Nonlinear association between proteinuria levels and the risk of cardiovascular disease events and all-cause mortality among chronic kidney disease patients

Abstract

Background

The association between proteinuria levels and cardiovascular disease (CVD) development and all-cause mortality in chronic kidney disease (CKD) patients remains controversial.

Methods

In this investigation, we conducted a retrospective analysis involving 1138 patients who were registered in the CKD-Research of Outcomes in Treatment and Epidemiology (ROUTE) study. The primary outcome of this study was the composite of cardiovascular events or all-cause death. Cox proportional hazards regression, smooth curve fitting, piecewise linear regression, and subgroup analyses were used.

Results

The mean age of the included individuals was 67.3 ± 13.6 years old. Adjusted hazard ratios (HRs) for UPCR in middle and high groups, compared to the low group, were 1.93 (95% CI: 1.28–2.91) and 4.12 (95% CI: 2.87–5.92), respectively, after multivariable adjustment. Further adjustments maintained significant associations; HRs for middle and high groups were 1.71 (95% CI: 1.12–2.61) and 3.07 (95% CI: 2.08–4.54). A nonlinear UPCR-primary outcome relationship was observed, with an inflection point at 3.93 g/gCr.

Conclusion

Among non-dialyzed patients with stage G2-G5 CKD, a nonlinear association between UPCR and the primary outcome was observed. A higher UPCR (when UPCR < 3.93 g/gCr) was an independent predictor of the primary outcome. Importantly, our study predates SGLT2 inhibitor use, showcasing outcomes achievable without these medications. Future research considerations will involve factors like SGLT-2 inhibitor utilization.

Keywords:

• Chronic kidney disease (CKD)
• urinary protein-to-creatinine ratio (UPCR)
• cardiovascular diseases
• all-cause death
• prognosis

Acknowledgments

We gratefully acknowledge Iimori Soichiro, Naito Shotaro, Noda Yumi, Sato Hidehiko, Nomura Naohiro, Sohara Eisei, Okado Tomokazu, Sasaki Sei, Uchida Shinichi, Rai, Tatemitsu for the data of this study.

Author contributions

Haiying Song and Qijun Wan designed the study and wrote the manuscript. Haiying Song, Yuheng Liao, and Haofei Hu performed the statistical analysis. All authors participated in writing and revising the manuscript and read and approved the final manuscript.

Ethics statement

The CKD-ROUTE study was approved by the ethical committees of Tokyo Medical and Dental University, School of Medicine (No. 883), and all other institutions participating in the study and was conducted in accordance with the ethical principles of the Declaration of Helsinki. The protocol was registered with the UMIN Clinical Trials Registry (UMIN000004461).

Informed consent statement

Patient consent was waived due to the retrospective and non-interventional nature of the study.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by the Shenzhen Key Medical Discipline Construction Fund (SZXK009), Sanming Project of Medicine in Shenzhen (SZSM202211013), and Shenzhen Second People’s Hospital Clinical Research Fund of Guangdong Province High-level Hospital Construction Project (20213357018) and Medical-Engineering Interdisciplinary Research Foundation of Shenzhen University (2023YG033).