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Effects of Blood Pressure According to Age on End-Stage Renal Disease Development in Patients With Diabetes: A Nationwide Population-Based Cohort Study

Background: Recent hypertension guidelines have recommended lower blood pressure (BP) targets in high-risk patients. However, there are no specific guidelines based on age or systolic and diastolic blood pressure (SBP and DBP, respectively). We aimed to assess the effects of age-related BP on development of end-stage renal disease (ESRD) in patients with diabetes. Methods: A total of 2 563 870 patients with diabetes aged >20 years were selected from the Korean National Health Screening Program from 2009 to 2012 and followed up until the end of 2019. Participants were categorized into age and BP groups, and the hazard ratios for ESRD were calculated. Results: During a median follow-up of 7.15 years, the incidence rates of ESRD increased with increasing SBP and DBP. The hazard ratio for ESRD was the highest in patients younger than 40 years of age with DBP≥100 mm Hg. The effect of SBP and DBP on ESRD development was attenuated with age (interaction P was <0.0001 for age and SBP, and 0.0022 for age and DBP). The subgroup analysis for sex, antihypertension medication, and history of chronic kidney disease showed higher hazard ratios for ESRD among males, younger than 40 years, not taking antihypertension medications and chronic kidney disease compared to those among females, older than 40 years, antihypertension medication, and nonchronic kidney disease groups. Conclusions: Higher SBP and DBP increase the risk of developing ESRD in patients with diabetes, and in particular, younger individuals face greater risk. Therefore, intensive BP management is warranted in younger patients to prevent ESRD.

D iabetes is a strong risk factor for end-stage renal disease (ESRD). 1 Hypertension also plays a crucial role in the development and progression of kidney failure. 2,3 Blood pressure (BP) rises with declining kidney function which in turn aggravates hypertension. Moreover, as chronic kidney disease (CKD) worsens, BP becomes more difficult to control, propagating a vicious cycle of worsening BP and renal function. Therefore, early diagnosis and prompt treatment of hypertension in high-risk patients are crucial. In addition, hypertension is common among young people and can cause harmful health effects even at a young age. 4 In recent hypertension guidelines, lower BP targets are recommended for high-risk patients, such as those with renal disease or diabetes. 5 However, the effects of BP on the development of ESRD according to age in patients with diabetes have not been investigated. In addition, a recent study identified numerous barriers to good BP control in young adults. 6 Therefore, this nationwide population-based study aimed to investigate the association between BP categories according to age and the risk of ESRD among patients with diabetes using the Korean National Health Insurance Service (KNHIS) database.

KNHIS Data
In this study, we used the national health insurance claims database established by the KNHIS, which includes all claims data provided by the KNHIS and Medical Aid programs. The KNHIS database is considered to represent the entire South Korean population, and the details of this database have been previously described. 7 Depending on their occupations, all insured Koreans undergo an annual or biennial health examination that is supported by the KNHIS. The sociodemographic data and all medical expenses for both inpatient and outpatient services, pharmacy dispensing claims, and mortality information are included in the database. Anonymized data are publicly available from the National Health Insurance Sharing Service and can be accessed at https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do.
This study was approved by the institutional review board of Chonnam National University Hospital, Korea (CNUH-EXP-2021-289) informed consent was waived and was performed in accordance with the ethical standards of the committee responsible for human experimentation and the Helsinki Declaration of 1975, as revised in 2013.

Subjects
Initially, 2 746 079 patients with diabetes who underwent health checkups from 2009 to 2012 were identified. Of these, we included patients who had undergone a repeat health checkup after 2 years. The index date was the date of the last health check-up. We excluded those aged <20 years because ESRD development is rare in this subpopulation. We also excluded subjects with malignancy or a history of ESRD before the index date and those with missing health examination data. Finally, 2 563 870 subjects with diabetes were included in the study. Systolic blood pressure (SBP) values from <100 to ≥160 mm Hg were divided into 5 groups at 20 mm Hg intervals, and DBP values from <70 to ≥110 mm Hg were divided into 6 groups at 10 mm Hg intervals. The detailed flowchart of the selection of study subjects is presented in Figure S1. The participants were followed up until one of the following occurred: a new diagnosis of ESRD, death, loss of health insurance qualification, or end of the study (December 31, 2019).

Definitions
Patients with diabetes were defined as follows: (1)  Clinical/Pathophysiological Implications?
Higher systolic BP and diastolic BP increase the risk of developing ESRD in patients with diabetes, and in particular, younger individuals face greater risk. Therefore, intensive BP management is warranted in younger patients to prevent ESRD. medication under the International Statistical Classification of Diseases, Tenth Revision (ICD-10) codes E11 to E14 from the insurance claims data, or (2) having a fasting plasma glucose ≥126 mg/dL in the health examination without a prescription for antidiabetic medication. 7 Antidiabetic medications included sulfonylureas, metformin, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, and insulins. Comorbidities were defined using ICD-10 diagnosis codes with health care usage and medication or health examination results, as in the previous studies. [8][9][10] Hypertension was defined as a previous diagnosis of hypertension according to the ICD-10, Clinical Modification codes (I10-I13, I15) or a recorded systolic BP (SBP) ≥140 mm Hg or diastolic BP (DBP) ≥90 mm Hg. BP was measured by trained clinicians at least twice using mercury or automatic sphygmomanometer in a sitting position, following a minimum of 5 min of rest in the appropriate position, after obtaining the anthropometric measurements. CKD was defined as an estimated glomerular filtration rate <60 mL/(min·1.73 m 2 ) and was calculated using CKD Epidemiology Collaboration equation. 11 Dyslipidemia was defined as a presence of ICD-10, Clinical Modification code E78, and history of lipid-lowering drug use or a total serum cholesterol concentration of ≥240 mg/dL in the health examination data. Congestive heart eGFR <60 mL/(min·1.73 m 2 ) using CKD-EPI formula. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASD, absolute standardized difference; BMI, body mass index; BP, blood pressure; CCB, calcium channel blocker; CHF, congestive heart failure; CKD, chronic kidney disease, CKD-EPI, CKD Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MI, myocardial infarction; OHA, oral hypoglycemic agents; PA, physical activity; TC, total cholesterol; and WC, waist circumference. *Alcohol consumption ≥30 g/d. †Low income 25%.

Outcomes
The end point of the study was incident ESRD, which was defined using a combination of ICD-10 codes (N18-19, Z49, Z94.0, and Z99.2) and a special code (V code) that was assigned in the initiation of renal replacement therapy (hemodialysis, V001; peritoneal dialysis, V003) or kidney transplantation (V005) during hospitalization. All medical expenses for dialysis are reimbursed using the Korean Health Insurance Review and Assessment Service database. These patients are also registered as special medical aid beneficiaries. Therefore, we were able to identify every patient with ESRD in the entire South Korean population and were able to analyze the data for all patients with ESRD who underwent dialysis. Codes for treatment or medical expense claims included V005 for kidney transplantation, V001 for hemodialysis, and V003 for peritoneal dialysis. We excluded individuals without previous CKD who had a transplant or dialysis code on the same date as an acute renal failure code. Subjects on continuous renal replacement therapy or acute peritoneal dialysis were also excluded.

Statistical Analyses
Data are presented as the mean±SD for continuous variables and numbers with proportions for categorical variables. Nonnormally distributed variables are presented as geometric means (95% CI). Intergroup differences were tested using a χ 2 test or ANOVA, as appropriate. The incidence rates of ESRD are presented per 1000 person-years. The absolute standardized difference, which is unaffected by the population number (unlike P), was calculated since the number of participants in the study was large. Multivariable Cox proportional hazard regression analysis was used to estimate the hazard ratios (HRs) and 95% CIs of the risk of ESRD associated with BP along with adjustment for age, sex, smoking, alcohol consumption, regular exercise, low-income status, use of insulin, number of oral hypoglycemic agents, duration of diabetes, previous history of hypertension and dyslipidemia, estimated glomerular filtration rate, antihypertension medication numbers and type, myocardial infarction, stroke, and congestive heart failure. In addition, subgroup analyses were performed in patients with diabetes according to sex, antihypertensive medication, and history of CKD. All data analyses were conducted using SAS software (version 9.4; SAS Institute, Cary, NC), and P<0.05 was considered statistically significant.   was lower in the incident ESRD group compared with the non-ESRD group. Comorbidities such as hypertension, dyslipidemia, myocardial infarction, stroke, congestive heart failure, and CKD were more prevalent in the ESRD group than in the non-ESRD group. The ESRD group showed a higher frequency of insulin use, higher frequency of patients with diabetes duration >5 years, higher number of patients taking more than 3 oral hypoglycemic agents, greater number of patients with higher fasting glucose levels but showed lower levels of high-density lipoprotein cholesterol and estimated glomerular filtration rate than that of the non-ESRD group ( Table 1). The baseline characteristics of all participants according to SBP (Table 2) and DBP (

Effects of Systolic BP or Diastolic BP on ESRD According to Age
The incidence rate for ESRD increased according to age and BP in both SBP and DBP categories (interaction P was <0.0001 for age and SBP, and 0.0022 for age and DBP). SBP<100 mm Hg was taken as the reference. In patients aged under 40 years old, the multivariableadjusted HR (95% CI) for ESRD was 2.184 (1.207-3.950) for SBP≥160 mm Hg (   the effect of DBP on ESRD development with increasing age (Table S4).
In subgroup analysis according to history of CKD, the CKD group showed a higher HR compared to the non-CKD group for SBP (

DISCUSSION
The present study demonstrated that increased levels of both SBP and DBP were associated with a higher risk of ESRD. Furthermore, the younger the age, the greater the effect of hypertension on the development of ESRD was, and this effect was especially notable in men under 40 years of age, those with DBP ≥110 mm Hg, and those not taking antihypertensive drugs.
In general, diabetic nephropathy is the major cause of ESRD and hypertension contributes to further progression of kidney disease and cardiovascular disease (CVD) risk in this population. 12 ESRD is an important determinant of morbidity and mortality in patients with diabetes. 13 Hypertension is a major risk factor for CVD, which is also an important contributor to morbidity and mortality in patients with diabetes. 14 The importance of BP reduction is strengthened by previous studies which have indicated that ≈10 mm Hg decline in SBP reduced the risk of CVD by 20%, heart failure by 28%, stroke by 27%, and all-cause mortality by 13%. 15 In addition, Figure. Incidence rate (IR) and hazard ratios (HR) for end-stage renal disease according to blood pressure group with age. Systolic blood pressure (A) and diastolic blood pressure (B). Adjusted for age, sex, income-low 25%, current smoker, alcohol consumption, regular exercise, hypertension, dyslipidemia, chronic kidney disease, diabetes duration ≥5 y, insulin, oral hypoglycemic agents ≥3. hypertension is a known independent risk factor for the development of ESRD. 16 Using a historical cohort study, Hsu et al. reported that compared with subjects with a BP less than 120/80 mm Hg, the adjusted relative risks for developing ESRD increased according to BP level and the risk for ESRD was higher in patients with diabetes compared to that in patients without. 17 A study using a large cohort of CKD showed that the risk of ESRD increased with SBP of 140 mm Hg or higher. 18 However, other studies have shown that an association exists between BP and ESRD risk at high DBP and that DBP is also known as an independent risk factor for ESRD. 19 Our study also showed that the risk for ESRD increased according to increasing SBP or DBP in all age groups, but effect of BP on ESRD weakened with age. The presence of hypertension at a young age increases the risk of cardiovascular events in middle age. 20 Hypertension contributes to early-onset coronary heart disease, heart failure, stroke, and transient ischemic attacks. 21 Although good national guidelines exist, the guidelines do not serve low-risk young patients with hypertension as effectively as they do older patients. Furthermore, risk assessment is challenging in young patients because of the limited validity of established risk assessment tools, and a greater focus on SBP, which is less well correlated with CVD outcome. 20,22 Additionally, the causes of high SBP and DBP among young adults may differ. A higher systemic vascular resistance is a major contributor to high DBP, whereas increased aortic stiffness and a reduced aortic diameter contribute to high SBP among young adults. 23 In the current study, the highest DBP (≥110 mm Hg) group showed the highest HR compared to the highest SBP (≥160 mm Hg) group, especially in the male patient subgroup.
Although intrinsic mechanisms that regulate arterial BP are similar in men and women, marked variations exist at the molecular, cellular, and tissue levels. Previous studies have reported that compared to the BP pattern in men, women tend to show a steeper elevation in BP with age, starting from young adulthood and continuing throughout life. 24 However, women have a longer lifespan than men and develop age and CVD-related pathologies later in life; these outcomes might be due in part to sex differences in cell injury and repair pathways that delay the chronic accumulation of senescent cells, end-organ damage, and the progression of CVD. 25 In this study, the subgroup analysis for sex also showed that the ESRD risk was higher in men than in women for both SBP and DBP.
The strengths of this study include the use of a large nationwide longitudinal health screening database with high participation and outcome ascertainment rates owing to electronic linkages to universal health insurance records. This database covers a wide range of the Korean diabetes population over a long follow-up duration and, hence, allows a sizable inclusion of young adults. The events in these young participants are considered premature ESRD, an important population health outcome measure, that has rarely been studied in a large sample size to date.
However, our study also has some limitations. First, although the 2017 American College of Cardiology/ American Heart Association guidelines recommend that at least 2 BP readings be obtained before determining the stage of BP, in the current study, participants were classed based on their BP readings assessed based on an average of two readings obtained during a single visit. However, in a real-world screening environment taking place on a nationwide scale, adherence to the protocol may be limited. Therefore, the BP measurements used for the classification might not have fully reflected a person's BP phenotype. Second, possible residual confounding, including sodium intake and psychological factors, may affect the association between BP and ESRD events. Third, our study was based on Korean patients with diabetes subscribing to a universal health insurance and screening program; the results should be interpreted with caution when applied to different populations or healthcare systems. Finally, longitudinal BP control or other covariates over time such as kidney function was not considered in this study.
In conclusion, among Korean patients with diabetes, those with elevated SBP or DBP were associated with a higher ESRD risk in all age groups than those with normal BP. The ESRD risk associated with BP was attenuated with age. In addition, the male patients with diabetes with high DBP and without antihypertensive medications should be screened and treated more aggressively given their particularly high risk of ESRD.

PERSPECTIVES
The incidence of ESRD is increasing according to the increasing prevalence of diabetes, and the social burden of ESRD is becoming greater. Slowing or stopping the progression to ESRD is an important public health goal. As a modifiable risk factor for ESRD, hypertension is a target that can be controlled. Our study demonstrated the enormous impact of BP on the development of ESRD, especially in young adults. 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 antihypertensive drug therapy are essential as continuing strategies to prevent ESRD.