Of the 6814 MESA participants, we excluded 3508 because of baseline hypertension, 151 because of an estimated GFR less than 60 mL/min per 1.73 m2, and 182 because of microalbuminuria (). In addition, we excluded 43 participants because of a missing cystatin C value or urinary albumin–creatinine ratio, 1 for an implausible cystatin C value, and 162 for not returning for future follow-up visits. These 162 participants had cystatin C levels (63.6 vs. 62.2 nmol/L) and urinary albumin–creatinine ratios (5.6 vs. 5.2 mg/g) similar to those of included participants. After exclusions, we analyzed 2767 participants.
The study population had a mean age of 58 years and a mean estimated GFR of 84 mL/min per 1.73 m2. A total of 1832 participants (66%) had a baseline systolic blood pressure less than 120 mm Hg and baseline diastolic blood pressure less than 80 mm Hg; 537 (20%) had a baseline systolic blood pressure of 120 to 129.9 mm Hg or baseline diastolic blood pressure of 80 to 84.9 mm Hg; and 398 (14%) had a baseline systolic blood pressure of 130 to 139.9 mm Hg or baseline diastolic blood pressure of 85 to 89.9 mm Hg.
Serum cystatin C levels were normally distributed, whereas urinary albumin–creatinine ratios were skewed to the right. The intraquartile range for the urinary albumin–creatinine ratio was 2.8 to 6.3 mg/g; 90% of participants had ratios less than 10 mg/g. Higher cystatin C levels were associated with older age and traditional cardiovascular risk factors, whereas lower cystatin C levels were associated with Asian ethnicity (). Similar to cystatin C, greater urinary albumin–creatinine ratios were associated with older age and greater baseline systolic blood pressure. In contrast to cystatin C, greater ratios were associated with female sex, Asian and Hispanic ethnicity, and diabetes. The urinary albumin–creatinine ratio was not associated with serum cystatin C level in this study population without clinical kidney disease (P = 0.65).
After the baseline examination, 2418 participants (87.4%) returned for both MESA follow-up examinations, 173 (6.3%) for only the second examination, and 176 (6.4%) for only the third examination. During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. Incident hypertension was more common with older age and among African-American participants (9.5 events per 100 person-years [CI, 8.1 to 11.1 events per 100 person-years]) than among Hispanic (6.8 events per 100 person-years [CI, 5.7 to 8.0 events per 100 person-years]), white (5.6 events per 100 person-years [CI, 4.9 to 6.4 events per 100 person-years]), and Asian (5.0 events per 100 person-years [CI, 3.8 to 6.5 events per 100 person-years]) participants. Among a subset of 274 participants whose incident hypertension was diagnosed by blood pressure measurements alone (without use of antihypertensive medication), 87% had isolated systolic hypertension.
Higher serum cystatin C levels and urinary albumin–creatinine ratio were associated with greater unadjusted incident hypertension rates during follow-up (). In contrast, serum creatinine levels within the normal range were not statistically associated with incident hypertension after adjustment for age, race, and sex. Serum creatinine levels of 61 to 91 μmol/L (0.8 to 1.19 mg/dL) and 92 to 114 μmol/L (1.2 to 1.5 mg/dL) were associated with 20% and 21% lower risks for hypertension (P = 0.056 and 0.23, respectively) compared with levels less than 61 μmol/L (<0.8 mg/dL).
Unadjusted and Adjusted Incidence Rates of Hypertension
After adjustment for age, race, and sex, higher cystatin C levels were associated with greater incident hypertension rates within each urinary albumin–creatinine ratio quartile (). Observed associations of cystatin C and urinary albumin–creatinine ratio with hypertension were attenuated by adjustment for demographic characteristics, body mass index, diabetes, and baseline blood pressure (). After adjustment, the association between urinary albumin and hypertension was notably attenuated. Inclusion of additional adjustment covariates did not further alter the magnitude of the observed associations and increased the proportion of missing data in the analyses. After full adjustment, higher cystatin C quartiles remained statistically associated with incident hypertension. The highest cystatin C quartile, levels greater than 67.5 nmol/L, was associated with a statistically significant 31% greater adjusted incidence of hypertension compared with the lowest quartile. No evidence indicated a multiplicative interaction among cystatin C levels, urinary albumin–creatinine ratios, and incident hypertension. Other covariates that were statistically associated with incident hypertension included older age, African-American race, diabetes (but not impaired fasting glucose), and greater baseline systolic blood pressure.
Incident hypertension rates within quartiles of serum cystatin C and sex-specific urinary albumin–creatinine ratio
After adjustment for established hypertension risk factors, each linear 15-nmol/L increase in cystatin C was associated with a 15% greater incidence of hypertension (P = 0.017). The second study outcome, a clinically meaningful increase in blood pressure, occurred in 1320 participants (48%). Associations of cystatin C with this outcome were weaker: After adjustment, each 15-nmol/L increase in cystatin C was associated with a 6% greater incidence of a clinically meaningful increase in blood pressure (P = 0.051).
Exclusion of 398 participants with borderline high blood pressure at baseline, defined as systolic blood pressure of at least 130 mm Hg or diastolic blood pressure of at least 85 mm Hg, resulted in a modest increase in the magnitude of the association between cystatin C and hypertension (18% greater incidence per 15-nmol/L increase [P = 0.019]) and between the urinary albumin–creatinine ratio and hypertension (33% greater incidence comparing the highest with the lowest sex-specific quartile [P = 0.053]). Similarly, associations of both cystatin C and urinary albumin–creatinine ratio with hypertension were qualitatively strengthened when analyses were restricted to participants with an estimated GFR of at least 90 mL/min per 1.73 m2. Associations of cystatin C levels with incident hypertension were similar among participants with and those without diabetes and across subgroups defined by baseline blood pressure category, age, race or ethnicity, and sex (P > 0.20 for all interactions) ().
Association of each 15-nmol/L increase in serum cystatin C level with incident hypertension within subgroups