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Higher Levels of Albuminuria Within the Normal Range Predict Incident Hypertension

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Higher Levels of Albuminuria Within the Normal Range Predict Incident Hypertension JASN Express. Published on June 25, 2008 as doi: 10.1681/ASN.2008010038 CLINICAL EPIDEMIOLOGY www.jasn.org Higher Levels of Albuminuria within the Normal Range Predict Incident Hypertension John P. Forman,* Naomi D.L. Fisher,† Emily L. Schopick,* and Gary C. Curhan* *Renal Division and Channing Laboratory and †Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts ABSTRACT Higher levels of albumin excretion within the normal range are associated with cardiovascular disease in high-risk individuals. Whether incremental increases in urinary albumin excretion, even within the normal range, are associated with the development of hypertension in low-risk individuals is unknown. This study included 1065 postmenopausal women from the first Nurses’ Health Study and 1114 premenopausal women from the second Nurses’ Health Study who had an albumin/creatinine ratio Ͻ25 mg/g and who did not have diabetes or hypertension. Among the older women, 271 incident cases of hypertension occurred during 4 yr of follow-up, and among the younger women, 296 incident cases of hypertension occurred during 8 yr of follow-up. Cox proportional hazards regression was used to examine prospec- tively the association between the albumin/creatinine ratio and incident hypertension after adjustment for age, body mass index, estimated GFR, baseline BP, physical activity, smoking, and family history of hypertension. Participants who had an albumin/creatinine ratio in the highest quartile (4.34 to 24.17 mg/g for older women and 3.68 to 23.84 mg/g for younger women) were more likely to develop hypertension than those who had an albumin/creatinine ratio in the lowest quartile (hazard ratio 1.76 [95% confidence interval 1.21 to 2.56] and hazard ratio 1.35 [95% confidence interval 0.97 to 1.91] for older and younger women, respectively). Higher albumin/creatinine ratios, even within the normal range, are independently associated with increased risk for development of hypertension among women without diabetes. The definition of normal albumin excretion should be reevaluated. J Am Soc Nephrol ●●: –, 2008. doi: 10.1681/ASN.2008010038 For decades, microalbuminuria has been recog- More recent studies have demonstrated that in- nized as a risk factor for progression of kidney dis- creasing levels of albumin excretion, even within ease, diabetic complications, and cardiovascular the normal range, are associated with increasing outcomes.1–4 Microalbuminuria has been pro- risk for cardiovascular end points among individu- posed as a generalized marker of vascular damage in als who do and do not have diabetes and are at high individuals both with and without diabetes, reflec- baseline cardiovascular risk, such as individuals tive of vascular endothelial dysfunction and ab- with multiple cardiovascular risk factors and those normal vascular permeability.5,6 Urinary albumin with left ventricular hypertrophy.8,9 Data from the excretion is typically categorized into normoalbu- Framingham study suggested that higher albumin/ minuria (0 to 20 ␮g/min, or Ͻ30 mg/d), mi- creatinine ratios (ACR), even within the normal croalbuminuria (20 to 200 ␮g/min, or 30 to 300 mg/d), and overt albuminuria (Ͼ200 ␮g/min, or Received January 11, 2008. Accepted April 24, 2008. Ͼ 300 mg/d) using fairly arbitrary cut points. The Published online ahead of print. Publication date available at upper limit of normal was defined in 1985 as the www.jasn.org. 95th percentile of albumin excretion rate among a Correspondence: Dr. John P. Forman, Channing Laboratory, 3rd cohort of Italians without diabetes; the upper limit floor; 181 Longwood Avenue, Boston, MA 02115. Phone: 617- of microalbuminuria was the limit of standard dip- 525-2092; Fax: 617-525-2008; E-mail: [email protected] sticks to detect albumin in 1981.7 Copyright ᮊ 2008 by the American Society of Nephrology J Am Soc Nephrol ●●: –, 2008 ISSN : 1046-6673/●●00- 1 CLINICAL EPIDEMIOLOGY www.jasn.org range, may be associated with the risk for hypertension; how- RESULTS ever, a sizable proportion of individuals in the highest quartile (which was associated with elevated risk) had microalbumin- In NHS I, the median ACR was 2.7 mg/g (interquartile range uria.10 [IQR] 1.7 to 4.3). The median age was 65 yr (IQR 60 to 70), and We examined prospectively the association between the the median body mass index (BMI) was 24.2 kg/m2 (IQR 21.9 baseline ACR and risk for development of hypertension among to 27.5). In NHS II, the median ACR was 2.4 mg/g (IQR 1.6 to 1065 older women without hypertension and diabetes and 3.7). The median age was 44 yr (IQR 41 to 47), and the median with normoalbuminuria from the first Nurses’ Health Study BMI was 24.5 kg/m2 (IQR 21.9 to 28.3). Baseline characteristics (NHS I) and among 1114 younger women without hyperten- are shown in Table 1 stratified by quartile of ACR. With in- sion and diabetes and with normoalbuminuria from the sec- creasing quartile of ACR in both cohorts, median BMI values ond Nurses’ Health Study (NHS II). were lower and median estimated GFR (eGFR) values were Table 1. Baseline characteristics according to quartile of ACRa Characteristic Quartile 1 Quartile 2 Quartile 3 Quartile 4 P NHS I ACR (mg/g; median ͓range͔) 0.97 (0.00 to 1.69) 2.22 (1.70 to 2.73) 3.42 (2.74 to 4.33) 6.46 (4.34 to 24.17) urine albumin (mg/L; median ͓IQR͔) 0.66 (0.00 to 1.16) 1.61 (1.14 to 2.21) 2.09 (1.52 to 3.07) 3.99 (2.60 to 7.12) Ͻ0.001 urine creatinine (mg/dl; median 76.9 (52.9 to 112.4) 73.9 (54.1 to 101.3) 60.7 (42.7 to 92.3) 55.8 (41.8 to 84.6) Ͻ0.001 ͓IQR͔) age (yr; median ͓IQR͔) 64 (59 to 69) 64 (60 to 70) 65 (59 to 70) 67 (61 to 72) 0.008 BMI (kg/m2; median ͓IQR͔) 24.9 (22.3 to 28.2) 24.6 (22.3 to 27.7) 23.8 (21.6 to 26.9) 23.6 (21.6 to 27.4) 0.030 physical activity (METS/wk; median 15.2 (8.4 to 29.4) 17.8 (8.6 to 34.2) 15.2 (6.2 to 28.9) 13.2 (5.1 to 27.7) 0.004 ͓IQR͔) SBP (mmHg; median ͓IQR͔) 120 (120 to 130) 120 (110 to 130) 120 (110 to 130) 120 (120 to 130) 0.070 DBP (mmHg; median ͓IQR͔) 80 (70 to 80) 80 (70 to 80) 80 (70 to 80) 80 (70 to 80) 0.400 MDRD eGFR (ml/min per 1.73 m2; 76 (65 to 85) 77 (69 to 87) 79 (69 to 90) 80 (70 to 91) 0.004 median ͓IQR͔) serum creatinine (mg/dl; median 0.81 (0.73 to 0.92) 0.80 (0.72 to 0.88) 0.78 (0.70 to 0.88) 0.77 (0.68 to 0.86) 0.001 ͓IQR͔) alcohol intake (g/d; median ͓IQR͔) 1.1 (0.0 to 9.7) 2.4 (0.0 to 9.5) 1.5 (0.0 to 7.2) 1.5 (0.0 to 6.9) 0.340 sodium intake (g/d; median ͓IQR͔) 1.9 (1.6 to 2.1) 1.9 (1.7 to 2.1) 1.8 (1.6 to 2.1) 1.9 (1.6 to 2.1) 0.650 current smoking (%) 7.3 5.9 8.0 6.5 0.970 past smoking (%) 43.1 43.4 47.2 45.2 0.460 white race (%) 85.8 88.6 87.6 88.3 0.510 family history of hypertension (%) 39.4 43.8 40.1 35.6 0.290 NHS II ACR (mg/g; median ͓range͔) 1.06 (0.00 to 1.62) 2.04 (1.63 to 2.43) 2.93 (2.44 to 3.67) 5.40 (3.68 to 23.84) urine albumin (mg/L; median ͓IQR͔) 1.07 (0.24 to 1.91) 2.60 (1.82 to 3.58) 3.23 (2.24 to 4.79) 6.48 (3.98 to 10.67) Ͻ0.001 urine creatinine (mg/dl; median 124.9 (88.7 to 175.3) 131.1 (96.8 to 176.4) 111.4 (72.9 to 162.2) 116.4 (75.2 to 162.9) Ͻ0.001 ͓IQR͔) age (yr; median ͓IQR͔) 44 (41 to 47) 44 (41 to 47) 43 (41 to 46) 44 (40 to 47) 0.280 BMI (kg/m2; median ͓IQR͔) 25.0 (22.0 to 28.2) 24.8 (22.0 to 28.3) 24.3 (22.3 to 28.3) 24.0 (21.6 to 28.1) 0.260 physical activity (METS/wk; median 12.5 (5.1 to 25.5) 12.1 (5.0 to 25.2) 14.2 (5.6 to 27.1) 11.5 (5.0 to 22.5) 0.620 ͓IQR͔) SBP (mmHg; median ͓IQR͔) 120 (110 to 120) 110 (110 to 120) 120 (110 to 120) 120 (110 to 120) 0.570 DBP (mmHg; median ͓IQR͔) 70 (70 to 80) 70 (70 to 80) 70 (70 to 80) 70 (70 to 80) 0.730 MDRD eGFR (ml/min per 1.73 m2; 86 (75 to 98) 94 (82 to 100) 96 (83 to 105) 96 (84 to 113) Ͻ0.001 median ͓IQR͔) serum creatinine (mg/dl; median 0.80 (0.70 to 0.88) 0.72 (0.70 to 0.80) 0.70 (0.66 to 0.80) 0.70 (0.60 to 0.80) Ͻ0.001 ͓IQR͔) alcohol intake (g/d; median ͓IQR͔) 1.5 (0.0 to 6.0) 1.1 (0.0 to 3.85) 1.0 (0.0 to 5.7) 0.9 (0.0 to 4.7) 0.370 sodium intake (g/d; median ͓IQR͔) 2.0 (1.7 to 2.2) 2.0 (1.7 to 2.2) 2.0 (1.7 to 2.2) 2.0 (1.7 to 2.2) 0.720 current smoking (%) 9.1 7.0 8.1 8.3 0.910 past smoking (%) 30.2 23.0 24.1 28.3 0.780 white race (%) 95.4 96.0 95.8 94.0 0.410 family history of hypertension (%) 55.0 48.0 50.2 56.2 0.610 aDBP, diastolic BP; METS, metabolic equivalent task score; SBP, systolic BP.
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