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Urinary Sodium-to-Potassium Ratio and Incident Chronic Kidney Disease

Results From the Korean Genome and Epidemiology Study
Published:November 03, 2022DOI:https://doi.org/10.1016/j.mayocp.2022.04.017

      Abstract

      Objective

      To evaluate the association of sodium-potassium intake balance on kidney function.

      Patients and Methods

      Data from the Korean Genome and Epidemiology Study were used. The participants were enrolled between June 1, 2001, and January 31, 2003, and were followed-up until December 31, 2016. The 24-hour excretion levels of sodium and potassium were calculated using the Kawasaki formula with spot urinary potassium and sodium measurements. Participants were categorized into tertiles according to the estimated 24-hour urinary sodium-to-potassium (Na/K) ratio. The primary outcome was incident chronic kidney disease (CKD), defined as an estimated glomerular filtration rate of <60 mL/min per 1.73 m2 in two or more consecutive measurements during the follow-up period.

      Results

      This study included 4088 participants with normal kidney function. The mean age was 52.4±8.9 years, and 1747 (42.7%) were men. The median estimated 24-hour urinary sodium excretion level, potassium excretion level, and Na/K ratio (inter quartile range) were 4.9 (4.1-5.8) g/d, 2.1 (1.8-2.5) g/d, and 2.3 (1.9-2.7) g/d, respectively. During 37,950 person-years of follow-up (median, 11.5 years), 532 participants developed CKD, and the corresponding incidence rate was 14.0 (95% CI, 12.9-15.3) per 1000 person-years. Multivariable Cox hazard analysis revealed that the risk of incident CKD was significantly lower in the lowest tertile than in the highest tertile (HR, 0.78; 95% CI, 0.63-0.97). However, no significant association was found with incident CKD risk when urinary excretion levels of sodium or potassium were evaluated individually.

      Conclusion

      A low urinary Na/K ratio may relate with lower CKD development risk in adults with preserved kidney function.

      Abbreviations and Acronyms:

      BP (blood pressure), CKD (chronic kidney disease), CVD (cardiovascular disease), eGFR (estimated glomerular filtration ratio), KoGES (Korean Genome and Epidemiology study), Na/K (sodium-to-potassium)
      Chronic kidney disease (CKD), a predisposition for cardiovascular disease (CVD) and premature death, is a major contributor to the increase in the global socioeconomic burden.
      • Kim K.M.
      • Oh H.J.
      • Choi H.Y.
      • Lee H.
      • Ryu D.R.
      Impact of chronic kidney disease on mortality: a nationwide cohort study.
      • Mills K.T.
      • Xu Y.
      • Zhang W.
      • et al.
      A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010.
      • Xie Y.
      • Bowe B.
      • Mokdad A.H.
      • et al.
      Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.
      • Bowe B.
      • Xie Y.
      • Li T.
      • et al.
      Changes in the US Burden of Chronic Kidney Disease From 2002 to 2016: An Analysis of the Global Burden of Disease Study.
      Although treatments for hypertension and diabetes — the most well-known risk factors for CKD — are widespread, the prevalence of CKD is growing steadily.
      • Ruggenenti P.
      • Perna A.
      • Loriga G.
      • et al.
      Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.
      • Emdin C.A.
      • Rahimi K.
      • Neal B.
      • Callender T.
      • Perkovic V.
      • Patel A.
      Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
      • Nam K.H.
      • Yun H.R.
      • Joo Y.S.
      • et al.
      Changes in obese metabolic phenotypes over time and risk of incident chronic kidney disease.
      • Park S.
      • Lee S.
      • Kim Y.
      • et al.
      Reduced risk for chronic kidney disease after recovery from metabolic syndrome: a nationwide population-based study.
      • Park J.I.
      • Baek H.
      • Jung H.H.
      Prevalence of chronic kidney disease in Korea: the Korean National Health and Nutritional Examination Survey 2011-2013.
      Once established, CKD is irreversible, and the identification and prevention of modifiable risk factors are important to reduce CKD-related morbidity and mortality.
      Because of their close association with hypertension, dietary sodium and potassium intakes have been closely associated with the risk of CKD.
      • Mente A.
      • O'Donnell M.J.
      • Rangarajan S.
      • et al.
      Association of urinary sodium and potassium excretion with blood pressure.
      • Kieneker L.M.
      • Bakker S.J.
      • de Boer R.A.
      • Navis G.J.
      • Gansevoort R.T.
      • Joosten M.M.
      Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease.
      • Yoon C.Y.
      • Noh J.
      • Lee J.
      • et al.
      High and low sodium intakes are associated with incident chronic kidney disease in patients with normal renal function and hypertension.
      Nonetheless, the investigations evaluating the dietary intakes of sodium and potassium as risk factors for CKD have been inconsistent and inconclusive. The PREVEND (Prevention of Renal and Vascular End-Stage Disease) study has shown that the risk of incident CKD was higher in people with low potassium intake, whereas no connection was identified with sodium intake.
      • Kieneker L.M.
      • Bakker S.J.
      • de Boer R.A.
      • Navis G.J.
      • Gansevoort R.T.
      • Joosten M.M.
      Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease.
      Another study involving 1030 adults revealed that the estimated urinary excretion levels of sodium or potassium were not related to the estimated glomerular filtration rate (eGFR) decline.
      • Elfassy T.
      • Zhang L.
      • Raij L.
      • et al.
      Results of the CARDIA study suggest that higher dietary potassium may be kidney protective.
      On the other hand, a recent investigation that assessed dietary sodium intake using a food frequency questionnaire showed that sodium intake was associated with CKD risk only in a subgroup of people.
      • Yoon C.Y.
      • Noh J.
      • Lee J.
      • et al.
      High and low sodium intakes are associated with incident chronic kidney disease in patients with normal renal function and hypertension.
      Recently, the balance between sodium and potassium intake, rather than the intake of each dietary element itself, has been proposed as a significant factor influencing outcome. In an evaluation of 103,570 people who participated in the PURE (Prospective Urban Rural Epidemiology) study, the combination of very high sodium intake with low potassium intake was associated with the highest cardiovascular event risk.
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.
      Additionally, a higher urinary sodium-to-potassium (Na/K) ratio, surrogates of the intake amounts, was found to increase the risk of CKD progression in patients with prevalent CKD.
      • Koo H.
      • Hwang S.
      • Kim T.H.
      • et al.
      The ratio of urinary sodium and potassium and chronic kidney disease progression: Results from the KoreaN Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD).
      Nonetheless, the effect of sodium-potassium intake balance on incident CKD development is not well known.
      Therefore, in this study, the association between sodium-potassium intake balance and CKD development in people with normal kidney function was evaluated. This was assessed using the urinary Na/K ratio as a representative of intake balance.

      Patients and Methods

      Study Population

      This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Yonsei University Health System Clinical Trial Center (9-2021-0021).
      Data were retrieved from the KoGES (Korean Genome and Epidemiology Study), a prospective community-based study. The KoGES consists of middle-aged (40-69 years of age) participants residing in Ansan (an urban area) or Ansung (a rural area), Korea. Detailed cohort profiles and methods for the development of the KoGES have been published previously.
      • Kim Y.
      • Han B.G.
      Cohort profile: the Korean Genome and Epidemiology Study (KoGES) Consortium.
      Participants who underwent urinary sodium and potassium measurements were screened. Patients with known kidney disease, proteinuria, or an eGFR <60 mL/min per 1.73 m2 at baseline were excluded. Participants who did not attend the follow-up visits were also excluded. The final analysis comprised 4088 people (Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org).

      Data collection

      Detailed data collection methods are described in the Supplemental Methods (available online at http://www.mayoclinicproceedings.org). Demographic data including age, sex, household income, marital status, education level, daily physical activity level, and medical history were recorded at baseline. Anthropometric data were collected by trained nurses using standardized protocols and calibrated devices. Blood samples were obtained after 8 hours or more of fasting and analyzed at a central laboratory. Serum creatinine levels were determined using the Jaffe assay. The eGFR was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      For substitution in the CKD-EPI equation, the creatinine levels were reduced by a 5% calibration factor for standardization with the value obtained by isotope dilution mass spectrometry reference method.
      • Levey A.S.
      • Coresh J.
      • Greene T.
      • et al.
      Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values.
      ,
      • Joffe M.
      • Hsu C.Y.
      • Feldman H.I.
      • Weir M.
      • Landis J.R.
      • Hamm L.L.
      Variability of creatinine measurements in clinical laboratories: results from the CRIC study.
      Proteinuria was classified based on a color scale that quantified proteinuria as absent, trace, 1+, 2+, or 3+. This scale correlates approximately with urine protein levels of less than 10, 10 to 20, greater than 30, greater than 100, and greater than 500 mg/dL, respectively.
      • Yang J.J.
      • Yang J.H.
      • Kim J.
      • et al.
      Reliability of quadruplicated serological parameters in the korean genome and epidemiology study.
      The presence of proteinuria was considered as a urinalysis result higher than trace level.

      Exposure and Outcome

      The primary exposure was the urinary Na/K ratio. Urine samples were collected in the morning after the first voiding at baseline. Urinary sodium, potassium, and creatinine levels were measured using a Cobas Integra 800 Analyzer (Roche Diagnostics) at a central laboratory. Twenty-four–hour urinary excretion levels of sodium and potassium were estimated from a fasting morning urine sample using the Kawasaki formula.
      • Kawasaki T.
      • Itoh K.
      • Uezono K.
      • Sasaki H.
      A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults.
      Additionally, for sensitivity analysis, Na/K estimates from the Tanaka formula were used.
      • Tanaka T.
      • Okamura T.
      • Miura K.
      • et al.
      A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen.
      The primary endpoint was incident CKD, which was defined as an eGFR less than 60 mL/min per 1.73 m2 at two or more consecutive measurements during the follow-up period. Participants were followed-up from the baseline visit to occurrence of the primary outcome, loss to follow-up, or up to 14 years from the baseline visit.

      Statistical Analysis

      Detailed statistical analysis methods are described in the Supplemental Methods. Statistical analyses were conducted using STATA version 16.1. (Stata Corp). The natural log-transformed urinary Na/K ratio was used as a continuous variable because of the skewed distribution. Cox proportional hazards regression analysis was used to evaluate the relationship between urinary Na/K ratio and CKD development. To test the nonlinear relationship between urinary Na/K ratio and incident CKD risk, restricted cubic spline analyses were conducted with the urinary Na/K ratio as a continuous variable. The missing values were accounted for less than 7% of all covariates (Supplemental Table 1, available online at http://www.mayoclinicproceedings.org), and multiple imputation by the chained equations method was used to impute 10 independent copies of the data for multivariable Cox proportional hazards models. In the time-updated model, the CVD history and systolic blood pressure (BP) was considered as time-updated covariates. A P value of less than .05 was considered statistically significant.

      Results

      Baseline Characteristics

      The baseline characteristics of the participants according to urinary Na/K ratios are shown in Table 1. The mean age was 52.4±8.9 years, and 1747 (42.7%) participants were male. The median estimated 24-hour urinary sodium excretion level, potassium excretion level, Na/K ratio (inter quartile range) were 4.9 (4.1-5.8) g/d, 2.1 (1.8-2.5) g/d, and 2.3 (1.9-2.7), respectively. Participants with a higher urinary Na/K ratio were younger, physically inactive, and had higher fasting glucose levels. The proportion of participants with either high sodium or potassium excretion amounts are shown in Supplemental Table 2 (available online at http://www.mayoclinicproceedings.org). Differences in the proportions of patients with hypertension, diabetes, or CVD were nonsignificant across the urinary Na/K ratio tertiles.
      Table 1Baseline Characteristics According to Urinary Na/K Ratio
      BMI, body mass index; BUN, blood urea nitrogen; CRP, C-reactive protein; HbA1c, glycated hemoglobin; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration; HDL-C, high-density lipoprotein cholesterol; MET, metabolic equivalent of task; Na/K, sodium-to-potassium; SBP, systolic blood pressure; USD, US dollars.
      ,
      All continuous variables are expressed as the mean±SD, median (IQR), or proportion (%).
      CharacteristicsTotal (N=4088)Tertile of urine Na/K excretion ratio
      1 (n=1364)2 (n=1362)3 (n=1362)
      Urinary electrolyte
       Urine sodium, mmol/L140 (104-178)125 (92-158)143 (105-181)157 (117-199)
       Urine potassium, mmol/L47 (31-68)77 (56-97)47 (34-61)30 (22-40)
      Estimated 24-h electrolyte excretion
       Urine sodium excretion, g/d
      Estimated using the Kawasaki formula.
      4.9 (4.1-5.8)4.2 (3.5-5.0)5.0 (4.3-5.8)5.6 (4.8-6.5)
       Urine potassium excretion, g/d
      Estimated using the Kawasaki formula.
      2.1 (1.8-2.5)2.4 (2.1-2.9)2.2 (1.9-2.5)1.8 (1.6-2.1)
      Urine Na/K excretion ratio
       Mean ± Standard deviation2.4±0.61.7±0.32.3±0.13.1±0.4
       Median (interquartile range)2.3 (1.9-2.7)1.8 (1.6-1.9)2.3 (2.2-2.4)3.0 (2.7-3.3)
      Demographic data
       Age, y52.4±8.953.3±8.852.4±9.051.7±8.8
       Male1747 (42.7)571 (41.9)570 (41.9)606 (44.5)
       Education
      Low1514 (37.0)564 (41.3)498 (36.6)452 (33.2)
      Mid971 (23.8)342 (25.1)338 (24.8)291 (21.4)
      High1603 (39.2)458 (33.6)526 (38.6)619 (45.4)
       Income per month, USD
      Low (< 850)1641 (41.2)651 (48.8)536 (40.8)454 (34.0)
      Mid (850 ∼ 1700)1858 (46.6)569 (42.7)602 (45.8)687 (51.4)
      High (≥1700)486 (12.2)113 (8.5)177 (13.5)196 (14.7)
       Married3639 (89.0)1204 (88.3)1213 (89.1)1222 (89.7)
       Smoking
      Never2545 (63.4)844 (63.2)864 (64.7)837 (62.3)
      Former472 (11.8)119 (8.9)174 (13.0)179 (13.3)
      Current997 (24.8)372 (27.9)298 (22.3)327 (24.3)
       Current drinker1761 (43.6)564 (42.0)566 (42.0)631 (46.8)
       Daily physical activity, MET·h1357±9131488±9731337±9091247±838
       Daily energy intake, 1000 kcal/d2.04±0.822.10±0.902.03±0.812.01±0.73
       BMI, kg/m224.5±3.124.4±3.224.6±3.124.6±3.1
       SBP, mm Hg121.5±18.9121.1±18.3121.8±18.5121.5±19.8
       DBP, mm Hg79.6±12.079.5±12.179.5±11.479.6±12.5
       Comorbidities
      Hypertension1376 (33.7)463 (33.9)444 (32.6)469 (34.4)
      Diabetes543 (13.3)159 (11.7)183 (13.4)201 (14.8)
      CVD102 (2.5)39 (2.9)32 (2.3)31 (2.3)
       Medication use
      Antihypertensive drugs, n (%)430 (11.7)164 (14.1)138 (11.2)128 (10.1)
      Diuretics, n (%)5 (0.1)2 (0.2)2 (0.2)1 (0.1)
      Laboratory parameters
       eGFR, mL/min per 1.73 m295.9±11.695.4±11.595.9±11.696.4±11.7
       Glucose, mg/dL85.1±19.383.6±17.285.1±18.786.6±21.7
       Albumin, g/dL4.1±0.24.1±0.24.1±0.24.1±0.2
       BUN, mg/dL14.1±3.514.3±3.714.1±3.513.9±3.4
       Total cholesterol, mg/dL185.1±33.2184.8±32.8186.2±33.1184.2±33.7
       HDL-C, mg/dL43 (37-49)43 (37-49)43 (37-49)43 (37-50)
       Triglyceride, mg/dL165.2±103.7166.7±102.8167.6±104.5161.4±103.9
       CRP, mg/L0.13 (0.05-0.24)0.14 (0.06-0.26)0.13 (0.05-0.24)0.12 (0.04-0.23)
       HbA1c, %5.8±0.95.8±0.85.8±0.85.8±0.9
      a BMI, body mass index; BUN, blood urea nitrogen; CRP, C-reactive protein; HbA1c, glycated hemoglobin; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration; HDL-C, high-density lipoprotein cholesterol; MET, metabolic equivalent of task; Na/K, sodium-to-potassium; SBP, systolic blood pressure; USD, US dollars.
      b All continuous variables are expressed as the mean±SD, median (IQR), or proportion (%).
      c Estimated using the Kawasaki formula.

      Urinary Na/K Ratio and CKD Development

      During 37,950 person-years of follow-up (median, 11.5 years), 532 participants developed CKD, and the corresponding CKD incidence rate was 14.0 (95% CI, 12.9 to 15.3) per 1000 person-years (Table 2). Cox proportional hazards analysis revealed that after adjustment for age, sex, and baseline eGFR, the HRs (95% CIs) were 0.77 (0.62 to 0.95) and 1.09 (0.88 to 1.34) for urinary Na/K tertiles 1 and 2 (comparison: tertile 3 [highest tertile]), respectively (model 1, Table 3). The results were similar after adjusting for socioeconomic and medical history–related factors (model 2). Additionally, the fully adjusted model including body mass index (BMI), systolic BP, C-reactive protein levels, high-density lipoprotein cholesterol levels, fasting glucose levels, physical activity levels, and daily dietary caloric intake showed that the lowest urinary Na/K ratio tertile had a 22% lower risk of CKD development than the highest tertile (HR, 0.78; 95% CI 0.63 to 0.97; model 3). The C-statistics of model 3 for predicting CKD development was 0.82 (95% CI: 0.78 to 0.86) (Supplemental Table 3, available online at http://www.mayoclinicproceedings.org). Similar results were observed when the log-transformed urinary Na/K ratio was treated as a continuous variable; for a log increase in the urinary Na/K ratio, the risk of CKD development was increased by 55% (HR, 1.55; 95% CI, 1.14 to 2.09) (Table 3). However, the association between incident CKD risk and individual urinary excretion of sodium or potassium was nonsignificant (Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org). Similarly, comparable results were noted when the time-updated models with CVD and systolic BP as time-varying covariates were evaluated (for a log increase in the urinary Na/K ratio: HR, 1.57; 95% CI, 1.16-2.13; model 3) (Supplemental Table 4, available online at http://www.mayoclinicproceedings.org). Spline regression analysis revealed that the HR for CKD development increased steeply up to 1 in analysis using log-transformed urine Na/K values, but there was no significant increase thereafter (Figure 1A). However, when the relationship between incident CKD risk and individual urinary excretion of sodium or potassium was assessed, no significant association was observed (Figures 1B and 1C).
      Table 2Incidence Rates of CKD Development According to Urinary Na/K Excretion Ratio
      CKD, chronic kidney disease; Na/K, sodium-to-potassium.
      ,
      CKD was defined as two consecutive occurrences of estimated glomerular filtration rate 60 mL/min per 1.73 m2 during follow-up.
      OutcomesOverallTertile of urinary Na/K excretion ratio tertile
      123P
      No. of participants4088136413621362
      No. of person-years37,95112,77212,59012,589
      Incidence of CKD, n532169192171
      Incidence rate per 1000 person-years14.0 (12.9-15.3)13.2 (11.4-15.4)15.2 (13.2-17.6)13.6 (11.7-15.8).27
      a CKD, chronic kidney disease; Na/K, sodium-to-potassium.
      b CKD was defined as two consecutive occurrences of estimated glomerular filtration rate 60 mL/min per 1.73 m2 during follow-up.
      Table 3Risk of Chronic Kidney Disease in the Tertiles of Urinary Na/K Ratio
      BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; Na/K, sodium-to-potassium.
      Model 1
      Model 1: Adjusted for age, sex, and eGFR.
      Model 2
      Model 2: Model 1 + education level, household income, diabetes, and cardiovascular disease.
      Model 3
      Model 3: Model 2 + BMI, systolic blood pressure, C-reactive protein level, HDL-C level, fasting glucose level, dietary energy intake, and physical activity level.
      HR (95% CI)PHR (95% CI)PHR (95% CI)P
      Continuous urine Na/K excretion ratio
      Urine Na/K ratio and C-reactive protein, HDL-C, and fasting glucose levels were natural log-transformed because of skewed distribution.
      1.56 (1.16-2.10).0041.49 (1.10-2.02).011.55 (1.14-2.09).01
      Urine Na/K excretion ratio tertile
       10.77 (0.62-0.95).020.79 (0.64-0.98).030.78 (0.63-0.97).03
       21.09 (0.88-1.34).351.10 (0.89-1.35).381.09 (0.88-1.34).42
       3Reference
      a BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; Na/K, sodium-to-potassium.
      b Model 1: Adjusted for age, sex, and eGFR.
      c Model 2: Model 1 + education level, household income, diabetes, and cardiovascular disease.
      d Model 3: Model 2 + BMI, systolic blood pressure, C-reactive protein level, HDL-C level, fasting glucose level, dietary energy intake, and physical activity level.
      e Urine Na/K ratio and C-reactive protein, HDL-C, and fasting glucose levels were natural log-transformed because of skewed distribution.
      Figure thumbnail gr1
      Figure 1Association of estimated 24-hour urinary electrolyte excretion with the risk of chronic kidney disease. A, Estimated urinary sodium-to-potassium (Na/K) ratio and the risk of chronic kidney disease. B, Estimated urinary sodium excretion and the risk of chronic kidney disease. C, Estimated urinary potassium excretion and the risk of chronic kidney disease Incident chronic kidney disease (CKD) was defined as two consecutive estimated glomerular filtration rate (eGFR) measurements of <60 mL/min per 1.73 m2 during follow-up. Models are adjusted for age, sex, eGFR, education level, household income, diabetes, cardiovascular disease, body mass index, systolic blood pressure, C-reactive protein level, high-density lipoprotein cholesterol level, fasting glucose level, and physical activity level. Urinary Na/K ratio and C-reactive protein, high-density lipoprotein cholesterol, and fasting glucose levels were natural log-transformed because of skewed distribution.

      Subgroup Analysis

      Subgroup analyses were performed in groups stratified by age (<60 or ≥60 years), sex (male or female), BMI (≤25 or >25 kg/m2), diabetes (with or without), and hypertension (with or without) to assess the effect modification of subgroups had on the relationship between urinary Na/K ratio and CKD development (Figure 2). There were no significant interactions in any of the subgroups, suggesting that the relationship between urinary Na/K ratio and CKD risk was maintained across the subgroups.
      Figure thumbnail gr2
      Figure 2Forest plot. Models are adjusted for age, sex, estimated glomerular filtration rate, education level, household income, diabetes, cardiovascular disease, body mass index (BMI), systolic blood pressure, C-reactive protein level, high-density lipoprotein cholesterol level, fasting glucose level, and physical activity level. Urinary sodium-to-potassium ratio and C-reactive protein, high-density lipoprotein cholesterol, and fasting glucose levels were natural log-transformed because of skewed distribution. BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension.

      Sensitivity Analysis

      When sensitivity analysis was performed excluding participants with less than 2 years of follow-up (n=221) or who developed the primary outcome within 2 years of enrollment (n=52), incident CKD risk was positively associated with increases in the urinary Na/K ratio (HR, 1.44; 95% CI, 1.05 to 1.97; model 3) (Supplemental Table 5, available online at http://www.mayoclinicproceedings.org). Similar associations were found in the analysis excluding participants with a baseline eGFR of less than or equal to 66 mL/min per 1.73 m2 to ensure a more definite decline in kidney function to define the primary outcome (HR, 1.49; 95% CI, 1.06 to 2.02; model 3) (Supplemental Table 6, available online at http://www.mayoclinicproceedings.org). Moreover, this positive relationship between the urinary Na/K ratio and CKD risk was maintained when CKD was defined as a single episode of eGFR less than 60 mL/min per 1.73 m2 during the follow-up period (HR, 1.36; 95% CI, 1.08 to 1.70) (Supplemental Table 7, available online at http://www.mayoclinicproceedings.org). The comparable associations resulted in a repeated base in the Tanaka equation (Supplemental Table 8, available online at http://www.mayoclinicproceedings.org).

      Discussion

      In this study, the association between the urinary Na/K ratio and CKD development was assessed in a community-based prospective cohort of adults with preserved kidney function. The risk of CKD development was significantly lower in the tertile with the lowest urinary Na/K ratio than in the tertile with the highest urinary Na/K ratio. Additionally, when the urinary Na/K ratio was considered a continuous variable, the risk of incident CKD increased in proportion with the increase in the urinary Na/K ratio. These associations were independent of confounding variables. Cubic spline analysis revealed that this steady increase in risk was valid for log-transformed urinary Na/K ratios lower than 1 and remained steady thereafter. However, no significant association was observed with incident CKD risk when the urinary excretion levels of sodium or potassium were evaluated individually.
      A higher urinary Na/K ratio was significantly associated with an increased risk of CKD in this study. However, a previous study of 7063 participants from Japan evaluating the association between repeated measurements of spot urine Na/K ratios and eGFR decline suggested that the possibility of the urinary Na/K ratio having a physiological relationship with eGFR decline would be low.
      • Tabara Y.
      • Takahashi Y.
      • Setoh K.
      • et al.
      Prognostic significance of spot urine Na/K for longitudinal changes in blood pressure and renal function: the Nagahama Study.
      This was because of the probable effect of regression to the mean. Although the urinary Na/K ratio was related to rapid eGFR decline, it was also positively correlated with the baseline eGFR. Compared with the values in that study, the baseline eGFR did not differ among the urinary Na/K ratio groups in this study. Additionally, only participants with preserved kidney function at baseline were included in the analysis, unlike former investigations that included those with prevalent CKD. Urinary excretion of sodium and potassium may not accurately represent their intake in patients with underlying kidney diseases.
      • Dougher C.E.
      • Rifkin D.E.
      • Anderson C.A.
      • et al.
      Spot urine sodium measurements do not accurately estimate dietary sodium intake in chronic kidney disease.
      ,
      • van Ypersele de Strihou C.
      Potassium homeostasis in renal failure.
      A recent investigation of 1030 adults from the CARDIA (Coronary Artery Risk Development In Young Adults) study showed that the Na/K ratio measured using 24-hour urine samples was significantly associated with CKD development in some of the examined multivariate models.
      • Elfassy T.
      • Zhang L.
      • Raij L.
      • et al.
      Results of the CARDIA study suggest that higher dietary potassium may be kidney protective.
      However, the significance was lost in the fully adjusted model. Compared with that in the current study, sodium excretion was relatively low in that study, while potassium excretion was comparable. Therefore, the actual range of analyzed urinary Na/K ratios in that investigation may have differed from the range in this study. Additionally, patients with hypertension accounted for 6.6% of the population in the CARDIA study, compared with 33.7% of the population in this study. Patients with hypertension are more sensitive to sodium than those without hypertension. This difference in cohort characteristics may have led to the difference in results. This possibility was supported by a recent study that showed a close association of sodium intake with CKD risk only in women with hypertension.
      • Yoon C.Y.
      • Noh J.
      • Lee J.
      • et al.
      High and low sodium intakes are associated with incident chronic kidney disease in patients with normal renal function and hypertension.
      The risk of CKD linearly decreased with lower urinary Na/K ratios, despite the relatively high intake of sodium in the participants. The WHO guidelines recommend a diet resulting in a urinary sodium excretion level of less than 2.0 g/d to minimize the risk of CVD.
      World Health Organization
      Guideline: Sodium Intake for Adults and Children.
      Noticeably, none of the participants in this study met the WHO recommendations. Restricting dietary intake with respect to recommendations is difficult. A survey from the United States, Mexico, France, and the United Kingdom reported that only 0.1% to 0.5% of the population complied with the WHO dietary intake goal.
      • Drewnowski A.
      • Rehm C.D.
      • Maillot M.
      • Mendoza A.
      • Monsivais P.
      The feasibility of meeting the WHO guidelines for sodium and potassium: a cross-national comparison study.
      Similarly, only 0.002% of total participants in the PURE study met the above guidelines.
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.
      Therefore, generously increasing the potassium intake rather than restricting the sodium intake could be a more achievable dietary goal to reduce the risk of CKD. This approach was supported by a recent study that showed that the risk of CVD was the lowest in those with a high potassium intake despite a moderate sodium intake.
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.
      However, further investigations including wide ranges of sodium and potassium intakes are required to confirm this possibility.
      The relationship between the urinary Na/K ratio and CKD development can be attributed to several mechanisms. Previous investigations have shown the dietary intakes of sodium and potassium to be closely related to BP. Positive dose-response associations between urinary sodium excretion and BP have been reported,
      • Jackson S.L.
      • Cogswell M.E.
      • Zhao L.
      • et al.
      Association between urinary sodium and potassium excretion and blood pressure among adults in the United States: National Health and Nutrition Examination Survey, 2014.
      whereas inverse relationships between urinary potassium excretion and BP have been observed.
      • Mente A.
      • O'Donnell M.J.
      • Rangarajan S.
      • et al.
      Association of urinary sodium and potassium excretion with blood pressure.
      ,
      • Jackson S.L.
      • Cogswell M.E.
      • Zhao L.
      • et al.
      Association between urinary sodium and potassium excretion and blood pressure among adults in the United States: National Health and Nutrition Examination Survey, 2014.
      A recent cluster randomized trial for sodium substitution with potassium-enriched salt showed that decreasing sodium intake and increasing potassium intake decreased BP, cardiovascular events, and mortality.
      • Neal B.
      • Wu Y.
      • Feng X.
      • et al.
      Effect of salt substitution on cardiovascular events and death.
      Considering that hypertension is one of the most well-known risk factors for CKD, the possibility of BP-related mediation in the association between the urinary Na/K ratio and incident CKD risk is high. However, the prevalence of hypertension did not differ among the urinary Na/K ratio groups at baseline. Additionally, the association between the urinary Na/K ratio and CKD development remained significant even after adjustment for hypertension. The presence of other mediators should also be considered. Recently, the urinary Na/K ratio has been reported to be linked to adverse metabolic outcomes, which could be another mediator leading to kidney function decline. An analysis of 3722 adults showed that the urinary Na/K ratio was correlated with insulin resistance.
      • Park Y.M.
      • Kwock C.K.
      • Park S.
      • Eicher-Miller H.A.
      • Yang Y.J.
      An association of urinary sodium-potassium ratio with insulin resistance among Korean adults.
      Additionally, a recent prospective observational study reported that the urinary Na/K ratio was significantly associated with the development of obesity, suggesting that an increase in the urinary Na/K ratio may induce metabolic derangements which may consequently affect kidney function.
      • Jain N.
      • Minhajuddin A.T.
      • Neeland I.J.
      • Elsayed E.F.
      • Vega G.L.
      • Hedayati S.S.
      Association of urinary sodium-to-potassium ratio with obesity in a multiethnic cohort.
      Dietary characteristics differ among ethnicities and cultural backgrounds, and this would have had influence on the amount of sodium and potassium intake in this study. Koreans are known to consume more sodium and less potassium compared with the Western population.
      Intersalt Cooperative Research Group
      Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion.
      In addition, main food sources that contribute to the sodium intake in Koreans are reported to be noodles, kimchi, and soups which are rarely consumed among Americans.
      • Jeong Y.
      • Kim E.S.
      • Lee J.
      • Kim Y.
      Trends in sodium intake and major contributing food groups and dishes in Korea: the Korea National Health and Nutrition Examination Survey 2013-2017.
      ,
      • Woodruff R.C.
      • Zhao L.
      • Ahuja J.K.C.
      • et al.
      Top food category contributors to sodium and potassium intake — United States, 2015-2016.
      Therefore, the findings of this study may be limited to the specific ethnic group of Asians included in the evaluation. Further assessments including other ethnic populations are needed to generalize the results to other nations.
      Obtaining 24-hour urine collections and ensuring their integrity and completeness are obstacles especially for epidemiological studies.
      • Jackson S.L.
      • Cogswell M.E.
      • Zhao L.
      • et al.
      Association between urinary sodium and potassium excretion and blood pressure among adults in the United States: National Health and Nutrition Examination Survey, 2014.
      ,
      • McLean R.M.
      Measuring population sodium intake: a review of methods.
      Therefore, spot urine estimates have been used for sodium and potassium excretion evaluation in several previous large-scale investigations.
      • Mente A.
      • O'Donnell M.J.
      • Rangarajan S.
      • et al.
      Association of urinary sodium and potassium excretion with blood pressure.
      ,
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.
      ,
      • Mente A.
      • O'Donnell M.
      • Rangarajan S.
      • et al.
      Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies.
      However, urinary electrolyte excretion fluctuates during the day due to ingestion, hydration, and sweating.
      • Yoshida M.
      • Koyama H.
      • Moji K.
      • et al.
      Daily response of blood pressure to day-to-day variation of urinary sodium to potassium ratio.
      In addition, casual morning urine measurements may not reflect circadian rhythm in day shift workers.
      • Moore-Ede M.C.
      • Herd J.A.
      Renal electrolyte circadian rhythms: independence from feeding and activity patterns.
      Despite the inevitable limitations, several evaluations have shown that spot urine estimates correlate with 24-hour urine excretion values.
      • Kawasaki T.
      • Itoh K.
      • Uezono K.
      • Sasaki H.
      A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults.
      ,
      • Tanaka T.
      • Okamura T.
      • Miura K.
      • et al.
      A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen.
      The Kawasaki formula had been shown to be more accurate in estimating 24-hour urinary sodium excretion amounts from spot urine measurements than the Tanaka formula.
      • Peng Y.
      • Li W.
      • Wang Y.
      • et al.
      Validation and assessment of three methods to estimate 24-h urinary sodium excretion from spot urine samples in Chinese adults.
      ,
      • Mente A.
      • O'Donnell M.J.
      • Dagenais G.
      • et al.
      Validation and comparison of three formulae to estimate sodium and potassium excretion from a single morning fasting urine compared to 24-h measures in 11 countries.
      In addition, the Kawasaki formula had been used in several large worldwide observational analyses evaluating the relation between urinary and potassium and adverse outcomes.
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.
      ,
      • Mente A.
      • O'Donnell M.
      • Rangarajan S.
      • et al.
      Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies.
      ,
      • O'Donnell M.
      • Mente A.
      • Rangarajan S.
      • et al.
      Urinary sodium and potassium excretion, mortality, and cardiovascular events.
      Therefore, the Kawasaki formula was used for estimating urinary sodium and potassium excretion amounts in this study. The mean sodium excretion amount of 4.9 g/d estimated through the Kawasaki formula was comparable to the 4.7 g/d mean 24-hour excretion amount in Koreans assessed in the INTERSALT (International Study of Sodium, Potassium, and Blood Pressure) study, suggesting that the probability of the spot urine estimation would not largely differ from the actual 24-hour excretion amount.
      Intersalt Cooperative Research Group
      Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion.
      Nonetheless, evaluations measuring sodium and potassium excretion amounts through actual 24-hour urine collections are needed to confirm the findings of this study.

      Study Limitations

      First, urine specimens for urine electrolyte measurements were collected only at baseline. As individuals’ dietary habits may change over time, sodium and potassium intake at baseline may not precisely reflect the dietary pattern of an individual during the observation period. Evaluations considering urinary excretion levels of electrolytes as time-varying variables are needed. Second, the primary outcome of the current study follows the Kidney Disease: Improving Global Outcomes definition of CKD which has been used in several epidemiologic studies.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      Chapter 2: definition, identification, and prediction of CKD progression.
      • Xie Y.
      • Bowe B.
      • Li T.
      • Xian H.
      • Yan Y.
      • Al-Aly Z.
      Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.
      • Targher G.
      • Mantovani A.
      • Pichiri I.
      • et al.
      Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes.
      However, the possibility of acute kidney injury being the reason for eGFR decline cannot be fully ruled out. Nonetheless, eGFR recovered to greater than or equal to 60 mL/min per 1.73m2 after primary outcome in only 6 (1.6%) people, suggesting that the probability of acute kidney injury being included as an outcome would not be high. Third, the detailed type of medications including antihypertensive medication had not been collected in the current study. However, the prevalence of diabetes, which would be one of the main indications for renin-angiotensin aldosterone system blockade use, was comparable among the Na/K tertile groups. In addition, the prevalence of antihypertensive medication use was, in fact, highest in the group with the lowest urine Na/K values. Therefore, the possibility of proteinuria being masked through renin-angiotensin aldosterone system blockade usage would not be high. Regarding diuretics, only five people were reported to be prescribed with diuretics, and the proportion of diuretic users was similar across the urine Na/K ratio tertile groups. Therefore, the use of diuretics may have had minimal effect on the results. Nevertheless, the likelihood of antihypertensive medication type being a bias of outcome cannot be completely eliminated, and other medications such as vasopressin may have influenced the urine sodium or potassium concentration. Fourth, because of the observational nature of the study, a clear causal relationship between the urinary Na/K ratio and CKD development cannot be concluded.

      Conclusion

      A low urinary Na/K ratio was associated with a decreased risk of CKD among adults with preserved kidney function. The balance between dietary sodium and potassium intakes may have a greater effect on kidney function than the dietary intake of sodium or potassium alone. However, further evaluations are required to confirm these findings.

      Potential Competing Interests

      The authors report no potential competing interests.

      Acknowledgments

      The authors thank the staff and participants of the Korean Genome and Epidemiology Study (KoGES) for important contributions.
      The epidemiologic data used in this study were obtained from the Korean Genome and Epidemiology Study (KoGES; 4851–302) of the National Research Institute of Health, Centers for Disease Control and Prevention, Ministry for Health and Welfare, Republic of Korea.
      Funding sources for KoGES had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

      Supplemental Online Material

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      • In the Limelight: December 2022
        Mayo Clinic ProceedingsVol. 97Issue 12
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