A nationwide cross-sectional survey on prevalence, management and pharmacoepidemiology patterns on hypertension in Chinese patients with chronic kidney disease

Limited data are available on epidemiology and drug use in Chinese hypertensive patients with chronic kidney disease (CKD). We determined the prevalence; awareness, treatment, and control rates of hypertension; anti-hypertensive use, expenditure pattern; and factors associated with hypertension prevalence and control in Chinese patients with CKD. This was one of the largest cross-sectional surveys that enrolled 6079 CKD participants (mean age, 51.0 ± 16.37 years) with or without hypertension from 22 centres across China. The prevalence, awareness, and treatment rates were 71.2%, 95.4%, and 93.7%, respectively. Control rates 1 and 2 (Blood pressure, BP <140/90 and <130/80 mmHg) were 41.1% and 15.0%, respectively. Patients were treated mostly with monotherapy (37.7%) or 2-drug anti-hypertensive combination (38.7%). Factors associated with prevalence of hypertension included age; smoking; body mass index; physical exercise; family history of hypertension; hyperuricaemia; and CKD. Control rate was associated with CKD stage, BP monitoring at home, and use of drug combinations. Despite high rates of awareness and treatment, the control rates are low. CKD stages 4 and 5 adversely affect the control rate. The results suggest the immediate need of comprehensive controlling measures to improve the control of hypertension in Chinese patients with CKD.

Scientific RepoRts | 6:38768 | DOI: 10.1038/srep38768 affect the control rate. The results suggest the immediate need of comprehensive controlling measures to improve the control of hypertension in Chinese patients with CKD.
Hypertension and chronic kidney disease (CKD) are interrelated and increasingly recognised as a serious global public health concern 1 . The estimated worldwide prevalence of CKD is 8% to16% 2 . Its prevalence is not only high in developed countries [3][4][5] but is also on the rise in developing countries 6,7 . In China, an estimated 10.8% of the population has CKD, and the prevalence has been observed to increase with increasing age 7,8 .
Hypertension is also highly prevalent in China (≈ 26.6%) and predominantly in men 9 . Hypertension became one of the most prominent risk factors and a comorbidity of CKD over a period of time (from 1990s to [2009][2010], and 24.2% elderly patients develop CKD as a result of hypertension 10 . In China, 2 studies reported the prevalence of hypertension in patients with CKD at 82.0% and 67.3%, respectively. However, despite high awareness and treatment rates reported in these studies, the control rates for hypertension were relatively very low 11,12 . Moreover, the control rate of hypertension is inversely associated with the CKD stage 13 . Uncontrolled hypertension is associated with poor prognosis of CKD, its progression to end-stage renal disease (ESRD), renal failure, and mortality. Patients with high-grade hypertension are at a higher risk of CKD progression 14 and other complications such as stroke, cardiovascular disease, and target organ damage (TOD) 15 . Although awareness and treatment of hypertension in patients with CKD are showing an improving trend, treatment and control of blood pressure (BP) at all the CKD stages remain suboptimal 16 .
Despite the recognition of hypertension and CKD as a major public health concern, epidemiologic research to provide insights into public health approaches on prevention and treatment of hypertension in patients with CKD is limited and very few studies have been conducted in China to determine the prevalence and control rate of hypertension in patients with CKD. Therefore, we determined the prevalence, awareness, control, and rate of reaching the target BP in hypertensive Chinese patients with CKD using a nationwide survey across China. We study also evaluated the anti-hypertensive drug use situation, pattern of expenditure on drugs and factors associated with hypertension prevalence and control.
Prevalence, Awareness, Treatment, and Control Rates of Hypertension. Overall, 4328 of the 6079 (71.2%) patients had hypertension. Prevalence of grade 1, 2, 3, and isolated systolic hypertension were 27.8%, 11.3%, 2.9%, and 22.9%. The overall prevalence, awareness, treatment and control rates are presented in Fig. 1. A total of 93 (2.3%) patients were diagnosed with hypertension after use of cortical hormone (n = 55, 1.3%), Chinese medicines (n = 17 0.4%), or other medicines (n = 25, 0.6%). Hypertension in these patients was possibly due to administration of previously administered therapy. Low prevalence of grade 3 in patients with CKD and high prevalence of patients with CKD stage 5 may indicate that small number of patients with CKD stage 5 have grade 3 hypertension. Among patients with hypertension, 4129 (95.4%) had been diagnosed and were aware of the disease before the study. The rate of treatment was 93.7%. Control rate 1 and control rate 2 were achieved by 41.1% and 15.0% patients, respectively with anti-hypertensive medications. Figure 2 shows reduction of BP post treatment from baseline. Among patients who were taking anti-hypertensive medications, BP was controlled in 1666 patients and lowered to a mean of 127.2/77.1 mmHg (± 8.74/7.36). The decrease in BP in the controlled group was significant compared with baseline (difference from baseline: − 9.4/4.2 mmHg, P = .0178). A total of 1778 patients had uncontrolled hypertension (did not achieve control rate 1 or 2). In these patients, BP at end of study was higher compared with the baseline mean BP, 154.1/88.2 mmHg (± 14.44/11.28), difference: + 17.5/6.9 mmHg]).
Patients who were aware of the disease also used non-drug treatments such as restricting salt intake (73.7%), controlling body weight (58.7%), cessation of smoking (17.7%) and alcohol consumption (24.3%), and starting physical activity (31.4%). Most of the patients (97.0%) started with anti-hypertensive therapy after diagnosis, and majority of the patients (85.3%) took the medications regularly.
Pattern of Anti-hypertensive Administration and Drug Expenditure. Monotherapy (37.7%) and therapy was administered in 2406 patients. CCBs were the major component of the drug combinations. A summary of CCB use in combinations is presented in Fig. 3. Anti-hypertensive drug expenditure patterns of patients are presented in Fig. 4. Patients spending on drugs through public medical insurance had employment (20.8%), retirement (38.8%), or small town insurance (6.9%).
Factors Associated With Prevalence, Awareness, Treatment, and Control Rates. All the independent factors were evaluated for association with prevalence, awareness, treatment, and control rates of hypertension using logistic regression. The analysis revealed that age, region or geography, smoking, BMI, lack of physical exercise, history of hypertension, hyperuricaemia; and stages of CKD had a significant positive association with prevalence of hypertension. In addition, awareness and treatment rates of hypertension were associated with age, region/geography, and glomerular filtration rate (GFR) staging. Apparently, level of education did not show any association with disease awareness and treatment. Control rates 1 and 2 for hypertension had association with age, gender, region, smoking, BMI, GFR staging, and self-monitoring of BP at home.

Discussion
The prevalence of hypertension and CKD is constantly increasing in China and has seen multiple fold increase over the past 3 decades [17][18][19] . Since there are only a few studies that have determined the epidemiology and control of hypertension in Chinese patients with CKD; reliable information is necessary for the development of health policies in China, to prevent and control hypertension in patients with CKD. As per our knowledge, this is one of the largest nationwide survey that analysed the prevalence of hypertension, awareness of the disease, rates of treatment, control of hypertension; anti-hypertensive drug use and drug expenditure pattern; and factors associated with prevalence, awareness, treatment, and control rates of hypertension in patients with CKD in China.
Nationwide surveys such as the Chronic Renal Insufficiency Cohort (CRIC) study, Chronic REnal Disease In Turkey (CREDIT) study, and study in Columbia revealed that the prevalence, awareness, and treatment rates for hypertension were high and the control rates were sub-optimal [20][21][22] . Data from the CRIC study showed prevalence of 85.7%, awareness rate of 98.9%, treatment rate of 98.3% and control rate of 67.1% (< 140/90 mmHg) and 46.1% < 130/80 130/80 mmHg 20 . The CREDIT study also reported a prevalence rate of 56.3%, awareness and treatment rates of 56.3%, 61.9% and 44.2%. The control rate was sub-optimal at 28.8% after treatment 21 . Sarafidis et al. reported a control rate of 13.2% despite high prevalence (86.2%), awareness (80.2%) and treatment rates (70.0%) 22 . Studies determining the control of hypertension in the United Kingdom and Japan also reported high prevalence (88.0% and 58.0%) and low control rates of hypertension (34.2% and 34.6%) in patients with CKD [23][24][25] . Similarly, a multinational survey was conducted in 2009 to 2010 across China that reported hypertension prevalence, awareness, and treatment rates of 82.0%, 90.7%, and 87.3%, respectively, in adult Chinese patients with CKD. The control rates were however very low at 29.6% for target BP of < 140/90 mmHg and 12.1% for target BP of < 130/80 mmHg. Another study by Zheng et al. showed that the rates of prevalence of hypertension in patients with CKD, awareness, and treatment were 67.3%, 85.8%, and 81.0%, respectively. The control rates of hypertension were 33.1% for BP < 140/90 mmHg and 14.1% for BP < 130/80 mmHg 12 . On similar lines, our study also reported high rates of prevalence of hypertension, awareness, and treatment. The control rate for target BP of < 140/90 mmHg was observed to be slightly higher in this study than the previous studies (41.1% vs 29.6% and 33.1%). Proportion of patients achieving target BP of < 130/80 mmHg was similar in our study and earlier studies (15.0% vs 12.1% and 14%). Low control rates in all the studies showed that hypertension in China is not optimally controlled in patients with CKD. This is an alarming situation considering the continuously increasing trend of hypertension in Chinese patients with CKD. The study also highlights relatively very low control rates of hypertension despite increased awareness and treatment. The control rate among different countries might vary due to ethnicity, economic or educational level differences, as reported by Sarafidis et al. Within the same country, improvement in economy and setting of the study (study conducted in rural or urban setting) may also improve the treatment and control rates.
The Chinese guidelines for the treatment of hypertension suggest the use of CCB, ACEI, ARB, diuretics, and β -blockers as monotherapy or combination therapy for hypertension management 15 . The JNC8 guidelines recommend the use of ACEI or ARB for CKD patients with hypertension 26 , whereas the European Society of Hypertension (ESH) guidelines recommend the use of all anti-hypertensive drugs except diuretics (in the haemodialysis patients) after dose determination based on hemodynamic instability and the ability of the drug to be dialysed 27 . In the present study, CCB, ARB, and β -blockers were the most prescribed medications in China.
Anti-hypertensive drug expenditure patterns also support the association of prevalence, awareness, and treatment of hypertension with older age, as approximately 39% patients were retired from work. The factors associated with prevalence, control, awareness, and treatments were determined. The risk of hypertension was more in older patients (42-65 and 65-80 years of age) than in relatively younger patients (18-45 years of age). Hypertension prevalence was associated more with patients from middle and southern China than those from north China. Smokers, patients with BMI > 18 kg/m 2 , lack of physical exercise, CV and metabolic co-morbidities, and CKD stages 2 to 5 were associated with a high prevalence of hypertension. In a study by Stevens et al., the prevalence of hypertension in participants with CKD aged 65 and older in KEEP and NHANES 1999 to 2006 were 94.5% and 91.6%, respectively 28 . Findings from this study were consistent with previous literature that showed older age, higher BMI, smoking, CV, and metabolic disease as the factors associated with a high prevalence of hypertension 11,22 . Awareness of hypertension was found to be higher in older patients and those with a family history of hypertension. Older age and geography were associated with a higher rate of treatment. Control rate 1 was determined primarily by CKD stage, BP monitoring at home, and use of drug combinations for treatment. Patients with CKD stage 4 and stage 5 were not able to achieve control rate 1. Anti-hypertensive therapy with ARBs as mono-or combination therapy improved the rate of hypertension control in Chinese patients with hypertension and CKD. Measurement of BP at home was responsible for increasing the awareness of patients toward the disease and medication, subsequently improving the BP control rate. Achievement of control rate 2 was positively associated with female gender, regular BP monitoring at home, and use of combination drug therapy. Overall, the control rate was low for patients taking anti-hypertensive medications. The findings highlight that high prevalence and control of hypertension were associated with renal function in adult patients with CKD.
The present study has the following strengths: (i) stringent use of a standard data collection protocol; (ii) inclusion of extensive data on demography, medical-related history, drug treatments, expenditure behaviour of patients, and factors associated with hypertension in patients with CKD; and (iii) analyses of data from a large sample size.
This study has certain limitations because of which the findings must be interpreted with caution. Most notably, the cross-sectional study design does not allow for causal associations to be established with certainty. Second, sampling was not done randomly. Number of patients was limited and out of those, ESRD patients accounted for a relatively large number. Third, potential limitation is that there might be some variation in evaluating laboratory parameters or BP measurement despite following the standardised protocol. Selection of hospitals from 3 developed cities of China limited the extrapolation of the results to the whole Chinese CKD population. Another potential limitation of our study is that we correlated the control of hypertension with GFR only, while the correlation between hypertension and albuminuria was not evaluated. Furthermore, well-designed, large sample cohort studies and randomised clinical trials are warranted to draw effective conclusions.
The prevalence, awareness, and treatment rates of hypertension in Chinese patients with CKD were high. However, the low control rates reflect the sub-optimal control of hypertension in patients with CKD. Association of monitoring BP indicated toward the need of greater awareness of the disease, whereas association of drug combinations with control rates suggested toward the need of developing effective interventions for managing hypertension in patients with CKD in China. Therefore, strategies to improve awareness and treatment of hypertension in patients with CKD are needed in China for better healthcare management.

Study Design and Population. The 'Research on hypertensive nephropathy and ischemic kidney diseases
National key technology R&D program (12-5) (Study No. 2011BAI10B00 (2011BAI10B06)' study was one of the largest multicentre, cross-sectional survey in China. A total of 22 hospitals (Supplementary Table S1) were selected from mid-China (n = 11), northern (n = 6), and southern China (n = 5).
Patients with CKD (aged > 15 years) were invited to participate in this survey. The inclusion criteria were: (i) age 16 to 85 years; (ii) CKD (stage 1-5) with or without hypertension. Patients were excluded if they had malignant tumour, BMI > 32 kg/m 2 ; coagulation disorder, drug abuse history or addicted to alcohol, severe CV or cerebrovascular disease, psychological disorder or were pregnant or lactating. Data Collection. The data were collected from 30 June 2012 to 30 December 2013 (18 months) using a standardised questionnaire. Before commencing the study, all investigators were trained on the study protocol. Trained investigators collected the demographic, clinical, laboratory, drug treatment (use of monotherapy or combination), drug expense, and BP data. In addition, the investigators completed case report form using a standardised protocol. The study flow diagram is presented in Fig. 5.
Scientific RepoRts | 6:38768 | DOI: 10.1038/srep38768 BP was measured by trained healthcare professionals (HCPs) in the morning (8 am to 11 am) as per standard protocol. Literature suggests taking a minimum 2 measurements for ensuring the accuracy of BP measurement. Therefore, before recording the BP, participants rested for approximately 5 minutes following which BP was measured twice using a mercury sphygmomanometer with at least a 1-minute interval between measurements in an ambulatory setting. Mean of the 2 measurements was considered for the analysis. If the difference between the 2 BP measurements was > 5 mmHg, one more measurement was taken, and mean of the 3 BP measurements was used 29,30 . Definitions of Hypertension, Awareness, Treatment, and Control Rates. Hypertension is defined as a systolic BP (SBP) of ≥ 140 mmHg or a diastolic BP (DBP) of ≥ 90 mmHg or undergoing treatment for hypertension. Grades 1, 2, and 3 of hypertension are defined as BP of 140-159/90-99, 160-179/100-109, and ≥ 180/≥ 110 mmHg. Participants with SBP of 130 to 139 mmHg or DBP of 85 to 89 mmHg were considered to be having critical or borderline hypertension, as it is not suitable to define these patients as normotensives. Isolated systolic hypertension was defined as BP ≥ 140/< 90 mmHg 27 . The ESH and the European Society of Cardiology (ESC) suggest maintaining a BP of < 140/90 mmHg in patients with CKD, whereas the Chinese 2010 Hypertension guidelines suggest maintaining BP of < 130/80 mmHg in such patients 15,27 . It is not possible to recommend specific BP targets in elderly adults with CKD due to lack of evidence and difference in target BP range of various guidelines 11 . Therefore, in this study target BP levels were chosen as < 140/90 (control rate 1; as per ESH/ESC, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP [JNC-8] Guidelines) 26,27 and < 130/80 mmHg (control rate 2; Chinese 2010 Hypertension guidelines) 15 with anti-hypertensive drug treatment. Awareness rate was defined as the proportion of patients with hypertension who were diagnosed with hypertension by a physician or HCP before enrolment into this study. Treatment rate was defined as the proportion of patients with hypertension receiving anti-hypertensive medications before enrolment in the study.

Definition of CKD.
In accordance with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, CKD was defined as GFR of < 60 mL/min/1.73 m 2 for ≥ 3 months. Patients were classified into different CKD stages based on their GFR. Definition of different stages of CKD is presented in Table 1 31 .