Abstract
Background Cardiovascular-kidney-metabolic (CKM) syndrome is staged to reflect increasing cardiometabolic risk. Substantial heterogeneity exists within stage 2, which includes individuals with metabolic risk factors or chronic kidney disease (CKD) without established cardiovascular disease and affect nearly half of US adults. This study aimed to develop and validate a sex-specific, clinically pragmatic model to subdivide CKM stage 2 into lower-risk (stage 2a) and higher-risk (stage 2b) subgroups
Methods We analyzed participants aged ≥18 years with CKM syndrome stage 2 from the 1999-2018 NHANES cycles linked to the US National Death Index. Participants were assigned to development and validation cohorts comprising five survey cycles each. Predictor variables were selected using modified LASSO-regression and Cox-regression model, with cardiovascular mortality as the primary outcome. Model performance was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and the C-statistics. TriNetX database with patient-level data from medical records was analyzed to provide clinical validation using major adverse cardiovascular events (MACE) as the outcome.
Results Stage 2b in women was defined by the presence of at least two of the following: age ≥66 years, CKD, diabetes, or hypertension (AUC 0.79; C-index 0.78). In men stage 2b required at least two of the following: age ≥61 years, CKD, diabetes, or current smoking (AUC 0.73; C-index 0.72). Discrimination was preserved in external validation (women: AUC 0.70, C-index 0.69; men: AUC 0.75, C-index 0.68) with significantly distinct 10-year absolute risk difference of cardiovascular death (women: 4.9% [95% CI 2.2-7.5]; men: 8.5% [95% CI 5.0-12.0]). In TriNetX database, 10-year MACE risk increased from 11.3% to 24.6% in women and from 13.1% to 30.8% in men from stage 2a to stage 2b.
Conclusions Subdividing CKM stage 2 into stages 2a and 2b identifies clinically meaningful differences in cardiovascular risk and may support targeted preventive strategies.
Competing Interest Statement
KMSO reports receiving research funding, honoraria or consultancy fees from Alexion, Alentis, Alnylam, Apellis, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis, REATA, Roche, Sanofi, Stadapharm, StreamedUp, Vifor, not related to this article. BMWS reports received lecture fees and honoraria from ADVITOS, Amgen, AstraZeneca, Bayer Vital, Berlin Chemie-Menarini, Boehringer Ingelheim, CytoSorbents, Daichii Sankyo, Miltenyi, Novartis, Pocard, Vifor, not related to this article.
Funding Statement
There is no funding source for this study.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This study received a waiver from the institutional review board at Hannover Medical School, since only de-identified patient data were included.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Sharing Statement
NHANES data are available from the NHANES web page. The data supporting this study’s findings are available from TriNetX, LLC, but restrictions apply to their availability. The data were accessed under license and cannot be publicly shared. Accredited researchers may obtain access through a data use agreement with TriNetX, LLC, which may involve licensing fees. The R code of the analysis is available from the authors on reasonable request.
Abbreviations
- AHA
- American Heart Association
- AUC
- Area under the receiver operating characteristic curve
- CI
- Confidence intervall
- CKD
- Chronic kidney disease
- CKM
- syndrome Cardiovascular-kidney-metabolic syndrome
- CVD
- Cardiovascular disease
- eGFR
- Estimated glomerular filtration
- HR
- Hazard ratio
- LASSO
- Least absolute shrinkage and selection operator
- MACE
- Major adverse cardiac events
- MetS
- Metabolic syndrome
- NHANES
- National Health and Nutrition Examination Survey
- UACR
- Urinary albumin to creatinine ratio
