Major adverse cardiovascular events and hyperuricemia as an effect-modifying factor in kidney transplant recipients

Abstract

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.

Keywords: Cardiovascular risk; Effect modification by hyperuricemia; Hyperuricemia; Hyperuricemia treatment; Kidney transplantation; Major adverse cardiovascular events; Uric acid.

Figure 1

Flow chart of kidney transplant recipients at the study centre, including the number of recipients lost to follow-up within 1 year.

Figure 2

Direct acyclic graph of relationships between study variables. BMI: Body mass index; CNI: Calcineurin inhibitor; CV: Cardiovascular; DM: Diabetes mellitus; GFR: Glomerular filtration rate; LVH: Left ventricular hypertrophy; MACE: Major adverse cardiovascular event.