Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study

Samantha J L Hayward; Nicholas C Chesnaye; Barnaby Hole; Ryan Aylward; Yvette Meuleman; Claudia Torino; Gaetana Porto; Maciej Szymczak; Christiane Drechsler; Friedo W Dekker; Marie Evans; Kitty J Jager; Christoph Wanner; Fergus J Caskey; EQUAL investigators

doi:10.1016/j.xkme.2023.100745

Protein Biomarkers and Major Cardiovascular Events in Older People With Advanced CKD: The European Quality (EQUAL) Study

Kidney Med. 2023 Nov 2;6(1):100745. doi: 10.1016/j.xkme.2023.100745. eCollection 2024 Jan.

Authors

Samantha J L Hayward^{1

2}, Nicholas C Chesnaye^{3

4}, Barnaby Hole^{2

5}, Ryan Aylward^{5

6}, Yvette Meuleman⁷, Claudia Torino⁸, Gaetana Porto⁹, Maciej Szymczak¹⁰, Christiane Drechsler¹¹, Friedo W Dekker⁷, Marie Evans¹², Kitty J Jager^{3

4}, Christoph Wanner¹¹, Fergus J Caskey^{2

5}; EQUAL investigators

Affiliations

¹ Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
² Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
³ Amsterdam UMC, University of Amsterdam, ERA Registry, Medical Informatics, Amsterdam, The Netherlands.
⁴ Amsterdam Public Health Research Institute, Quality of Care, Amsterdam, The Netherlands.
⁵ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
⁶ Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
⁷ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Institute of Clinical Physiology, National Research Council, Reggio Calabria, Italy.
⁹ GOM Bianchi Melacrino Morelli, Reggio Calabria, Italy.
¹⁰ Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.
¹¹ Division of Nephrology, University Hospital of Wurzburg, Wurzburg, Germany.
¹² Department of Clinical Sciences Intervention and Technology, Karolinska Institutet and Karolinska, Stockholm, Sweden.

Abstract

Rationale & objective: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).

Study design: The European Quality (EQUAL) is an observational cohort study that enrolled people aged ≥65 years with an estimated glomerular filtration rate ≤20 mL/min/1.73 m².

Setting & participants: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).

Exposure: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.

Outcome: MACE.

Analytical approach: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.

Results: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.

Limitations: Single protein concentration measurements and limited follow-up time.

Conclusions: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies.

Plain-language summary: Kidney disease increases the risk of heart disease, stroke, and other vascular conditions. Blood tests that predict the likelihood of these problems may help to guide treatment, but studies are needed in people with kidney disease. We analyzed blood tests from older people with kidney disease, looking for proteins associated with higher risk of these conditions. Nine proteins were identified, of which 3 showed a strong effect after all other information was considered. This work supports previous research regarding 4 of these proteins and identifies 5 additional proteins that may be associated with higher risk. Further work is needed to confirm our findings and to determine whether these proteins can be used to guide treatment.

Keywords: Biomarker; cardiovascular disease; chronic kidney disease.