Aggregate risk score based on markers of hepatic steatosis, systemic inflammation, and renal stress to predict MACE across the CKM spectrum

Q: What are the key findings of this study?

Having ≥2 elevated biomarkers (FLI, CysC, hsCRP) predicted higher MACE risk across CKM stages, with a 1.95-fold higher risk in Stage 0 (95% CI 1.45-2.61).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0–3 (n=382797). Intervention: High-Risk biomarker profile (≥2 elevated biomarkers: Fatty Liver Index, Cystatin C, hsCRP) vs. Low-Risk group (0–1 elevated biomarker). Primary outcome: Incident Major Adverse Cardiovascular Events (MACE) (HR 1.95, 95% CI 1.45-2.61).

Q: What does this research mean for the field?

An aggregate risk score combining elevated Fatty Liver Index, Cystatin C, and hsCRP independently predicts major adverse cardiovascular events across all CKM stages, with the highest relative risk in stage 0 individuals. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

B Zhang; C Zhao; R Ran; S Chen; Z Lian; M Liu; X Zheng; Tao Shi; Y Li; D Wang; W Cai; Y Yan; G Li

doi:10.1093/eurheartj/ehag785.3316

October 1, 2026European Heart JournalOpen Access

Aggregate risk score based on markers of hepatic steatosis, systemic inflammation, and renal stress to predict MACE across the CKM spectrum

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Key result

Multiple elevated biomarkers linked to ~95% higher MACE risk across CKM stages.

HR 1.95
95% CI 1.45-2.61
n=382,797

Why the study?

The stage-specific evolution of risk drivers in Cardiovascular-Kidney-Metabolic (CKM) syndrome remains underexplored, prompting evaluation of the comparative and cumulative prognostic value of Fatty Liver Index (FLI), Cystatin C (CysC), and hsCRP for MACE across CKM stages 0-3.

Does an aggregate risk score of ≥2 elevated biomarkers (Fatty Liver Index, Cystatin C, and hsCRP) predict incident MACE across Cardiovascular-Kidney-Metabolic (CKM) stages 0–3 compared to having 0–1 elevated biomarkers?

Key Points

To evaluate the individual and combined prognostic ability of markers for fatty liver, kidney stress, and systemic inflammation to predict major adverse cardiovascular events across stages 0 to 3 of cardiovascular-kidney-metabolic syndrome.
Analyzed 382,797 participants from the UK Biobank categorized into CKM stages 0–3 over a median follow-up of 15.2 years.
Evaluated incident major adverse cardiovascular events (MACE) using multivariable Cox proportional hazards models adjusted for established clinical risk factors.
Applied a cumulative risk strategy classifying participants as high risk (≥2 elevated biomarkers among FLI, CysC, and hsCRP) versus low risk (0–1 elevated biomarkers) and assessed discrimination via C-index.
High biomarker risk showed a significant interaction across CKM stages (P for interaction = 0.022), conferring the highest relative risk in stage 0 for MACE (HR 1.95, 95% CI 1.45–2.61) and cardiovascular death (HR 2.28, 95% CI 1.28–4.06).
The categorical biomarker model fit the data significantly better than a linear model (Chi-square 17,396.04 vs. 17,269.82; P < 0.001).
Adding the cumulative biomarker score to the standard clinical risk model improved discrimination from a C-index of 0.717 to 0.730.

Study Design

Type

Cohort (n=382,797)

Multicenter

Yes

Structured PICO

Does an aggregate risk score of ≥2 elevated biomarkers (Fatty Liver Index, Cystatin C, and hsCRP) predict incident MACE across Cardiovascular-Kidney-Metabolic (CKM) stages 0–3 compared to having 0–1 elevated biomarkers?

P

Population

382,797 UK Biobank participants classified into CKM stages 0–3 followed for a median of 15.2 years.

E

Exposure

High-Risk cumulative biomarker category (≥2 elevated biomarkers among Fatty Liver Index [FLI], Cystatin C [CysC], and high-sensitivity C-reactive protein [hsCRP])

C

Comparator

Low-Risk cumulative biomarker category (0–1 elevated biomarker among FLI, CysC, and hsCRP)

O

Outcome

Incident Major Adverse Cardiovascular Events (MACE) over a median follow-up of 15.2 yearscomposite

Main Result

Hazard Ratio: 1.95 (95% CI 1.45–2.61)

Implication

An aggregate biomarker score integrating hepatic steatosis (FLI), renal stress (CysC), and systemic inflammation (hsCRP) improves MACE risk discrimination across CKM stages 0–3, particularly unmasking residual risk in Stage 0 and 1 individuals.

Abstract

Background The stage-specific evolution of risk drivers in Cardiovascular-Kidney-Metabolic (CKM) syndrome remains underexplored. This study evaluated the comparative and cumulative prognostic value of Fatty Liver Index (FLI), Cystatin C (CysC), and high-sensitivity C-reactive protein (hsCRP) for Major Adverse Cardiovascular Events (MACE) across CKM stages 0–3. Methods We analyzed 382,797 participants from the UK Biobank classified into CKM stages 0–3. Multivariable Cox proportional hazards models were used to assess the risk of incident MACE associated with the three biomarkers. The primary analysis employed a binary cumulative risk strategy, categorizing participants into High-Risk (≥2 elevated biomarkers) and Low-Risk (0–1 factor) groups. Survival analyses were performed with models adjusted for established risk factors. Model discrimination was evaluated using the C-index. Results Over a median follow-up of 15.2 years, elevated FLI, CysC, and hsCRP were independently associated with MACE across all CKM stages. The categorical model provided a superior fit compared to the linear model (Chi-square 17,396.04 vs. 17,269.82; P < 0.001). Significant interactions were observed between the binary risk strategy and CKM stages (P for interaction = 0.022), with the highest relative risk observed in the early stages. In Stage 0, high-risk individuals faced a 1.95-fold higher risk of MACE (95% CI 1.45–2.61) and a 2.28-fold higher risk of cardiovascular death (95% CI 1.28–4.06). Adding the cumulative risk strategy to the clinical model improved the C-index from 0.717 to 0.730. Conclusion An aggregate score based on FLI, CysC, and hsCRP is a potent, stage-dependent predictor of future MACE risk across the CKM spectrum. By unmasking residual risk in seemingly low-risk Stage 0 and 1 populations, this strategy provides a critical window for biomarker-guided primordial prevention.Figure 1Figure 2

Discussion

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Cite This Study

Zhang et al. (2026) conducted a cohort in Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0–3 (n=382,797). High-Risk biomarker profile (≥2 elevated biomarkers: Fatty Liver Index, Cystatin C, hsCRP) vs. Low-Risk group (0–1 elevated biomarker) was evaluated on Incident Major Adverse Cardiovascular Events (MACE) (HR 1.95, 95% CI 1.45-2.61). Having ≥2 elevated biomarkers (FLI, CysC, hsCRP) predicted higher MACE risk across CKM stages, with a 1.95-fold higher risk in Stage 0 (95% CI 1.45-2.61).

synapsesocial.com/papers/6ae13d9e043bfbd635332cea https://doi.org/10.1093/eurheartj/ehag785.3316

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Aggregate risk score based on markers of hepatic steatosis, systemic inflammation, and renal stress to predict MACE across the CKM spectrum

Key Points

Study Design

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Aggregate risk score based on markers of hepatic steatosis, systemic inflammation, and renal stress to predict MACE across the CKM spectrum

Key Points

Study Design

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

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