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

Abstract

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

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

“…Although the cross-sectional associations between NAFLD and CKD stages are strong and consistent across a wide range of patient populations, the data on whether NAFLD per se is causally linked to the development and progression of CKD remain debateable 105 106…”

Progression and new onset of nonalcoholic fatty liver disease in living kidney donors compared to healthy controls

“…It is clear that these two conditions share risk factors and consequences such as HTN, diabetes mellitus, atherogenic dyslipidemia, obesity, and insulin resistance . However, it remains unclear how these two conditions affect each other and whether independent casualty and “crosstalk” between them exist …”

“…[38][39][40] However, it remains unclear how these two conditions affect each other and whether independent casualty and "crosstalk" between them exist. 7,41 Living kidney donors are ideal subjects to assess the association of NAFLD with reduced eGFR in an isolated setting, as they have reduced eGFR due to nephrectomy and not the result of other comorbidities or to underlying kidney disease. However, it is still unknown whether kidney donation is associated with an increased incidence or accelerated progression of NAFLD.…”

Cardiometabolic effects of antidiabetic drugs in non‐alcoholic fatty liver disease

“…Sodium-glucose cotransporter-2 (SGLT-2) inhibitors block glucose reabsorption in the proximal tubules of the kidneys, increasing urinary glucose excretion and reducing the amount of circulating glucose, and thereby decreasing the plasma glucose level (Musso et al, 2016). Three SGLT-2 inhibitors, canagliflozin, dapagliflozin and empagliflozin, are approved by the American and European authorities for the treatment of patients with type 2 diabetes (European Medicines Agency, 2017; US Food and Drug Administration, 2017).…”