The Metabolic Dysfunction–Associated Steatotic Liver Disease–CKD Axis: Intersecting Pathways and Opportunities for Early Intervention

Abstract

Chronic kidney disease (CKD) and metabolic dysfunction–associated steatotic liver disease (MASLD) are highly prevalent, overlapping conditions with significant health burdens. CKD affects > 650 million people worldwide and is a leading cause of morbidity and mortality, whereas MASLD affects nearly one-third of adults worldwide and increases risks of cardiovascular disease, kidney disease, and cancer. This review synthesizes epidemiologic and mechanistic evidence linking MASLD and CKD, with attention to clinical implications, screening, and management strategies. Studies consistently demonstrate a higher prevalence of CKD among patients with MASLD, with greater risk in those with advanced disease such as metabolic dysfunction–associated steatohepatitis and fibrosis. Shared mechanisms, including insulin resistance; systemic inflammation; renin-angiotensin-aldosterone system activation; and metabolic risk factors such as obesity, hypertension, and diabetes, contribute to kidney injury in this population. The coexistence of MASLD and CKD underscores the need for multidisciplinary approaches to care. Early identification of CKD in patients with MASLD, combined with aggressive management of metabolic risk factors, may improve outcomes. Further research is needed to refine screening strategies, clarify pathophysiologic pathways, and optimize treatment for this growing patient population.

The term nonalcoholic steatohepatitis was first introduced in 1980 by Jurgen Ludwig to describe liver injury characterized by steatosis, inflammation, and hepatocyte ballooning in patients with obesity and metabolic abnormalities. Over time, recognition of similar findings in patients previously diagnosed with “cryptogenic cirrhosis” led to the broader concept of nonalcoholic fatty liver disease, defined by hepatic steatosis unrelated to alcohol or other liver diseases. To better capture its metabolic origins, a multisociety panel later replaced nonalcoholic fatty liver disease with MASLD, defined by hepatic steatosis with coexisting cardiometabolic risk factors such as obesity, insulin resistance, hypertension, or dyslipidemia.¹ MASLD encompasses 2 subtypes—metabolic dysfunction–associated steatotic liver and metabolic dysfunction–associated steatohepatitis (MASH); the latter representing a more active, inflammatory form that can progress to cirrhosis. Beyond liver injury, MASLD is a multisystem disorder that increases the risk of cardiovascular and kidney disease, as well as several malignancies, underscoring its broad clinical significance.

CKD is defined by an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m² or urine albumin-to-creatinine ratio (ACR) ≥ 30 mg/g for ≥ 3 months.² CKD has a high prevalence affecting 14% of the United States adult population and is associated with higher risk of morbidity and mortality, including cardiovascular disease, stroke, hospitalization and all-cause mortality.³ Globally, in 2017, a systematic analysis of global burden of disease, injuries and risk factors study project showed 697.5 million cases of all-stage CKD with a global prevalence of 9.1 %.⁴ CKD has risen from 19th to 11th in rank among leading causes of mortality between 1990 and 2019 due to aging and increase in the prevalence of risk factors, including diabetes mellitus (DM) and hypertension.⁵

Prospective and cross-sectional studies conducted over the years have demonstrated a higher prevalence of CKD among patients with MASLD, with more severe liver disease contributing to an increased risk of CKD. With the rising prevalence of risk factors such as obesity and DM that contribute to MASLD, the incidence of CKD is expected to grow. This underscores the need for further research into the complex interplay between these 2 commonly occurring conditions. The focus of the current review is to describe the available evidence linking MASLD and CKD, discuss the pathophysiology of CKD among patients with MASLD, propose CKD screening criteria among patients with MASLD, review the available treatment options in this arena, and describe comprehensive care options among these patients.

Prevalence of CKD in MASLD

Two meta-analyses encompassing 42 studies reported a 2-fold increase in CKD incidence among patients with MASLD compared with those without MASLD (odds ratio (OR): 2.12, 95% confidence interval [CI]: 1.69–2.66; hazard ratio [HR]: 1.79, 95% CI: 1.65–1.95).^6,7 Among these, 13 studies using liver biopsy data demonstrated that advanced fibrosis was associated with a significantly higher prevalence (OR: 5.20, 95% CI: 3.14–8.61) and incidence (HR: 3.29, 95% CI: 2.30–4.71) of CKD. In addition, greater MASLD severity (defined by either high-intermediate nonalcoholic fatty liver disease fibrosis score (≥ 1.455) or increased serum gamma-glutamyltransferase level (≥ 109 U/L) correlated with an increased CKD risk (HR: 1.50, 95% CI: 1.25–1.74).

A retrospective study further confirmed an elevated CKD incidence in patients with decompensated cirrhosis, who had a higher risk compared with those with compensated disease (adjusted HR: 2.28 vs. 1.47). Pooling data from these 2 meta-analyses, the prevalence of CKD in MASLD patients ranged from 20% to 55% (Supplementary Tables S1 and S2 and Table 1).

Table 1.

Meta-analysis showing the association between MASLD and CKD

	Year	Author	Number and type of studies	Number of subjects	Outcome (Adjusted analysis)	Comments
1.	2014	Giovanni Musso et al.6	33 studies: 16 population based; 17 hospital-based (20 cross-sectional and 13 longitudinal)	63,902	(a) MASLD: OR: 2.12, 95% CI (1.69–2.66). Prevalence of CKD; HR: 2.12, 95% CI (1.42–3.17) for incident CKD (b) MASH: OR: 2.53, 95 % CI (1.58–4.05) Prevalence of CKD; HR: 3.29, 95% CI (2.30–4.71) for incident CKD (c) Advanced fibrosis: OR: 5.20, 95% CI (3.14–8.61) for prevalent CKD and HR: 3.29 (2.30–4.71) for incident CKD	MASH has a higher prevalence and incidence of CKD than simple steatosis. 13 studies (2205 participants) Defined as MASLD by liver histology
2.	2017	Mantovani et al.7	9 observational studies	96,595	(a) MASLD-Random effects HR 1.37, 95% CI (1.20–1.53) for incident CKD. (b) Severe MASLD (ultrasound and noninvasive fibrosis markers)- HR: 1.50, 95% CI (1.25–1.74) for incident CKD. Median follow-up: 5.2 yrs	40% increase in the risk of incident CKD. Subjects predominantly of Asian decent No biopsy proven studies were included
3.	2022	Mantovani et al.8	13 observational studies	1,222,032	MASLD: random effects. HR: 1.43, 95% CI: (1.33–1.54) for incident CKD. Median follow-up 9.7 yrs	1.45-fold risk of incident CKD stage ≥ 3

CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; MASH, metabolic dysfunction associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; OR, odds ratio.

Risk Factors and Pathophysiology Linking MASLD and CKD

The association between MASLD and CKD is multifactorial, involving both traditional and nontraditional risk factors. Traditional risk factors such as DM, hypertension, smoking, dyslipidemia, and hypothyroidism are highly prevalent in individuals with MASLD and are independently linked to CKD. This overlap complicates the ability to isolate MASLD as a standalone contributor to kidney dysfunction. For instance, current smoking and poorly controlled DM—both established CKD risk factors—are key drivers of MASLD introducing confounding in observational studies assessing the liver-kidney axis.

Emerging data highlight the role of nontraditional, MASLD-specific factors in increasing CKD risk, independent of classical metabolic comorbidities. A study of 1763 patients with diabetes from China found that histologic severity of MASLD, particularly advanced hepatic fibrosis, was independently associated with increased albuminuria (odds ratio: 1.52, 95% CI: 1.02–2.28), even after adjusting for metabolic confounders.⁹ Nonobese individuals with MASLD appear to be at elevated CKD risk, with a Korean prospective study reporting a 12.9% CKD prevalence in this subgroup.¹⁰ Moreover, abdominal obesity—more so than generalized obesity—may play a significant mediating role. In a recent population-based analysis, individuals with both MASLD and abdominal obesity had a significantly higher CKD prevalence than those with MASLD alone (30.3% vs. 16.1%, P < 0.001). Waist circumference, waist-hip ratio, and lipid accumulation product had stronger mediating effects (65.2%, 70.7%, and 72.0%, respectively) than body mass index (32.6%).¹¹

Liver-derived indices predictive of steatosis and fibrosis have been implicated in CKD risk. The fatty liver index, an accessible noninvasive biomarker, has been shown to correlate with incident CKD; inclusion of fatty liver index in risk models significantly improved prediction accuracy.¹² Longitudinal studies further support this association: a 5-year follow-up from a metabolically healthy cohort showed a significant relationship between higher baseline fibrosis-4 index (FIB-4) scores and accelerated eGFR decline.¹³ The UK Biobank, a large prospective cohort study involving > 337,000 participants followed-up with for a median of 12.8 years, revealed that individuals with MASLD were twice as likely to progress to end-stage kidney disease (HR: 2.03, 95% CI: 1.68–2.46). Notably, there was a graded association between liver fibrosis severity and end-stage kidney disease risk, emphasizing the prognostic relevance of hepatic fibrosis in kidney outcomes.¹⁴

The interplay between MASLD and CKD extends beyond shared risk factors, involving several overlapping mechanistic pathways (Figure 1). Chronic low-grade inflammation driven by hepatic and systemic macrophage activation leads to cytokine release, whereas oxidative stress contributes to tubular injury and glomerulosclerosis. Insulin resistance, a hallmark of MASLD, disrupts kidney hemodynamics and promotes lipotoxicity through ectopic fat deposition. Gut dysbiosis further amplifies systemic inflammation and uremic toxin accumulation, accelerating organ injury. In addition, MASLD-associated endothelial dysfunction and subclinical atherosclerosis may exacerbate kidney microvascular damage. Collectively, these mechanisms highlight MASLD as a systemic disorder with significant kidney implications.^8,15, 16, 17

Figure 1.

Figure illustrating the major factors contributing to the pathophysiology of CKD MASLD and CV disease. CKD- chronic kidney disease; CV disease- cardiovascular disease; MASLD- metabolic dysfunction associated steatotic liver disease; RAAS- renin angiotensin aldosterone system.

Clinical Implications

The growing recognition of MASLD as a multisystemic disorder has significant implications for kidney health. Emerging evidence indicates that MASLD contributes to the progression of CKD through multiple mechanisms, including insulin resistance, systemic inflammation, altered lipid metabolism, and endothelial dysfunction. Given this strong association, it is critical to understand the clinical implications of MASLD-induced CKD progression and implement strategies for early identification and intervention.

Early Screening for CKD in MASLD Patients

MASLD is an independent risk factor for CKD, necessitating proactive screening in affected individuals. Traditional CKD risk factors such as diabetes and hypertension frequently coexist with MASLD, further amplifying kidney disease progression. However, even in the absence of overt metabolic syndrome, MASLD itself has been shown to accelerate kidney dysfunction through mechanisms such as increased oxidative stress and activation of the renin-angiotensin-aldosterone system (RAAS).

Increased Cardiovascular Risk in MASLD-Associated CKD

The development of CKD in patients with MASLD significantly heightens the risk of cardiovascular complications. CKD is well-established as a major risk factor for atherosclerosis, left ventricular hypertrophy, and heart failure; and MASLD further exacerbates this risk because of chronic systemic inflammation and dyslipidemia.

Implications for Disease-Modifying Therapies

Given the intertwined nature of MASLD, CKD, and cardiovascular disease, treatment approaches should target multiple pathways.

Role of Noninvasive Liver Fibrosis Markers in Predicting CKD Risk

Noninvasive markers of MASLD offer a safer alternative to liver biopsy, avoiding its associated risks and complications while still providing valuable diagnostic and prognostic insights (Table 2). A systematic review of 21 studies (306,633 patients) found that noninvasive liver disease biomarkers, including the FIB-4, nonalcoholic fatty liver disease fibrosis score, and aspartate aminotransferase–to–platelet ratio index, correlate with increased CKD incidence.¹⁸ In the general population, the fatty liver index, a simple and noninvasive predictor of MASLD, has been shown to predict CKD risk in a 10-year follow-up study from Japan.^12,18

Table 2.

Predictive utility of non-invasive liver fibrosis markers for CKD risk in MASLD

Fibrosis marker	Risk of incident CKD	Comments
FIB-4	High FIB-4 score increases risk. OR: 2.51, 95% CI: 1.87–3.37 Higher FIB-4 (> 2.67) vs. lower FIB-4 (< 1.30)- OR: 3.53, 95% CI: 2.12–5.90	Regression analysis influenced by hypertension, MASLD, and BMI
NFS	High NFS increases risk. OR: 2.49, 95% CI: 1.89–3.30 Higher NFS score (> 0.676) vs. lower NFS score (< −1.455). OR: 3.43, 95% CI: 2.06–5.72	--
APRI	High APRI score (≥ 0.5) vs. low APRI (< 0.5). OR: 1.40, 95% CI: 1.14–1.72	--

APRI, aspartate aminotransferase–to-platelet ratio index; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; FIB-4, fibrosis-4 index; MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, nonalcoholic fatty liver disease; NFS- NAFLD fibrosis score; OR, odds ratio.

A recent Chinese study on 68 patients with MASLD with paired liver biopsies introduced qFibrosis, an AI-based parameter derived from 184 fibrosis markers. Over a 23-month follow-up, a 20% relative increase in qFibrosis correlated with eGFR decline. Notably, fibrosis changes in the central vein and pericentral regions were more strongly linked to eGFR decline than other areas.¹⁹

Bidirectional Screening Strategies: Identifying MASLD in CKD and CKD in MASLD

Given the substantial overlap in risk factors, screening for MASLD in patients with CKD represents an important but currently underexplored opportunity. MASLD should be suspected in individuals with any one of the following: hepatic steatosis on imaging, unexplained elevations in aspartate aminotransferase or alanine aminotransferase, ≥2 metabolic risk factors (obesity, dyslipidemia, type 2 DM [T2DM], hypertension), or a first-degree relative with MASLD cirrhosis.²⁰ Although no formal guidelines exist, a practical approach is to incorporate liver ultrasound during routine CKD evaluations to detect steatosis, with referral to gastroenterology for staging when fatty changes are identified. This is particularly relevant because disease-modifying therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and novel agents such as Resmetirom, have shown potential to reverse liver injury when initiated early, ultimately improving outcomes in this high-risk population.

Conversely, screening for CKD in patients with MASLD is essential to identify high-risk individuals who may benefit from early intervention and closer monitoring. Routine CKD screening in MASLD involves measuring serum creatinine to estimate GFR and assessing urine albumin levels to detect albuminuria. In individuals with extreme high or low muscle mass, serum cystatin C can provide a more accurate GFR estimation. CKD is defined as an eGFR < 60 ml/min per 1.73 m² using the 2021 CKD-Epidemiology formula, with a combined creatinine-cystatin C equation offering superior accuracy when cystatin C is used.² Albuminuria, classified by a urine ACR as A1 (< 30 mg/g), A2 (30–300 mg/g), and A3 (≥ 300 mg/g), is strongly associated with CKD progression and increased cardiovascular risk. Annual eGFR and ACR monitoring is reasonable for all patients with MASLD given their approximately 40% higher risk of CKD, with more frequent testing (every 6 months) warranted in advanced liver disease or progressive fibrosis.²¹ Fibrosis scores such as FIB-4 or nonalcoholic fatty liver disease fibrosis score can guide follow-up intensity, whereas the kidney failure risk equation—using age, sex, eGFR, and ACR—helps predict 2- and 5-year kidney failure risk, informing nephrology referral when the 5-year risk exceeds 5%, as recommended by UK NICE guidelines.²² Identifying high-risk individuals using the kidney failure risk equation enables timely initiation of risk-modifying therapies to slow disease progression and reduce complications (Figure 2).

Figure 2.

Figure showing proposed CKD screening for patients with MASLD. eGFR, estimated glomerular filtration rate; KFRE, kidney failure risk equation; RAASi, renin angiotensin aldosterone inhibitors; SGLT2i, sodium-glucose cotransporter-2 inhibitor; ∗∗∗/ˆˆ Combined creatinine and cystatin C eGFR in patients with very low or very high muscle mass.

Therapeutic Approaches for Managing MASLD and CKD

Lifestyle Interventions

A recent systematic review of 7 international guidelines highlights lifestyle modifications as the cornerstone for managing MASLD.²³ Although high-quality long-term evidence on their efficacy remains limited, all major guidelines advocate structured diet and exercise programs to achieve weight loss, which is the primary driver of hepatic fat reduction and fibrosis regression. For individuals with overweight or obesity, a 7% to 10% weight loss is recommended, whereas nonobese patients benefit from a more modest 3% to 5% weight loss, leading to a 30% to 40% reduction in intrahepatic fat content and approximately 45% improvement in hepatic fibrosis scores.^23,24

Despite a lack of head-to-head trials comparing specific diets, available data suggest that reducing saturated fat, refined carbohydrates, and processed meats significantly lowers hepatic steatosis and insulin resistance.23, 24, 25 A calorie-restricted diet (1500–1800 kcal/d for men and 1200–1500 kcal/d for women) combined with adherence to the Mediterranean diet has been linked to a 24% reduction in cardiovascular disease risk and a 20% to 30% improvement in metabolic parameters.²⁶ This dietary approach is particularly effective because of its antiinflammatory properties and high unsaturated fat content from extra virgin olive oil, nuts, and fatty fish.

For patients with CKD, a small randomized crossover trial in stages 3 to 4 found that the Mediterranean diet led to a 15% improvement in serum CO₂ levels, a 20% reduction in sodium intake, and stable potassium levels, suggesting its safety and efficacy.²⁷ The 2020 KDOQI guidelines recommend Mediterranean diet for patients with CKD across all stages, because it has been shown to lower blood pressure, reduce lipid abnormalities, and decrease net acid production.²⁸ Other validated dietary approaches, including the Japanese diet, Dietary Approaches to Stop Hypertension, and the National Cholesterol Education Program, have demonstrated similar metabolic benefits.^24,29,30 Plant-based diets—rich in fruits, vegetables, whole grains, and low-fat dairy—help mitigate hypertension, diabetes, and obesity, slow eGFR decline, reduce proteinuria and metabolic acidosis, and improve quality-of-life measures, collectively supporting their role in delaying CKD progression. A plant-based diet is rich in antiinflammatory nutrients, fiber, and phytochemicals, and has been shown to reduce proteinuria and decrease metabolic acidosis.^31,32

Physical activity is another critical component of MASLD and CKD management. Regular aerobic and resistance training (≥ 30 minutes, 3–5 times/wk) is associated with a 35% reduction in hepatic fat accumulation and a 50% improvement in insulin sensitivity.³³ Although data on exercise in CKD remains limited, a meta-analysis of 13 randomized controlled trials (RCTs) involving 421 patients with nondialysis CKD found that structured exercise therapy improved eGFR (mean difference: 2.62 ml/min per 1.73 m²), reduced systolic and diastolic blood pressure (systolic blood pressure reduction by 5.8 mm Hg, diastolic blood pressure reduction by 2.5 mm Hg), and decreased body mass index by 2.1 kg/m².³⁴

In addition, a low sodium intake (< 2 g/d or < 90 mmol/d) is widely recommended for patients with CKD and MASLD, because it lowers blood pressure and albuminuria by up to 30%.³⁵ Protein restriction (0.8 g/kg/d) is advised in CKD stages G3 to G5, because studies have shown that high-protein diets accelerate kidney function decline by 20% to 30% over 5 years, while moderate protein intake preserves kidney function and reduces uremic toxin production.³⁶

Current and Emerging Pharmacologic Strategies for MASLD and CKD

Sodium-Glucose Cotransporter-2 Inhibitors

Preclinical studies in MASH models have shown that sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy reduces intrahepatic fat accumulation by 40% to 50%, suppresses inflammatory signaling through NF-κB and TGF-β pathways, and decreases hepatic fibrosis progression via downregulation of profibrotic genes (Table 3). Clinical data in MASLD further support these findings. In a case-control study of patients with T2DM and MASLD, SGLT2i use was associated with a 22% reduction in major adverse cardiovascular events (HR: 0.78, 95% CI: 0.70–0.87), a 17% reduction in liver fibrosis progression (HR: 0.83, 95% CI: 0.75–0.91), and significant improvements in FIB-4 and aspartate aminotransferase–to–platelet ratio index scores.³⁷ A pooled meta-analysis of 5 phase 3 trials of luseogliflozin demonstrated a 15% to 20% reduction in the fatty liver index and improved Hepamet Fibrosis Scores in diabetic Japanese patients with alanine aminotransferase > 30 and FIB-4 index >1.3.³⁸ In an RCT comparing tofogliflozin with glimepiride, 48-week therapy with SGLT2i led to histological improvement in steatosis, hepatocellular ballooning, and lobular inflammation, alongside downregulation of proinflammatory and fibrogenic genes.³⁹ MRI-based studies have similarly shown a 20% to 25% reduction in hepatic fat fraction after 24 weeks of SGLT2i treatment in patients with MASLD and T2DM.⁴⁰ Retrospective data indicate a lower risk of liver cirrhosis (HR: 0.80, 95% CI: 0.76–0.84), cardiovascular disease (HR: 0.82, 95% CI: 0.79–0.85) and CKD (HR: 0.66, 95% CI: 0.62–0.70) among patients with diabetic MASLD using SGLT2i compared with other glucose-lowering drugs.⁴¹

Table 3.

Table showing therapeutic role of SGLT2 inhibitors, GLP-1 receptor agonists, RAAS inhibitors, and MRAs in CKD and MASLD

Medication class	Indications in CKD	Benefits in CKD and MASLD	Key clinical points (side effects / monitoring)
SGLT2 inhibitors	Diabetic kidney disease; proteinuric CKD with eGFR ≥ 20 ml/min per 1.73 m2	Slows CKD progression, reduces albuminuria; decreases hepatic steatosis and inflammation	Risk of genital mycotic infections, volume depletion, and rare euglycemic ketoacidosis; monitor kidney function, especially with diuretic use
GLP-1 receptor agonists	Diabetes with ASCVD risk; obesity in CKD	Promotes weight loss, improves glycemic control; reduces liver fat and improves aminotransferases	GI symptoms (nausea, vomiting), contraindicated in gastroparesis; some agents require subcutaneous administration, which may affect adherence
RAAS inhibitors (ACEi/ARB)	Hypertension, proteinuric CKD, heart failure	Reduces proteinuria, slows CKD progression; improves insulin sensitivity, potentially mitigating MASLD progression	Monitor for hyperkalemia, AKI, and cough (with ACEi); routine serum creatinine and potassium monitoring recommended, especially after initiation or dose escalation
MRAs (spironolactone, eplerenone, finerenone)	Resistant hypertension; Proteinuric CKD; Heart failure with reduced ejection fraction	Reduce proteinuria, antiinflammatory and antifibrotic effects; finerenone shown to improve kidney and CV outcomes in DKD; may reduce hepatic fibrosis in MASLD	Risk of hyperkalemia, especially with impaired kidney function or concurrent RAAS inhibitors; monitor potassium and kidney function closely; endocrine side effects with spironolactone (e.g., gynecomastia)

ACEi, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV cardiovascular; DKD, diabetic kidney disease; GLP-1, glucagon-like peptide-1; MASLD, metabolic dysfunction–associated steatotic liver disease; MRAs, mineralocorticoid receptor antagonists; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose cotransporter-2.

SGLT2i improve MASLD through several interrelated metabolic and molecular pathways. By promoting kidney glucose excretion, they induce a negative energy balance that leads to modest weight loss of approximately 2 to 4 kg and a consequent reduction in hepatic fat deposition.⁴² Enhanced lipolysis mediated by zinc-alpha-2-glycoprotein activation further stimulates the cyclic adenosine monophosphate pathway, facilitating lipid mobilization and hepatic fat clearance.^43,44 In addition, SGLT2i promote ketogenesis through upregulation of 3-hydroxybutyrate dehydrogenase 1, increasing β-hydroxybutyrate levels that inhibit interferon regulatory factor-4, thereby reducing hepatic CD8⁺ T-cell infiltration and inflammation.⁴⁵ In addition, they suppress hepatic gluconeogenesis and glycogenolysis, lowering hepatic glucose output and limiting glucose-driven lipogenesis and oxidative stress.^43,44

SGLT2i are well-established for their nephroprotective effects, with multiple RCTs and meta-analyses showing delayed CKD progression, reduced albuminuria, and lower cardiovascular mortality in patients with and without diabetes. These benefits extend to patients with an eGFR ≥ 20 ml/min per 1.73 m², which is now considered the threshold for initiating therapy. The CREDENCE trial was the first dedicated CKD study assessing canagliflozin in patients with T2DM and albuminuric CKD (eGFR: 30–90 ml/min per 1.73 m², urine ACR > 300 mg/g), demonstrating a 30% reduction in composite kidney outcomes (HR: 0.70, 95% CI: 0.59–0.82) and lower cardiovascular death and heart failure hospitalization (HR: 0.69, 95% CI: 0.57–0.83).⁴⁶ The DAPA-CKD trial evaluated dapagliflozin in patients with CKD with and without diabetes and reported a 39% reduction in kidney failure progression (HR: 0.61, 95% CI: 0.51–0.72) and a 28% reduction in all-cause mortality (HR: 0.71, 95% CI: 0.55–0.92), with consistent benefits in patients with nondiabetic CKD.⁴⁷ Similarly, the EMPA-KIDNEY trial demonstrated a 28% reduction in kidney disease progression (HR: 0.72, 95% CI: 0.64–0.82) and lower cardiovascular mortality and heart failure hospitalization across a broad CKD spectrum (eGFR ≥ 20 ml/min per 1.73 m², with and without albuminuria).⁴⁸ A recent meta-analysis of 10 trials showed that SGLT2i significantly reduced CKD progression, serious AKI, and kidney failure, with consistent benefits across eGFR and albuminuria levels in both diabetic and non-diabetic patients.⁴⁹

The nephroprotective mechanisms of SGLT2i include restoration of tubuloglomerular feedback to reduce glomerular hyperfiltration, a 30% to 40% decline in albuminuria, attenuation of oxidative stress and inflammation to prevent tubulointerstitial fibrosis, and improved hemodynamics through reductions in systolic blood pressure (∼4–6 mm Hg) and extracellular fluid overload. These agents are initiated at eGFR ≥ 20 ml/min per 1.73 m² and are generally well-tolerated, though clinicians should monitor genital tract infections and rare cases of euglycemic ketoacidosis. A recent population-based cohort study showed a similar risk of urinary tract infections after 1 year of treatment among SGLT2i and GLP-1RA initiators, although the risk of mycotic genital infections was 3-fold higher in SGLT2i during the first year after drug initiation.⁵⁰ Patients are advised to withhold therapy 3 to 4 days before major surgery or prolonged fasting to minimize ketoacidosis risk. An initial decline in eGFR of approximately 3 to 5 ml/min per 1.73 m² is commonly observed after initiation of SGLT2i therapy and reflects a hemodynamic adjustment rather than true kidney injury. This reduction, typically acceptable if within 30% of baseline, often stabilizes over time; to mitigate excessive volume depletion, concurrent diuretic therapy may be reduced or temporarily withheld as clinically appropriate when initiating therapy with SGLT2i.

GLP-1RAs in MASLD and CKD

In a large US national cohort study, GLP-1RAs significantly reduced the risk of cirrhosis development (HR: 0.86, 95% CI: 0.75–0.98), hepatic decompensation (HR: 0.75, 95% CI: 0.55–1.01), hepatocellular carcinoma (HR: 0.89, 95% CI: 0.40–2.01), and all-cause mortality (HR: 0.89, 95% CI: 0.81–0.98) in patients with MASLD and diabetes.⁵¹ Importantly, the benefits were most pronounced with semaglutide, which showed a greater reduction in MASLD progression than dulaglutide and liraglutide. Notably, no significant benefit was observed in patients with cirrhosis, reinforcing the need for early intervention in MASLD before significant fibrosis or cirrhosis develops. Histological studies have further validated GLP-1RA–induced MASH resolution. In an RCT, liraglutide demonstrated a significant improvement in MASH resolution (39% vs. 9% with placebo).⁵² Similarly, semaglutide led to MASH resolution in 36% to 59% of patients, compared with 17% in placebo groups, while reducing hepatic steatosis, lobular inflammation, and hepatocellular ballooning.⁵³

In addition to hepatic benefits, GLP-1RAs have consistently demonstrated cardiovascular protection in high-risk populations, particularly those with MASLD and T2DM. A meta-analysis of major GLP-1RA cardiovascular outcomes trials including studies on liraglutide, semaglutide, albiglutide, and dulaglutide, found that GLP-1RA therapy was associated with a 12% to 26% reduction in major adverse cardiovascular events (HR: 0.74–0.88).⁵⁴ Dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists, such as tirzepatide, have shown even greater metabolic and cardiovascular improvements. In the SURPASS-3 MRI trial, tirzepatide led to a 26.5% absolute reduction in liver fat content and significant decreases in visceral and ectopic fat stores.⁵⁵ The next-generation triple GLP-1/glucose-dependent insulinotropic polypeptide/glucagon receptor coagonist, retatrutide, has demonstrated additional lipid and blood pressure-lowering effects, further supporting its therapeutic role in MASLD and CKD.⁵⁶

These drugs provide direct kidney protection through anti-inflammatory effects, improvement of endothelial function, and reduction of albuminuria. A meta-analysis of 6 clinical trials demonstrated a 25% lower risk of kidney failure with GLP-1RA therapy (HR: 0.75, 95% CI: 0.68–0.83).⁵⁷ Two major trials have strengthened the evidence base for their use in CKD (Table 4). The FLOW trial, a phase 3 study of semaglutide in patients with and without diabetes, showed a 22% reduction in the composite end point of kidney failure, ≥50% eGFR decline, or major cardiovascular events.⁵⁹ Similarly, the SELECT trial in obese patients with cardiovascular disease found that semaglutide significantly reduced eGFR decline and slowed CKD progression, effects that appeared independent of weight loss.⁵⁸ These findings reinforce GLP-1RAs as effective therapies for high-risk patients with MASLD, CKD, and T2DM. The most common side effects of GLP-1 receptor agonists include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which are typically dose-dependent and transient; rarely, these agents have been associated with pancreatitis and, in isolated reports, medullary thyroid carcinoma. No dosage adjustments are necessary in patients with kidney dysfunction.

Table 4.

Table comparing the salient features of Select and Flow trials

	SELECT trial58	FLOW trial59
Population	Aged ≥ 45 yrs, pre-existing CV disease, BMI ≥ 27 kg/m2, nondiabetics	Type 2 diabetes mellitus, CKD: eGFR of 50–75 ml/min per 1.73 m2 and urine ACR of 300–5000 mg/g or eGFR of 25 to < 50 ml/min per 1.73 m2 and urine ACR > 100 and < 5000 mg/g
Intervention	Once-weekly subcutaneous semaglutide 2.4 mg or placebo	Once-weekly subcutaneous semaglutide 1 mg or placebo
Outcome Definitions	Primary CV end point was composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke	Major kidney disease event: composite of the onset of kidney failure (dialysis, transplantation, or an eGFR < 15 ml/min per 1.73 m2), ≥ 50% reduction in the eGFR from baseline, (or) death from kidney-related or CV causes
Effect Sizes	Decreased risk of outcome among users of semaglutide; HR: 0.80; 95% CI: 0.72–0.90	Decreased risk of outcome among users of semaglutide; HR: 0.79; 95% CI: 0.66–0.88
Comments	Among users of Semaglutide, the incidence of the prespecified main composite kidney end point (death from kidney disease, initiation of CKRT, onset of persistent eGFR < 15 ml/min per 1.73 m2, persistent ≥ 50% reduction in eGFR or onset of persistent macroalbuminuria) was lower (HR: 0.78; 95% CI: 0.63–0.96)58	Among users of Semaglutide, there was a lower rate of eGFR decline (HR: 0.82; 95% CI: 0.68–0.98) and all-cause mortality (HR: 0.80; 95% CI: 0.67–0.95)

ACR, albumin-to-creatinine ratio; BMI, body mass index; CI, confidence interval; CV, cardiovascular; BMI, body mass index; CKRT, continuous kidney replacement therapy; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio.

Mineralocorticoid Receptor Antagonists in MASLD and CKD

The RAAS is a key driver of insulin resistance, inflammation, and fibrosis in metabolic disorders, including MASLD. Experimental studies in mouse models have demonstrated that mineralocorticoid receptor antagonists (MRAs), such as eplerenone and spironolactone, significantly attenuate macrovesicular steatosis and hepatic fibrosis induced by high-fat and high-fructose diets.^60,61 These agents have been shown to reduce hepatic lipid accumulation, suppress inflammatory cytokines, and prevent fibrosis progression, suggesting potential therapeutic benefits in MASLD. However, clinical data in humans remain limited, and prospective RCTs are needed. Beyond liver disease, MRAs have well-established benefits in heart failure and CKD. They have demonstrated significant reductions in heart failure–related mortality and hospitalizations in patients with HFrEF and HFpEF. Finerenone, a nonsteroidal MRA, has shown superior cardio-renal benefits with a lower risk of hyperkalemia compared with spironolactone and is approved for eGFR ≥ 25 ml/min per 1.73 m².^62,63 In the FIDELIO-DKD and FIGARO-DKD trials, finerenone reduced the risk of kidney failure and cardiovascular mortality by 18% (HR: 0.82, 95% CI: 0.72–0.92) in patients with CKD and T2DM.^64,65 A pooled analysis of these studies (FIDELITY analysis) further confirmed that finerenone improved kidney outcomes (HR: 0.77, 95% CI: 0.67–0.88) and reduced albuminuria by approximately 30%.⁶⁶ In a large real-world cohort of patients with heart failure, nonsteroidal MRA (e.g., finerenone) was associated with significantly improved 1-year outcomes, including lower mortality, hospitalization, and worsening heart failure, compared with steroidal MRAs, without increased safety risk.⁶⁷ Steroidal MRAs (spironolactone and eplerenone) commonly cause hyperkalemia, gynecomastia, and menstrual irregularities because of nonselective hormonal effects, whereas nonsteroidal agents such as finerenone exhibit a lower risk of endocrine adverse effects while retaining the potential for mild hyperkalemia. In the CONFIDENCE study, patients with T2DM, eGFR of 30 to 90 ml/min per 1.73 m², and albuminuria (100 to < 5000 mg/g) on RAAS blockade were randomized to finerenone, empagliflozin (10 mg/d), or their combination. After 6 months, combination therapy achieved a 29% to 32% greater reduction in urinary ACR than either drug alone and produced a 7.4 mm Hg systolic blood pressure drop—over twice that observed with monotherapy—without an increase in serious adverse events leading to discontinuation.⁶⁸

RAAS inhibitors

RAAS inhibitors (RAASi), including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, have demonstrated therapeutic benefits in MASLD and CKD. In animal studies, RAASi have shown promise in reducing liver fibrosis, fat accumulation, and necroinflammation.⁶⁹ However, human studies present mixed results. A nested case-control study did not find an overall association between RAASi use and reduced MASLD development or progression but suggested potential benefits in specific subgroups, such as individuals with obesity.⁷⁰ Currently, no RCTs have conclusively established the efficacy of RAASi in treating MASLD in humans.

RAASi are cornerstone therapies in managing CKD because of their kidney protective effects.⁷¹ They effectively reduce proteinuria, slow kidney function decline, and prevent kidney fibrosis, thereby delaying the progression to end-stage kidney disease.⁷² A meta-analysis highlighted that RAAS blockade therapy for ≥ 1 year can prevent CKD progression to end-stage renal disease and reduce premature mortality.⁷³ In patients with advanced CKD, RAASi have been associated with a reduced risk of kidney failure requiring treatment compared with placebo or non-RAASi antihypertensive agents over a median follow-up of 34 months.⁷⁴ However, clinicians should monitor for potential adverse effects, such as hyperkalemia, which occurs in approximately 9.2% of RAASi-treated patients, with a 3-fold higher incidence in those with stage 4 and 5 CKD than in patients with a eGFR > 60 ml/min per 1.73 m².⁷⁵ In summary, though RAASi are well-established in managing CKD across the entire eGFR spectrum, their role in MASLD requires further investigation through well-designed clinical trials to elucidate their potential benefits and risks in this context.

Bariatric Surgery in MASLD and CKD

Bariatric surgery has emerged as a promising intervention for MASLD resolution. A multicenter RCT demonstrated higher histologic resolution rates of MASH with Roux-en-Y gastric bypass and sleeve gastrectomy (56%–57%) compared with lifestyle interventions (16.5%).⁷⁶ Furthermore, long-term data from the Swedish Obese Subjects Study revealed a 78.5% reduction in albuminuria and lower risk of CKD progression following bariatric surgery.^77,78

Gut Microbiome Modulation and Probiotics

The gut microbiota is increasingly recognized as a key driver of both MASLD and CKD, with dysbiosis influencing inflammation, metabolic dysfunction, and disease progression in each condition. Disturbances in gut microbial composition can disrupt the gut–liver axis in MASLD, increasing intestinal permeability, systemic inflammation, and hepatic fat accumulation, ultimately accelerating the transition from steatosis to steatohepatitis and fibrosis.⁷⁹ Early therapeutic strategies such as probiotics, prebiotics, synbiotics, and fecal microbiota transplantation have shown encouraging effects, including improvements in liver enzymes, steatosis, and liver stiffness in MASLD, particularly with Lactobacillus- and Bifidobacterium-based formulations.80, 81, 82 Although still experimental, fecal microbiota transplantation has demonstrated potential benefits in restoring microbial balance and improving liver histology.^80,81

Gut dysbiosis in CKD similarly fosters the generation of uremic toxins, systemic inflammation, and progressive renal impairment.⁸³ Microbiome-directed interventions may mitigate these pathways, with probiotics reducing toxin levels such as indoxyl sulfate and p-cresyl sulfate, and prebiotics promoting short-chain fatty acid–producing bacteria that support gut and immune health.^83,84 Synbiotics may enhance these effects, and dietary fiber has also been shown to improve microbial composition and inflammatory profiles. Despite promising early data, the use of microbiome-targeted therapies in MASLD and CKD remains exploratory, underscoring the need for larger trials to clarify optimal strains, dosing, duration, and long-term safety.^80,81,84,85

Emerging Therapies Targeting Lipid Metabolism

Dysregulation of lipid metabolism plays a pivotal role in the pathogenesis and progression of both MASLD and CKD, making it a key therapeutic target. Among emerging strategies, thyroid hormone receptor-β (THR-β) agonists such as Resmetirom have shown promise by selectively enhancing hepatic lipid oxidation and suppressing lipogenesis, leading to significant reductions in liver fat content and improvements in liver histology.^86,87 Another class under investigation is farnesoid X receptor agonists, including obeticholic acid, which modulate bile acid signaling, regulate lipid metabolism, and exert antiinflammatory effects. Clinical trials have demonstrated that farnesoid X receptor agonists can reduce hepatic steatosis and fibrosis, offering potential benefits for patients with MASLD.⁸⁸

Resmetirom received accelerated US Food and Drug Administration (FDA) approval in March 2024 for treating MASH with moderate to advanced fibrosis (F2–F3) in patients with eGFR ≥ 45 ml/min per 1.73 m². In the MAESTRO-NASH trial, resmetirom achieved both primary endpoints—resolution of steatohepatitis without worsening fibrosis (26%–30% vs. 10% with placebo) and fibrosis improvement without worsening steatohepatitis (24%–26% vs. 14%).⁸⁶ The US FDA label does not require a liver biopsy; patient selection relies on noninvasive liver disease assessment–based evidence of steatosis and fibrosis among individuals with cardiometabolic risk factors and minimal alcohol intake (< 20 g/d for women, < 30 g/d for men). Imaging modalities such as vibration-controlled transient elastography (LSM: 8–15 kPa), or magnetic resonance elastography (LSM: 3.1–4.4 kPa) may guide diagnosis. Resmetirom can be used with statins—up to atorvastatin 40 mg, pravastatin 40 mg, rosuvastatin 20 mg, or simvastatin 20 mg daily. Together, these agents represent a promising frontier in tackling lipid dysregulation and fibrogenesis in MASLD and CKD, though ongoing studies are needed to better define their long-term efficacy and safety.

The Role of a Metabolic Clinic in Managing High-Risk Patients with Cardiometabolic and Kidney Disorders

A metabolic clinic provides a specialized, multidisciplinary setting for the early identification and integrated management of patients with overlapping metabolic, cardiovascular, and kidney disorders such as HTN, DM, obesity, MASLD, obstructive sleep apnea, and CKD (Figure 3). By centralizing care, these clinics enable early detection of metabolic dysfunction and end-organ injury through comprehensive evaluations that may include cardiac, kidney, hepatic, and sleep assessments. Patients with cardiovascular-kidney-metabolic syndrome stages 3 and 4 are ideal candidates for referral, because early and coordinated interventions can prevent progression to advanced organ damage and reduce long-term healthcare costs.

Figure 3.

Figure showing the referral criteria and flow of metabolic clinic. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; Cr, creatinine; eGFR, estimated glomerular filtration rate; EKG, electrocardiogram; HbA1C, hemoglobin A1c; liver US, liver ultrasound; MASLD, metabolic dysfunction associated liver disease; OSA, obstructive sleep apnea; TTE, transthoracic echocardiogram; urine ACR, urine albumin:creatinine ratio.

Management within a metabolic clinic relies on a team-based approach led by internal medicine physicians and supported by nephrology, cardiology, endocrinology, hepatology, and sleep specialists. Advanced testing such as echocardiography, FibroScan, renin–aldosterone profiling, and Lp(a) measurement, helps refine risk stratification and guide therapy. Implementation of guideline-directed medical treatment targeting heart, liver, kidney, and metabolic pathways ensures holistic, evidence-based care. This model not only streamlines patient experience by reducing fragmented referrals but also promotes better long-term outcomes across interconnected cardiometabolic systems.

Summary

This review underscores the complex bidirectional relationship between MASLD and CKD, emphasizing shared metabolic, hemodynamic, and inflammatory pathways that drive disease progression. Early recognition and integrated management strategies are essential to mitigate kidney and cardiovascular risk. Advances in pharmacotherapy, noninvasive diagnostics, and multidisciplinary care models hold promise for improving outcomes in this high-risk population.

Disclosure

GG received grants from NIH/ NIDDK, NIH/ NIAID, and Merck; consulting fees from CareDx, Natera, Eurofins-Viracor, Mallinckrodt, Novartis; Payment for CareDx, and Alexion. AS received grants from Stravitz-Sanyal Institute for Liver Disease; Elsevier and Wolter Kluwersas royalty for Zakim and Boyers Textbook Hepatology, and UptoDate; consulting fees from Genfit, Akero therapeutics, Novo Nordisk, Zydus, Histoindex, Alnylam, Regeneron, Merck, Eli Lilly, Salix, Poxel, Hanmi, 89Bio, Pliant, Chemomab, Boston Pharma, Glazo Smith Kline, AstraZeneca, Boehringer Ingelhiem, Inventia, Path AI, Genentech, Amgen, Metadeq, Myovant, Avant Sante, Resolution Therapeutics; DSM of Corcept; Chair of Liver Forum; stocks with Rivus, Tiziana, Durect, Inversago. All the other authors declared no competing interests.

Supplementary Material

Supplementary File (PDF)

Supplementary References. Figure S1. Figure illustrating the eGFR based cut-off for initiating risk modifying drugs in MASLD and CKD. Table S1. List of longitudinal studies describing association of MASLD with CKD. Table S2. List of retrospective studies describing association of MASLD with CKD.