Reconciling diagnostic definitions for proposing metabolic dysfunction-associated steatotic liver disease in chronic kidney disease risk
Editorial

Reconciling diagnostic definitions for proposing metabolic dysfunction-associated steatotic liver disease in chronic kidney disease risk

Tsubasa Tsutsumi1,2 ORCID logo, Takumi Kawaguchi2, Hiroyuki Suzuki2,3, Ryuki Hashida4, Shuhei Fukunaga2, Masahito Nakano2, Mary E. Rinella1

1Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, IL, USA; 2Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; 3Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Department of Orthopedics, Kurume University School of Medicine, Kurume, Japan

Correspondence to: Tsubasa Tsutsumi, MD, PhD. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637, USA; Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. Email: tsubasa@uchicagomedicine.org.

Comment on: Heo JH, Lee MY, Kim SH, et al. Comparative associations of non-alcoholic fatty liver disease and metabolic dysfunction-associated steatotic liver disease with risk of incident chronic kidney disease: a cohort study. Hepatobiliary Surg Nutr 2024;13:801-13.

Keywords: Chronic kidney disease (CKD); non-alcoholic fatty liver disease (NAFLD); diagnostic criteria; metabolic dysfunction-associated steatotic liver disease (MASLD); consensus definition

Submitted Jun 15, 2025. Accepted for publication Aug 22, 2025. Published online Sep 26, 2025.

doi: 10.21037/hbsn-2025-404

The recent international consensus proposing metabolic dysfunction-associated steatotic liver disease (MASLD) as a replacement for non-alcoholic fatty liver disease (NAFLD) marks a pivotal shift (1). This change aims to more accurately reflect the underlying metabolic abnormalities of the disease and reduce stigma. A core principle of this evolution was to establish a clear, globally applicable definition that ensures we all speak the same language. To this end, a careful and conservative approach was taken, requiring only one of five cardiometabolic risk factors (CMRFs) for diagnosis. This inclusive threshold was chosen first to identify the broad disease population, recognizing that risk stratification for more severe outcomes is a subsequent step dependent on the number and severity of these factors. Additionally, the new definition was benchmarked to the existing NAFLD definition—maintaining strict alcohol exclusion thresholds—to preserve the continuity and immense value of decades of natural history data (2).

Before discussing the specifics of the Heo et al. (3) study, it is important to understand its place in the recent changes in the nomenclature of liver disease. The shift from NAFLD to MASLD was not direct one. It was preceded by the influential proposal of metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020. The MAFLD (4) definition aimed to replace the exclusionary nature of NAFLD with positive criteria centered on metabolic dysfunction. One key hypothesis was that MAFLD would be superior to NAFLD in identifying patients at high risk for extrahepatic complications, such as chronic kidney disease (CKD). This hypothesis was subsequently supported by several key studies. For instance, a cross-sectional analysis by Sun et al. found a higher prevalence of CKD in individuals with MAFLD compared to those with NAFLD (5). In addition, a consensus statement on MAFLD and CKD risk was developed using the Delphi method, and it was unanimously agreed that the prevalence of CKD was higher in MAFLD patients than in non-MAFLD groups (6). The “MASLD” definition used by Heo et al. (3) is substantively closer to the MAFLD concept than to the final, consensus-based MASLD definition because it includes homeostatic model assessment of insulin resistance (HOMA-IR) and requires multiple metabolic hits. Therefore, their study can be seen as an implicit validation of the MAFLD principle that stricter metabolic criteria identify a higher-risk group. However, it is equally important to recall why the global community ultimately adopted MASLD over MAFLD. Concerns about MAFLD’s complex criteria and the need for a simpler, more broadly applicable standard led to the new consensus (1).

It is within this essential context that we review the work by Heo et al., “Comparative associations of non-alcoholic fatty liver disease and metabolic dysfunction-associated steatotic liver disease with risk of incident chronic kidney disease: a cohort study” (3). The study presents an ambitious prospective analysis in a large Korean cohort, concluding that their definition of MASLD better identifies individuals at high risk for CKD or abnormal albuminuria. However, several critical considerations arise. The most fundamental issue is the divergence of the MASLD diagnostic criteria employed in their study from the international consensus definition. Heo et al. (3) diagnosed “MASLD” using a diagnostic framework wherein hepatic steatosis must coexist with one of three conditions: overweight/obesity (defined as a body mass index ≥23 kg/m2), type 2 diabetes, or metabolic dysfunction defined by the presence of at least two of seven risk factors [which included insulin resistance (HOMA-IR) score ≥2.5 or a plasma high-sensitivity C-reactive protein (hs-CRP) level ≥0.2 mg/dL] (Table 1). In contrast, the MASLD consensus requires the presence of at least one of five CMRFs, with neither HOMA-IR nor hs-CRP listed among these primary diagnostic criteria. Their approach is notably more akin to the previously proposed MAFLD definition (7), for which concerns were raised during the consensus process regarding not only the complexity and standardization of criteria like HOMA-IR, but also the potential for these broader criteria to identify a heterogeneous population with a distinct natural history (1).

Table 1

Comparison of MASLD diagnostic criteria

Feature Definition for "MASLD" by Heo et al. (3) International consensus definition for MASLD (1)
Prerequisite Hepatic steatosis (ultrasound) Hepatic steatosis (imaging or biopsy)
Basis for defining metabolic dysfunction At least 1 of the following three conditions: (I) BMI ≥23 kg/m2 (for Asians); (II) type 2 diabetes; (III) presence of ≥2 of 7 metabolic risk factors† Presence of at least 1 of 5 CMRFs‡
Specific factors included by Heo et al. (not primary CMRFs in consensus) (3) HOMA-IR >2.5, hs-CRP ≥0.2 mg/dL These factors are not primary CMRFs
Suggested link to MAFLD-like criteria Inclusion of HOMA-IR and hs-CRP may use MAFLD-like criteria (7) Simplified from some MAFLD complexities (e.g., direct insulin resistance measures are not primary criteria) to enhance clinical applicability and standardization
Consideration of alcohol intake in MASLD diagnosis No explicit limit in their definition. Heo et al.’s (3) “MASLD-only” group may include individuals with significant alcohol intake if NAFLD criteria are not met Diagnosis of MASLD generally implies the absence of other causes like significant alcohol intake (which would classify as MetALD or ALD if specific alcohol thresholds are met)

†, Heo et al.’s seven metabolic risk factors (3): (I) waist circumference: ≥90 cm (male), ≥80 cm (female); (II) triglycerides: ≥150 mg/dL; (III) HDL-C: <40 mg/dL (men), <50 mg/dL (women); (IV) blood pressure: ≥130/85 mmHg or antihypertensive treatment; (V) prediabetes: fasting glucose 100–125 mg/dL or HbA1c 5.7–6.4%; (VI) HOMA-IR >2.5; (VII) hs-CRP ≥0.2 mg/dL; ‡, Rinella et al.’s five cardinal CMRFs (1): (I) BMI ≥25 kg/m2 (or ≥23 kg/m2 for Asians) or waist circumference ≥94 cm (male), ≥80 cm (female) (or ethnicity-adjusted); (II) fasting glucose ≥5.6 mmol/L (100 mg/dL), 2-hour glucose ≥7.8 mmol/L (140 mg/dL), HbA1c ≥5.7%, or diagnosis/treatment for type 2 diabetes; (III) blood pressure ≥130/85 mmHg or treatment for hypertension; (IV) triglycerides ≥1.70 mmol/L (150 mg/dL) or lipid-lowering therapy; (V) HDL-C ≤1.0 mmol/L (40 mg/dL) for men, ≤1.3 mmol/L (50 mg/dL) for women or lipid-lowering therapy. ALD, alcohol-associated liver disease; BMI, body mass index; CMRFs, cardiometabolic risk factors; HOMA-IR, homeostatic model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic dysfunction and alcohol-associated liver disease; NAFLD, non-alcoholic fatty liver disease.

This distinction highlights a fundamental principle of the new nomenclature: the consensus MASLD definition was deliberately designed as a broad diagnostic foundation, not as a self-contained risk stratification tool. Risk stratification for outcomes like metabolic dysfunction-associated steatohepatitis, cardiovascular disease, or CKD is a subsequent step, logically driven by the number and severity of a patient’s underlying CMRFs. The fact that Heo et al. (3), while citing the consensus paper, effectively use unique criteria under the “MASLD” label significantly impacts the interpretation of their findings. Furthermore, the classification of participant subgroups warrants scrutiny. In Heo et al.’s study (3), the “MASLD-only” group meets their unique MASLD criteria but not NAFLD criteria, implying it could include individuals with significant alcohol consumption who also have metabolic dysfunction. This composition is conceptually closer to “MetALD” (metabolic dysfunction and alcohol-associated liver disease) and creates a potential for misclassification and confusion when comparing risk profiles. It is now understood that alcohol and metabolic disorders share many common mechanisms of liver damage (8). Therefore, it has become increasingly important in clinical practice to accurately diagnose the primary factors causing damage (metabolic, alcohol-related, or both) and establish treatment strategies based on etiology. A classification with an ambiguous approach to alcohol, such as that in the study by Heo et al. (3), precludes this essential clinical judgment. In this light, the international consensus that clearly distinguishes among MASLD, MetALD, and alcohol-associated liver disease (ALD) represents a rational and necessary advance that is aligned with this biological reality.

These definitional issues are critical, yet we must also congratulate the authors on the commendable strengths of their study. The large cohort of over 214,000 individuals and the longitudinal design provide robust, high-quality evidence. The study powerfully reminds us of the strong link between metabolic abnormalities and kidney damage. Indeed, this clinical association is supported by growing mechanistic evidence. Recent concepts suggest that MASLD and CKD may share a common pathophysiology rooted in altered mitochondrial function, positioning them as two facets of a single systemic metabolic disease (9). Preclinical research supports this view. For example, studies using advanced magnetic resonance imaging (MRI) in animal models of MASLD have demonstrated renal alterations, such as changes in hemodynamics and oxygenation (10). These findings provide tangible evidence that kidney damage originates from metabolic dysfunction. However, this raises a key point: a new, bespoke definition of MASLD to identify CKD risk may not be necessary. The risk factors themselves, particularly diabetes and insulin resistance, as highlighted by their use of HOMA-IR, are already well-known drivers of CKD. The clinical takeaway should not be to adopt a new, non-standard definition, but to recognize that the presence of these specific risk factors within the MASLD population signals the need for heightened CKD surveillance.

This brings us to the broader question: are NAFLD and consensus-defined MASLD largely equivalent, allowing for continued use of existing data? Recent research provides a reassuring answer. Younossi et al. demonstrated that the vast majority of NAFLD patients [99.8% in tertiary care and approximately 95% in the U.S. population-based National Health and Nutrition Examination Survey (NHANES) III] meet the consensus criteria. Their study further showed high concordance in clinical profiles [including CKD prevalence, which was very similar at 13.38% in NAFLD and 13.85% in MASLD, both significantly higher than in their non-steatotic liver disease (SLD) counterparts], non-invasive tests (NITs) thresholds, and mortality risk (after adjustment for CMRFs), supporting the interchangeability of data (11). This growing consensus that the clinical characteristics, complications, and progression of NAFLD and MASLD overlap and are essentially interchangeable has been echoed by other experts (12). This perspective of “NAFLD ≈ MASLD (data interchangeability)” is strongly corroborated from our research group (13). In a study of 7,286 Japanese health check examinees, 93.3% of patients with NAFLD also met the MASLD criteria. Crucially, the prevalence and 10-year cumulative incidence of CKD were virtually identical between the NAFLD and MASLD groups (log-rank P=0.925). This led us to conclude that data obtained on CKD using the term NAFLD can be extrapolated to MASLD. This high degree of similarity has also been demonstrated by our group across a range of other clinical contexts in Asian populations (13-21) (Figure 1). These collective findings provide a reassuring message: the rich legacy of NAFLD research remains largely relevant and applicable in the MASLD era.

Figure 1 Multiorgan distribution of similar disease prevalence and clinical incidence between patients with NAFLD and MASLD (13-21). CLDQ-NAFLD values and SWE (kPa) values are presented as median (interquartile range). ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CLDQ-NAFLD, chronic liver disease questionnaire-NAFLD; COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; QOL, quality of life; SWE, shear wave elastography.

In conclusion, the essential advance of the new international consensus lies not merely in replacing “NAFLD” with “MASLD”, but in establishing a comprehensive SLD framework. This framework provides clear categories for different etiologies, such as MASLD, MetALD, and ALD, freeing us from the simplistic and often inaccurate dichotomy of “non-alcoholic” versus “alcoholic”. In this context, the finding by Heo et al. (3) that their “MASLD” better predicts CKD risk likely stems from their use of a unique, more metabolically stringent definition rather than the globally accepted one. Their valuable longitudinal analysis, however, powerfully underscores the importance of the known interplay between metabolic dysfunction and CKD. It must be emphasized that the MASLD definition itself serves as a diagnostic foundation, not a prognostic tool. The path forward lies not in creating bespoke definitions for each comorbidity but in using the standardized international SLD classification framework to precisely evaluate risk drivers across diverse etiologies. This approach enables more appropriate risk stratification by considering the fundamental pathophysiology of CKD, such as the effects of hyperglycemia, hypertension, and insulin resistance. Doing so will promote the development of optimized preventive strategies and targeted therapeutic interventions, ultimately improving the prognosis for the many individuals burdened by both steatotic liver disease and associated kidney impairment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-404/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-404/coif). T.T. reports consulting fees from Madrigal. T.K. reports honoraria from ASKA Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Kowa Company, Ltd., AbbVie GK., Eisai Co., Ltd., EA Pharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Pharma Co., Ltd., Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K. M.E.R. reports consulting fees from Akero, 89Bio, Boehringer Ingelheim, Intercept Pharmaceuticals, Histoindex, Madrigal, NGM Biopharmaceuticals, Novo Nordisk, Eli Lilly, Sagimet Biosciences, Sonic Incytes, Cytodyn, and GSK; leadership or fiduciary role with Akero, Madrigal, Eli Lilly and Novo Nordisk. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Cite this article as: Tsutsumi T, Kawaguchi T, Suzuki H, Hashida R, Fukunaga S, Nakano M, Rinella ME. Reconciling diagnostic definitions for proposing metabolic dysfunction-associated steatotic liver disease in chronic kidney disease risk. Hepatobiliary Surg Nutr 2025;14(5):883-888. doi: 10.21037/hbsn-2025-404

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