The Interplay of Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: A Call for Integrated Management

Chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) are two prevalent conditions that pose significant public health challenges globally. CKD affects about 800 million individuals worldwide [1], an epidemic due to the burden of hypertension, diabetes, and obesity in the general population. Patients with CKD are at high risk for end-stage kidney disease, cardiovascular disease, and all-cause mortality. Similarly, NAFLD, characterized by ectopic fat accumulation in the liver, affects approximately 30% of the global population and is closely associated with metabolic abnormalities such as insulin resistance, dyslipidemia, and obesity [2]. It can be estimated that about 25%–50% of patients with CKD have NAFLD (Fig. 1).

The coexistence of CKD and NAFLD carries a high risk for adverse health outcomes, particularly cardiovascular disease [3] (Fig. 1). Understanding the CKD-NAFLD interaction and developing integrated prevention and treatment strategies is a public health priority. NAFLD may contribute to the progression of CKD through mechanisms such as systemic inflammation, oxidative stress, and insulin resistance. Conversely, CKD can exacerbate liver disease by altering lipid metabolism and worsening insulin resistance [4], resulting in metabolic abnormalities [2, 5].

Recent studies have highlighted the importance of early detection and lifestyle interventions in managing CKD and NAFLD. Weight loss, dietary modifications, and increased physical activity have been shown to improve liver function and slow the progression of kidney disease [6]. Furthermore, pharmacological treatments targeting metabolic pathways, such as SGLT2 inhibitors and GLP-1 receptor agonists, benefit both conditions.

Genetic predisposition can incite CKD and NAFLD. Gene variants such as patatin-like phospholipase domain-containing protein 3 and transmembrane 6 superfamily member 2 are associated with increased susceptibility to liver disease, while apolipoprotein L1 variants are linked to a higher risk of CKD in specific populations. Understanding these genetic factors could lead to more personalized approaches to preventing and treating these diseases.

Addressing the combined burden of CKD and NAFLD requires a holistic, integrated approach, including lifestyle interventions, pharmacotherapy, and, in the near future, genetic screening. Collaborative research and healthcare policy efforts are essential to mitigate the impact of CKD and NAFLD on global health.

The study by Park et al. [7], published in this issue of the Journal, is a nationwide cohort study in Korea investigating the association of NAFLD with cardiovascular and kidney outcomes in 816,857 patients with stage G3–G4 CKD (eGFR 15–59 mL/min/1.73 m²) extracted from the Korean National Health Insurance Service database. The Korean health database is extensive, encompassing various health-related data collected from a large population of about 50 million over many years. This comprehensive dataset includes information from national health insurance records, health examinations, and various health surveys, providing a robust basis for observational research. The consistency of the data is generally high due to standardized data collection methods and regular updates. While observational research using this database can generate valuable insights, potential biases and confounding factors inherent in non-randomized data cannot be overemphasized. The study utilized the Fatty Liver Index (FLI) as a surrogate marker for NAFLD and examined its association with cardiovascular and kidney outcomes over a median follow-up of 7.7 years. This index is calculated from simple, widely available clinical data, including serum triglycerides, body mass index, liver enzyme gamma-glutamyl transpeptidase serum levels, and waist circumference. The FLI is considered a valid surrogate marker for NAFLD. It is widely used as a noninvasive tool to screen for hepatic steatosis in the general population. The FLI has been validated in various studies and is recognized for its ability to predict the presence of NAFLD and roughly estimate the severity of the condition [8].

Park et al. [7] observed a stepwise increase in the risk of composite cardiovascular and kidney events with higher FLI categories. Specifically, compared to individuals with an FLI <30, those with FLI 30–59 and ≥60 had significantly higher hazard ratios for composite outcomes, cardiovascular events, and kidney events. This association was maintained after multiple adjustments for potential confounders, including age, sex, comorbidities, and lifestyle factors.

This study improves our understanding of NAFLD and CKD epidemiology and their health risks. The large sample size and comprehensive national health insurance database data provide robust evidence of the association between NAFLD and adverse outcomes in CKD patients. This large-scale analysis enhances the generalizability of the findings within the Korean population.

Park et al. [7] examined various outcomes, including composite cardiovascular and kidney events, as well as individual events such as myocardial infarction, ischemic stroke, coronary revascularization, and end-stage kidney disease. This comprehensive assessment provides a detailed understanding of the impact of NAFLD on CKD patients. In this study, the association between FLI and kidney outcomes was more pronounced in individuals with an eGFR of 45–59 mL/min/1.73 m², while no significant association was observed in those with more advanced CKD (eGFR 15–44 mL/min/1.73 m²), which may seem counterintuitive. This could be due to several factors. First, patients with more severe CKD might have already experienced cardiovascular events or other complications, leading to a form of survivor bias where only those less susceptible to such outcomes remain in the study cohort. Second, in patients with severe CKD, the risk of non-cardiovascular mortality (e.g., from kidney failure or infections) might overshadow the risk of cardiovascular events, making it less apparent in statistical analyses. Third, patients with more severe CKD might receive more aggressive management for cardiovascular risk factors, such as stricter blood pressure control or the use of medications like statins, which could mitigate the observed risk. Similar patterns have been observed in other diseases. For example, in diabetes research, the “obesity paradox” describes how overweight or mildly obese individuals sometimes have better survival rates than those with normal weight, possibly due to more aggressive management of their condition or other protective factors. Another example is heart failure, where patients with mild to moderate disease might show different risk profiles compared to those with severe heart failure, potentially due to similar biases and interventions.

While the study by Park et al. [7] is robust and comprehensive, several aspects warrant further discussion. The reliance on FLI is not as definitive as imaging or biopsy for diagnosing NAFLD. This could introduce misclassification bias, potentially affecting the study’s findings. Future studies should aim to incorporate more definitive diagnostic tools to validate these results. As previously alluded to, the observational nature of the study limits the ability to establish causality between NAFLD and adverse outcomes. Finally, the study was exclusively based on Korean patients, which may limit the generalizability of the findings to other ethnic groups. Given the genetic and lifestyle differences across populations, similar studies in diverse cohorts are needed to confirm these associations globally. Despite extensive statistical adjustments, residual confounding cannot be entirely ruled out. Factors such as dietary habits, genetic predispositions, and environmental influences might also play a role in the observed associations. Future research should aim to control for a broader range of potential confounders.

Future studies should incorporate liver imaging (e.g., ultrasound, MRI) and biopsy to confirm NAFLD diagnosis and validate the findings from FLI-based studies. This would provide more definitive evidence of the relationship between NAFLD and adverse outcomes in CKD patients. Randomized controlled trials should be performed to determine whether interventions targeting NAFLD (e.g., lifestyle modifications, pharmacotherapy) can improve cardiovascular and kidney outcomes in CKD patients. These studies would help establish causality and inform clinical practice.

Similar studies should be conducted in diverse populations to confirm the generalizability of the findings. Elucidating the mechanisms linking NAFLD to adverse cardiovascular and kidney outcomes is fundamental. This includes exploring the roles of systemic inflammation, oxidative stress, and metabolic dysregulation in mediating these associations. Longitudinal studies with repeated measures of FLI and other relevant biomarkers would provide insights into the temporal relationship between NAFLD progression and adverse outcomes. This would help identify critical windows for intervention. Future research should integrate genetic and environmental factors to better understand the interplay between NAFLD and CKD.

As the burden of CKD and NAFLD continues to rise globally, integrated management strategies addressing both conditions are crucial to improving patient outcomes and reducing healthcare costs. By addressing the critical aspects and pursuing the suggested research directions, we can enhance our understanding of the interplay between NAFLD and CKD and develop more effective strategies for managing these complex conditions.

The authors have no conflicts of interest to declare.

The study was not supported by any sponsor or funder.

C.Z. and F.M. conceived and wrote the manuscript.