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 proliferator–activated 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.

Background: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. Methods: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. Results: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. Conclusions: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients.

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6‐D₂‐glucose and U‐¹³C‐glucose) in the basal state and during an oral glucose tolerance test. The best‐performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test‐derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61‐0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63‐0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45‐0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). Conclusion: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD. (Hepatology 2016;63:107–116)