Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Yue-Miao Zhang; Jie Zheng; Tom R Gaunt; Hong Zhang

doi:10.3389/fbioe.2020.00662

Mendelian Randomization Analysis Reveals a Causal Effect of Urinary Sodium/Urinary Creatinine Ratio on Kidney Function in Europeans

Front Bioeng Biotechnol. 2020 Jul 7:8:662. doi: 10.3389/fbioe.2020.00662. eCollection 2020.

Authors

Yue-Miao Zhang¹, Jie Zheng², Tom R Gaunt^{2

3}, Hong Zhang¹

Affiliations

¹ Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
² MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Bristol, United Kingdom.
³ National Institute for Health Research (NIHR), Bristol Biomedical Research Centre, Bristol, United Kingdom.

Abstract

Salt restriction was recommended in clinical practice guideline for chronic kidney disease (CKD) treatment, but its effect on kidney outcomes remains conflicting. We aimed to test the causal effect of salt intake, using estimated 24-h sodium excretion from spot urinary sodium/urinary creatinine (UNa/UCr) ratio as a surrogate, on renal function using two-sample Mendelian randomization (MR). Genetic instruments for UNa/UCr were derived from a recent genome-wide association study of 218,450 European-descent individuals in the UK Biobank. Kidney outcomes were creatinine-based estimated glomerular filtration rate (eGFRcrea) (N = 567,460) and CKD (eGFRcrea < 60 ml/min/1.73 m², N cases = 41,395, N controls = 439,303) from the CKDGen consortium. Cystatin C-based eGFR (eGFRcys) and eGFRcrea single-nucleotide polymorphisms associated with blood urea nitrogen (BUN) were used for sensitivity analyses. MR revealed a causal effect of UNa/UCr on higher eGFRcrea [β = 0.14, unit change in log ml/min/1.73 m² per UNa/UCr ratio; 95% confidence interval (CI) = 0.07 - 0.20, P = 2.15 × 10^-5] and a protective effect against CKD risk (odds ratio = 0.24, 95% CI = 0.14 to 0.41, P = 1.20 × 10^-7). The MR findings were confirmed by MR-Egger regression, weighted median MR, and mode estimate MR, with less evidence of existence of horizontal pleiotropy. Consistent positive causal effect of UNa/UCr on eGFRcys was also detected. On the other hand, bidirectional MR suggested inconclusive results of CKD, eGFRcrea, eGFRcrea (BUN associated), and eGFRcys on UNa/UCr. The average 24-h sodium excretion was estimated to be approximately 2.6 g per day for women and 3.7 g per day for men. This study provides evidence that sodium excretion, well above the recommendation of <2 g per day of sodium intake, might not have a harmful effect on kidney function. Clinical trials are warranted to evaluate the sodium restriction target on kidney function.

Keywords: Mendelian randomization; causal effect; kidney function; salt restriction; urinary sodium/urinary creatinine ratio.

Abstract

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