Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD.

Identification of biomarkers for the diagnosis of chronic kidney disease (CKD) with non-alcoholic fatty liver disease (NAFLD) by bioinformatics analysis and machine learning

“…NAFLD and CKD are both significant global public health burden, and there is evidence that NAFLD is independently associated with a high risk of CKD despite the exclusion of other metabolic diseases, while the underlying mechanisms are not clear (26). In our study, by obtaining DEGs and important module genes by WGCNA, 45 NAFLD-related share genes were obtained, and their enrichment analysis revealed that immune, inflammatory and programmed cell death pathways were significantly enriched.…”

Serum PRO‐C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort

“…45,46 Finally, the hepato-renal reflex may also play a potential role in promoting the occurrence and development of MAFLD-CKD. 47 Given the close association between MAFLD and CKD, it is reasonable to hypothesize that the severity of MAFLD may exacerbate the risk of developing MAFLD-CKD. There is little evidence that patients with MAFLD with steatohepatitis or severe fibrosis have a higher risk of MAFLD-CKD than individuals without fibrosis or with isolated steatosis.…”

Liver stiffness as a cornerstone in heart disease risk assessment

“…[22][23][24][25] Furthermore, subclinical portal hypertension can occur in non-cirrhotic MASLD, which can impair renal vasoregulation. 26,27 Recently, it was shown that hepatic steatosis does not predict incident CVD and related mortality when taking into account changes in cardiovascular risk factors over time, 28 suggesting that especially MASLD-related hepatic inflammation and fibrosis with resulting liver stiffness are the most important contributors to the onset and progression of CVD. [29][30][31][32][33] Of note, increased liver stiffness does not solely result from liver disease-related fibrogenesis but also from increased central venous pressure and congestive hepatopathy.…”