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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Major adverse cardiovascular events and hyperuricemia as an effect-modifying factor in kidney transplant recipients
Elizabete Junk, Lilian Tzivian, Inese Folkmane, Kristofs Folkmanis, Janis Jushinskis, Gunta Strazda, Valdis Folkmanis, Viktorija Kuzema, Aivars Petersons
Elizabete Junk, Department of Internal Diseases, St. Bonifatius Hospital Lingen, Lingen 49808, Germany
Elizabete Junk, Lilian Tzivian, Inese Folkmane, Kristofs Folkmanis, Gunta Strazda, Valdis Folkmanis, Faculty of Medicine and Life Sciences, University of Latvia, Riga LV-1004, Latvia
Lilian Tzivian, Institute of Occupational, Social and Environmental Medicine, Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University of Dusseldorf, Düsseldorf 40225, Germany
Inese Folkmane, Viktorija Kuzema, Centre of Nephrology, Pauls Stradiņš Clinical University Hospital, Riga LV-1002, Latvia
Kristofs Folkmanis, International Center for Robotic Urology, Kreisklinikum Siegen, Siegen 57076, North Rhine-Westphalia, Germany
Janis Jushinskis, Centre of Transplantation, Pauls Stradiņš Clinical University Hospital, Riga LV-1002, Latvia
Janis Jushinskis, Viktorija Kuzema, Aivars Petersons, Faculty of Medicine, Riga Stradins University, Riga LV-1007, Latvia
Co-first authors: Elizabete Junk and Lilian Tzivian.
Author contributions: Junk E, Tzivian L, and Folkmane I were responsible for methodology, writing review and editing; Junk E and Tzivian L were responsible for formal analysis; Junk E, Tzivian L, and Folkmanis V were responsible for writing original draft preparation; Junk E and Folkmane I were responsible for conceptualization; Junk E, Folkmane I, Jushinskis J, Strazda G, and Kuzema V were responsible for investigation; Junk E and Folkmanis K were responsible for data curation; Tzivian L was responsible for software and validation; Folkmane I, Jushinskis J, Kuzema V, and Petersons A were responsible for resources; Folkmane I, Strazda G, and Petersons A were responsible for supervision; all of the authors read and approved the final version of the manuscript to be published.
Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Scientific Research Ethics Committee of the Institute of Cardiology and Regenerative Medicine of the University of Latvia (No. 5/2021).
Informed consent statement: Informed consent was obtained from all subjects involved in the study.
Conflict-of-interest statement: The authors declare no conflicts of interest.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at
folkmane.inese@inbox.lv. Participants’ informed consent for data sharing was not obtained but the presented data are anonymized and risk of identification is low.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Inese Folkmane, MD, PhD, Professor, Centre of Nephrology, Pauls Stradiņš Clinical University Hospital, Pilsoņu 13, Riga LV-1002, Latvia.
folkmane.inese@inbox.lv
Received: October 13, 2024
Revised: January 31, 2025
Accepted: February 20, 2025
Published online: September 18, 2025
Processing time: 186 Days and 13.1 Hours
BACKGROUND
Major adverse cardiovascular (CV) events (MACEs) are the primary cause of morbidity and mortality in kidney transplantation (KT) recipients. The risk for MACEs is impacted by an array of traditional and transplant-related non-traditional CV risk factors.
AIM
To investigate the association between potential CV risk factors related to KT and MACEs, and their potential modification by hyperuricemia (HU).
METHODS
The relationship between CV risk factors related to KT and MACEs was examined in a cohort of 545 patients who underwent transplantation between 2008 and 2019. The mean age of patients at KT was 55.0 years ± 14.2 years (range 15.0–89.0 years). Univariate and multivariate logistic regression models were constructed to identify risk factors influencing MACEs. To explore the potential effect modification by uric acid (UA), patients were categorized into groups based on UA levels: (1) Low (< 356 μmol/L); (2) Normal (356–416 μmol/L); (3) High (416–475 μmol/L); and (4) Very high (> 475 μmol/L).
RESULTS
MACEs occurred in 145 of 545 (26.6%) KT recipients. The most prevalent comorbidities were hypertension (87%), dyslipidemia (78%), secondary hyperparathyroidism (68%), HU (63%) and anemia (33%). In the multivariate logistic regression model, the most significant factors associated with MACEs were previous CV events [odds ratio (OR) = 70.6, 95%CI: 24.9–200.1], left ventricular hypertrophy (LVH) (OR = 12.6, 95%CI: 2.7– 58.3), HU treatment (OR = 4.3, 95%CI: 2.4–7.6), and anemia (OR = 5.3, 95%CI: 2.9–9.8). Effect modification by the presence of HU revealed that independent factors associated with MACEs were age (OR = 1.03, 95%CI: 1.0–1.1), previous CV events (OR = 41.7, 95%CI: 13.6–127.6), LVH (OR = 15.3, 95%CI: 2.0–116.6), HU treatment (OR = 2.5, 95%CI: 1.3–4.6) and anemia (OR = 5.4, 95%CI: 2.8–10.5). Effect modification by UA levels dichotomized at 475 μmol/L (very high level of UA) revealed that HU treatment was not associated with MACEs in groups with or without very high UA levels.
CONCLUSION
A very high level of UA was observed to act as an effect-modifying factor for MACEs, especially when combined with other risk factors such as age, previous CV events, LVH, and anemia.
Core Tip: The relationship between hyperuricemia (HU) and major adverse cardiovascular (CV) events (MACEs) after kidney transplantation (KT) remains a topic of contention. We investigated the association between potential CV risk factors related to KT and MACEs, and their potential modification by HU. A very high level (> 475 μmol/L) of uric acid was found to act as an effect-modifying factor for MACEs, especially when combined with other risk factors such as previous CV events and anemia. This study makes an innovative contribution to the field by demonstrating the role of HU as a modulating factor on MACEs after KT.
