The Japan Multicenter Investigation for Cardiovascular DiseaseB (JMIC-B) was a clinical study in which either nifedipine retard or an angiotensin-converting enzyme (ACE) inhibitor was administered for 3 years to hypertensive patients with coronary artery disease. As a result, there was no difference in the incidence of cardiac events between the two treatment groups, which suggests that strict control of blood pressure (BP) is more important than the class of drug used.1
In hypertensive patients with diabetes (high-risk patients), there was also no significant difference in the incidence of cardiac events between the two treatments.2Furthermore, quantitative coronary angiography confirmed the preventive effect of nifedipine retard on arteriosclerosis.3
Moreover, among hypertensive patients with a history of myocardial infarction, the incidence of angina pectoris requiring hospitalization was significantly lower in the nifedipine retard group than the ACE inhibitor group.4It was also found that reverse remodeling of the left ventricle and cardiac function can both be improved by decreasing BP.5
Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular events, and the estimated glomerular filtration rate (eGFR) can be used as an index of CKD.6–8
CKD can be diagnosed if eGFR is lower than 60 mL/min/1.73 m2. eGFR becomes lower with aging. For renal protection, it is important to prevent eGFR from becoming lower and improve low eGFR.
We analyzed the results of JMIC-B and investigated whether antihypertensive therapy can improve low eGRF in hypertensive patients with CKD.
Materials and Methods
Hypertensive patients who were younger than 75 years and had coronary artery disease were registered to participate in JMIC-B. Among 1650 patients, 780 patients with eGFR data (0 and 36 months) were selected for this investigation. eGFR was obtained from 4 variables in the Modification of Diet in Renal Disease (MDRD) study equation.9,10 BP was measured 3 times and the average of the last 2 readings was used.1 Serum creatinine was assayed by the enzymatic method.
We used estimated marginal means for comparison of eGFR (Figure 1). Estimated marginal means was obtained by a linear mixed effect model in which eGFR <60 or eGFR ≥60 and time was set as fixed effects, patients as a random effect, and propensity score as a covariate.
Propensity score was calculated using a logistic regression model by setting eGFR <60 or eGFR ≥60 as a dependent variable, and sex, age, and use of diuretics and use of ACE inhibitors (baseline clinical characteristics) as independent variables. C statistics were 0.664. Correction of P value for multiple pairwise comparison was done by Bonferroni correction.
Propensity score was obtained using a logistic regression model by setting nifedipine or ACE inhibitor as a dependent variable, and myocardial infarction, angina pectoris, hyperlipidemia, and antiplatelets as independent variables (Figures 3 and 4). C Statistics was 0.607.
Data were analyzed using IBM SPSS Statistics version 19 (BM Corp, Armonk, NY). Differences were regarded as significant at P<.05 (2-sided). Data are shown as mean±standard deviation.
The Table shows the baseline clinical characteristics of 780 patients according to whether they had CKD. There were significant differences in sex, age, serum creatinine and use of diuretics and ACE inhibitors. Figure 1 shows changes in eGFR during 3-year antihypertensive therapy in hypertensive patients with CKD and those without CKD: eGFR was significantly increased in those with CKD and was significantly decreased in those without CKD. Figure 2 shows the percentages of those whose eGFR was decreased and then increased after 3-year antihypertensive therapy according to baseline eGFR, which we stratified into 7 groups.
Table TABLE. Baseline Clinical Characteristics
Number of Patients
eGFR <60 (98 Patients)
eGFR ≥60 (682 Patients)
Abbreviations: ACE, angiotensin-converting enzyme; AHA, American Heart Association; BP, blood pressure; CAG, coronary angiography; eGFR, estimated glomerular filtration rate; PTCA, percutaneous transluminal coronary angioplasty. Statistics is the same as in Table I.
52 (53.1)/46 (46.9)
483 (70.8)/199 (29.2)
Coronary artery disease
Silent myocardial ischemia
History of smoking
CAG (within past 1 y)
PTCA (within past 1 y)
Number of diseased vessels (AHA ≥75%)
Left main trunk
BP, mm Hg
Heart rate, per min
Body mass index, kg/m2
Serum creatinine, μmol/L
Serum cholesterol, mmol/L
Medications used before observation period
Calcium channel blockers
The Cochrane-Armitage trend test was significant. The baseline eGFR and percentage of decrease or increase were significantly related. There was no statistical difference in systolic or diastolic BP among 7 groups. The effect of nifedipine and ACE inhibitors on eGFR is shown in Figures 3 and 4. With eGFR <60, eGFR was significantly improved, while with eGFR ≥60, eGFR was significantly decreased. There were no significant inter-drug differences.
CKD can be diagnosed if eGFR is <60 mL/min/1.73 m2. Relationships between CKD and cardiovascular diseases (CVDs) have been gaining attention: the risk of CVD increases with eGFR <60. Low eGFR is likely to lead to dialysis. It has been reported that eGFR becomes lower with aging. These findings suggest that it is important to prevent eGFR from becoming lower or improve low eGFR. In recent years, relationships between lipids and CKD have been shown. It has also been investigated whether HMG-CoA reductase inhibitors can inhibit eGFR from becoming lower.11,12 It is known that hypertension worsens renal function, but it remains unknown whether antihypertensive therapy can improve low eGFR. To resolve this question, we analyzed the results of JMIC-B. Of the 1650 patients in the study, 780 whose eGFR was measured at 0 and 36 months were used for the analysis (Table I).
In hypertensive patients without CKD, 3-year antihypertensive therapy significantly decreased eGFR, while in those with CKD, it significantly increased eGFR (Figure 1). The decrement in eGFR in patients without CKD (from 91.84 to 88.95 mL/min/1.73m2), while statistically significant, does not correlate with a clinically significant fall. Antihypertensive therapy does not worsen eGFR in patients without CKD. We also stratified baseline eGFR into 7 groups, instead of 2 groups (eGFR <60 or ≥60) and investigated the percentage of patients whose eGFR was decreased and increased in each group. The Cochrane-Armitage trend test was significant: eGFR was decreased in a greater number of patients, with baseline eGFR being higher, while eGFR was increased in a greater number of patients, with baseline eGFR being lower (Figure 2). There were no significant differences in BP in any groups.
In our study, nifedipine and ACE inhibitors were used. There were no significant differences in the improvement of eGFR according to the type of therapeutic drugs (Figures 3 and 4). However, the results might not be generalized to all classes of antihypertensive medications.
Normal renal autoregulation enables the kidney to maintain a fairly constant renal blood flow and glomerular filtration rate as the mean arterial pressure varies between 80 mm Hg and 160 mm Hg.13 Hypertension increases intraglomerular pressure and causes glomerular disorders. For the normalization of intraglomerular pressure, it is assumed to be necessary to decrease systemic BP. The results of our analysis support this assumption. The Irbesartan Diabetic Nephropathy Trial (IDNT)14 and Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL)15 studies suggest that ACE inhibitors and ARBs are effective in inhibiting nephropathy from progressing. It has also been reported that calcium channel blockers also inhibit the progression of nephropathy in type II diabetes patients with hypertension, such as ACE inhibitors.16
In 1989, a preliminary study by Pettinger and colleagues17 suggested the potentiality for producing a significant improvement of renal function in hypertension-induced renal disease. In 2012, Hu and colleagues18 reported that kidney function can improve in patients with hypertensive CKD. They showed that 31 of 949 patients demonstrated clearly positive eGFR slopes, which could not be explained by random measurement variation.
There are limitations to our study. eGFR is associated with random measurement error, and the recovery of renal function might merely reflect regression to the mean. Small improvement in eGFR in patients with reduced eGFR and the slight deterioration in those with higher eGFR also might represent regression to the mean. Our study is not a placebo-controlled trial.
Large scale placebo-controlled trials of patients with low eGFR using various kinds of antihypertensive agents (angiotensin receptor blockers, ACE inhibitors, calcium channel blockers) are necessary.
Disclosures: This study was partly supported by a grant-in-aid from the Positive Health Promotion Foundation. There is no conflict of interest.