Renal Function Mediates Link Between Lp(a), Adverse Cardiovascular Outcomes

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Renal function may mediate the association between lipoprotein (a) and major adverse cardiac and cerebrovascular events (MACCE) in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), according to new research.¹

Among ≥10,000 eligible patients undergoing PCI, elevated Lp(a) was significantly associated with increased MACCE risk in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, but the association was weakened to diminished in patients with mild to normal renal function.

“Concomitant measurement of renal function is warranted for better risk stratification in CAD patients with elevated Lp(a),” wrote the investigative team, led by Junqing Yuan, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, and Peking Union Medical College.

Prior evidence has supported the causal role of elevated Lp(a) in the development of cardiovascular diseases (CVD). Guidelines from the European Society of Cardiology recommend initiating an Lp(a) measurement at least once in a lifetime to identify cardiovascular risk.² Chronic kidney disease (CKD) has also risen as a notable contributor to the global burden of CVD—as eGFR decreases, the prevalence of CVD rises, in tandem with an increasing risk of cardiac mortality.³

However, it remains unclear how renal dysfunction could impact the relationship of Lp(a) with cardiovascular risk in patients with CAD.¹ In the current analysis, Yuan and colleagues examined the impact of Lp(a) across renal function levels and the combined effect of Lp(a) and renal dysfunction with cardiovascular outcomes in patients with CAD undergoing PCI.

The post hoc analysis was based on a large, prospective observational cohort that enrolled 10,724 adults undergoing PCI from January to December 2013 in a hospital in a cardiovascular center in China. After excluding 289 patients due to missing baseline creatinine and Lp(a) data, 10,435 patients of East Asian ethnicity were eligible for analysis.

Participants were separated into three groups by baseline eGFR level, according to National Kidney Foundation classification: normal renal function (≥90 ml/min/1.73 m2), mild renal dysfunction (60-90 ml/min/1.73 m2), and moderate to severe renal dysfunction (<60 ml/min/1.73 m2).

Follow-up data were obtained by investigators blinded to baseline data at 1 month, 2 months, 1 year, 2 years, and 5 years after discharge. The analysis’ primary end point was MACCE, defined as a composite of all-cause death, nonfatal myocardial infarction, ischemic stroke, and unplanned revascularization.

Among the study population, 62% had normal renal function, 34% had mildly impaired renal function, and 4% had moderate to severe renal dysfunction. At baseline, the median eGFR and Lp(a) were 94.1 ml/min/1.73 m2 and 185.4 mg/dl, respectively. A total of 2144 (20.5) MACCE events occurred across a median follow-up period of 5.1 years.

After multivariable adjustment, investigators found higher Lp(a) levels were significantly associated with higher MACCE risk (≥30 vs. <30 mg/dL; hazard ratio [HR], 1.12; 95% CI, 1.03 - 1.23). Meanwhile, the significant associations between Lp(a) and higher risks of MACCE were only identified in patients with eGFR <60 ml/min/1.73 m2 (HR, 1.31; 95% CI, 1.08 - 1.60).

Those with increasing Lp(a) had significantly higher MACCE rates in impaired renal function groups (eGFR 60–90 ml/min/1.73 m²: 24.1% vs. 19.9%, P = .004; eGFR <60 ml/min/1.73 m²: 39.3% vs. 26.5%, P = .008). This finding was not observed in patients with normal renal function (19.9% vs. 19.1%; P = .470).

Yuan and colleagues identified a significant interaction for MACCE between renal categories and Lp(A) (P = .026). Only individuals with both eGFR <60 ml/min.1.73 m2 and elevated LP(a) experienced a significantly higher risk and cumulative incidence of MACCE (adjusted HR, 1.92; 95% CI, 1.43 - 2.57).

“The possible underlying mechanisms of our findings could be explained by the amplified pro-inflammatory and pro-calcifying effects of Lp(a) (mainly by oxidized phospholipids) in CKD, as CKD also induces a pro-inflammatory state and vascular calcification, which are vital risk factors for CVD,” investigators wrote.

References

1. _{Zeng G, Zhu P, Yuan D, et al. Renal function alters the association of lipoprotein(a) with cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a prospective cohort study. Clin Kidney J. 2024;17(3):sfae032. Published 2024 Feb 9. doi:10.1093/ckj/sfae032}
2. _{Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk [published correction appears in Eur Heart J. 2020 Nov 21;41(44):4255]. Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455}
3. _{Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339-352. doi:10.1016/S0140-6736(13)60595-4}