The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial

Zeeuw, Dick de; Bekker, Pirow; Henkel, Elena; Hasslacher, C.; Gouni‐Berthold, Ioanna; Mehling, Heidrun; Potarca, Antonia; Tesař, Vladimı́r; Heerspink, Hiddo J.L.; Schall, Thomas J.

doi:10.1016/s2213-8587(15)00261-2

Cited by 233 publications

(170 citation statements)

References 17 publications

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“…170 The inhibition of MCP-1 may exert reno-protective effects in combination with renin-angiotensin-aldosterone system (RAAS) inhibition. CCR2 inhibition with CCX140-B exerts a renoprotective effect with capacity of lowering albuminuria on top of current standard of care with RAAS inhibition in patients with T2DM and diabetic nephropathy 171 .…”

Section: [H2] Influence Of Chemokinesmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Section: [H2] Influence Of Chemokinesmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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“…In the kidney, tubule cells and podocytes secrete chemokines CCL2 and CCL5 in response to diverse proinflammatory stimuli to promote tubulointerstitial inflammation and fibrosis, which are reversed by chemokine antagonists (81). On this basis, chemokine antagonists are advancing to the clinical stage of development: The smallmolecule CCR2 antagonist CCX140-B has reduced albuminuria and slowed eGFR decline in diabetic nephropathy (82), whereas the dual chemokine receptor CCR2/CCR5 antagonists BMS-813160, PF-04634817, and cenicriviroc are being evaluated in diabetic nephropathy (clinical trial reg. nos.…”

Section: Targeting Molecular Effectors Of Inflammation and Fibrosismentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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“…Significant improvement in the slope of decline of GFR over that achieved with the standard of care treatment was also observed beside the improved glycemic control [6] . The results of phase 3, however, did not confirm the signi ficant impact on GFR but did confirm the antiproteinuric and the glycemic favorable outcomes reported in phase 2 [154] . CCX168 is another inhibitor that targets C5aR, the chemoattractant receptor that binds to the complement fragment C5a.…”

Section: Sharaf El Din Uaa Et Al Stop Chronic Kidney Disease Progrementioning

confidence: 59%

Stop chronic kidney disease progression: Time is approaching

Din¹,

Salem²,

Abdulazim³

2016

WJN

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Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the antisenescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.

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The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial

Cited by 233 publications

References 17 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Stop chronic kidney disease progression: Time is approaching

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