Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample
2006; Elsevier BV; Volume: 69; Issue: 11 Linguagem: Inglês
10.1038/sj.ki.5000378
ISSN1523-1755
AutoresCaroline S. Fox, Martin G. Larson, Shih‐Jen Hwang, Eric Leip, Nader Rifai, Daniel Levy, Emelia J. Benjamin, Joanne M. Murabito, James B. Meigs, Ramachandran S. Vasan,
Tópico(s)Renal function and acid-base balance
ResumoExperimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3–49%), and twofold higher (95% CI 72–150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1–44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage. Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3–49%), and twofold higher (95% CI 72–150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1–44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage. Increased urinary albumin excretion predicts decline in kidney function.1.Adler A.I. Stevens R.J. 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Nichols R. et al.Intersalt revisited: further analyses of 24 h sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group.BMJ. 1996; 312: 1249-1253Crossref PubMed Scopus (667) Google Scholar, 33.Luft F.C. Fineberg N.S. Sloan R.S. Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake.Hypertension. 1982; 4: 805-808Crossref PubMed Scopus (144) Google Scholar, 34.Kumanyika S.K. Hebert P.R. Cutler J.A. et al.Feasibility and efficacy of sodium reduction in the trials of hypertension prevention, phase I. Trials of Hypertension Prevention Collaborative Research Group.Hypertension. 1993; 22: 502-512Crossref PubMed Scopus (94) Google Scholar The baseline characteristics of our sample are shown in Table 1. Figure 1 displays the distribution of urine albumin/creatinine ratio (UACR) (box plots showing median and interquartile ranges for unadjusted values) according to quintiles of serum aldosterone (panel a) and urinary sodium index (panel b).Table 1Baseline characteristics of study sample (n=2700)Age58±10Female (%)53Systolic blood pressure (mm Hg)128±19Diastolic blood pressure (mm Hg)76±9Hypertension (%)39Hypertension treatment (%)26Diuretic use (%)aIncludes lasix, thiazides, and potassium-sparing diuretics.7Angiotensin-converting enzyme inhibitor use (%)10Left ventricular hypertrophy by electrocardiogram with strain (%)0.3Total/HDL cholesterol4.4±1.5Body mass index (kg/m2)27.9±5.1Diabetes (%)9Current smoking (%)15Serum creatinine (mg/dl)0.9±0.2Prevalent cardiovascular disease (%)9Menopausal status (%) Pre-menopausal58 Post-menopausal, taking hormone replacement therapy14 Post-menopausal, not taking hormone replacement therapy28Serum aldosteronebMedian (25th, 75th percentile). (ng/dl)10 (7, 14)Urinary sodium indexed to urinary creatininebMedian (25th, 75th percentile). (mmol/g)96 (62, 141)Urinary albumin indexed to urinary creatininebMedian (25th, 75th percentile). (mg/g)6.1 (2.8, 14.2)Data are mean±standard deviation unless otherwise specified.HDL, high-density lipoprotein.a Includes lasix, thiazides, and potassium-sparing diuretics.b Median (25th, 75th percentile). Open table in a new tab Data are mean±standard deviation unless otherwise specified. HDL, high-density lipoprotein. In age- and sex-adjusted models, each standard deviation increment in log urine sodium index was associated with a 22% higher UACR (P<0.001). Multivariable models yielded similar results (36% higher UACR per standard deviation increase in log urinary sodium index, P-value <0.0001). In quintile-based analyses, the fourth quintile of urinary sodium index was associated with a 24% higher adjusted UACR (95% confidence interval (CI) 3–49%), whereas the upper quintile was associated with a doubling of UACR (95% CI 72–150%; Table 2) relative to the lowest quintile that served as referent. The association between log urinary sodium index and log UACR was maintained in secondary analyses excluding participants on diuretics (Table 3), participants with prevalent cardiovascular disease, diabetes, chronic kidney disease, and hypertension.Table 2Linear regression for quintiles of aldosterone and urinary sodium indexed to urinary creatinine and UACRaModels adjusted for age, sex, diabetes, diuretic use, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum creatinine, and smoking. All models contain both log aldosterone and log urine sodium index.Multiplicative effect on UACR (95% confidence interval)P-value for trendQuintile of UNACRbCompared between each quintile and the referent category; quintile cut points are 55, 83, 111, and 155 mmol/g for UNACR and 6.0, 8.0, 11.0, and 14.0 ng/dl for aldosterone. First (referent)1.0 Second0.95 (0.8–1.14) Third1.11 (0.93–1.34) Fourth1.24 (1.03–1.49) Fifth2.08 (1.72–2.50)Trend across quintiles1.19 (1.15–1.25)<0.0001Quintile of aldosteronebCompared between each quintile and the referent category; quintile cut points are 55, 83, 111, and 155 mmol/g for UNACR and 6.0, 8.0, 11.0, and 14.0 ng/dl for aldosterone. First (referent)1.0 Second1.07 (0.89–1.28) Third1.07 (0.90–1.26) Fourth1.06 (0.88–1.29) Fifth1.21 (1.01–1.44)Trend across quintiles1.05 (1.00–1.09)=0.02UACR, urinary albumin indexed to urinary creatinine; UNACR, urinary sodium indexed to urinary creatinine.a Models adjusted for age, sex, diabetes, diuretic use, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum creatinine, and smoking. All models contain both log aldosterone and log urine sodium index.b Compared between each quintile and the referent category; quintile cut points are 55, 83, 111, and 155 mmol/g for UNACR and 6.0, 8.0, 11.0, and 14.0 ng/dl for aldosterone. Open table in a new tab Table 3Linear regression for quintiles of aldosterone and urinary sodium indexed to creatinine and UACR by subgroupsaModels adjusted for age, sex, diabetes, diuretic use, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum creatinine, and smoking. All models contain both log aldosterone and log urine sodium index.Quintile rank on UACR (95% confidence interval)P-valueTrend across UNACR quintilesbComparison between each quintile and the referent category; quintile cut-points are 55, 83, 111, and 155 mmol/g for UNACR and 6.0, 8.0, 11.0, and 14.0 ng/dl for aldosterone. Participants not on diuretics1.19 (1.14, 1.25)<0.0001 No diabetes1.20 (1.15, 1.26)<0.0001 No chronic kidney disease1.20 (1.15, 1.26)<0.0001 No hypertension1.19 (1.13, 1.26)<0.0001 No CVD1.19 (1.14, 1.24)<0.0001 Gender Men1.19 (1.11, 1.28)<0.0001 Women1.19 (1.13, 1.25)<0.0001 Age ≤60 years1.24 (1.17, 1.31) 60 years1.15 (1.08, 1.22) 60 years1.02 (0.96, 1.09)0.56CVD, cardiovascular disease; UACR, urinary albumin indexed to urinary creatinine; UNACR, urinary sodium indexed to urinary creatinine.a Models adjusted for age, sex, diabetes, diuretic use, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum creatinine, and smoking. All models contain both log aldosterone and log urine sodium index.b Comparison between each quintile and the referent category; quintile cut-points are 55, 83, 111, and 155 mmol/g for UNACR and 6.0, 8.0, 11.0, and 14.0 ng/dl for aldosterone. Open table in a new tab UACR, urinary albumin indexed to urinary creatinine; UNACR, urinary sodium indexed to urinary creatinine. CVD, cardiovascular disease; UACR, urinary albumin indexed to urinary creatinine; UNACR, urinary sodium indexed to urinary creatinine. Log aldosterone was associated with log UACR in age- and sex-adjusted models (9% higher per standard deviation increase in log aldosterone, P=0.005), but not in fully adjusted models (P=0.09). In quintile-based analyses, the upper quintile of serum aldosterone was associated with 21% higher UACR (95% CI 1–44%; Table 2) compared to the referent group. Adjusted UACR in the second, third, and fourth quintiles of serum aldosterone were not different from the referent group. When analyses were performed excluding participants with prevalent cardiovascular disease, hypertension, or chronic kidney disease, these findings were no longer statistically significant (Table 3). The associations of urinary sodium index with UACR did not vary by age or sex (Table 3). For aldosterone, relations were weakly significant among younger individuals and women. Because the top quintile of serum aldosterone may have the greatest effect on UACR, we examined whether the magnitude of this effect differed by quintile of urinary sodium index. There was no interaction between the top quintile of serum aldosterone and the top quintile of urinary sodium index with regard to their effects on UACR (P-value=0.31). We observed that urinary sodium index is strongly and positively associated with UACR. In our sample, serum aldosterone was weakly associated with UACR in a nonlinear fashion; only the top quintile of serum aldosterone was associated with higher adjusted UACR levels. Our data indicating a positive association of urine sodium index with UACR are consistent with animal studies indicating that high salt intake has a deleterious effect on the renal vasculature. Rats given saline to drink demonstrate vascular and glomerular sclerosis, interstitial fibrosis of the glomeruli and renal tubules18.Yu H.C. Burrell L.M. Black M.J. et al.Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats.Circulation. 1998; 98: 2621-2628Crossref PubMed Scopus (273) Google Scholar and increased albuminuria,35.Blasi E.R. Rocha R. Rudolph A.E. et al.Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.Kidney Int. 2003; 63: 1791-1800Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar possibly due to hyperfiltration with resultant increased albumin excretion.36.Boero R. Pignataro A. Quarello F. Salt intake and kidney disease.J Nephrol. 2002; 15: 225-229PubMed Google Scholar Alterations in charge-dependent selective permeability of the glomerular basement membrane have also been described with salt loading and likely contribute to the development of albuminuria. Experimental models of nitric oxide blockade demonstrate profound albuminuria, glomerulosclerosis, and hypertension that is potentiated by dietary salt excess.21.Hertzan-Levy S. Skutelsky E. Arad T. et al.Glomerular basement membrane polyanion distribution and nitric oxide in spontaneous hypertensive rats: effects of salt loading and antihypertensive therapy with propranolol.Am J Hypertens. 2000; 13: 838-845Crossref PubMed Scopus (6) Google Scholar, 37.Yamada S.S. Sassaki A.L. 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Dietary sodium and target organ damage in essential hypertension.Am J Hypertens. 2002; 15: 222-229Crossref PubMed Scopus (187) Google Scholar In a large community-based sample enriched for participants with high urinary albumin excretion, urinary sodium was positively associated with urinary albumin excretion.31.Verhave J.C. Hillege H.L. Burgerhof J.G. et al.Sodium intake affects urinary albumin excretion especially in overweight subjects.J Intern Med. 2004; 256: 324-330Crossref PubMed Scopus (157) Google Scholar We extend these findings now to a community-based sample not enriched for hypertension or greater urinary albumin excretion. We also provide a more detailed analysis illustrating the robustness of this association among multiple subgroups. Not all prior findings have been consistent: an analysis of nutrient intake in relation to urinary albumin excretion in the INTERMAP study failed to find an association with urinary sodium.39.Daviglus M.L. Greenland P. Stamler J. et al.Relation of nutrient intake to microalbuminuria in nondiabetic middle-aged men and women: International Population Study on Macronutrients and Blood Pressure (INTERMAP).Am J Kidney Dis. 2005; 45: 256-266Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Differences from our study may have arisen because in the INTERMAP study urinary albumin was evaluated as a dichotomous outcome (<30 and 30–299.9 mg/24 h), whereas we examined UACR as a continuous variable. Our cross-sectional data are consistent with a moderately deleterious effect of aldosterone on albuminuria only in the setting of relatively higher aldosterone levels (values in the top quintile). Aldosterone may mediate kidney injury through renal inflammation, fibrosis, and thrombosis, and these effects may be potentiated by salt intake.35.Blasi E.R. Rocha R. 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Further, we were able to evaluate confounding by use of medications, including angiotensin-converting enzyme inhibitors and diuretics, by conducting subgroup analyses. Important limitations of our investigation include the use of spot urine specimen for assessment of albuminuria, urine sodium index, and serum aldosterone. However, UACR on a spot urine specimen has been shown to approximate 24-h urine collections,41.Nathan D.M. Rosenbaum C. Protasowicki V.D. Single-void urine samples can be used to estimate quantitative microalbuminuria.Diabetes Care. 1987; 10: 414-418Crossref PubMed Scopus (174) Google Scholar and urine sodium, when indexed to urinary creatinine, has been shown to reasonably reflect 24-h urine sodium excretion and dietary intake,42.Flack J.M. Grimm Jr, R.H. Staffileno B.A. et al.New salt-sensitivity metrics: variability-adjusted blood pressure change and the urinary sodium-to-creatinine ratio.Ethn Dis. 2002; 12: 10-19PubMed Google Scholar, 43.Correa P. Montes G. Cuello C. et al.Urinary sodium-to-creatinine ratio as an indicator of gastric cancer risk.Natl Cancer Inst Monogr. 1985; 69: 121-123PubMed Google Scholar although prospective studies have not confirmed that spot urinary sodium approximates dietary sodium intake. The use of a single estimation of serum aldosterone instead of 24-h urinary aldosterone may have attenuated associations and limited our ability to detect more modest effects of aldosterone on UACR. The predominantly Caucasian study sample limits the generalizability of our findings to other ethnicities. Levels of UACR in the range of our community-based study sample have not been shown to be associated with significant renal injury. Therefore, the generalizability of these findings to clinically significant chronic kidney disease progression is uncertain. However, levels of UACR in this range are clearly related to cardiovascular disease risk.44.Arnlov J. Evans J.C. Meigs J.B. et al.Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.Circulation. 2005; 112: 969-975Crossref PubMed Scopus (581) Google Scholar Lastly, our study is cross-sectional, and therefore causality cannot be inferred. Our findings may have public health relevance, because of our results suggesting that higher salt intake is associated with greater UACR. Not only is albuminuria an early indicator of kidney dysfunction, but it is also associated with incident cardiovascular disease,44.Arnlov J. Evans J.C. Meigs J.B. et al.Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.Circulation. 2005; 112: 969-975Crossref PubMed Scopus (581) Google Scholar, 45.Gerstein H.C. Mann J.F. 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Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril.Kidney Int. 1989; 36: 272-279Abstract Full Text PDF PubMed Scopus (322) Google Scholar Our observational data, if confirmed, would support recommendations for limiting dietary sodium intake, with the added possible benefit of lowering UACR. In our large community-based sample, urinary sodium index was strongly associated with UACR, whereas a weaker nonlinear positive relation with serum aldosterone was noted. These observations are consistent with the hypothesis that higher salt intake may be associated with early renovascular damage. Additional research is warranted to confirm our findings, and if confirmed further elucidate the mechanisms underlying the association between aldosterone, sodium, and albuminuria.
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