Antihypertensive treatment and risk of cardiovascular mortality in patients with chronic kidney disease diagnosed based on the presence of proteinuria and renal function: A large longitudinal study in Japan.

Several recent clinical trials and meta-analyses have shown that lowering blood pressure reduces the risk of cardiovascular disease. However, current evidence that describes general demographics in blood pressure and mortality with chronic kidney disease is sparse in Japan. Using a population-based longitudinal cohort that received annual health checkups in Japan in 2008, hypertensive status, self-reported use of antihypertensive drugs, and prognosis were examined through 2012. Chronic kidney disease was defined as positive proteinuria or estimated glomerular filtration rate <60 ml/min/1.73 m2. Subjects were 40 to 74 years old (n = 227,204) with median 3.6 years follow-up period, and patients with and without chronic kidney disease were analyzed separately (n = 183,586 and n = 43,618, respectively). Cardiovascular disease mortality, comprising coronary heart diseases and stroke as entered in the national death registry using ICD-10 coding, was examined. Among all subjects, 346 deaths (96 in chronic kidney disease and 250 in non-chronic kidney disease) due to cardiovascular disease occurred. Compared with cardiovascular disease mortality in chronic kidney disease patients with untreated normal blood pressure, the multivariable adjusted hazard ratio was 3.08 (95% confidence interval: 1.75-5.41) for those with untreated hypertension, 2.30 (1.31-4.03) for those who became normotensive after treatment, and 3.28 (1.91-5.64) for those who remained hypertensive despite treatment. In non-chronic kidney disease subjects, the ratios were 1.90 (1.33-5.41), 1.95 (1.35-2.80), and 1.77 (1.18-2.66), respectively. These results from a nationwide cohort could be one of representative demographics of controlling blood pressure and cardiovascular disease deaths when treating patients with chronic kidney disease in Japan in recent years. Even after development and spread of anti-hypertensive drugs, preventing development of hypertension is preferable, because any hypertension treatment status comparing untreated normal blood pressure was a risk of cardiovascular mortality at baseline year.

Introduction

High blood pressure (BP) confers a risk of cardiovascular disease (CVD) [1-3]. Compared with the general population, patients with chronic kidney disease (CKD) have a high risk of CVD mortality [4]. Guidelines recommend lower BP targets in the CKD population than in the general population to slow the progression of CKD [5,6]. Antihypertensive therapy is well known to reduce CVD risk in the general population [7,8]. However, there is little evidence regarding BP treatment and CVD death in patients with CKD.

Numerous observational studies focused on general populations have found that, for a given baseline BP, the risk of CVD is higher for people who use antihypertensive medications than for those who do not [1,9-14]. However, most of them failed to consider participants’ renal function and proteinuria, which are well-known determinants of cardiovascular risk, because the cohorts were established decades ago, before the current definitions of CKD were developed. A recent meta-analysis of data from randomized, controlled trials showed the effectiveness of BP reduction by antihypertensive medications [15]. However, systematic searches of 123 randomized trials demonstrated that only a few reported the renal function of the cohort. For example, of 31 BP-lowering trials assessing different BP targets, only 6 studies selected cohorts that included CKD patients [16-21], whereas 12 studies defined no-CKD cohorts, and the remaining 13 did not report the renal function of their cohorts. These results also indicate the rarity of longitudinal cohorts that include a well-identified CKD population for assessing CVD mortality.

The present study evaluated a longitudinal, general-population cohort of 227,204 persons who received annual health checkups, including examinations for proteinuria and renal function according to “The Specific Health Check and Guidance in Japan” program in 2008, and followed their prognosis and cause of death through December 2012. In subpopulations with and without CKD diagnosed based on the presence of proteinuria and renal function, risks for all-cause and CVD mortality were examined among various categories of BP control. This analysis provides information about the representative status of BP control and CVD mortality of Japanese people with CKD in recent years.

Methods

Patients and methods

This longitudinal cohort study was conducted according to the guidelines of the Declaration of Helsinki and was granted ethics approval by the relevant institutional review boards (University of Tsukuba for ethical issues approved as No. 999, UMIN: 000019774). Original Ethics Committee approval was obtained from Fukushima Medical University (IRB #1485, #2771).

The study was performed as part of the prospective ongoing “Research on the Positioning of Chronic Kidney Disease in Specific Health Check and Guidance (so-called “Tokutei-Kenshin”) in Japan” project [22]. Other details, such as the participants’ areas of residence, were reported previously [23-25]. Outliers were deleted through winsorization; they accounted for 0.01%–0.1% of the total. The raw database was solely used and managed by the statistician, and the principal analyses to identify those who died among screened subjects were completed by March 2015 and recently reported [26]. Subsequent analyses were done using a standard analysis file (SAF) without any personal identifiers.

The duration of follow-up of the subjects was 1 to 4 years (2008 through 2012, median duration was 3.6 years). The net subject population comprised 227,204 people (59.0% [n = 134,103] were women) aged from 40 to 74 years and for whom all of the data necessary for our research purposes were available. The data included information about age, sex, body mass index (BMI), systolic BP, diastolic BP, smoking habit, use of antihypertensive, lipid-lowering, and hypoglycemic drugs (obtained by self-reported questionnaire), and the results of dipstick urinalyses for proteinuria and blood tests for glucose levels, creatinine concentration, and lipid status.

Mortality surveillance

The underlying causes of death were coded according to ICD-10. Follow-up was conducted through December 2012. Incidents of CVD death were defined by ICD coding as I20-29 and I60-69.

Measurement of parameters

Urinalysis by the dipstick method was performed on a single spot-urine specimen collected early in the morning. Urine dipstick results for proteinuria were interpreted by the medical staff at each local medical institution and recorded as −, +/−, 1+, 2+, and 3+. In Japan, the Japanese Committee for Clinical Laboratory Standards (http://jccls.org/) recommends that all urine dipstick results of 1+ correspond to a urinary protein level of 30 mg/dl; proteinuria was defined as 1+ or greater. Serum creatinine was measured using the enzymatic method. The glomerular filtration rate (GFR) was estimated using the formula of the Japanese Society of Nephrology [27]. CKD was defined as positive proteinuria or estimated GFR (eGFR) <60 ml/min/1.73 m2. Hyperglycemia was defined as HbA1c ≥6.5%, and hypertension was defined as systolic BP ≥140 mmHg and diastolic BP ≥90 mmHg. Hypercholesterolemia was defined as low-density lipoprotein cholesterol ≥140 mg/dl, high-density lipoprotein cholesterol ≤40 mg/dl, or triglycerides ≥200 mg/dl. These comorbid conditions at the baseline year were used for the risk analysis.

Statistical analysis

The primary outcomes for the analysis were all-cause and CVD deaths during the follow-up period. Variables were age, sex, HbA1c, hypertension, renal function, proteinuria, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides, cigarette smoking, use of antihypertensive medication, use of lipid-lowering drugs, and treatment for diabetes. The hypertension treatment category was defined according to BP levels (normal, <140/<90 mmHg; hypertensive, ≥140/≥90 mmHg), as directed in the hypertension guidelines [28]. When the systolic and diastolic BPs were in different categories, the subject was assigned to the hypertension treatment category. After subjects were categorized according to BP, they were allocated to untreated normal, untreated hypertensive, treated normotensive, and treated hypertensive groups. Hazard ratios of the incidence of CVD were estimated using the Cox regression model (SAS version 9.4, SAS Institute, Cary, NC, USA). Other statistical analyses and graphical analyses were performed using Stata version 14 and GraphPad Prism version 6. A P value <0.05 was considered significant.

Results

Table 1 presents the mean ages of the subjects and the means and proportions of risk factors at the baseline year, according to hypertension treatment category. Compared with subjects with untreated, normal BP at baseline, untreated hypertensive subjects were a mean of 2.4 years older, and the treated population was 5.5 years older on average; in addition, BMI was higher in hypertensive subjects, regardless of treatment category. Furthermore, eGFR was 1.3 ml/min/1.73 m2 lower in the subpopulation with untreated hypertension and 5 ml/min/1.73 m2 lower in subjects who remained hypertensive despite treatment, compared with that of subjects with untreated normal BP. The rate of positive proteinuria was higher in hypertensive than in normotensive subjects, and those with treated hypertension had the highest rate of positive proteinuria. The use of lipid-lowering drugs and of diabetes treatment paralleled that of hypertensive drugs. Finally, the rate of cigarette smoking was lower in treated than in untreated populations.

Table 1

Study population.

		Normotensive	Hypertensive	Normotensive	Hypertensive
		Untreated	Untreated	Treated	Treated	P
Number		127,312	37,867	34,662	27,363
Sex	%, women	63.4	52.9	56.6	53.2	<0.001
Age	years	60.4 ± 9.4	62.8 ± 8.2	65.9 ± 6.4	65.9 ± 6.5	<0.001
Height	cm	157.2 ± 8.4	157.5 ± 8.8	156.0 ± 8.4	156.4 ± 8.6	<0.001
Weight	kg	56.0 ± 10.0	59.3 ± 10.9	59.4 ± 10.4	60.9 ± 10.8	<0.001
Body mass index	kg/m2	22.6 ± 3.1	23.8 ± 3.3	24.3 ± 3.3	24.8 ± 3.5	<0.001
Systolic blood pressure	mmHg	118.9 ± 12.0	148.9 ± 12.8	126.2 ± 9.0	149.3 ± 11.5	<0.001
Diastolic blood pressure	mmHg	71.7 ± 8.5	86.9 ± 9.8	74.7 ± 7.8	84.8 ± 9.5	<0.001
Triglycerides	mg/dl	112 ± 76	132 ± 96	125 ± 76	133 ± 89	<0.001
High-density lipoprotein	mg/dl	63 ± 16	61 ± 16	59 ± 15	59 ± 15	<0.001
Low-density lipoprotein	mg/dl	126 ± 31	129 ± 32	120 ± 28	123 ± 29	<0.001
HbA1c	%	5.3 ± 0.6	5.4 ± 0.8	5.5 ± 0.7	5.5 ± 0.8	<0.001
eGFR	ml/min/1.73 m2	75.8 ± 15.5	74.5 ± 15.9	70.8 ± 16.2	71.0 ± 16.3	<0.001
Proteinuria	%, + or more	3.2	6.7	7.8	11.2	<0.001
Use of antihypertensive drugs	%, yes	0	0	100	100	–
Lipid-lowering drug use	%, yes	8.8	7.4	28.8	26.0	<0.001
Diabetes treatment	%, yes	3.0	3.1	9.4	10.4	<0.001
Cigarette smoking	%, yes	14.4	14.3	10.8	10.6	<0.001

Low eGFR; less than 60 ml/min/1.73 m2

The characteristics of subjects with and without CKD are shown in Table 2. The trends in mean age, BMI, eGFR, and proportions of positive proteinuria, medication use, and cigarette smoking between subjects with and without CKD (Table 2) paralleled those between hypertension treatment categories (Table 1). Within a hypertension treatment category, subjects with CKD tended to include fewer women and have a higher mean age, higher BMI, worse dyslipidemia and hyperglycemia and a higher rate of positive proteinuria than did those without CKD (Table 2).

Table 2

Baseline characteristics of subpopulations with and without chronic kidney disease (CKD).

		Normotensive	Hypertensive	Normotensive	Hypertensive
CKD (-)		Untreated	Untreated	Treated	Treated	P
Number		108653	30341	25236	19356
Sex	%, women	65.0	55.3	60.4	57.8	<0.001
Age	years	59.7 ± 9.5	62.4 ± 8.3	65.5 ± 6.6	65.4 ± 6.7	<0.001
Height	cm	157.0 ± 8.4	157.2 ± 8.8	155.6 ± 8.4	155.9 ± 8.5	<0.001
Weight	kg	55.7 ± 10.0	58.8 ± 10.8	58.7 ± 10.2	60.1 ± 10.7	<0.001
Body mass index	kg/m2	22.5 ± 3.1	23.7 ± 3.3	24.2 ± 3.3	24.6 ± 3.5	<0.001
Systolic blood pressure	mmHg	119 ± 12	149 ± 13	126 ± 9	149 ± 11	<0.001
Diastolic blood pressure	mmHg	72 ± 9	87 ± 10	75 ± 8	85 ± 9	<0.001
Triglycerides	mg/dl	111 ± 75	130 ± 95	122 ± 74	129 ± 88	<0.001
High-density lipoprotein	mg/dl	63 ± 16	62 ± 16	60 ± 15	60 ± 15	<0.001
Low-density lipoprotein	mg/dl	126 ± 31	129 ± 32	120 ± 28	123 ± 29	<0.001
HbA1c	%	5.3 ± 0.6	5.4 ± 0.7	5.4 ± 0.7	5.5 ± 0.7	<0.001
eGFR	ml/min/1.73 m2	78.9 ± 13.9	78.1 ± 13.8	76.6 ± 13.1	76.8 ± 13.1	<0.001
Low eGFR	%, yes	0	0	0	0	-
Proteinuria	%, + or more	0	0	0	0	-
Use of antihypertensive drugs	%, yes	0	0	100	100	-
Use of lipid-lowering drug	%, yes	8.4	7.2	28.0	25.7	<0.001
Diabetes treatment	%, yes	2.8	2.9	8.5	9.0	<0.001
Cigarette smoking	%, yes	14.8	14.3	10.8	10.4	<0.001
CKD (+)
Number		18659	7526	9426	8007
Sex	%, women	53.9	43.0	46.4	41.8	<0.001
Age	years	64.0 ± 7.7	64.9 ± 7.2	67.0 ± 5.9	67.0 ± 6.0	<0.001
Height	cm	158.1 ± 8.3	158.6 ± 8.6	157.3 ± 8.4	157.7 ± 8.5	<0.001
Weight	kg	57.7 ± 10.2	61.1 ± 10.9	61.2 ± 10.5	62.9 ± 10.7	<0.001
Body mass index	kg/m2	23.0 ± 3.1	24.2 ± 3.4	24.7 ± 3.4	25.2 ± 3.5	<0.001
Systolic blood pressure	mmHg	120 ± 12	150 ± 14	126 ± 9	150 ± 12	<0.001
Diastolic blood pressure	mmHg	72 ± 8	88 ± 10	74 ± 8	85 ± 10	<0.001
Triglycerides	mg/dl	121 ± 79	141 ± 102	132 ± 80	142 ± 93	<0.001
High-density lipoprotein	mg/dl	61 ± 16	59 ± 16	56 ± 15	57 ± 15	<0.001
Low-density lipoprotein	mg/dl	128 ± 31	130 ± 33	120 ± 28	123 ± 30	<0.001
HbA1c	%	5.3 ± 0.7	5.5 ± 1.0	5.5 ± 0.8	5.6 ± 0.9	<0.001
eGFR	ml/min/1.73 m2	58.0 ± 12.6	60.0 ± 15.6	55.2 ± 13.3	56.7 ± 14.7	<0.001
Low eGFR	%, yes	82.8	74.5	82.6	76.8	<0.001
Proteinuria	%, + or more	21.9	33.9	29.0	38.7	<0.001
Use of antihypertensive drugs	%, yes	0	0	100	100	-
Us of lipid-lowering drugs	%, yes	11.0	7.9	31.1	27.0	<0.001
Diabetes treatment	%, yes	4.3	3.9	11.9	13.9	<0.001
Cigarette smoking	%, yes	12.4	14.2	11.0	10.9	<0.001

Low eGFR; less than 60 ml/min/1.73 m2

During follow-up, 2745 all-cause deaths (2107 non-CKD subjects and 638 CKD subjects) and 346 CVD deaths (250 non-CKD subjects and 96 CKD subjects) occurred in this cohort. The all-cause mortality and CVD mortality in subjects with and without CKD according to proteinuria and renal function are shown in Table 3. Dividing the number of all-cause mortalities and CVD deaths in each hypertension treatment category by the total number of subjects in that subpopulation showed increased rates of both all-cause and CVD mortalities in these subjects, regardless of their CKD status, compared to subjects with untreated, normal BP (Table 3).

Table 3

Number, all-cause mortality, and mortality due to cardiovascular disease (CVD) in subpopulations with and without chronic kidney disease (CKD) according to proteinuria (UP) and renal function (eGFR).

		Normotensive	Hypertensive	Normotensive	Hypertensive
		Untreated	Untreated	Treated	Treated
	UP
Number	(-)	123199	35270	31915	24216
	(+)	4113	2597	2747	3147
All-cause mortality	(-)	1179 (0.96%)	435 (1.23%)	464 (1.45%)	341 (1.41%)
	(+)	79 (1.92%)	78 (3.00%)	83 (3.02%)	86 (2.73%)
CVD mortality	(-)	98 (0.08%)	61 (0.17%)	70 (0.22%)	55 (0.23%)
	(+)	6 (0.15%)	19 (0.73%)	15 (0.55%)	22 (0.70%)
	Low eGFR
Number	(-)	111868	32290	26892	21230
	(+)	15444	5577	7770	6133
All-cause mortality	(-)	1008 (0.90%)	426 (1.32%)	389 (1.45%)	284 (1.34%)
	(+)	250 (1.62%)	87 (1.56%)	158 (2.03%)	143 (2.33%)
CVD mortality	(-)	87 (0.08%)	62 (0.19%)	57 (0.21%)	44 (0.21%)
	(+)	17 (0.11%)	18 (0.32%)	28 (0.36%)	33 (0.54%)
	CKD
Number	(-)	108653	30341	25236	19356
	(+)	18659	7526	9426	8007
All-cause mortality	(-)	961 (0.88%)	372 (1.23%)	352 (1.39%)	244 (1.26%)
	(+)	297 (1.59%)	141 (1.87%)	195 (2.07%)	183 (2.29%)
CVD mortality	(-)	83 (0.08%)	51 (0.17%)	52 (0.21%)	36 (0.19%)
	(+)	21 (0.11%)	29 (0.39%)	33 (0.35%)	41 (0.51%)

The hazard ratio (HR) for all-cause mortality in each hypertensive status is shown in Fig 1. Subjects with and without proteinuria (Fig 1A) or low eGFR (Fig 1B) and those with and without CKD were analyzed separately, regardless of how the condition was defined (i.e., “overall CKD”) (Fig 1C). Using the untreated normotensive subpopulation as a reference, the risk of all-cause mortality among patients with proteinuria was significantly increased among those with untreated hypertension (age- and sex-adjusted HR, 1.38 [95% confidence interval 1.01–1.89]; multivariable-adjusted HR, 1.45 [1.06–1.99]; Fig 1A). However, among subjects with low eGFR (Fig 1B) and those with overall CKD (Fig 1C), the HR for all-cause mortality did not differ significantly between subjects with untreated normotension and those with untreated hypertension, those who became normotensive during treatment, or those who remained hypertensive despite treatment. Overall, analyses for all-cause mortality risk did not identify hypertensive status as an independent risk factor in subjects diagnosed with CKD according to the presence of proteinuria or decreased renal function.

Fig 1

Risk of all-cause mortality in each hypertension treatment category.

The multivariable-adjusted hazard ratio and 195% confidence interval for all-cause death in each hypertension treatment category are shown. The reference category is untreated, normal blood pressure. The subgroups reflect the presence (or absence) of proteinuria (A), reduced renal function (B), or chronic kidney disease (C). Adjusted factors for death were: age; sex; cigarette smoking; body mass index; proteinuria; levels of triglycerides, high-density lipoprotein, and low-density lipoprotein; use of lipid-lowering drugs; HbA1c; and treatment for diabetes.

In contrast to all-cause mortality, relative to those for the subpopulation with untreated normal BP, the adjusted HRs for CVD mortality in subjects without proteinuria, without low eGFR, and without CKD showed significance (Fig 2). Moreover, HRs for CVD mortality in subjects with CKD were mostly significant and varied widely in each hypertension treatment category (filled circles in Fig 2): from 2.12 to 4.61 in subjects with proteinuria, from 2.27 to 3.08 in those with low eGFR, and from 2.30 to 3.28 in those with overall CKD. Summarizing the above, these analyses identified every hypertension treatment category as a risk factor for CVD mortality both in non-CKD and in CKD status, independent of well-known CVD risk factors, such as age, sex, BMI, and cigarette smoking.

Fig 2

Risk of all cardiovascular mortality in each hypertension treatment category.

The multivariable-adjusted hazard ratio and 95% confidence interval for cardiovascular mortality in each hypertensive treatment category are shown. The reference category is untreated, normal blood pressure. The subgroups reflect the presence (or absence) of proteinuria (A), reduced renal function (B), and chronic kidney disease (C). Adjusted factors for death were: age; sex; cigarette smoking; body mass index; proteinuria; levels of triglycerides, high-density lipoprotein, and low-density lipoprotein; use of lipid-lowering drugs; HbA1c; and treatment for diabetes.

Discussion

When compared with the general population, patients with CKD are at increased risk for CVD mortality [4,29]. General-population-based observational studies have shown that, for a given BP at baseline, CVD risk is higher in subjects who use antihypertensive medications than in those who do not [9-14]. Although the cohorts in the cited studies were well defined and rigorously followed, all of the cohorts were established decades ago (i.e., 1970 [9,10], 1991 through 1998 [11], 1967 through 1996 [13], and 1991 through 1996 [14]). In addition, their results were evaluated in the context of then-contemporary clinical practice. Therefore, most of the evidence [2,30-34] does not take into consideration the renal function of the participants, because the cohorts were also built without the conception of CKD from Kidney Disease: Improving Global Outcomes (KDIGO) in 2002 [6]. Because the timing and breadth of the recruitment might affect the characteristics of cohort subjects because of changes in clinical practice regarding the treatment of hypertension, use of a cohort with well-identified renal function and consistent baseline year data facilitates assessment of the relationship between BP control at baseline and CVD mortality in patients with CKD.

In this analysis, a general-population-based cohort established in 2008 was examined for which data regarding proteinuria, renal function, other CVD risk factors, and ICD-coded cause of death were available. In this cohort, age, risks, and proportions of patients at baseline year differed significantly between subjects with untreated normal BP and those in other hypertension treatment categories. Because ageing is associated with a decline in eGFR and increases in BP and the rate of positive proteinuria [35], the older age and lower eGFR seen in treated or hypertensive subjects are unsurprising (Table 1). Similarly, within the same hypertension treatment category, subjects with CKD tended to be older than those without CKD (Table 2).

Previous Japanese general-population–based cohorts established from 1980 through 1995 [2, 31–34] comprised 27.4% with untreated hypertension. Research and development in anti-hypertensive drugs has been remarkable. As examples, angiotensin-converting enzyme inhibitors began to be prescribed in 1982 to 1998 and angiotensin receptor blockers began in 1998 to 2012, and their market share in Japan continues to grow. Our investigation shows the rate of untreated hypertension was subjects with CKD (17.3%) than hose without CKD (16.5%), suggesting successful spread of anti-hypertensive drugs in recent years (Table 2).

A collaborative prospective meta-analysis of randomized trials to examine the cardiovascular effects of lowering BP in people with CKD according to renal function [36], which covers 152,290 participants, including 30,295 with eGFR <60 ml/min/1.73 m2. Another [15] performed a meta-analysis of systematic searches of BP-lowering trials to examine the effects of a 10-mmHg reduction in systolic BP on the relative risk of major CVD in 30,766 participants from 18 cohorts. However, neither of these previous studies [15,36] directly showed the effect of BP reduction in patients with proteinuria. Though our study could not show any effect of interventional BP control on CVD mortality in patients with proteinuria, markedly high HR (4.61) in untreated hypertension category for CVD mortality in positive proteinuria population implies importance of BP control in such patients (Fig 2A).

The strength of this study was that it evaluated a large general population (i.e., more than 100,000 subjects) with available data regarding renal function, proteinuria, and CVD (i.e., stroke and cardiac events) mortality according to ICD-10 coding. These features allowed us to perform sub-analyses of the CKD and non-CKD subjects enrolled, showing that the risk of CVD in patients who remained hypertensive despite treatment differed between those with and without CKD, between those with and without proteinuria, and between those with and without low eGFR.

However, this study had several limitations. First, the database did not have details of the types of antihypertensive drugs used, such as renin-angiotensin-targeted drugs, which affect the incidence of CVD [37], because this information was self-reported and not obtained through medical records or claims. Second, the follow-up time (maximum, 4 years) was much shorter than in previous studies. Because this observational study could not show cause/result relationship, evidence for interventional benefit of BP control was not obtained.

Nevertheless, the results from a nationwide cohort could be one of representative demographics of controlling blood pressure and cardiovascular disease deaths when treating patients with CKD in Japan in recent years. Even after current development and sufficient spread of anti-hypertensive drugs, preventing development of hypertension is preferable, because any hypertension treatment status comparing untreated normal blood pressure was a risk of CVD mortality at baseline year.

10 Oct 2019

PONE-D-19-26343

Antihypertensive treatment and risk of cardiovascular mortality in patients with chronic kidney disease diagnosed based on the presence of proteinuria and renal function: A large longitudinal study in Japan

PLOS ONE

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Reviewer #1: In the present study, Kei Nagai et al. examined mortality due to cardiovascular disease (CVD) among subjects who underwent annual health check in Japan. Study population was approx. 220 thousand and the follow up period was 4 years. The health check participants were separated into chronic kidney disease (CKD) and non-CKD subjects. They were also divided by their blood pressure/hypertension treatment categories. The following was one of the major findings: in CKD patients, compared with CVD mortality in patients with untreated normal blood pressure, the multivariable adjusted hazard ratio was 3.08 (95% confidence interval: 1.75–5.41) for those with untreated hypertension and 2.30 (1.31–4.03) for those who became normotensive after treatment, and 3.28 (1.91–5.64) for those who remained hypertensive despite treatment. They concluded, among subjects with CKD, patients who become normotensive during treatment have a lower risk of CVD than those who remain hypertensive, suggesting the effectiveness of BP reduction in preventing CVD death in CKD patients. Unfortunately, findings presented in this work do not support this conclusion.

[Major Points]

1) Since CVD mortality in CKD patients with normotensive/hypertension treated category (0.35%) was lower than that with hypertensive/untreated category (0.39%), the authors interpreted that the findings support treatment of hypertension in CKD patients to reduce CVD death. However, this is an observational study and cause/result relationship and speculation for prospective interventional benefits cannot be obtained, since patients in these 2 categories may have different basal backgrounds. For instance, patients with untreated hypertension may have lower socioeconomical conditions and may be less concerned about their health. Normotensive patients under hypertension treatment may have a better chance to be diagnosed other disorders during their periodical hospital visit and receive better care. There is no guarantee that untreated subjects remain untreated for 4 years.

2) Indeed, CVD mortality in non-CKD subjects were 0.21% for normotensive/hypertension treated category and 0.17% for hypertensive/untreated category (Table 3). Furthermore, CVD mortality in overall population (including CKD and non-CKD) were 0.27% for normotensive/treated category and 0.22% for hypertensive/untreated category (by reviewer’s calculation from Table 3). These findings prove that authors’ logic is inconsistent to established effects of hypertension treatment to reduce CVD death in CKD and non-CKD subjects.

3) As the authors described, previous studies reported CVD mortality among subjects with reduced renal function. The present study is distinct in that not only reduced renal function but also proteinuria was analyzed.

4) Median follow up period should be described in the abstract.

5) CVD mortality in CKD and non-CKD subjects should be described in the abstract.

[Minor Points]

1) A term “hypertensive category” is often used in the manuscript but it implies the extent of hypertension: for instance, 140, 160 and 180 mmHg. Other term, such as hypertension treatment categories, should be appropriate.

2) Line 138: >5 years should be replaced by 5.5 years.

Reviewer #2: Nagai et al reported the association between antihypertensive treatment and CVD mortality in patients with CKD who received annual health checkups. This study is a longitudinal general-population cohort with a large number of subject and showed the clear results of an increased mortality in those with hypertension or with hypertensive treatment, thus the data is of clinical importance. However, this manuscript has some major problems.

1)In Fig2, authors showed hazard ratio of hypertensive group or treated groups, referencing untreated normal blood pressure. Authors conclusion is the effectiveness of BP reduction in preventing CVD in CKD patients, however, in this manuscript, it is unclear whether hazard ration between untreated hypertensive people, treated normal BP people and treated hypertensive people in CKD is statistically different. Authors should clearly show this point.

2)In Fig2, authors showed hazard ration of CVD mortality in non-CKD people. These data revealed the CVD risk of hypertension, however did not show the effectiveness of hypertensive treatment for the prevention of CVD risk in non-CKD people. Is BP control not effective for the CVD reduction in non-CKD hypertensive subjects in this study? Authors should describe the results although this manuscript targets CKD patients.

3) Table3 showed CVD mortality in those with CKD and without CKD. In conclusions, authors described “…CVD mortality risk seems to be higher in CKD patients than in non-CKD patients.”. Authors should show statistical significance.

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Reviewer #2: No

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Submitted filename: comment to authors PONE-D-19-26343.docx

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30 Oct 2019

To the reviewers;

Reviewer #1:

[Major points]

1-1) Since CVD mortality in CKD patients with normotensive/hypertension treated category (0.35%) was lower than that with hypertensive/untreated category (0.39%), the authors interpreted that the findings support treatment of hypertension in CKD patients to reduce CVD death. However, this is an observational study and cause/result relationship and speculation for prospective interventional benefits cannot be obtained, since patients in these 2 categories may have different basal backgrounds. For instance, patients with untreated hypertension may have lower socioeconomical conditions and may be less concerned about their health. Normotensive patients under hypertension treatment may have a better chance to be diagnosed other disorders during their periodical hospital visit and receive better care. There is no guarantee that untreated subjects remain untreated for 4 years.

---Thank you for your comment and we recognize this observational study cannot show the interventional effect of BP control on CVD mortality and hard to discuss magnitude of HRs due to unadjustable factors among hypertension treatment categories before baseline year such as socioeconomical status and hospital visiting. Therefore, we would like to add limitation in the second last paragraph of the discussion and deleted description to compare HRs between two hypertension treatment categories other than reference group.

1-2) CVD mortality in non-CKD subjects were 0.21% for normotensive/hypertension treated category and 0.17% for hypertensive/untreated category (Table 3). Furthermore, CVD mortality in overall population (including CKD and non-CKD) were 0.27% for normotensive/treated category and 0.22% for hypertensive/untreated category (by reviewer's calculation from Table 3). These findings prove that authors' logic is inconsistent to established effects of hypertension treatment to reduce CVD death in CKD and non-CKD subjects.

---Thank you for your thoughtful comment. Related to your 1st major point, we recognized that it is hazardous to compare HRs each other between two hypertension treatment categories other than reference group (i.e. untreated normal BP). We would like to correct the conclusions from “effect of hypertension treatment on mortality” into “current demographics of hypertension treatment in Japan”. Please approve to mix up discussion and conclusion sections in order to keep context fluency (PLoS One editorial approves it by the author instruction).

1-3) As the authors described, previous studies reported CVD mortality among subjects with reduced renal function. The present study is distinct in that not only reduced renal function but also proteinuria was analyzed.

---Thank you for your suggestion, we highlighted strong point of our study to deal with proteinuria, in the fourth paragraph of the revised discussion.

1-4) Median follow up period should be described in the abstract.

---Thank you for your comment. We added follow-up period in the revised abstract and method section.

1-5) CVD mortality in CKD and non-CKD subjects should be described in the abstract.

---Thank you for your comment. We added description regarding CVD mortality in the revised abstract.

[Minor points]

2-1) A term "hypertensive category" is often used in the manuscript but it implies the extent of hypertension: for instance, 140, 160 and 180 mmHg. Other term, such as hypertension treatment categories, should be appropriate.

---Thank you so much for your suggestion and we agree with you. We used “hypertension treatment category” throughout this manuscript.

2-2) Line 138: >5 years should be replaced by 5.5 years.

---Thank you for comment. Please make sure it in the revised version.

Reviewer #2:

1) In Fig2, authors showed hazard ratio of hypertensive group or treated groups, referencing untreated normal blood pressure. Authors conclusion is the effectiveness of BP reduction in preventing CVD in CKD patients, however, in this manuscript, it is unclear whether hazard ration between untreated hypertensive people, treated normal BP people and treated hypertensive people in CKD is statistically different. Authors should clearly show this point.

---Thank you for your thoughtful comment. As another reviewer and you pointed out, we recognized that it is hard to compare HRs each other between two hypertension treatment categories (ie. untreated hypertension vs treated normal BP), other than reference group (untreated normal BP). We would like to correct the conclusions from “effect of hypertension treatment” into “current demographics of hypertension treatment in Japan”. Please approve to mix up discussion and conclusion sections in order to keep context fluency (PLoS One editorial approves it by the author instruction).

2) In Fig2, authors showed hazard ration of CVD mortality in non-CKD people. These data revealed the CVD risk of hypertension, however did not show the effectiveness of hypertensive treatment for the prevention of CVD risk in non-CKD people. Is BP control not effective for the CVD reduction in non-CKD hypertensive subjects in this study? Authors should describe the results although this manuscript targets CKD patients.

---Related to your 1st point, we should not have compared HRs between untreated hypertension and treated normal BP, among CKD subjects as well as among non-CKD. We appropriately deleted description regarding effectiveness of BP control and just touched on the previous works in CKD cohort and implication of marked CVD mortality risk in patients with positive proteinuria in the fourth paragraph of the revised manuscript.

3) Table3 showed CVD mortality in those with CKD and without CKD. In conclusions, authors described "...CVD mortality risk seems to be higher in CKD patients than in non-CKD patients.". Authors should show statistical significance.

---Thank you for your thoughtful comment. Related to your former comments, we revised conclusion, because it is difficult to compare HRs among hypertension treatment categories. Please make sure the last paragraph of the revised discussion section.

To the editorial;

We deeply recognized your journal office has been afraid of overlapping contents in our current and previous manuscripts. In advance of launching this cohort study using health checkups before 2008, our committee determined “one project, one publication-policy”. It means that each researcher has been analyzed based on the standard analytical file exactly for the purposes of testing his or her original scientific interest - in chronic kidney disease (CKD), clinical relevance of dipstick proteinuria for general population and distribution of hypertension and its treatment in Japan, etc. – with prior consultation. And then, the steering committee (SC) has supervised and carefully checked possibility of overlapping each other before submitting manuscript. In other words, our policy secures independence of each project and helps to avoid any double publications.

This project focused on demographics of hypertension and its treatment, while the previous one (PLoS One 14: e0223005) focused on sequential results of CKD diagnosis (ie. renal function and proteinuria) and its mortality risk. Therefore, we would like to propose obvious independence between these two projects.

Please refer our position paper shown below and you can see the list (attached in the end of this letter) and find “Antihypertensive treatment and risk of CVD death (Kunihiro Yamagata)”. Unfortunately, though the most updated list of our projects including “Cause-specific mortality in the general population with transient dipstick-proteinuria (PLoS One 14: e0223005)” is not published yet, SC authorized “Cause-specific mortality...” as independent project of “Antihypertensive treatment and risk of CVD death”.

*Clin Exp Nephrol. 2017 Dec;21(6):978-985. doi: 10.1007/s10157-017-1392-y. Epub 2017 Mar 3.

Mortality risk among screened subjects of the specific health check and guidance program in Japan 2008-2012.

Iseki K, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Konta T, Kasahara M, Shibagaki Y, Yoshida H, Moriyama T, Kondo M, Iseki C, Watanabe T; “Design of the comprehensive health care system for chronic kidney disease (CKD) based on the individual risk assessment by Specific Health Check”.

Submitted filename: RtoRs-2019-10-POne-r1.docx

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14 Nov 2019

Antihypertensive treatment and risk of cardiovascular mortality in patients with chronic kidney disease diagnosed based on the presence of proteinuria and renal function: A large longitudinal study in Japan

PONE-D-19-26343R1

Dear Dr. Yamagata,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Kojiro Nagai

Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

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Reviewer #2: Partly

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

22 Nov 2019

PONE-D-19-26343R1

Antihypertensive treatment and risk of cardiovascular mortality in patients with chronic kidney disease diagnosed based on the presence of proteinuria and renal function: A large longitudinal study in Japan

Dear Dr. Yamagata:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

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on behalf of

Dr. Kojiro Nagai

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