Urinary sodium excretion and kidney failure in nondiabetic chronic kidney disease
2014; Elsevier BV; Volume: 86; Issue: 3 Linguagem: Inglês
10.1038/ki.2014.59
ISSN1523-1755
AutoresLi Fan, Hocine Tighiouart, Andrew S. Levey, Gerald J. Beck, Mark J. Sarnak,
Tópico(s)Blood Pressure and Hypertension Studies
ResumoCurrent guidelines recommend under 2g/day sodium intake in chronic kidney disease, but there are a few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-h urinary sodium excretion was 3.46g/day. Kidney failure developed in 617 participants, and the composite outcome was reached in 723. In the primary analyses, there was no association between 24-h urine sodium and kidney failure (HR 0.99 (95% CI 0.91–1.08)) nor on the composite outcome (HR 1.01 (95% CI 0.93–1.09)), each per 1g/day higher urine sodium. In exploratory analyses, there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a two-slope model, when urine sodium was under 3g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1g/day and with lower risk of kidney failure in those with baseline proteinuria of ⩾1g/day. There was no association between urine sodium and kidney failure when urine sodium was⩾3g/day. Results were consistent using first baseline and time-dependent urinary sodium excretion. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored. Current guidelines recommend under 2g/day sodium intake in chronic kidney disease, but there are a few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-h urinary sodium excretion was 3.46g/day. Kidney failure developed in 617 participants, and the composite outcome was reached in 723. In the primary analyses, there was no association between 24-h urine sodium and kidney failure (HR 0.99 (95% CI 0.91–1.08)) nor on the composite outcome (HR 1.01 (95% CI 0.93–1.09)), each per 1g/day higher urine sodium. In exploratory analyses, there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a two-slope model, when urine sodium was under 3g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1g/day and with lower risk of kidney failure in those with baseline proteinuria of ⩾1g/day. There was no association between urine sodium and kidney failure when urine sodium was⩾3g/day. Results were consistent using first baseline and time-dependent urinary sodium excretion. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored. Data from clinical trials and observational studies have convincingly demonstrated that increased sodium intake leads to higher blood pressure.1.Sacks F.M. Svetkey L.P. Vollmer W.M. et al.Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med. 2001; 344: 3-10Crossref PubMed Scopus (3944) Google Scholar,2.Forman J.P. Scheven L. de Jong PE, et al. Association between sodium intake and change in uric acid, urine albumin excretion, and the risk of developing hypertension.Circulation. 2012; 125: 3108-3116Crossref PubMed Scopus (72) Google Scholar Current guidelines therefore recommend low sodium intake for management and prevention of hypertension. The Kidney Disease Improving Global Outcomes guideline recommends a sodium intake of <2g/day but acknowledges that this recommendation is based primarily on data in the general population and not on hard clinical end points, as well as on the inference that interventions that reduce blood pressure will reduce progression of kidney disease; therefore, it was given a 1C recommendation.3.Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.Kidney Int Suppl. 2012; 2: 337-414Abstract Full Text Full Text PDF Scopus (415) Google Scholar There are fewer data, particularly trial data, relating sodium intake to the long-term outcomes of cardiovascular disease (CVD), mortality, and kidney failure. A recent meta-analysis4.He F.J. MacGregor G.A. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials.Lancet. 2011; 378: 380-382Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar in the general population has suggested a modest effect of reduced salt intake on CVD outcomes, but observational data in the general population and in individuals with diabetes have created some controversy in that low sodium intake has been associated with higher risk of mortality and kidney failure.5.O'Donnell M.J. Yusuf S. Mente A. et al.Urinary sodium and potassium excretion and risk of cardiovascular events.JAMA. 2011; 306: 2229-2238Crossref PubMed Scopus (460) Google Scholar, 6.Stolarz-Skrzypek K. Kuznetsova T. Thijs L. et al.Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion.JAMA. 2011; 305: 1777-1785Crossref PubMed Scopus (456) Google Scholar, 7.Ekinci E.I. Clarke S. Thomas M.C. et al.Dietary salt intake and mortality in patients with type 2 diabetes.Diabetes Care. 2011; 34: 703-709Crossref PubMed Scopus (254) Google Scholar, 8.Thomas M.C. Moran J. Forsblom C. et al.The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866Crossref PubMed Scopus (270) Google Scholar In patients with chronic kidney disease (CKD), studies have shown that low sodium intake reduces urinary excretion of protein, which in turn is a risk factor of kidney disease progression.2.Forman J.P. Scheven L. de Jong PE, et al. Association between sodium intake and change in uric acid, urine albumin excretion, and the risk of developing hypertension.Circulation. 2012; 125: 3108-3116Crossref PubMed Scopus (72) Google Scholar,9.Swift P.A. Markandu N.D. Sagnella G.A. et al.Modest salt reduction reduces blood pressure and urine protein excretion in black hypertensives: a randomized control trial.Hypertension. 2005; 46: 308-312Crossref PubMed Scopus (147) Google Scholar The benefit of low sodium has been particularly noted in those treated with renin-angiotensin-aldosterone system inhibitors.10.Vogt L. Waanders F. Boomsma F. et al.Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan.J Am Soc Nephrol. 2008; 19: 999-1007Crossref PubMed Scopus (297) Google Scholar, 11.Slagman M.C. Waanders F. Hemmelder M.H. et al.Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial.BMJ. 2011; 343: d4366Crossref PubMed Scopus (201) Google Scholar, 12.Lambers Heerspink H.J. Holtkamp F.A. Parving H.H. et al.Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.Kidney Int. 2012; 82: 330-337Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 13.Vegter S. Perna A. Postma M.J. et al.Sodium intake, ACE inhibition, and progression to ESRD.J Am Soc Nephrol. 2012; 23: 165-173Crossref PubMed Scopus (232) Google Scholar There are no studies of which we are aware in nondiabetic CKD, with multiple measures of baseline and follow-up of urinary sodium excretion, long-term follow-up, and with a large number of kidney failure outcomes. We therefore evaluated the association of 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality in the long-term follow-up of participants in the Modification of Diet in Renal Disease (MDRD) Study. In exploratory analyses, we also evaluated whether the association of urine sodium with kidney failure varies by glomerular filtration rate (GFR), level of proteinuria, and angiotensin-converting enzyme (ACE) inhibitor use given their potential relationships with both sodium intake and kidney failure.2.Forman J.P. Scheven L. de Jong PE, et al. Association between sodium intake and change in uric acid, urine albumin excretion, and the risk of developing hypertension.Circulation. 2012; 125: 3108-3116Crossref PubMed Scopus (72) Google Scholar,8.Thomas M.C. Moran J. Forsblom C. et al.The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866Crossref PubMed Scopus (270) Google Scholar,11.Slagman M.C. Waanders F. Hemmelder M.H. et al.Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial.BMJ. 2011; 343: d4366Crossref PubMed Scopus (201) Google Scholar, 12.Lambers Heerspink H.J. Holtkamp F.A. Parving H.H. et al.Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.Kidney Int. 2012; 82: 330-337Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 13.Vegter S. Perna A. Postma M.J. et al.Sodium intake, ACE inhibition, and progression to ESRD.J Am Soc Nephrol. 2012; 23: 165-173Crossref PubMed Scopus (232) Google Scholar, 14.He F.J. Marciniak M. Visagie E. et al.Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives.Hypertension. 2009; 54: 482-488Crossref PubMed Scopus (192) Google Scholar We also evaluated interactions by blood pressure target and protein-intake targets given the randomized nature of the study. Mean (SD) age of participants was 51.7±12.4 years, 60% were male and 85% white. Twenty-four percent of the cohort had polycystic kidney disease, 31% had glomerular diseases, and 45% were classified as having other forms of kidney disease. Five percent of participants had a history of diabetes and 13% had a history of CVD. Mean (s.d.) measured GFR was 32.5±12.0ml/min per 1.73m2, median (25th, 75th) 24-h proteinuria was 0.32 (0.07, 1.51) g/day, mean (s.d.) 24-h urinary sodium excretion was 3.46±1.13g/day, and 36% of participants were receiving ACE inhibitors at baseline (Table 1).Table 1Baseline characteristics by baseline mean 24-h urinary sodium excretion24-h Urinary sodium excretion, g/dayVariableOverall n=840Quartile 1 n=210Quartile 2 n=210Quartile 3 n=210Quartile 4 n=210P-value for linear trend24-h Urinary sodium excretion (g/day)3.46±1.132.14±0.443.05±0.173.70±0.214.96±0.78NAAge (years)51.7±12.451.1±12.752.4±12.853.3±12.350.1±11.60.408Men (%)60.537.652.967.184.3<0.001White (%)85.081.084.387.687.10.047Kidney disease diagnosis (%)0.020 Polycystic kidney disease23.827.126.722.918.6 Glomerular disease31.425.732.429.538.1 Other44.847.141.047.644.3BMI (kg/m2)27.1±4.424.9±3.826.4±4.227.7±4.129.5±4.3<0.001Systolic BP (mmHg)131.9±17.6129.9±17.5132.5±17.8132.9±18.9132.4±15.90.077Diastolic BP (mmHg)81.0±10.179.4±9.980.7±9.981.2±10.482.6±10.00.001Diabetes (%)5.13.32.47.17.60.010History of CVD (%)13.19.515.216.211.40.522Current smoker (%)9.88.69.110.011.50.291LDL (mg/dl)147.4±41.3146.7±41.3153.0±44.1146.4±38.0143.6±41.20.450HDL (mg/dl)39.9±14.345.2±16.441.0±13.437.8±13.535.4±11.5<0.001mGFR (ml/min per 1.73m2)32.5±12.030.4±12.831.6±11.731.6±11.636.5±11.0<0.001Urinary protein excretion (g/day)0.32 (0.07, 1.51)0.25 (0.07, 1.03)0.19 (0.06, 1.24)0.53 (0.07, 1.69)0.53 (0.08, 2.00)0.002Urinary creatinine excretion (g/day)1.40 (1.06, 1.70)1.31 (1.05, 1.74)1.31 (1.05, 1.63)1.42 (1.08, 1.74)1.33 (1.05, 1.64)0.884Blood pressure target0.174 Usual target blood pressure (%)48.646.745.749.552.3 Low target blood pressure (%)51.453.354.350.547.6 ACEi (%)36.032.434.340.536.70.198 Diuretic (%)40.533.839.546.741.90.038Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mGFR, measured glomerular filtration rate.Note: data presented as mean±s.d., percentage or median (25th, 75th). Conversion factors for units: urinary sodium excretion in mEq/day to g/day, × 0.02299; cholesterol, LDL and HDL cholesterol in mg/dl to mmol/l, × 0.02586; mGFR in ml/min per 1.73m2 to ml/s per 1.73m2, × 0.01667. Open table in a new tab Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; mGFR, measured glomerular filtration rate. Note: data presented as mean±s.d., percentage or median (25th, 75th). Conversion factors for units: urinary sodium excretion in mEq/day to g/day, × 0.02299; cholesterol, LDL and HDL cholesterol in mg/dl to mmol/l, × 0.02586; mGFR in ml/min per 1.73m2 to ml/s per 1.73m2, × 0.01667. Participants in the higher quartiles of urinary sodium excretion were more likely to be male, have a history of diabetes, have higher body mass index, measured GFR, and proteinuria, and have lower levels of high-density lipoprotein cholesterol. Urinary excretion of creatinine was similar in each of the quartiles. Median follow-up time was 6 years (range, 0.25–18.61 years) for kidney failure. A total of 617 (9.53 per 100 patient-years) patients developed kidney failure and 723 (11.17 per 100 patient-years) reached the composite outcome of kidney failure or all-cause mortality. In quartiles 1–4, the event rates per 100 patient-years for kidney failure were 9.68, 9.48, 10.81, and 8.33; and 10.93, 11.27, 12.68, and 9.98 for the composite outcome, respectively. In unadjusted and adjusted Cox regression models, there was no association between urine sodium and kidney failure or the composite outcome (Table 2 and Figure 1). There was also no deviation from linearity in these relationships. Results were similar using only the first baseline and cumulative mean time-dependent values for 24-h urinary sodium excretion (Supplementary Table S1 online).Table 2Association of mean baseline 24-h urinary sodium excretion with kidney failure and the composite outcome of kidney failure or mortality in entire cohortUnadjusted modelAdjusted modelaAdjusted for age, sex, race, cause of kidney disease, measured glomerular filtration rate, log urine protein, body mass index, systolic blood pressure (BP), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, history of cardiovascular disease, angiotensin-converting enzyme inhibitor use, diuretics use, MDRD (Modification of Diet in Renal Disease) Study A or B, and randomization to BP and dietary protein target.Event N (%)HR (95% CI)P-valueHR (95% CI)P-valueKidney failure617 (73.5)0.98 (0.91, 1.05)0.5380.99 (0.91, 1.08)0.863Composite outcome723 (86.1)1.00 (0.94, 1.06)0.9261.01 (0.93, 1.09)0.804Abbreviations: CI, confidence interval; HR, hazard ratio.HRs were per 1g/day higher urine sodium.a Adjusted for age, sex, race, cause of kidney disease, measured glomerular filtration rate, log urine protein, body mass index, systolic blood pressure (BP), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, history of cardiovascular disease, angiotensin-converting enzyme inhibitor use, diuretics use, MDRD (Modification of Diet in Renal Disease) Study A or B, and randomization to BP and dietary protein target. Open table in a new tab Download .doc (.06 MB) Help with doc files Supplementary Material Abbreviations: CI, confidence interval; HR, hazard ratio. HRs were per 1g/day higher urine sodium. Figure 2 demonstrates the adjusted hazard ratios (HRs) and interaction P-values for 24-h urinary sodium excretion and kidney failure overall and in subgroups. There was a significant interaction between 24-h urinary sodium and urinary protein excretion (P=0.019 in the adjusted model) for kidney failure. The optimal knot for the two-slope model for urine sodium corresponded to 3g/day. Table 3 shows the HRs for kidney failure and the composite outcome in the subgroups with baseline urine protein levels<1g/day and⩾1g/day. When 24-h urinary sodium excretion was<3g/day, a 1g/day higher urine sodium was associated with a 72% increased risk of kidney failure (HR 1.72 (95% CI, 1.31–2.24)) in patients with baseline proteinuria<1g/day, and a 39% lower risk of kidney failure (HR 0.61 (95% CI, 0.42–0.89)) in those with baseline proteinuria⩾1g/day. In contrast, after adjustment, there was no association between 24-h urinary sodium excretion and kidney failure in patients with urine sodium⩾3g/day. Figure 3 demonstrates these results graphically. Results were for the most part consistent with the composite outcome (Table 3) and in sensitivity analyses using first baseline and cumulative mean time-dependent 24-h urinary sodium excretion (Supplementary Tables S2 and S3 online, respectively).Table 3Association of mean baseline 24-h urinary sodium excretion with kidney failure and composite outcome by baseline urinary protein excretionUnadjusted modelAdjusted modelaAdjusted for age, sex, race, cause of kidney disease, measured glomerular filtration rate, log urine protein, body mass index, systolic blood pressure (BP), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, history of cardiovascular disease, angiotensin-converting enzyme inhibitor use, diuretics use, MDRD (Modification of Diet in Renal Disease) Study A or B, and randomization to BP and dietary protein target.24-h Urine sodium<3g/day24-h Urine sodium⩾3g/day24-h Urine sodium<3g/day24-h Urine sodium⩾3g/dayEventbEvent numbers are applicable for unadjusted and adjusted models.HR (95% CI)P-valueEventbEvent numbers are applicable for unadjusted and adjusted models.HR (95% CI)P-valueHR (95% CI)P-valueHR (95% CI)P-valueKidney failure Baseline urine protein excretion<1g/day1451.37 (1.05, 1.78)0.0202450.85 (0.74, 0.97)0.0211.72 (1.31, 2.24)<0.0010.86 (0.73, 1.02)0.084 Baseline urine protein excretion⩾1g/day680.57 (0.40, 0.81)0.0021590.93 (0.80, 1.08)0.3220.61 (0.42, 0.89)0.0120.97 (0.82, 1.16)0.779Composite outcome of kidney failure or all-cause mortality Baseline urine protein excretion<1g/day1711.42 (1.11, 1.81)0.0053050.88 (0.78, 1.00)0.0481.60 (1.26, 2.05)<0.0010.90 (0.78, 1.04)0.170 Baseline urine protein excretion⩾1g/day740.58 (0.41, 0.80)0.0011730.93 (0.80, 1.07)0.3120.64 (0.45, 0.93)0.0190.97 (0.82, 1.15)0.760Abbreviations: CI, confidence interval; HR, hazard ratio.HRs were per 1g/day higher urine sodium. Interaction P-values between baseline urine sodium and proteinuria were<0.001 for kidney failure and the composite outcome in the adjusted models.a Adjusted for age, sex, race, cause of kidney disease, measured glomerular filtration rate, log urine protein, body mass index, systolic blood pressure (BP), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, history of cardiovascular disease, angiotensin-converting enzyme inhibitor use, diuretics use, MDRD (Modification of Diet in Renal Disease) Study A or B, and randomization to BP and dietary protein target.b Event numbers are applicable for unadjusted and adjusted models. Open table in a new tab Figure 3Unadjusted (a) and adjusted (b) restricted cubic splines for mean baseline 24-h urinary sodium excretion and kidney failure stratified by baseline proteinuria. Splines were plotted using four default knots. P-values for nonlinearity of urine sodium were 0.005 in unadjusted model and 0.003 in adjusted model. Thin dashed lines indicate 95% confidence intervals, and rugs at the bottom and top show location of each value for 24-h urine sodium in those with baseline urine protein<1g/day and⩾1g/day, respectively. The spline in panel b is adjusted for age, sex, race, cause of kidney disease, measured glomerular filtration rate, log urine protein, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, history of cardiovascular disease, angiotensin-converting enzyme inhibitor use, diuretic use, MDRD (Modification of Diet in Renal Disease) Study A or B, randomization to blood pressure and dietary protein target, and interaction between urine sodium and baseline urine protein.View Large Image Figure ViewerDownload (PPT) Abbreviations: CI, confidence interval; HR, hazard ratio. HRs were per 1g/day higher urine sodium. Interaction P-values between baseline urine sodium and proteinuria were<0.001 for kidney failure and the composite outcome in the adjusted models. In the current study, we demonstrate no association between 24-h urinary sodium excretion and either kidney failure or a composite outcome of kidney failure and mortality. These relationships were robust in multivariable analyses and despite several sensitivity analyses including time-dependent analyses. In exploratory analyses, we noted an interaction with urine protein, whereby, in individuals consuming <3 g of sodium per day, higher urinary sodium was associated with an increased risk of kidney failure in those with baseline proteinuria<1g/day and with a lower risk of kidney failure in those with baseline proteinuria⩾1g/day. We did not note any interactions of urinary sodium with baseline GFR, ACE inhibitor use, or blood pressure and protein-intake randomization targets. It is well accepted that sodium intake has an effect on blood pressure, and randomized trials of lowering sodium intake have resulted in decreases in blood pressure.1.Sacks F.M. Svetkey L.P. Vollmer W.M. et al.Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med. 2001; 344: 3-10Crossref PubMed Scopus (3944) Google Scholar This has led to recommendations in both the general population and CKD to reduce sodium intake.3.Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.Kidney Int Suppl. 2012; 2: 337-414Abstract Full Text Full Text PDF Scopus (415) Google Scholar,15.World Health Organization WHO forum on reducing salt intake in populations. 2006http://www.who.int/dietphysicalactivity/Salt_Report_VC_april07.pdfGoogle Scholar There are few clinical trial data, however, on the effect of sodium intake on either mortality or CVD outcomes. In the general population, sodium lowering trials have at most a modest effect on reducing CVD outcomes,4.He F.J. MacGregor G.A. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials.Lancet. 2011; 378: 380-382Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar perhaps related to the requirement for long follow-up and large studies to achieve adequate statistical power for these outcomes. Recent observational studies in patients with diabetes and CVD and in the general population have added controversy to this topic by demonstrating higher CVD and kidney failure outcomes in those with lowest sodium intake. In patients with both type 1 and type 2 diabetes, observational studies have demonstrated that low sodium intake may be associated with increased risk of all-cause mortality and CVD mortality.7.Ekinci E.I. Clarke S. Thomas M.C. et al.Dietary salt intake and mortality in patients with type 2 diabetes.Diabetes Care. 2011; 34: 703-709Crossref PubMed Scopus (254) Google Scholar,8.Thomas M.C. Moran J. Forsblom C. et al.The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866Crossref PubMed Scopus (270) Google Scholar In addition, low sodium intake was also associated with kidney failure in those with macroalbuminuria.8.Thomas M.C. Moran J. Forsblom C. et al.The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866Crossref PubMed Scopus (270) Google Scholar In a post hoc analysis of individuals at high CVD risk enrolled in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (N=28,000) trials, a J-shaped relationship was noted between CVD events and sodium intake.5.O'Donnell M.J. Yusuf S. Mente A. et al.Urinary sodium and potassium excretion and risk of cardiovascular events.JAMA. 2011; 306: 2229-2238Crossref PubMed Scopus (460) Google Scholar Similar J-shaped results were also reported in a general population study of 3681 individuals.6.Stolarz-Skrzypek K. Kuznetsova T. Thijs L. et al.Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion.JAMA. 2011; 305: 1777-1785Crossref PubMed Scopus (456) Google Scholar It has been argued that several of these studies may have been biased by inaccurate assessment of sodium intake owing to estimation by spot urine samples,5.O'Donnell M.J. Yusuf S. Mente A. et al.Urinary sodium and potassium excretion and risk of cardiovascular events.JAMA. 2011; 306: 2229-2238Crossref PubMed Scopus (460) Google Scholar inaccuracy of 24-h urine sample collections,6.Stolarz-Skrzypek K. Kuznetsova T. Thijs L. et al.Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion.JAMA. 2011; 305: 1777-1785Crossref PubMed Scopus (456) Google Scholar and small sample sizes.8.Thomas M.C. Moran J. Forsblom C. et al.The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes.Diabetes Care. 2011; 34: 861-866Crossref PubMed Scopus (270) Google Scholar Either way, the results have suggested that there is more to be learned in this area and that there may be individuals who are at higher risk of sodium restriction.16.Kotchen T.A. Cowley Jr., A.W. Frohlich E.D. Salt in health and disease—a delicate balance.N Engl J Med. 2013; 368: 1229-1237Crossref PubMed Scopus (100) Google Scholar Patients with CKD have a high prevalence of hypertension and are at particularly high risk for mortality as well as progression of kidney disease;17.Mahmoodi B.K. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.Lancet. 2012; 380: 1649-1661Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar,18.Fox C.S. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.Lancet. 2012; 380: 1662-1673Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar therefore, evaluation of the effect of sodium intake is of critical public health importance in this population. Unfortunately, there are very few observational studies of sodium intake and no RCTs with long-term hard outcomes in this population. In the Ramipril Efficiency in Nephropathy study, lower sodium intake defined as 24-h urinary sodium/creatinine excretion<100mEq/g (approximately 2.87 g sodium per day) was associated with slower progression in those treated with ramipril; however, no data are provided on the control group.13.Vegter S. Perna A. Postma M.J. et al.Sodium intake, ACE inhibition, and progression to ESRD.J Am Soc Nephrol. 2012; 23: 165-173Crossref PubMed Scopus (232) Google Scholar In a combined analysis of the Irbesartan Diabetic Nephropathy Trial and The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan trials, low sodium intake, defined as the first tertile of 24-h urinary sodium/creatinine ratio, was only of benefit in patients treated with an angiotensin receptor blocker. Our study adds to this literature by providing the most comprehensive assessment of sodium intake compared with the published literature, and the ability to evaluate a large number of long-term outcomes. Our primary results demonstrated that there was no association between 24-h urinary sodium excretion and either kidney failure or the composite outcome in a large cohort of predominantly nondiabetic CKD patients. There are several potential interpretations of our results. First, it is possible that, indeed, sodium intake is not a risk factor for progression of kidney disease or, stated differently, is a relatively minor risk factor compared with other established risk factors for progression of CKD. Our results are consistent with data from the African American Study of Kidney Disease and Hypertension and a recent analysis of individuals with type 2 diabetes without macroalbuminuria from the ONTARGET study, in which urine sodium was not associated with progression of kidney disease in adjusted analyses.19.Norris K.C. Greene T. Kopple J. et al.Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease.J Am Soc Nephrol. 2006; 17: 2928-2936Crossref PubMed Scopus (124) Google Scholar,20.Dunkler D. Dehghan M. Teo K.K. et al.Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus.JAMA Intern Med. 2013; 173: 1682-1692PubMed Google Scholar Second, it is possible that given previous data, which suggest that both high sodium and low sodium may be associated with adverse outcomes through different mechanisms, the effect of each may negate the other. We did not, however, note any overt deviations from linearity or U-shaped relationships. Third, given the strong interrelationships of sodium intake with blood pressure and proteinuria, and the difficulty of distinguishing confounding vs. mediating relationships in observational studies, it is possible that we may have missed a significant relationship. In exploratory analyses, however, we noted an interaction of urine sodium with proteinuria such that when urine sodium was<3g/day, higher urine sodium was associated with increased risk of kidney failure in patients with proteinuria 10g/day, mean arterial pressure >125mmHg, and previous kidney transplantation. A total of 840 participants were randomized. GFR was measured by using urinary iothalamate clearance. After a 3-month baseline period, participants with GFR 25–55ml/min per 1.73m2 entered study A and participants with GFR 13–24ml/min per 1.73m2 entered study B. Participants in study A were randomized to a usual protein (1.3g/kg/day) or low protein (0.58g/kg/day) diet. In study B, participants were randomly assigned to a low protein diet (0.58g/kg/day) or a very low protein diet (0.28g/kg/day) supplemented with a mixture of keto-acids and amino acids. Participants, both in study A and study B, were randomly assigned to either a usual blood pressure target or low blood pressure target. The low target blood pressure was a mean arterial pressure 125/75mmHg) for patients aged 18–60 years and 61 years. The usual target blood pressure was a mean arterial pressure <107mmHg (equivalent to a blood pressure of 140/90mmHg) for patients aged 18–60 years and 61 years. Dietary sodium intake was not restricted in either study. All laboratory samples were measured at the MDRD Study Central Biochemistry Laboratory (Department of Biochemistry, Cleveland Clinic Foundation, Cleveland, OH). The mean baseline 24-h urinary sodium excretion for each participant was calculated from either three (n=200) or four (n=640) 24-h urine collections during the baseline period. In sensitivity analyses, we used the first baseline measurement of urinary sodium excretion, as dietary sodium may have changed during the baseline period, and the cumulative mean time-dependent values for 24-h urinary sodium excretion during follow-up to account for changes in sodium intake during follow-up. For each participant, a median (25th, 75th) of 33 (25, 39) 24-h urinary sodium excretions was measured during follow-up. The 24h urinary sodium excretion is a good proxy for sodium intake in the steady state. Our primary outcomes were kidney failure (defined as initiation of dialysis or transplantation) and, given any possibility of competing risk due to mortality, a composite of kidney failure or all-cause mortality. Kidney failure outcomes were obtained from the United States Renal Data System and survival status from the National Death Index. We define survival time for each participant as time from randomization to kidney failure, death, or administrative censoring at 31 December 2007, whichever comes first. Data collection procedures were approved by the Cleveland Clinic and Tufts Medical Center Institutional Review Boards. Covariates included demographic factors (age, race, and sex); comorbid conditions (CVD, which was defined as coronary artery disease, cerebral vascular disease, or peripheral vascular disease, and diabetes); cause of kidney disease (polycystic kidney disease, glomerular disease, or other); kidney measures (measured GFR and urine protein); other cardiovascular and kidney-related risk factors (smoking, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol); medications (ACE inhibitors and diuretics); MDRD Study A or B; and randomization assignments. All covariates were measured at the last visit before randomization. The 24-h urine creatinine was used to assess accuracy of the urine collections. The distribution of demographic data and laboratory variables was compared across quartiles of mean 24-h urinary sodium excretion using the χ2-test for categorical variables and the Kruskal-Wallis test or Mann-Whitney’s U-test for continuous variables, as appropriate. Restricted cubic splines were used to explore the association of urine sodium with kidney failure and composite outcome in unadjusted and adjusted analyses. Cox proportional hazards regression models were used to evaluate the relationship between 24-h urinary sodium excretion and kidney failure and composite outcome in the primary analysis. The following potential confounding covariates were included in all models: age, baseline GFR, sex, race, smoking, diabetes, history of CVD, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log urine protein, cause of kidney disease, ACE inhibitor use, diuretic use, MDRD Study A or B, and randomization groups. We then performed exploratory analysis to evaluate the following pre-specified interactions with 24-h urinary sodium excretion using multivariable Cox regression models: level of GFR based on MDRD Study A or B; baseline urine protein level ( 1g/day;25.Peterson J.C. Adler S. Burkart J.M. et al.Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar ACE inhibitor use; and randomization to usual or low BP target as well as randomization to usual, low protein, or very low protein diet. When the interaction was significant, we used restricted cubic splines to explore the functional form of urine sodium on kidney failure by allowing a different form by the interaction variable. The splines plotted for the model with urine protein interaction suggested a two-slope model. We searched for the corresponding optimal knot based on models with the lowest -2 log likelihood. All analyses were performed using the SAS software (version 9.3, SAS Institute, Cary, NC) and R project for Windows (version 2.15.1 and 2.13.1). All hypothesis tests were two-sided, and statistical significance defined as a P-value<0.05. This research was supported by the Division of Nephrology, First Affiliated Hospital of Sun Yat-sen University, China; a UL1 TR000073 from the NIH CTSA; and a K24 DK078204 from the National Institute of Diabetes and Digestive and Kidney Diseases (to MJS). Table S1. Association of first baseline and time-dependent cumulative mean 24-h urinary sodium excretion with kidney failure and composite outcome in entire cohort. Table S2. Association of first baseline measurement of 24-h urinary sodium excretion with kidney failure and composite outcome in subgroups defined by baseline urinary protein excretion. Table S3. Association of time-dependent cumulative mean 24-h urinary sodium excretion with kidney failure and composite outcome in subgroups defined by baseline urinary protein excretion. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki
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