionally, expert opinion reports [76][12], position statements [77][13] and guidelines [78][14] have suggested that physical exercise needs to be considered as a standard of care treatment in patients with CKD. However, the available clinical evidence is mainly from small, short-duration (3–6 months) exercise intervention studies, and no conclusion could be reached for elderly ESKD patients [79,80][15][16]. In addition, major hurdles include the low percentage of patients who can actually perform physical exercise and a lack of resources to start an exercise program in dialysis units [80][16].

4. Targeting Cell Senescence

Senescence has been linked to the progression of muscle injury and age-related sarcopenia [81,82][17][18]. Recently, Huang et al. [61][19] observed that the administration of a senolytics cocktail to CKD mice for 8 weeks eliminated the disease-related elevation of senescence markers and depressed the high levels of SASP cytokines. Pharmacologically active compounds that manipulate cellular senescence have recently shown great promise in pre-clinical stages, and some of them are now being tested in clinical trials to reduce kidney fibrosis and chronic kidney damage. Senotherapeutic drugs induce the selective cell death of senescent cells (senolytics) or suppress markers of senescence (senomorphics), in particular the SASP. A number of agents with antiaging activity are currently under study. Another option to treat/prevent cell senescence is given by senostatics. Senostatics are drugs that “downregulate” the senescent phenotype without removing senescent cells. RAAS and the mineralocorticoid blockade, atorvastatin, rosiglitazone and omega-3 fatty acids are being re-examined for this purpose [83,84][20][21]. In addition, metformin and sirolimus (a mTOR inhibitor) have senostatic properties, since they both activate autophagy, improve mitochondrial function and can extend the lifespan. Other candidate drugs include inhibitors of IkB kinase, NF-κB and the Janus kinase pathway, which inhibit pro-inflammatory signaling pathways, disrupting SASP production. Recently, it has been observed that both the ketone body beta-hydroxybutyrate and sodium-glucose cotransporter-2 inhibition, whose action seems to increase the transcription factor Nrf2 anti-oxidant response, may down-regulate senescence [85,86][22][23].
Senomorphics can modulate the functions and morphology of senescent cells, or delay the progression of young cells to senescent cells. In general, senomorphics suppress SASP via targeting NF-κB, mTOR, IL-1a, p38 MAPK and other signaling pathways. Certain compounds have the dual capacity to function as both a senomorphic and a senolytic [87][24].

5. Nuclear-Factor-Erythroid-2-Related Factor 2 Agonists

Nuclear-factor-erythroid-2-related factor 2 (Nrf2) plays a strong anti-inflammatory role in many different tissues via the inhibition of the NF-κB signaling pathway. There is some evidence from experimental muscle atrophy models that Nrf2 agonists are protective against wasting. Male dystrophin-deficient (a model for Duchenne’s dystrophy) mice treated with the Nrf2 activator sulforaphane (SFN) underwent an increased expression of muscle heme oxygenase-1 and a decreased expression of NF-κB (p65) tumor necrosis factor-α, interleukin-1β and interleukin-6. In addition, the SFN treatment decreased the expression of NF-κB (p65). Collectively, these results showed that SFN-induced Nrf2 could alleviate muscle inflammation through inhibiting the NF-κB signaling pathway [88][25]. Recently, it has been also shown that cannabinoid CB2 receptor activation protects skeletal muscle due to ameliorating oxidative damage and promoting early skeletal muscle myogenesis, in part via Nrf2 signaling [89][26].
Nrf2 was shown to be down-regulated in the muscle of patients with CKD and in dialysis-treated ESKD patients [50,90][27][28], which suggests that it may serve as a potential therapeutic target. Among several Nrf2 agonists, bardoxolone methyl has been studied in large clinical trials [91,92][29][30]. In addition to bardoxolone, other Nrf2 agonists have been developed and are under evaluation in kidney and other organ diseases [93][31].

6. Targeting Inflammation to Treat Cardiovascular Disease in Patients with Chronic Kidney Disease

A current hypothesis is that controlling the inflammatory response through anti-cytokine therapies improves cardiovascular risk factors and, potentially, survival [93][31]. Given the number of levels in the regulation of the NLRP3 inflammasome, different sequences of its priming and activation steps can be targeted. Current treatments for NLRP3-related diseases include DAMP-inhibiting molecules, colchicine or biological agents that target TLR4, IL-6, IL-1β, IL-18 or their receptors [21,93][31][32]. In this regard, IL-1β inhibition has been shown to decrease the rate of adverse cardiovascular events in high-risk atherosclerosis patients with CKD [93][31]. Common concerns are related to long-term treatment toxicities, or to the physiologically protective role of inflammation as a defense mechanism against bacteria, viruses and fungi. In models of virus-mediated diseases, NLRP3-KO mice underwent more severe diseases than infected WT animals [94][33]. Therefore, studies have addressed the issue of safety, tolerability and feasibility, in addition to the efficacy of anti-cytokine therapies. In addition, several new molecules are being tested. The issue of anti-cytokine therapy to treat cardiovascular complications has been addressed by recent reviews [93,95][31][34].

7. Targeting Inflammation to Treat Protein Energy Wasting

Pre-clinical studies suggest that blocking IL-1 signaling may be a new, promising treatment for CKD-associated muscle wasting. Anakinra blunts both IL-1α and IL-1β signaling through the IL-1 receptor [96][35]. The sub-cutaneous administration of Anakinra normalized muscle function in a mouse model of Duchene muscular dystrophy, an X-linked muscle disease characterized by muscle inflammation that is associated with increased circulating serum levels of IL-1β [97][36]. A 4-week treatment with Anakinra was shown to be safe in ESKD patients, and also significantly reduced blood CRP and IL-6 levels, but its effect on nutrition and muscle wasting has not been studied [98][37]. Dember et al. [99][38] randomized 80 inflamed hemodialysis patients to placebo or Anakinra for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. A decrease in hsCRP by 41% in the Anakinra group and 6% in the placebo group (not statistically significant) was observed. Anakinra was well tolerated and did not cause infections or bone marrow toxicity. These promising safety data and potential efficacy provide support for conducting larger trials of IL-1 inhibition to improve outcome in ESKD patients.
Recently, Cheung et al. [100][39] evaluated the efficacy of Anakinra in a mouse model of CKD-associated cachexia. Anakinra reduced the serum concentration and muscle expression of IL-6, TNF-α and IL-1β in CKD mice. This was accompanied by a reduced or normalized expression of negative regulators of muscle mass (Atrogin-1, Murf-1 and Myostatin). In addition, Anakinra attenuated the expression of transcriptional regulators of adipose tissue browning in inguinal white adipose tissue (WAT) of WT/CKD mice relative to controls. These data suggest that the IL-1 receptor antagonism may represent a novel targeted treatment for treating inflammation, adipose tissue browning and muscle wasting in CKD.
TLR4 activation is another possible target for approaches, either dietary or pharmacological, to disrupt the feed-forward loop of inflammation and wasting in uremia. TAK-242 (resatorvid) is a small-molecule inhibitor of TLR4 signaling that selectively binds to TLR4 and interferes with interactions between TLR4 and its adaptor molecules [23,101][40][41]. WResearchers recently observed that resatorvid prevented the uremic serum-induced increase in the inflammatory response in myotubes [50][27]. Resatorvid was previously used with success to prevent muscle wasting induced by sepsis in mice [102][42]; however, in a study of patients with sepsis and shock or respiratory failure, TAK-242 was well tolerated, but failed to suppress cytokine levels [103][43]. In CKD, the therapeutic target challenge remains as the suppression cytokine levels, as there is no information in patients with a micro-inflammatory state.

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