Metabolic dysfunction-associated steatotic liver disease and chronic kidney disease: From epidemiology and pathophysiology to clinical prediction and treatment options

Abstract
MASLD and CKD frequently coexist due to shared metabolic risk factors. The 2023 nomenclature of MASLD emphasizes cardiometabolic risk. MASLD is an independent risk factor for CKD, and risk increases with steatosis severity and fibrosis. CKD may also promote MASLD fibrosis progression. Common mechanisms include genetic variants (PNPLA3, HSD17B13), insulin resistance, dyslipidemia, hypertension, hyperglycemia, chronic inflammation, oxidative stress, gut dysbiosis, and portal hypertension. The MAFLD/MASLD criteria outperform NAFLD in identifying CKD risk. Non‑invasive fibrosis scores (FIB‑4, NFS) and liver stiffness measurement help stratify risk. Therapeutic options include lifestyle intervention, GLP‑1 receptor agonists, SGLT‑2 inhibitors, statins, RAAS inhibitors, PPAR agonists, and FXR agonists. This review summarizes common pathophysiology, epidemiological evidence, predictive tools, and potential treatments for MASLD–CKD comorbidity.

Introduction
MASLD (formerly NAFLD/MAFLD) is defined by hepatic steatosis plus at least one cardiometabolic risk factor. It affects ~1.27 billion people globally. CKD affects ~788 million adults. Both are increasing and share metabolic dysfunction as a core driver. MASLD is an independent risk factor for CKD, and CKD may worsen liver fibrosis. This review covers shared mechanisms, epidemiological links, prediction models, and management strategies.

Common Pathophysiological Mechanisms

• Genetic factors: PNPLA3 rs738409 (I148M) is associated with lower eGFR and increased CKD risk in MASLD patients. HSD17B13 rare A allele protects kidney function.

• Insulin resistance: Promotes hepatic lipid accumulation, inflammation, and renal hemodynamic changes, podocyte damage, and fibrosis.

• Lipid disorders and lipotoxicity: Accumulation of triglycerides, diacylglycerols, ceramides drives liver injury; uremic toxins enhance lipolysis and inflammation in CKD.

• Hypertension: Activates RAAS, causing glomerular hyperfiltration and sclerosis; also promotes portal hypertension and gut‑liver axis disruption.

• Hyperglycemia: Increases IR, lipotoxicity, mitochondrial dysfunction, and inflammatory cytokines, damaging both organs.

• Immune inflammation: Hepatic macrophages (Kupffer cells) shift to pro‑inflammatory M1 phenotype; cytokines and chemokines promote fibrosis in liver and kidney.

• Gut microbiota dysbiosis: Altered bile acid metabolism, decreased SCFAs, increased TMAO, and changes in bacterial composition (e.g., Bacteroides, Firmicutes, Lactobacillus) contribute to both diseases.

• Portal hypertension: Increases intrahepatic resistance, triggers hepatorenal reflex, and reduces renal blood flow.

Epidemiological and Clinical Evidence
MASLD/MAFLD criteria better identify CKD risk than NAFLD (Table 3). Meta‑analyses show MAFLD increases CKD risk by ~29–38% (HR 1.29–1.38). The risk rises with liver fibrosis stage. Advanced fibrosis (F3/4) is a stronger predictor than steatosis alone. CKD also predicts MASLD fibrosis progression. Coexisting MASLD and CKD increases cardiovascular events, all‑cause mortality, and end‑stage renal disease.

Biomarkers and Clinical Prediction Models

• Traditional biomarkers: Albuminuria (uACR), eGFR, N‑acetyl‑β‑D‑glucosaminidase, neutrophil gelatinase‑associated lipocalin, liver‑type fatty acid‑binding protein.

• Liver fibrosis markers: FIB‑4, NFS, APRI, PRO‑C3, enhanced liver fibrosis, CK‑18.

• Inflammatory markers: CRP, IL‑6, IL‑8, TNF‑α.

• Novel markers: Bile acids (taurocholic, glycocholic), gut microbial metabolites (SCFAs, TMAO), grip strength.

• Predictive scores: FIB‑4 (cut‑off 1.0148) and NFS (cut‑off –1.1711) effectively exclude CKD in MASLD. LSM ≥8 kPa indicates CKD risk. The PERIOD score (PRO‑C3, PRO‑C6, BMI, hypertension, diabetes) improves accuracy.

Potential Clinical Management Strategies

• Lifestyle intervention: Low‑calorie diet and exercise remain foundational.

• GLP‑1 receptor agonists (liraglutide, semaglutide): Improve steatohepatitis, fibrosis, and reduce CKD progression. Semaglutide approved for MASH with fibrosis.

• SGLT‑2 inhibitors (empagliflozin, dapagliflozin): Reduce hepatic fat, inflammation, and provide cardiorenal protection.

• Statins: Lower lipids, reduce liver fibrosis, delay eGFR decline.

• RAAS inhibitors (ACEIs/ARBs, finerenone): Block Ang II–mineralocorticoid receptor axis, reduce fibrosis in liver and kidney. Finerenone is a novel non‑steroidal MRA with dual benefits.

• PPAR agonists: Pemafibrate (PPARα) improves hypertriglyceridemia and renal fibrosis; pioglitazone (PPARγ) increases insulin sensitivity.

• FXR agonists: Vonafexor reduces liver fat and may improve eGFR in mild‑to‑moderate CKD.

Discussion and Future Directions
Despite strong associations, bidirectional causality remains uncertain. Most studies are cross‑sectional; large prospective cohorts are needed. MASLD subtypes (obese vs. lean, diabetic vs. non‑diabetic) and CKD stages require stratification. Co‑infection with HBV/HCV may confound risk. Future research should integrate multi‑omics, develop machine‑learning prediction models, and conduct prospective intervention trials to validate dual‑organ benefits of existing and novel drugs.

Conclusions
MASLD and CKD share genetic, metabolic, inflammatory, and gut microbiota‑mediated pathways. The MAFLD/MASLD criteria are superior to NAFLD for identifying CKD risk. Liver fibrosis severity is a key predictor. Non‑invasive scores (FIB‑4, NFS) and LSM help stratify patients. Lifestyle intervention is fundamental, and several drug classes (GLP‑1 RAs, SGLT‑2is, RAAS inhibitors, PPAR agonists, FXR agonists) offer promising dual‑organ protection. Future efforts should focus on integrated prediction models and mechanism‑based therapies for precise management of this common comorbidity.

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https://www.xiahepublishing.com/2310-8819/JCTH-2025-00612

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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