Although hypertension is a well-known risk factor for chronic kidney disease (CKD), the blood pressure (BP) at which antihypertensive interventions should be initiated remains to be determined. Therefore, we investigated the association between BP and CKD in treatment-naïve individuals.
This prospective cohort study considered 7,343 individuals in the Korean Genome and Epidemiology Study who were not taking antihypertensive medications. Subjects were categorized into six groups according to their systolic BP (SBP) and five groups according to their diastolic BP (DBP). The primary outcome was incident CKD, which was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 or the development of proteinuria. The secondary outcome was incident cardiovascular disease (CVD).
In the time-varying Cox models, the hazard ratios (95% confidence interval [CI]) for CKD were 1.39 (1.10–1.77) with SBP 130–139 mmHg, 1.79 (1.40–2.28) with SBP 140–159 mmHg, and 3.22 (2.35–4.40) with SBP ≥ 160 mmHg, compared with SBP 100–119 mmHg. In addition, the hazard ratios (95% CI) for CKD were 1.88 (1.48–2.37) with DBP 90–99 mmHg and 4.30 (3.20–5.76) with DBP ≥ 100 mmHg, compared with DBP 70–79 mmHg. A significantly increased CVD risk was also observed in subjects with SBP ≥ 130 mmHg or DBP ≥ 90 mmHg.
Our findings indicate that SBP ≥ 130 mmHg and DBP ≥ 90 mmHg are associated with an increased risk of CKD. Therefore, BP-lowering strategies should be considered starting at those thresholds to prevent CKD development.
Hypertension (HTN) is a well-known risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD) [
Although intensive BP control can lower CVD risk and mortality, the results of large randomized controlled trials (RCTs) have raised concerns that strict BP control can produce an increased risk of CKD [
Thus, substantial uncertainty remains regarding the best BP level for CKD prevention, particularly among individuals without underlying kidney disease who are not taking antihypertensive medication. Therefore, we examined the association between BP and incident CKD risk in a large Korean population who had not taken any antihypertensive medication.
In this study, we used data from the Korean Genome and Epidemiology Study (KoGES), a prospective community-based cohort study of people living in urban and rural areas. The study profile and methods used have already been described [
This study was carried out in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Korean Health and Genomic Study at the Korea National Institute of Health and the Institutional Review Board of Soonchunhyang University Hospital (No. 2019-03-022).
Demographic and socioeconomic data were collected at baseline. Height and body weight were measured following standard methods with the patient wearing light clothes, and body mass index (BMI) was determined as kg/m2. Educational status was divided into three categories: low, lower than middle school; intermediate, middle school; and high, higher than middle school. Income status was classified into three categories: low, <$850 per month; intermediate, >$850 to <$1,700 per month; and high, >$1,700 per month. Smoking status was divided into three categories: current smokers, former smokers, and never smokers. Diabetes mellitus (DM) was defined as fasting glucose ≥126 mg/dL, post-load glucose ≥ 200 mg/dL after a 75-g oral glucose tolerance test, hemoglobin A1c ≥ 6.5%, a medical history of DM, or the use of oral medication or insulin. Subjects with a history of dyslipidemia or using lipid-lowering medications were defined as having dyslipidemia. Blood samples were collected after overnight fasting. Urine samples were collected in the morning after the first voiding and were assessed for the presence of protein using a dipstick. Proteinuria was defined as 1+ or greater.
Using a mercury sphygmomanometer, trained nurses measured BP after the subjects had been in a relaxed state for at least 10 minutes in a sitting position. The arm with the higher reading was used. The participants were divided into six categories according to SBP (<100, 100–119, 120–129, 130–139, 140–159, and ≥160 mmHg) and five categories according to DBP (<70, 70–79, 80–89, 90–99, and ≥100 mmHg).
The primary outcome was incident CKD, which was defined as eGFR of <60 mL/min/1.73 m2 or the development of proteinuria at least twice during follow-up. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [
Continuous variables are expressed as means ± standard deviations, and categorical variables are expressed as numbers and percentages. Continuous data were tested for homogeneity of variances using Levene’s test. When variances were not homogeneous, Welch’s analysis of variance was used to assess differences among BP groups, with a Tukey or Games-Howell
The baseline characteristics of the eligible participants according to their SBP categories are presented in
During a median follow-up period of 10 years (interquartile range, 6–12 years), 603 incident CKD events (8.2%) occurred, and the crude incidence rate was 9.67 (95% confidence interval [CI], 8.92–10.48) per 1,000 person-years. During follow-up, 2,028 participants were censored when they started taking antihypertensive medication, and their median follow-up period was 6 years (interquartile range, 4–9 years). The CKD incidence tended to increase significantly in the higher baseline SBP and DBP groups (p for trend <0.001, both) (
The Kaplan-Meier survival curves show a statistically significant difference in incident CKD between the BP groups. When comparing the groups using SBP 100–119 mmHg as the reference, the cumulative CKD-free survival rate was significantly lower in all the groups with SBP ≥ 120 mmHg (log-rank test p < 0.001 for all) (
We further conducted a sensitivity analysis in which baseline and time-varying BPs were treated as continuous variables to assess the consistency of our findings. When evaluating the nonlinear relationship between BP and CKD risk using restricted cubic spline models, the CKD risk increased incrementally with higher baseline and time-varying SBPs (
In subgroup analyses, we assessed interactions between time-varying BPs and stratified subgroups (time-updated age, sex, time-updated BMI, baseline DM, and time-updated total cholesterol) using a likelihood ratio test. Subjects were categorized into two groups based on SBP ≥ 130 mmHg and DBP ≥ 90 mmHg, both of which are associated with increased CKD risk. The association of SBP and DBP with incident CKD was consistent across all subgroups (
Because the BP thresholds associated with an increased CVD risk might differ from those associated with CKD risk, we also analyzed the incident CVD risk according to BP. During follow-up, 404 CVD events (5.5%) occurred, and the crude incidence rate was 7 (95% CI, 6–7) per 1,000 person-years. The multivariable Cox proportional hazard regression analysis for incident CVD is presented in
Using data from 7,343 subjects not taking antihypertensive medications, we demonstrated a graded association between time-varying BP and CKD development. Compared with the reference categories of SBP 100–119 mmHg and DBP 70–79 mmHg, CKD risk increased from SBP ≥ 130 mmHg and DBP ≥ 90 mmHg. Those BP thresholds were consistent when evaluating the association between BP and CVD risk. These results indicate that BP control interventions in treatment-naïve individuals should start when the SBP or DBP reaches 130 mmHg or 90 mmHg, respectively, to prevent CVD and CKD.
Several observational studies have shown that an increase in SBP is associated with a substantial risk of CKD in the general population [
The relationship between baseline BP and CKD was J-shaped; however, after accounting for time-varying risk factors, that association disappeared, and CKD risk remained similar among subjects with BP lower than the threshold values. A J- or U-shaped relationship between BP values and CVD was previously reported [
Although high SBP has been reported to be associated with both renal and cardiovascular complications [
In our study, the relationship between SBP and CKD was more pronounced in participants younger than 60 years than in those older than 60 years. Although the prevalence of HTN and CKD increases with age [
The strengths of our study include a well-validated, representative cohort consisting only of individuals not taking antihypertensive medication. This stringent approach helped us to show a correct and natural course of CKD development in subjects who had not taken antihypertensive medications. Moreover, our cohort had a long follow-up duration, and changes in risk factors over time were considered through the use of time-varying covariates. Nevertheless, this study also has some limitations. First, our observational study cannot exclude the possibility of residual confounding by unmeasured variables, despite our comprehensive adjustment for confounders. Second, some misclassification could arise because BP was measured biennially and was not measured using 24-hour ambulatory monitoring [
In conclusion, an SBP ≥ 130 mmHg or DBP ≥ 90 mmHg was associated with an increased risk of incident CKD in treatment-naïve individuals. Therefore, BP-lowering interventions should be considered when BP exceeds those thresholds to prevent CKD in treatment-naïve individuals.
All authors have no conflicts of interest to declare.
This research was supported by the Soonchunhyang University Research Fund (20200027).
Conceptualization: HK, DCH
Data curation: HK, HL, SHK
Formal analysis, Visualization: HK, HL, JSJ
Funding acquisition: HK
Methodology: HK, HL, HN
Project administration: HK
Writing–original draft: HL
Writing–review & editing: All authors
All authors read and approved the final manuscript.
The authors thank the National Research Institute of Health for access to KoGES data.
The cumulative CKD-free survival rate gradually decreased as BP increased in groups with SBP ≥120 mmHg and DBP ≥80 mmHg compared with the SBP 100–119 mmHg and DBP 70–79 mmHg groups, respectively.
BP, blood pressure; CKD, chronic kidney disease; DBP, diastolic blood pressure; SBP, systolic blood pressure.
All of the curves show an increased risk of CKD with higher BPs, and those relationships are clearer with time-varying BPs. Baseline data were adjusted for age, sex, educational attainment, income level, smoking status, BMI, history of DM and dyslipidemia, eGFR, total cholesterol, albumin, and hemoglobin levels. Time-updated data were adjusted for baseline sex, educational attainment, income level, smoking status, history of DM and dyslipidemia, eGFR, and albumin and time-updated age, BMI, total cholesterol, and hemoglobin.
Solid line, estimated hazard ratio; dashed line, 95% confidence interval; dotted line, hazard ratio of 1. BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.
The association between incident CKD and time-varying BP showed a similar pattern independent of sex, time-updated BMI, history of DM, and time-updated total cholesterol, but not independent of age. The risk of incident CKD was greater among those aged <60 years than among those aged ≥60 years. Data were adjusted for baseline sex, educational attainment, income level, smoking status, history of DM and dyslipidemia, eGFR, and albumin and time-updated age, BMI, total cholesterol, and hemoglobin. Forest plots show the HR (dots) and 95% CI (horizontal bars) of time-updated BP (SBP ≥130 mmHg and DBP≥90 mmHg) for incident CKD in the subgroups defined by demographic and clinical characteristics.
BMI, body mass index; BP, blood pressure; CI, confidence interval; CKD, chronic kidney disease; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HR, hazard ratio; SBP, systolic blood pressure.
Baseline characteristics of the participants
Variable | SBP (mmHg) |
|||||
---|---|---|---|---|---|---|
<100 (n = 397) | 100–119 (n = 3,016) | 120–129 (n = 1,628) | 130–139 (n = 1,148) | 140–159 (n = 889) | ≥160 (n = 265) | |
Age (yr) | 46.7 ± 6.5 | 48.9 ± 7.7 | 51.2 ± 8.4 | 53.9 ± 9.0 | 56.0 ± 8.4 | 58.2 ± 7.8 |
Female sex | 279 (70.3) | 1600 (53.1) | 747 (45.9) | 521 (45.4) | 442 (49.7) | 147 (55.5) |
SBP (mmHg) | 93.6 ± 4.3 | 109.8 ± 5.4 | 123.3 ± 3.0 | 132.8 ± 2.9 | 146.2 ± 5.5 | 169.1 ± 10.5 |
DBP (mmHg) | 64.3 ± 5.7 | 75.1 ± 6.7 | 82.7 ± 6.7 | 88.3 ± 7.3 | 94.4 ± 8.4 | 101.9 ± 11.1 |
Body mass index (kg/m2) | 23.1 ± 2.5 | 24.0 ± 2.9 | 24.6 ± 3.1 | 24.7 ± 3.1 | 25.0 ± 3.3 | 25.0 ± 3.4 |
Education | ||||||
Low | 67 (16.9) | 672 (22.4) | 498 (30.9) | 473 (41.5) | 423 (48.0) | 146 (57.3) |
Intermediate | 84 (21.2) | 712 (23.7) | 389 (24.1) | 249 (21.8) | 195 (22.1) | 56 (22.0) |
High | 245 (61.9) | 1,614 (53.8) | 724 (44.9) | 418 (36.7) | 264 (29.9) | 53 (20.8) |
Income | ||||||
Low | 57 (14.4) | 741 (25.0) | 530 (33.2) | 467 (41.5) | 416 (48.1) | 154 (59.7) |
Intermediate | 116 (29.3) | 915 (30.8) | 503 (31.5) | 316 (28.1) | 242 (28.0) | 62 (24.0) |
High | 223 (56.3) | 1,310 (44.2) | 562 (35.2) | 343 (30.5) | 206 (23.8) | 42 (16.3) |
Married | 392 (98.7) | 2,963 (98.8) | 1,596 (98.5) | 1,120 (98.9) | 874 (99.1) | 257 (98.5) |
Smoking | ||||||
Never | 281 (70.8) | 1,776 (58.9) | 913 (56.1) | 627 (54.6) | 520 (58.5) | 167 (63.0) |
Former | 31 (7.8) | 430 (14.3) | 265 (16.3) | 212 (18.5) | 144 (16.2) | 31 (11.7) |
Current | 85 (21.4) | 810 (26.9) | 450 (27.6) | 309 (26.9) | 225 (25.3) | 67 (25.3) |
Diabetes mellitus | 9 (2.3) | 122 (4.0) | 89 (5.5) | 87 (7.6) | 55 (6.2) | 16 (6.0) |
Dyslipidemia | 9 (2.3) | 69 (2.3) | 29 (1.8) | 20 (1.7) | 21 (2.4) | 2 (0.8) |
Fasting glucose (mg/dL) | 81.8 ± 18.2 | 85.2 ± 19.0 | 86.7 ± 21.0 | 87.5 ± 18.3 | 89.4 ± 22.9 | 90.8 ± 23.4 |
Creatinine (mg/dL) | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 |
eGFR (mL/min/1.73 m2) | 96.7 ± 13.4 | 94.6 ± 13.2 | 93.2 ± 13.2 | 92.4 ± 12.2 | 91.1 ± 12.2 | 89.7 ± 12.4 |
Total cholesterol (mg/dL) | 181.4 ± 30.5 | 188.1 ± 33.9 | 190.3 ± 34.6 | 191.6 ± 35.9 | 194.1 ± 36.8 | 191.8 ± 38.1 |
Triglyceride (mg/dL) | 127.4 ± 73.0 | 145.0 ± 91.9 | 164.8 ± 108.8 | 172.4 ± 106.1 | 179.2 ± 119.2 | 180.0 ± 107.5 |
HDL-C (mg/dL) | 45.9 ± 9.8 | 44.9 ± 9.7 | 44.4 ± 9.9 | 44.7 ± 10.3 | 45.3 ± 10.4 | 45.8 ± 11.3 |
LDL-C (mg/dL) | 110.1 ± 28.6 | 114.4 ± 31.4 | 113.4 ± 32.1 | 112.7 ± 33.2 | 113.7 ± 33.9 | 110.5 ± 35.7 |
Albumin (g/dL) | 4.2 ± 0.3 | 4.2 ± 0.3 | 4.3 ± 0.3 | 4.2 ± 0.3 | 4.3 ± 0.3 | 4.2 ± 0.3 |
Hemoglobin (g/dL) | 12.9 ± 1.5 | 13.5 ± 1.6 | 13.8 ± 1.6 | 13.8 ± 1.6 | 13.8 ± 1.5 | 13.6 ± 1.5 |
Data are expressed as counts (%) for categorical variables and as means ± standard deviations for continuous variables.
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.
Relationship between blood pressure and incident chronic kidney disease
Variable | Baseline |
Time-varying |
||||||
---|---|---|---|---|---|---|---|---|
Unadjusted |
Adjusted |
Unadjusted |
Adjusted |
|||||
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
SBP (mmHg) | ||||||||
<100 | 1.13 (0.74–1.72) | 0.57 | 1.66 (1.08–2.54) | 0.02 | 0.84 (0.56–1.25) | 0.39 | 1.12 (0.75–1.67) | 0.57 |
100–119 | (Reference) | (Reference) | (Reference) | (Reference) | ||||
120–129 | 1.62 (1.28–2.05) | <0.001 | 1.35 (1.06–1.71) | 0.01 | 1.16 (0.90–1.48) | 0.25 | 0.93 (0.73–1.19) | 0.55 |
130–139 | 2.99 (2.37–3.77) | <0.001 | 1.96 (1.54–2.48) | <0.001 | 2.13 (1.69–2.69) | <0.001 | 1.39 (1.10–1.77) | 0.007 |
140–159 | 4.98 (3.93–6.30) | <0.001 | 2.66 (2.08–3.40) | <0.001 | 3.18 (2.53–3.99) | <0.001 | 1.79 (1.40–2.28) | <0.001 |
≥160 | 9.19 (6.45–13.11) | <0.001 | 3.78 (2.62–5.47) | <0.001 | 7.13 (5.28–9.62) | <0.001 | 3.22 (2.35–4.40) | <0.001 |
DBP (mmHg) | ||||||||
<70 | 1.02 (0.74–1.41) | 0.90 | 1.44 (1.04–2.01) | 0.03 | 0.99 (0.74–1.31) | 0.93 | 1.05 (0.79–1.40) | 0.73 |
70–79 | (Reference) | (Reference) | (Reference) | (Reference) | ||||
80–89 | 1.46 (1.17–1.81) | 0.001 | 1.35 (1.09–1.69) | 0.007 | 1.21 (0.98–1.50) | 0.07 | 1.19 (0.97–1.47) | 0.10 |
90–99 | 2.31 (1.83–2.92) | <0.001 | 1.90 (1.50–2.40) | <0.001 | 1.89 (1.49–2.38) | <0.001 | 1.88 (1.48–2.37) | <0.001 |
≥100 | 3.94 (2.94–5.29) | <0.001 | 3.00 (2.22–4.05) | <0.001 | 3.79 (2.84–5.05) | <0.001 | 4.30 (3.20–5.76) | <0.001 |
CI, confidence interval; DBP, diastolic blood pressure; HR, hazard ratio; SBP, systolic blood pressure.
Baseline data were adjusted for age, sex, educational attainment, income level, smoking status, body mass index (BMI), history of diabetes mellitus (DM) and dyslipidemia, estimated glomerular filtration rate (eGFR), total cholesterol, albumin, and hemoglobin.
Data were adjusted for baseline sex, educational attainment, income level, smoking status, history of DM and dyslipidemia, eGFR, and albumin and time-updated age, BMI, total cholesterol, and hemoglobin.
Relationship between blood pressure and incident cardiovascular disease
Variable | Baseline |
Time-varying |
||||||
---|---|---|---|---|---|---|---|---|
Unadjusted |
Adjusted |
Unadjusted |
Adjusted |
|||||
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
SBP (mmHg) | ||||||||
<100 | 0.31 (0.13–0.76) | 0.01 | 0.40 (0.16–0.99) | 0.05 | 0.56 (0.31–1.02) | 0.06 | 0.69 (0.38–1.26) | 0.23 |
100–119 | (Reference) | (Reference) | (Reference) | (Reference) | ||||
120–129 | 1.63 (1.24–2.14) | <0.001 | 1.36 (1.03–1.79) | 0.03 | 1.51 (1.14–2.00) | 0.004 | 1.26 (0.95–1.69) | 0.11 |
130–139 | 2.81 (2.14–3.69) | <0.001 | 1.93 (1.45–2.55) | <0.001 | 2.20 (1.65–2.94) | <0.001 | 1.61 (1.19–2.18) | 0.002 |
140–159 | 3.51 (2.61–4.72) | <0.001 | 2.11 (1.55–2.89) | <0.001 | 3.39 (2.57–4.48) | <0.001 | 2.34 (1.72–3.17) | <0.001 |
≥160 | 6.19 (3.97–9.65) | <0.001 | 3.19 (2.01–5.05) | <0.001 | 4.58 (2.98–7.06) | <0.001 | 2.88 (1.84–4.50) | <0.001 |
DBP (mmHg) | ||||||||
<70 | 0.64 (0.40–1.02) | 0.06 | 0.79 (0.50–1.27) | 0.33 | 0.71 (0.48–1.05) | 0.08 | 0.80 (0.54–1.19) | 0.27 |
70–79 | (Reference) | (Reference) | (Reference) | (Reference) | ||||
80–89 | 1.28 (0.98–1.67) | 0.07 | 1.16 (0.89–1.51) | 0.29 | 1.15 (0.89–1.49) | 0.28 | 1.04 (0.80–1.35) | 0.76 |
90–99 | 2.18 (1.66–2.87) | <0.001 | 1.70 (1.29–2.26) | <0.001 | 1.93 (1.46–2.55) | <0.001 | 1.69 (1.26–2.25) | <0.001 |
≥100 | 3.49 (2.47–4.94) | <0.001 | 2.49 (1.74–3.55) | <0.001 | 3.92 (2.81–5.47) | <0.001 | 3.31 (2.34–4.70) | <0.001 |
CI, confidence interval; DBP, diastolic blood pressure; HR, hazard ratio; SBP, systolic blood pressure.
Baseline data were adjusted for age, sex, educational attainment, income level, smoking status, body mass index (BMI), history of diabetes mellitus (DM) and dyslipidemia, estimated glomerular filtration rate (eGFR), total cholesterol, albumin, and hemoglobin.
Data were adjusted for baseline sex, educational attainment, income level, smoking status, history of DM and dyslipidemia, eGFR, and albumin and time-updated age, BMI, total cholesterol, and hemoglobin.