Original Article

Association Between Urinary Sodium, Creatinine, Albumin, and Long-Term Survival in Chronic Kidney DiseaseNovelty and Significance

Emily P. McQuarrie, Jamie P. Traynor, Alison H. Taylor, E. Marie Freel, Jonathan G. Fox, Alan G. Jardine, Patrick B. Mark
https://doi.org/10.1161/HYPERTENSIONAHA.113.03093
Hypertension. 2014;64:111-117
Originally published April 14, 2014

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Abstract

Dietary sodium intake is associated with hypertension and cardiovascular risk in the general population. In patients with chronic kidney disease, sodium intake has been associated with progressive renal disease, but not independently of proteinuria. We studied the relationship between urinary sodium (UNa) excretion and UNa to creatinine ratio and mortality or requirement for renal replacement therapy in chronic kidney disease. Adult patients attending a renal clinic who had ≥1 24-hour UNa measurement were identified. Twenty-four-hour UNa measures were collected and UNa to creatinine ratio calculated. Time to renal replacement therapy or death was recorded. Four hundred twenty-three patients were identified with mean estimated glomerular filtration rate of 48 mL/min per 1.73 m2. Ninety patients required renal replacement therapy and 102 patients died. Mean slope decline in estimated glomerular filtration rate was −2.8 mL/min per 1.73 m2 per year. Median follow-up was 8.5 years. Patients who died or required renal replacement therapy had significantly higher UNa excretion and UNa to creatinine ratio, but the association with these parameters and poor outcome was not independent of renal function, age, and albuminuria. When stratified by albuminuria, UNa to creatinine ratio was a significant cumulative additional risk for mortality, even in patients with low-level albuminuria. There was no association between low UNa and risk, as observed in some studies. This study demonstrates an association between UNa excretion and mortality in chronic kidney disease, with a cumulative relationship between sodium excretion, albuminuria, and reduced survival. These data support reducing dietary sodium intake in chronic kidney disease, but additional study is required to determine the target sodium intake.

Introduction

Experimental and population studies have established dietary sodium intake as a key mediator of blood pressure,1 with sodium reduction demonstrating a fall in systolic blood pressure of 3 to 5 mm Hg.2,3 The Trial of Hypertension Prevention (TOHP) demonstrated a 25% cardiovascular risk reduction with a low sodium diet.4 Population extrapolations suggest that salt-related blood pressure elevation accounts for 14% of strokes and 9% of myocardial infarctions.5 Damaging effects of dietary sodium on end organs have been shown in hypertension, including left ventricular hypertrophy and albuminuria.6–8 However, conflicting data exist, with a Cochrane Review finding no definitive evidence that sodium intake directly has an effect on cardiovascular risk.9

Sodium intake is widely thought to influence the progression of chronic kidney disease (CKD), independently of the effects on blood pressure.10 Experimental evidence suggests a direct pathogenic role for increased sodium intake in renal failure,11 and sodium reduction has been shown to reduce proteinuria in CKD.12,13 One Italian study14 showed patients with low urinary sodium (UNa) excretion to have lower baseline creatinine clearance, but slower long-term progression of CKD. Long-term follow-up from the Ramipril in Nondiabetic Renal Failure (REIN) cohort demonstrated that higher UNa to creatinine ratio (UNa:Cr) was associated with the progression to end-stage renal failure.15

UNa excretion (mmol/24 hours) is a reliable method of measuring sodium intake, independent of dietary assessment, even in patients with reduced estimated glomerular filtration rate (eGFR), where 90% of ingested sodium is excreted in the urine.2 UNa mirrors dietary sodium intake in patients with CKD.16 The kidney adapts to reduced nephron mass by altering sodium handling and increasing fractional excretion of sodium. Because overall GFR declines with falling nephron mass, there is an increase in single nephron GFR, decreased proximal tubular sodium reabsorption, and altered capacity of the distal tubule to reabsorb sodium,17 increasing fractional excretion of sodium. Therefore, the kidneys maintain sodium homeostasis between intake and excretion.

Measuring urinary creatinine excretion takes account of muscle mass, and calculating UNa:Cr may minimize the inaccuracy associated with 24-hour collections. One caveat is that lower urinary creatinine has been associated with worse outcome.18 In this study, we assessed whether UNa excretion, corrected for urinary creatinine, as a method to maximize the utility of 24-hour urine collection correlates with renal outcome or patient survival in CKD.

Patients

Adult patients attending renal clinics at Glasgow Royal Infirmary between 1992 and 2007 who had ≥1 24-hour UNa measurement were identified using the electronic patient records. Patients were advised to collect urine for 24 hours after the first void. Urinary electrolytes were measured using flame photometry in a standard laboratory. The 24-hour UNa:Cr was calculated as millimoles per millimoles; UNa:Cr has no units. The date of first UNa measurement was deemed the date of study entry. Trained nurses measured blood pressure manually 3 times, using standardized sphygmomanometers; the mean of the last 2 measurements was recorded. Height and weight were recorded. Baseline drug therapy, eGFR using the 4-variable Modification of Diet in Renal Disease formula, and albuminuria as urinary albumin to creatinine ratio (uACR) were also recorded. The electronic patient record was updated prospectively. General advice was given regarding reducing sodium intake, but a dietician did not routinely assess the patients. Patients receiving renal replacement therapy (RRT) at the time of measurement, patients without weight recording, and patients without eGFR recording at the time of UNa measurement and ≥1 additional reading were excluded. Patients with decline in eGFR >10 mL/min per 1.73 m2 per year were excluded to provide a cohort with slowly progressive CKD. The West of Scotland Ethics committee granted a waiver to approve this study as analysis of routinely collected clinical data.

Outcomes and Analysis

Dates of starting RRT or death were recorded. Each outcome was analyzed separately and together, censoring for death after starting RRT. Annual decline in eGFR was calculated. Baseline demographics were compared using Student t test, Mann–Whitney U test, χ2 test, or 1-way ANOVA as appropriate with mean values and standard deviation presented for normally distributed data and median and interquartile range for nonnormally distributed data. Correlations between UNa measures and other factors were ascertained using Spearman or Pearson correlation coefficients. Kaplan–Meier survival analysis was performed for time to RRT or death for patients divided by quartiles of UNa:Cr or stratified by group of UNa:Cr and uACR based on the median value for each, with significance estimated by the log-rank method. Cox survival analysis was performed to determine independent predictors of RRT and death, with variables identified as significantly influential on outcome by univariate analysis entered into a backward stepwise regression model.19 Different measures of UNa excretion were entered separately because of collinearity. Data were analyzed using SPSS version 21 (IBM, Armonk, NY), with Kaplan–Meier curves drawn with KMWin20 using R (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Demographics

Table 1 summarizes baseline demographics for the cohort. Four hundred twenty-three patients were included. Of these, 50.1% were men with mean age of 51.1 (SD, 16.8) years. Figure S1 in the online-only Data Supplement shows the overall cohort with excluded subjects. Mean baseline eGFR was 48 (SD, 28) mL/min per 1.73 m2. Mean UNa was 155.8 (SD, 66.0) mmol/24 hours, and mean UNa:Cr was 16.4 (SD, 5.9). One hundred fifty-four patients had repeat UNa available. Median time to repeat sampling was 385 (interquartile range, 800) days. Repeat UNa correlated with first UNa (R=0.56; P<0.001) with a difference between mean first and second UNa of 2.0 mmol/24 hours. Average change in UNa was −2.5%. Primary renal disease was specified in 199 (47.0%) patients and was renovascular disease (n=68), diabetic nephropathy (n=39), tubulointerstitial disease/polycystic kidney disease (n=51), glomerulonephritis (n=39), and others (n=8). The remainder was recorded as CKD of unknown cause.

View this table:
Table 1.

Baseline Demographics of Cohort

UNa Excretion in Patients With CKD

Patients with lower eGFR had lower UNa levels, particularly in CKD stage 5 (Figure 1A), although there were significant differences across all CKD groups (1-way ANOVA; P<0.001). UNa:Cr increased with progressive CKD (Figure 1B). To ascertain the factors correlated with UNa excretion, the following factors were entered into a correlation matrix: UNa, UNa:Cr, age, weight, eGFR, blood pressure, and uACR. UNa correlated with higher weight (R=0.37; P<0.001), higher eGFR (0.206; P=0.001), log10 uACR (−0.15; P=0.003), mean arterial pressure (0.10; P=0.041), but not systolic blood pressure or diastolic blood pressure. UNa was not significantly correlated with age. UNa was higher in men (174 versus 137 mmol/24 hours; P<0.001). UNa was lower in patients prescribed diuretics (145 versus 159 mmol/24 hours; P=0.05), but there were no significant differences in UNa between those receiving and those not receiving angiotensin-converting enzyme inhibitors.

Figure 1.
Figure 1.

A, Bar chart of mean urinary sodium excretion (mmol/24 h) and 1 SD by chronic kidney disease (CKD) stage; P<0.001 by 1-way ANOVA. B, Bar chart of mean urinary sodium to creatinine ratio (UNa:Cr) and 1 SD by CKD stage; P<0.001 by 1-way ANOVA.

UNa:Cr correlated with age (R=0.30; P<0.001), systolic blood pressure (0.22; P<0.001), mean arterial pressure (0.12; P=0.02), lower eGFR (−0.23; P<0.001), and higher log10 uACR (0.15; P=0.003). There were no significant correlations with diastolic blood pressure or weight. UNa:Cr was higher in women (17.5 versus 15.3; P<0.001) and in patients prescribed diuretics (P<0.001) but not angiotensin-converting enzyme inhibitors.

UNa and Albumin Excretion

To assess the interaction between uACR and UNa:Cr, subjects were divided into groups based on high or low uACR and UNa:Cr, respectively, with subjects allocated to high or low group based on uACR or UNa:Cr being above or below the median value for the cohort. The cut points were 11 mg/mmol and 16.0 for uACR and UNa:Cr, respectively. The 4 groups are shown in Table 2 with significant differences in age, renal function, and blood pressure being demonstrated across the groups.

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Table 2.

Demographics of Patients by Stratum of Combined uNA:Cr and uACR

UNa and Albumin Excretion and Death and Need for RRT

Ninety patients (21.3%) required RRT and 102 patients died (24.1%) during follow-up. The cause of death was cardiovascular disease (n=25), infection (n=13), malignancy (n=2), known other (n=19), and unknown (n=43). Forty-eight patients died after receiving RRT. One hundred forty-four (34.0%) patients either required RRT or died. Censoring for death or RRT, median follow-up for the cohort was 8.5 (interquartile range, 6.7) years. Mean slope decline in eGFR was −2.8 (4.0) mL/min per 1.73 m2 per year. Characteristics of patients who died or required RRT during follow-up are shown in Table S1. Kaplan–Meier analysis demonstrated that highest UNa or UNa:Cr groups exhibited reduced patient survival and combined patient and renal survival (P<0.001; Figure S2). Higher UNa:Cr was not associated with significantly reduced time to requirement for RRT (P=0.087). Effect of interaction between uACR and UNa:Cr was tested using the groups in Table 2. Patients with higher UNa:Cr were at greater risk of both death and requirement for RRT, irrespective of uACR status (Figure 2B). Increased uACR was an additional risk for reduced patient and renal survival (Figure 2). The effect of interaction between UNa:Cr and uACR on survival analysis to death, RRT, or either death or RRT was also performed with patients stratified by diuretic use (Figures S3 and S4) or by eGFR >45 or <45 mL/min per 1.73 m2 (Figure S5). To assess the implications of UNa and albuminuria, survival analysis was performed with patients stratified into high and low UNa and albuminuria groups based on median UNa (143 mmol/24 hours) and uACR (11 mg/mmol). In these analyses, patients with lower UNa had relatively improved outcome, with patients in higher albuminuria groups having poorer outcome (Figure S6).

Figure 2.
Figure 2.

A, Kaplan–Meier survival plot of time to death by group of urinary sodium to creatinine ratio (UNa:Cr) and albuminuria. Kaplan–Meier survival plot of survival to requirement for renal replacement therapy by group of UNa:Cr and albuminuria (1=low UNa:Cr, low urinary albumin to creatinine ratio [uACR]; 2=high UNa:Cr, low uACR; 3=low UNa:Cr, high uACR; 4=high UNa:Cr, high uACR). Comparison by log-rank test and estimate of significance for both A and B; P<0.001.

Cox Regression Analyses

Cox regression analysis was performed to identify independent predictors of death, RRT, or RRT or death (Table 3; Tables S2 and S3). Albuminuria, eGFR, and age were independent predictors of death, whereas UNa:Cr was not an independent predictor of death (P=0.085). Albuminuria and eGFR were predictors of need for RRT, whereas eGFR while diuretic use appeared protective. Albuminuria and age were predictors of the combined outcome of death or RRT. Additional analyses were performed separately for subjects receiving or not receiving diuretic therapy with consistent results irrespective of diuretic status (Tables S4–S9). Figure 3 demonstrates hazard plots for risk of death or RRT stratified by combined UNa:Cr group and albuminuria after adjusting for age, sex, eGFR, mean arterial pressure, diuretic, and angiotensin-converting enzyme inhibitor usage. This demonstrates the association between cumulative uACR and UNa:Cr grouping and significantly increased the risk of death or RRT.

View this table:
Table 3.

Cox Regression Survival Analyses for End Point of Death (Death as the Dependent Variable; n=102)

Figure 3.
Figure 3.

Hazard plot of risk of death or renal replacement therapy by combined urinary sodium to creatinine ratio (UNa:Cr) and albuminuria (1=low UNa:Cr, low urinary albumin to creatinine ratio [uACR]; 2=high UNa:Cr, low uACR; 3=low UNa:Cr, high uACR; 4=high UNa:Cr, high uACR) after adjusting for age, sex, estimated glomerular filtration rate (eGFR), proteinuria, mean arterial pressure (MAP), and diuretic or angiotensin-converting enzyme inhibitors (ACEi) usage. Variables included in the Cox regression model were age, eGFR, sex, MAP, log10 uACR, UNa:Cr, ACEi use, and diuretic use.

Discussion

In this study, we demonstrate an association between UNa excretion, a marker of dietary sodium intake, and mortality in patients with CKD. However, this relationship did not persist after adjusting for age, renal function, blood pressure, and albuminuria. UNa was associated with the risk of requiring RRT, but not independent of albuminuria or baseline eGFR, findings similar to post hoc analyses of the REIN studies.15

The mean sodium excretion in our cohort was equivalent to a dietary salt intake of 9.1 g per day, lower than the United Kingdom average, reflecting the combined effects of dietary advice and malnutrition in CKD.21 We adjusted UNa for urinary creatinine excretion, which corrects for muscle mass, but may also take into account reduced GFR, or reduced tubular secretion of creatinine in CKD. The use of 24-hour UNa:Cr rather than 24-hour UNa may reduce the bias associated with incomplete urine collections, similar to using the uACR to estimate albumin excretion. Because uACR also depends on urinary creatinine, its prognostic role is also determined by low urinary creatinine, which reflects frailty and low muscle mass. Low urinary creatinine may also partly explain the prognostic value of UNa:Cr in our study. Twenty-four-hour urine collection remains the best method for assessing sodium excretion, and our UNa:Cr was derived from a 24-hour collection. Spot samples are less representative because of circadian variation in sodium excretion.

We observed lower UNa excretion in patients with lower eGFR, perhaps because of reduced dietary intake related to poor appetite. Alternatively, despite increasing fractional sodium excretion, the failing kidneys may be unable to excrete sodium fully. However, even if sodium is stored in nonosmotically active form, as recently proposed,22 the accumulation of vast amounts of sodium over a prolonged period would overwhelm storage sites. Thus, even in advanced CKD, patients are in sodium balance, and UNa reflects dietary intake.

There are multiple mechanisms for sodium-mediated damage. Hemodynamic effects mediated via volume retention include increased shear stress, endothelial dysfunction, elevated cardiac preload, vascular stiffness, and elevated afterload and left ventricular hypertrophy. Nonhemodynamic factors such as oxidative stress via superoxide production23 and inflammation have also been demonstrated.24,25

Damaging effects of dietary sodium intake on end organs have been shown in various populations. A study of normotensive and never-treated hypertensives showed that high dietary sodium intake was associated with left ventricular hypertrophy and albuminuria.6 The Framingham Offspring Study demonstrated increasing UNa to be associated with increasing uACR,7,8 using spot UNa samples normalized to creatinine. Using spot samples could introduce variability because UNa excretion may vary throughout the day. The large Scottish Heart Health Study, drawn from a population similar to ours, showed that UNa predicted coronary heart disease in women.26

Controversy exists regarding the influence of low sodium intake on cardiovascular events in the general population. A large pan-European study in patients without cardiovascular disease found low UNa excretion to be associated with increased cardiovascular risk.27 Post hoc analyses of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assesment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trials in patients at high cardiovascular risk demonstrated J-shaped relationships between UNa and outcome,28 whereas data from ONTARGET suggest that sodium intake does not per se increase the risk of CKD in diabetes mellitus.29 Therefore, in non-CKD populations, although reduction in dietary sodium intake may be beneficial, there may be a lower threshold of optimum sodium intake.

In patients with CKD, proteinuria (or albuminuria) is a major predictor of both CKD progression30 and predicts cardiovascular disease in both CKD and the general population.31,32 In univariate analyses, we demonstrated that increased UNa excretion has cumulative effects with albuminuria on both renal and patient survival in patients with low and high urinary albumin excretion. Lowering dietary sodium intake has been shown to reduce proteinuria, independent of blood pressure.12 The antiproteinuric response to renin–angiotensin system inhibitors is augmented by a low sodium diet.33 A recent crossover study has shown salt restriction to have dramatic effects on blood pressure, vascular function, and proteinuria in patients with CKD.34 These results provide powerful arguments for salt restriction in CKD. Although observational, our study adds weight to the notion that sodium restriction is beneficial. A prospective randomized controlled trial in optimally treated patients with CKD is required, addressing the effects of reduced sodium intake on mortality, cardiovascular events, and commencement of RRT.

Our study has several limitations. This was a retrospective cohort study using prospectively collected data. Patients were prescribed several different medications. Variations in diet during follow-up are not accounted for, but in a subset of patients with 2 collections, UNa was relatively constant over time. An assessment of nutritional status would be useful. We do not have causes of death for all patients. Despite attempting to ensure complete urinary collections, some may be incomplete. As an observational study, we report associations and cannot prove causality. There may be collinearity between some of the variables in the multivariate model. We have not assessed the effect of sodium intake on nonfatal cardiovascular events. Because low urinary creatinine is a major component of poor outcome, it is difficult to dissociate any relationship between UNa:Cr, uACR, and outcome and that driven solely by urinary creatinine.18 A larger study would be required to prove this. Nonetheless, UNa:Cr represents a useful marker for monitoring sodium intake and may be a target for interventional studies examining long-term effect of sodium reduction in CKD.

Perspectives

A high 24-hour UNa:Cr, reflective of proportionally high dietary sodium intake in CKD, is associated with significantly increased risk of death, but not independent of eGFR, age, and albuminuria. There is a cumulative relationship between UNa:Cr and albuminuria on adverse outcomes. These are novel findings and the first to observe a relationship between sodium intake and mortality in CKD. Further long-term studies to determine optimal sodium intake in CKD are required.

Sources of Funding

This work was funded by Syskid European Union’s FP7, grant agreement number HEALTH-F2-2009-241544. E.M. Freel is funded by a Medical Research Council Clinician Scientist Fellowship (reference number G0802803). This work is also supported by Darlinda’s Charity for Renal Research.

Disclosures

None.

Footnotes

  • Received December 27, 2013.
  • Revision received March 15, 2014.
  • Accepted March 18, 2014.

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Novelty and Significance

What Is New?

  • Urinary sodium (UNa) to creatinine ratio is higher with increasing severity of chronic kidney disease (CKD).

  • High UNa intake reflected by a high UNa or high UNa to creatinine ratio is associated with reduced survival in patients with CKD irrespective of albuminuria status.

  • Association between high UNa or high UNa to creatinine ratio and increased need for renal replacement therapy is not independent of baseline renal function or albuminuria.

What Is Relevant?

  • These data support the notion of reducing dietary sodium intake in patients with CKD.

  • The major benefit of sodium reduction is likely to be on patient survival and not on progression of renal disease.

  • Further study is required to inform target levels of sodium intake in patients with CKD.

Summary

We have demonstrated an association between UNa excretion and mortality in CKD and a cumulative relationship between sodium excretion, albuminuria, and reduced survival.

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  • Association Between Urinary Sodium, Creatinine, Albumin, and Long-Term Survival in Chronic Kidney DiseaseNovelty and Significance
    Emily P. McQuarrie, Jamie P. Traynor, Alison H. Taylor, E. Marie Freel, Jonathan G. Fox, Alan G. Jardine and Patrick B. Mark
    Hypertension. 2014;64:111-117, originally published April 14, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.113.03093
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