Blood Pressure Predicts Risk of Developing End-Stage Renal Disease in Men and Women
Blood pressure as a risk factor for development of end-stage renal disease has not been fully studied, particularly in women. We studied the development of end-stage renal disease from 1983 through 2000 in 98 759 subjects, 46 881 men and 51 878 women, 20 to 98 years of age, who were screened in 1983 in Okinawa, Japan. Data for all dialysis patients registered from 1983 to 2000 in Okinawa were used to identify the screened subjects in whom end-stage renal disease developed. In follow-up, 400 subjects, 231 men and 169 women, had end-stage renal disease. Age, body mass index, and adjusted relative risk for systolic and diastolic blood pressure for both men and women were measured. When these results were compared with an optimal blood pressure, the relative risk of development of end-stage renal disease for those with high-normal blood pressure and hypertension were significant in both men and women. Hypertension is a significant risk factor for development of end-stage renal disease not only in men but also in women. Control of blood pressure within normal levels should be stressed as a strategy to prevent end-stage renal disease in both men and women.
The number of new dialysis patients is increasing annually, and the reasons for this increase are not clear. The prevalence of dialysis patients was 1752 per million persons in Okinawa, Japan.1 Higher blood pressure was a significant predictor of end-stage renal disease (ESRD) in hypertensive men.2 In men screened for the Multiple Risk Factor Intervention Trial, high-normal and high blood pressure were judged to be strong independent risk factors for ESRD.3 However, these data concerned men only2,3 or were not stratified by gender.4 We previously reported from the 10-year follow-up of a screened cohort in Okinawa that high diastolic blood pressure (DBP) was a significant predictor of ESRD but that systolic blood pressure (SBP) was not.4 In the current study, we extended the follow-up period in our cohort by 6 years and prospectively studied the development of ESRD in 46 876 men and 51 878 women screened by the Okinawa General Health Maintenance Association in 1983; we also examined the effect of blood pressure on the risk of development of ESRD in women.
All individuals who were from 20 to 98 years of age and who participated in the 1983 mass health screening examination in Okinawa, Japan, were eligible for the study. Dialysis patients who had been among the 1983 mass screening participants and who became dialysis patients from 1983 to 2000 were identified through the Okinawa Dialysis Study (OKIDS) registry.1 Furthermore, patient identification was verified by reviewing the medical records of the dialysis unit. The cumulative incidence of ESRD and the relative risk (RR) of developing ESRD according to blood pressure levels taken from the mass screening registry were determined.
Mass Screening Registry
The large community-based health examination program is performed annually by the Okinawa General Health Maintenance Association, under the direction of Drs K. Kinjo and Y. Ikemiya. Each program participant is interviewed regarding his or her health status and given a physical examination, urinalysis, and blood tests. All blood pressure measurements were done with a mercury sphygmomanometer by a trained nurse or doctor while the patient was seated. One reading was taken and used in our analysis. Phases I and V Korotkoff sounds were used to determine SBP and DBP, respectively.
The computer database includes data acquired from April 1, 1983, through March 31, 1984. The database includes the participant’s name, birth date, sex, zip code, employment group code, residential code, and the results of clinical and laboratory tests. The 107 192 participants were made up of 51 122 men and 56 070 women. According to the 1980 census, the total population of Okinawa older than 15 years of age was 781 166 (377 479 men and 403 687 women). Therefore, the estimated proportion of the adult population older than 20 years of age in 1983 who participated in the mass screening was ≈13.7% (13.6% in men and 13.9% in women). Of all the screened subjects, information about screening blood pressure or body mass index (BMI: body weight/height2, kg/m2) was available from 46 881 men and 51 818 women. Detailed data form the mass screening registry have been published elsewhere.5
Since 1971, all patients receiving chronic dialysis, living on Okinawa, have been registered in an independent program1 the OKIDS registry. Characteristics and other epidemiological features of the patients enrolled in this registry were reported previously.1,6,7 Patients with intermittent or continuous ambulatory peritoneal dialysis were also included in the registry. The medical records of the dialysis patients who participated in the 1983 screening were reviewed with the complete cooperation and collaboration of the staff from the dialysis units of the OKIDS registry.
Data are expressed as mean ±SD. A probability value <0.05 was considered to be significant. The relation of blood pressure to ESRD was investigated with logistic regression analysis using StatView 5.0 (SAS Institute). Models were adjusted for age (years) and BMI (kg/m2).
Blood pressure was categorized according to criteria for adults 20 years of age and older from the classification of blood pressure in the Japanese Society of Hypertension Guidelines (JSH 2000),8 which is substantially similar to the sixth report of the Joint National Committee (JNC VI)9 and the 1999 WHO-ISH classification.10
The effect of SBP on the development of ESRD, as compared with that of DBP, was evaluated. Dipstick measurement of proteinuria at the initial screening in 1983 enabled us to analyze the relation of blood pressure to the incidence of ESRD while taking into account renal injury at baseline. Proteinuria was defined as 1+ or more by dipstick test.
The baseline characteristics of subjects in the study are shown in Table 1. Blood pressure categories and baseline characteristics of the subjects are shown in Table 2. During follow-up, ESRD developed in 231 men and 169 women (400 subjects). The 400 dialysis patients who participated in the 1983 screening were younger and had a higher percentage of glomerulonephritis than did the 4610 patients registered in the OKIDS registry from 1983 through 2000 (Table 3). The leading cause of ESRD in the 400 dialysis patients was chronic glomerulonephritis, followed by diabetes mellitus and nephrosclerosis. Cumulative incidence of ESRD during follow-up according to blood pressure categories is shown in Figure 1. Rates for development of ESRD increased as the severity of the rise in blood pressure increased from optimal to severe.
|Values are expressed as mean±SD except where otherwise indicated. BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure.|
|*Dipstick positive proteinuria of 1+ or higher.|
|n||46 881||51 878||98 759|
|SBP, mm Hg||132±18||129±20||130±19|
|DBP, mm Hg||80±11||77±11||78±11|
|Variable||Optimal||Normal||High Normal||Mild HT||Moderate HT||Severe HT||Total|
|Values are expressed as mean±SD except where otherwise indicated. HT indicates hypertension.|
|Men, n||8168||11 677||9116||12 438||4135||1347||46 881|
|SBP, mm Hg||110±6||121±4||131±4||142±8||160±11||181±16||132±18|
|DBP, mm Hg||68±6||75±6||79±6||86±7||94±9||105±12||80±11|
|Women, n||15 019||11 158||7724||12 051||4571||1355||51 878|
|SBP, mm Hg||108±7||121±4||131±4||144±8||163±8||185±15||129±20|
|DBP, mm Hg||66±6||75±6||78±6||85±7||92±9||102±12||77±11|
|Variable||OKIDS 1983–2000 (n=4610)||Screened Patients Who Developed ESRD (n=400)||P|
|Values are expressed as mean±SD or percentage. OKIDS indicates Okinawa Dialysis Study; ESRD, end-stage renal disease.|
|Age at start of dialysis, y||57±16||53±13||<0.0001|
|Renal disease, %|
|Polycystic kidney disease||2.4||2.5||0.93|
|Systemic lupus erythematosus||2.2||1.5||0.47|
There was a significant positive association between SBP and DBP and the risk of development of ESRD in men and women: the RR) for SBP (10 mm Hg) was 1.29 (95% CI=1.22 to 1.38, P<0.0001) in men and 1.34 (95% CI=1.25 to 1.43, P<0.0001) in women; RR for DBP (10 mm Hg) was 1.56 (95% CI=1.40 to 1.74, P<0.0001) in men and 1.69 (95% CI=1.49 to 1.91, P<0.0001) in women.
Blood Pressure Categories and Risk of ESRD
The estimated RR (adjusted for age and BMI at baseline) of ESRD according to the 6 blood pressure categories in men and women is shown in Figure 2. Compared with an optimal blood pressure, level the risk of development of ESRD in subjects increased with each of the 5 successively more severe categories of blood pressure. After adjusting for blood pressure, the risk of development of ESRD was positively associated with BMI in men (RR=1.06; 95% CI=1.02 to 1.10) but not in women (RR=1.00; 95% CI=0.96 to 1.05).
Proteinuria was present in 5.7% of men and in 5.1% of women. After adjusting for presence of proteinuria in addition to age and BMI, there was a significant positive association between the risk of development of ESRD and SBP and DBP in men and women: RR for SBP (10 mm Hg) was 1.22 (95% CI=1.14 to 1.30, P<0.0001) in men and 1.02 (95% CI=1.01 to 1.03, P<0.0001) in women; RR for DBP (10 mm Hg) was 1.03 (95% CI=1.02 to 1.04, P<0.0001) in men and 1.47 (95% CI=1.30 to 1.67, P<0.0001) in women. In the analysis, RR of development of ESRD was significant for proteinuria in men and women with adjustment for SBP: RR for proteinuria was 11.29 (95% CI=8.63 to 14.77, P<0.0001) in men and 12.50 (95% CI=9.07 to 17.22, P<0.0001) in women.
Patients with diabetes mellitus as a primary cause of ESRD were 61 men and 36 women among the 400 patients with ESRD. When excluding the patients with diabetic ESRD, there was a also a significant positive association between the risk of development of nondiabetic ESRD and SBP and DBP in men and women adjusted for age and BMI (Table 4). There was also a significant positive association between the risk of development of diabetic ESRD and SBP in men and SBP and DBP in women adjusted for age and BMI.
|Variable||Men, Adjusted Relative Risk||Women, Adjusted Relative Risk|
|95% CI*||P||95% CI*||P|
|CI indicates confidence interval.|
|*Adjusted for age and body mass index.|
|Diabetic ESRD (n=61/36, men/women)|
|SBP, 10 mm Hg||1.21 (1.07–1.38)||0.002||1.30 (1.12–1.50)||0.0004|
|DBP, 10 mm Hg||1.17 (0.93–1.46)||0.16||1.36 (1.02–1.81)||0.03|
|Nondiabetic ESRD (n=171/133)|
|SBP, 10 mm Hg||1.32 (1.23–1.42)||<0.0001||1.35 (1.25–1.45)||<0.0001|
|DBP, 10 mm Hg||1.71 (1.52–1.93)||<0.0001||1.78 (1.55–2.05)||<0.0001|
Joint Effect of Systolic and Diastolic Pressure on Risk of ESRD
The joint effects of stratified SBP and DBP to RR of development of ESRD with age and BMI adjustment are shown in Figure 3. The RR of development of ESRD was remarkably increased for men and women with hypertensive levels of both SBP and DBP.
The major findings of this 17-year follow-up study are that hypertension was an independent risk factor for development of ESRD in a large screened cohort of 46 881 men and 51 878 women in Okinawa, Japan. Our results validate the usefulness of the JNC VI, 1999 WHO/ISH classification and JSH 2000 categories in predicting the incidence of ESRD in both men and women.
Hypertension is a strong risk factor for development of ESRD in men.2,3 We examined 107 192 screened subjects over 20 years of age for an 11-year period and determined that DBP was a significant risk factor for development of ESRD.4 In the current study, we observed the cohort for 17 years and showed that both SBP and DBP were independent risk factors for ESRD. Furthermore, our results indicate that high-normal blood pressure and hypertension are independent risk factors for ESRD as compared with an optimal blood pressure not only in men but also in women.
Obesity has been reported as a risk factor of renal injury.11–14 On the other hand, BMI is increased with blood pressure.4,15 Therefore, there is the possibility that the association between BMI and ESRD was confounded with blood pressure. However, even after adjustment for blood pressure, the results of the present study suggest that BMI is a significant positive predictor of ESRD in men. Our previous study showed that no significant association was found between BMI and ESRD in men, but a negative association was observed in women.16 The duration of the study is shorter than that of the present study (10 years versus 17 years). This may be a reason for the different result. However, the gender difference in the association between BMI and ESRD may exist. Precise analyses are currently undergoing.
There were several limitations to our study. During follow-up, all of the new patients with ESRD were detected; however, information about subjects who died from any other causes was not available, and those subjects were not excluded from the logistic regression analysis in the current study. Therefore, we underestimated the risk of blood pressure as a predictor of ESRD in the logistic regression analysis. Blood pressure was measured on only one occasion, which also limited the strength of the association between the risk of development of ESRD and blood pressure.3 Information about antihypertensive therapy was not collected in the cohort. In the 1997 screening done by OGHMA in which data about antihypertensive therapy were collected,15 5% of persons who were 40 years or older were treated with antihypertensive medication. Treated patients could be categorized as being at a less severe stage of hypertension, and this would also weaken the estimated risk of blood pressure as a risk factor for development of ESRD.
Although preexisting renal disease may contribute to the elevation of blood pressure, whether renal disease was already present in our screened subjects was not assessed at baseline. However, dipstick proteinuria was examined in all subjects, and proteinuria was present in 5.6% of men and in 5.1% of women. Although the risk of development of ESRD based on SBP and DBP was reduced when adjusted for proteinuria in multiple logistic models, the significance of blood pressure was still remarkable. Both proteinuria and hypertension can be causes and effects of renal disease. Proteinuria at baseline was the stronger predictor of subsequent ESRD when both variables were considered together. These relations are very similar to previous observations.17,18 Evaluation of clinical proteinuria is important and could be an excellent marker of organ damage of the kidney.
Since 1991, diabetes mellitus has been increasing rapidly as the primary cause for new dialysis patients in Okinawa.1 In the current study, 24% of ESRD cases were caused by diabetes mellitus. Even after excluding the diabetic patients with ESRD from all causes of ESRD, meaning that nondiabetic patients with ESRD were considered as an outcome in logistic analysis, the risks of development of ESRD according to SBP and DBP were still significant. SBP in men and SBP and DBP in women were also significant risk factors for development of diabetic ESRD. These results suggest that high blood pressure is an independent risk factor for the development of both nondiabetic and diabetic ESRD.
In the African American Study of Kidney Disease and Hypertension (AASK) trial,19 the differences in the achieved BP level (128/78 mm Hg versus 141/85 mm Hg) did not make a difference in glomerular filtration rate slope (−2.21 mL/min per 1.73 m2 versus −1.95 mL/min per 1.73 m2) during 4 years. These data argue that the lowest blood pressure make not be any more protective of renal function decline than high normal or mildly elevated blood pressures. However, subjects and outcome in the AASK trial were different from the current study. Furthermore, duration of follow-up in the AASK trial was shorter than that in the current study (4 years versus 17 years). In one study, followed-up for 9.8 years, the time-averaged blood pressure was predictive of the change in serum creatinine concentration.20 It needs a long observation to provide the statistical power to demonstrate an effect of blood pressure on the development of ESRD.2
The incidence of ESRD is increasing, and the social burden of ESRD is becoming greater. Slowing or stopping the progression to renal failure has gained an important public health priority. As a modifiable risk factor for ESRD, hypertension is a target that can be controlled. Prevention of hypertension should be emphasized as a primary way to prevent ESRD, which means that a controlled study analyzing the multiple risk factors for hypertension is needed. Furthermore, early detection of persons with hypertension and treatment with the antihypertensive therapy are essential as continuing strategies to prevent ESRD.
The authors thank Mr Masanori Itokazu and Mr Kaoru Shiroma of the Okinawa General Health Maintenance Association for technical assistance. The authors also thank the OKIDS-affiliated group and Dr Kunitoshi Iseki (principal investigator).
- 1 Iseki K, Tozawa M, Iseki C, Takishita S, Ogawa Y. Demographic trends in the Okinawa Dialysis Study (OKIDS) registry (1971–2000). Kidney Int. 2002; 61: 668–675.CrossrefMedlineGoogle Scholar
- 2 Perry HM Jr, Miller JP, Fornoff JR, Baty JD, Sambhi MP, Rutan G, Moskowitz DW, Carmody SE. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995; 25: 587–594.CrossrefMedlineGoogle Scholar
- 3 Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996; 334: 13–18.CrossrefMedlineGoogle Scholar
- 4 Iseki K, Ikemiya Y, Fukiyama K. Blood pressure and risk of end-stage renal disease in a screened cohort. Kidney Int. 1996; 55 (suppl 55): S-69–S-71.Google Scholar
- 5 Iseki K, Kimura Y, Wakugami K, Okumura K, Muratani H, Ikemiya Y, Fukiyama K. Comparison of the effect of blood pressure on the development of stroke, acute myocardial infarction, and end-stage renal disease. Hypertens Res. 2000; 23: 143–149.CrossrefMedlineGoogle Scholar
- 6 Tozawa M, Iseki K, Iseki C, Takishita S. Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis. Kidney Int. 2002; 61: 717–726.CrossrefMedlineGoogle Scholar
- 7 Tozawa M, Iseki K, Iseki C, Oshiro S, Higashiuesato Y, Yamazato M, Tomiyama N, Tana T, Takishita S. Analysis of drug prescription in chronic hemodialysis patients. Nephrol Dial Transplant. 2002; 17: 1819–1824.CrossrefMedlineGoogle Scholar
- 8 Japanese Society of Hypertension Guidelines Subcommittee for the Management of Hypertension. Guidelines for the Management of Hypertension for General Practitioners. Hypertens Res. 2001; 24: 613–634.CrossrefMedlineGoogle Scholar
- 9 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157: 2413–2446.CrossrefMedlineGoogle Scholar
- 10 Guidelines Subcommittee. World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens. 1999; 17: 151–183.MedlineGoogle Scholar
- 11 Metcalf P, Baker J, Scott A, Wild C, Scragg R, Dryson E. Albuminuria in people at least 40 years old: effect of obesity, hypertension, and hyperlipidemia. Clin Chem. 1992; 38: 1802–1808.CrossrefMedlineGoogle Scholar
- 12 Kasiske BL, Crosson JT. Renal disease in patients with massive obesity. Arch Intern Med. 1986; 146: 1105–1109.CrossrefMedlineGoogle Scholar
- 13 Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall JE. Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol. 2001; 12: 1211–1217.CrossrefMedlineGoogle Scholar
- 14 Tozawa M, Iseki K, Iseki C, Oshiro S, Ikemiya Y, Takishita S. Influence of smoking and obesity on the development of proteinuria. Kidney Int. 2002; 62: 956–962.CrossrefMedlineGoogle Scholar
- 15 Tozawa M, Oshiro S, Iseki C, Sesoko S, Higashiuesato Y, Tana T, Ikemiya Y, Iseki K, Fukiyama K. Multiple risk factor clustering of hypertension in a screened cohort. J Hypertens. 2000; 18: 1379–1385.CrossrefMedlineGoogle Scholar
- 16 Iseki K, Ikemiya Y, Fukiyama K. Predictors of end-stage renal disease and body mass index in a screened cohort. Kidney Int. 1997; 52 (suppl 63): S-169–S-170.Google Scholar
- 17 Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int. 1996; 49: 800–805.CrossrefMedlineGoogle Scholar
- 18 Locatelli F, Marcelli D, Comelli M, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A. Proteinuria and blood pressure as causal components of progression to end-stage renal failure: Northern Italian Cooperative Study Group. Nephrol Dial Transplant. 1996; 11: 461–467.CrossrefMedlineGoogle Scholar
- 19 Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG, African American Study of Kidney Disease, and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002; 288: 2421–2431.CrossrefMedlineGoogle Scholar
- 20 Rosansky SJ, Hoover DR, King L, Gibson J. The association of blood pressure levels and change in renal function in hypertensive and nonhypertensive subjects. Arch Intern Med. 1990; 150: 2073–2076.CrossrefMedlineGoogle Scholar