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.
Highlights
MATERIALS AND METHODSChronic kidney disease (CKD) accounts for 10% to 15% population worldwide, which is associated with high annual rates of mortality and cardiovascular complications (Xie et al, 2018)
For eGFRcrea, the inverse variance weighted (IVW) Mendelian randomization (MR) suggested that urinary sodium/urinary creatinine (UNa/UCr) was positively associated with 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, Figure 2A]
The IVW MR suggested that increased UNa/UCr was associated with reduced chronic kidney disease (CKD) risk [odds ratio (OR) = 0.24, 95% CI = 0.14 to 0.41, P = 1.20 × 10−7, Figure 2B]
Summary
MATERIALS AND METHODSChronic kidney disease (CKD) accounts for 10% to 15% population worldwide, which is associated with high annual rates of mortality and cardiovascular complications (Xie et al, 2018). The Working Group graded this recommendation as “1C,” indicating that controlling salt intake can be evaluated as a candidate for developing a policy or a performance measure (Grade level 1), but from low quality of evidence (Grade C). This recommendation was mainly based on expert opinion and extrapolation from previous studies between sodium intake and blood pressure. Observational epidemiology studies have indicated that sodium intake was positively associated with blood pressure and proteinuria, which are strong predictors of CKD progression and cardiovascular diseases (CVDs) (He et al, 2013). During the 2017 KDIGO controversies conference, stakeholders questioned whether a level 1C recommendation of sodium restriction (
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