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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate (eGFR) is <60 mL/min/1.73 m2. Low eGFR is likely to increase the incidence of cardiovascular events and lead to dialysis. Therefore, it is important to prevent eGFR from decreasing eGFR. However, it still remains unknown whether antihypertensive therapy can prevent low eGFR from becoming even lower and improve eGFR in hypertensive patients with CKD. The authors analyzed the results of the Japan Multicenter Investigation for Cardiovascular DiseaseB (JMIC-B) and investigated the effects of antihypertensive therapy on eGFR. In hypertensive patients with CKD (eGFR <60), eGFR was significantly increased from 51.87±6.21 (n=98) to 57.55±19.00 (P<.001) after 3 years of antihypertensive therapy. In patients without CKD (eGFR ≥60), eGFR was significantly decreased from 91.84±23.27 (n=682) to 88.95±23.67 (P<.001). Regardless of the type of antihypertensive drugs used, eGFR was significantly increased in patients with CKD and was significantly decreased in patients without CKD. This paper shows that antihypertensive therapy can improve eGFR in hypertensive patients with CKD. J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.

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

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

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.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

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 P Value
eGFR <60 (98 Patients)eGFR ≥60 (682 Patients)
  1. 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.

Male/female  52 (53.1)/46 (46.9)483 (70.8)/199 (29.2)<.001
Age, y 68±864±8<.001
Coronary artery disease
 Myocardial infarction44 (44.9)285 (41.8).560
Angina pectoris57 (58.2)448 (65.7).145
Silent myocardial ischemia10 (10.2)77 (11.3).749
Complications
 Hyperlipidemia27 (27.6)168 (24.6).533
Diabetes mellitus21 (21.4)146 (21.4).996
Others22 (22.4)120 (17.6).244
History of smoking 26 (26.5)229 (33.6).164
CAG (within past 1 y) 56 (57.1)443 (65.0).132
PTCA (within past 1 y) 23 (23.5)195 (28.6).291
Number of diseased vessels (AHA ≥75%)
 1 vessel31 (31.6)255 (37.4).269
2 vessel18 (18.4)135 (19.8).739
3 vessel5 (5.1)46 (6.7).538
Left main trunk0 (0)3 (0.4)1.000
BP, mm Hg
 Systolic BP143±17147±19.089
Diastolic BP80±1183±11.057
Heart rate, per min 73±872±10.397
Body mass index, kg/m2 24.2±2.924.1±2.9.763
Serum creatinine, μmol/L 115.4±20.476.5±16.7<.001
Serum cholesterol, mmol/L 5.30±0.775.17±0.87.163
Medications used before observation period
 Nitrates70 (71.4)448 (65.7).261
Diuretics10 (10.2)34 (5.0).036
β-Blockers20 (20.4)138 (20.2).968
α-Blockers3 (3.1)35 (5.1).613
Calcium channel blockers47 (48.0)336 (49.3).809
ACE inhibitors21 (21.4)94 (13.8).046
Antihyperlipidemic drugs37 (37.8)192 (28.2).051
Antiplatelets58 (59.2)368 (54.0).331
image

Figure 1.  The effects of 3-year antihypertensive therapy in patients with chronic kidney disease (CKD) and without CKD.

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Figure 2.  The percentages of patients whose estimated glomerular filtration rate (eGFR) was decreased and increased after 3-year antihypertensive therapy according to baseline eGFR (7 groups). DBP indicates diastolic blood pressure; SBP, systolic blood pressure.

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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.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

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.

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Figure 3.  The effects of drugs on estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD).

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image

Figure 4.  The effects of drugs on estimated glomerular filtration rate (eGFR) in patients without chronic kidney disease (CKD).

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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.

Study Limitations

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

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.

Conclusions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References

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.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Study Limitations
  7. Conclusions
  8. References
  • 1
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  • 2
    Yui Y, Sumiyoshi T, Kodama K, et al.Nifedipine retard was as effective as angiotensin converting enzyme inhibitors in preventing cardiac events in high-risk hypertensive patients with diabetes and coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) subgroup analysis. Hypertens Res.2004;27:449456.
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    Shinoda E, Yui Y, Kodama K, et al.Quantitative coronary angiogram analysis. Nifedipine retard versus angiotensin-converting enzyme inhibitors (JMIC-B side arm study). Hypertension.2005;45:11531158.
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    Brenner BM, Cooper ME, de Zeeuw D, et al.Effects of losaltan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med.2001;345:861869.
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