2 Furthermore, quantitative coronary angiography

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1 ORIGINAL PAPER Estimated Glomerular Filtration Rate Reversal by Blood Pressure Lowering in Chronic Kidney Disease: Japan Multicenter Investigation for Cardiovascular DiseaseB CKD Study Yoshiki Yui, MD; 1 Kazuhisa Kodama, MD; 2 Atsushi Hirayama, MD; 3 Saichi Hosoda, MD; 4 Chuichi Kawai, MD; 5 and the Japan Multicenter Investigation for Cardiovascular DiseaseB (JMIC-B) Study Group From the Kyoto University Hospital, Kyoto, Japan; 1 Amagasaki Central Hospital, Osaka, Japan; 2 Nihon University School of Medicine, Tokyo, Japan; 3 The Sakakibara Heart Institute, Tokyo, Japan; 4 and Takeda General Hospital, Kyoto, Japan 5 Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate () is <60 ml min 1.73 m 2. Low is likely to increase the incidence of cardiovascular events and lead to dialysis. Therefore, it is important to prevent from decreasing. However, it still remains unknown whether antihypertensive therapy can prevent low from becoming even lower and improve 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. In hypertensive patients with CKD ( <60), was significantly increased from (n=98) to (P<.001) after 3 years of antihypertensive therapy. In patients without CKD ( 60), was significantly decreased from (n=682) to (P<.001). Regardless of the type of antihypertensive drugs used, was significantly increased in patients with CKD and was significantly decreased in patients without CKD. This paper shows that antihypertensive therapy can improve in hypertensive patients with CKD. J Clin Hypertens (Greenwich). 2013; 15: Ó2012 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. 2 Furthermore, 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. 4 It 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 () can be used as an index of CKD. 6 8 Address for correspondence: Yoshiki Yui, MD, Department of Cardiovascular Medicine, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto , Japan yoshiki@kuhp.kyoto-u.ac.jp Manuscript received: September 20, 2012; revised: October 22, 2012; accepted: October 26, 2012 DOI: /jch CKD can be diagnosed if is lower than 60 ml min 1.73 m 2. becomes lower with aging. For renal protection, it is important to prevent from becoming lower and improve low. 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 data (0 and 36 months) were selected for this investigation. 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 (Figure 1). Estimated marginal means was obtained by a linear mixed effect model in which <60 or 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 <60 or 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 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 Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 No 3 March

2 inhibitor as a dependent variable, and myocardial infarction, angina pectoris, hyperlipidemia, and antiplatelets as independent variables (Figures 3 and 4). C Statistics was 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 meanstandard deviation. RESULTS 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 during 3-year antihypertensive therapy in hypertensive patients with CKD and those without CKD: was significantly increased in those with CKD and was significantly decreased in those without CKD. Figure 2 shows the percentages of those whose was decreased and then increased after 3-year antihypertensive therapy according to baseline, which we stratified into 7 groups. The Cochrane-Armitage trend test was significant. The baseline 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 is shown in Figures 3 and 4. With <60, was significantly improved, while with 60, was significantly decreased. There were no significant inter-drug differences. DISCUSSION CKD can be diagnosed if is <60 ml min 1.73 m 2. Relationships between CKD and cardiovascular diseases (CVDs) have been gaining attention: the risk of CVD increases with <60. Low is likely to lead to dialysis. It has been TABLE. Baseline Clinical Characteristics Number of Patients <60 (98 Patients) 60 (682 Patients) P Value Male female 52 (53.1) 46 (46.9) 483 (70.8) 199 (29.2) <.001 Age, y <.001 Coronary artery disease Myocardial infarction 44 (44.9) 285 (41.8).560 Angina pectoris 57 (58.2) 448 (65.7).145 Silent myocardial ischemia 10 (10.2) 77 (11.3).749 Complications Hyperlipidemia 27 (27.6) 168 (24.6).533 Diabetes mellitus 21 (21.4) 146 (21.4).996 Others 22 (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 vessel 31 (31.6) 255 (37.4) vessel 18 (18.4) 135 (19.8) vessel 5 (5.1) 46 (6.7).538 Left main trunk 0 (0) 3 (0.4) BP, mm Hg Systolic BP Diastolic BP Heart rate, per min Body mass index, kg m Serum creatinine, lmol L <.001 Serum cholesterol, mmol L Medications used before observation period Nitrates 70 (71.4) 448 (65.7).261 Diuretics 10 (10.2) 34 (5.0).036 b-blockers 20 (20.4) 138 (20.2).968 a-blockers 3 (3.1) 35 (5.1).613 Calcium channel blockers 47 (48.0) 336 (49.3).809 ACE inhibitors 21 (21.4) 94 (13.8).046 Antihyperlipidemic drugs 37 (37.8) 192 (28.2).051 Antiplatelets 58 (59.2) 368 (54.0).331 Abbreviations: ACE, angiotensin-converting enzyme; AHA, American Heart Association; BP, blood pressure; CAG, coronary angiography;, estimated glomerular filtration rate; PTCA, percutaneous transluminal coronary angioplasty. Statistics is the same as in Table I. 172 The Journal of Clinical Hypertension Vol 15 No 3 March 2013 Official Journal of the American Society of Hypertension, Inc.

3 * * **P= mL/min/1.73m 2 <60mL/min/1.73m 2 n=682 n=602 n=595 n=682 n=98 n=87 n=88 n=98 **P=0.197 **P=0.001 **P=0.005 *Welch s t-test FIGURE 1. The effects of 3-year antihypertensive therapy in patients with chronic kidney disease (CKD) and without CKD. FIGURE 2. The percentages of patients whose estimated glomerular filtration rate () was decreased and increased after 3-year antihypertensive therapy according to baseline (7 groups). DBP indicates diastolic blood pressure; SBP, systolic blood pressure. Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 No 3 March

4 <60 **P=0.007 **P=0.021 **P=0.845 Nifedipine ACE inhibitor n=44 n=54 n=38 n=49 n=39 n=44 n=49 n=54 **P=0.121 **P=0.002 **P=0.046 *Student t-test FIGURE 3. The effects of drugs on estimated glomerular filtration rate () in patients with chronic kidney disease (CKD). 60 **P=0.006 **P=0.034 **P=0.061 Nifedipine ACE inhibitor n=352 *P=0.538 n=311 *P=0.015 n=304 n=352 # P=0.752 # P=0.338 n=330 n=291 n=291 n=330 * **P=0.013 P**=0.018 #Student t-test *Welch s t-test FIGURE 4. The effects of drugs on estimated glomerular filtration rate () in patients without chronic kidney disease (CKD). reported that becomes lower with aging. These findings suggest that it is important to prevent from becoming lower or improve low. In recent years, relationships between lipids and CKD have been shown. It has also been investigated whether HMG-CoA reductase inhibitors can inhibit from becoming lower. 11,12 It is known that hypertension worsens renal function, but it remains unknown whether antihypertensive therapy can improve low. To resolve this question, we analyzed the results of JMIC-B. Of the 1650 patients in the study, 780 whose 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, while in those with CKD, it significantly increased (Fig- 174 The Journal of Clinical Hypertension Vol 15 No 3 March 2013 Official Journal of the American Society of Hypertension, Inc.

5 ure 1). The decrement in in patients without CKD (from to ml min 1.73m 2 ), while statistically significant, does not correlate with a clinically significant fall. Antihypertensive therapy does not worsen in patients without CKD. We also stratified baseline into 7 groups, instead of 2 groups ( <60 or 60) and investigated the percentage of patients whose was decreased and increased in each group. The Cochrane-Armitage trend test was significant: was decreased in a greater number of patients, with baseline being higher, while was increased in a greater number of patients, with baseline 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 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 colleagues 17 suggested the potentiality for producing a significant improvement of renal function in hypertension-induced renal disease. In 2012, Hu and colleagues 18 reported that kidney function can improve in patients with hypertensive CKD. They showed that 31 of 949 patients demonstrated clearly positive slopes, which could not be explained by random measurement variation. STUDY LIMITATIONS There are limitations to our study. is associated with random measurement error, and the recovery of renal function might merely reflect regression to the mean. Small improvement in in patients with reduced and the slight deterioration in those with higher also might represent regression to the mean. Our study is not a placebo-controlled trial. CONCLUSIONS Large scale placebo-controlled trials of patients with low 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. Yui Y, Sumiyoshi T, Kodama K, et al. Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res. 2004;27: 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: 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: Yui Y, Shinoda E, Kodama K, et al. Nifedipine retard prevents hospitalization for angina pectoris better than angiotensin-converting enzyme inhibitors in hypertensive japanese patients with previous myocardial infarction (JMIC-B substudy). J Hypertens. 2007;25: Yui Y, Kodama K, Hirayama A, et al. Reverse remodeling and improved function by antihypertensive treatment in hypertensive patients with coronary artery disease. J Hypertens. 2010;28: Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351: Solomon SD, Rice MM, A Jablonski K, et al. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial. Circulation. 2006;114: Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351: Levy AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145: Moe S, Druke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69: Shepherd J, Kastelein John JP, Bittner V, et al. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to new Targets (TNT) Study. Clin J Am Soc Nephrol. 2007;2: Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular diseases in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54: Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med. 2002;347: Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345: 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: Baba S; J-MIND Study Group. Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics. Diabetes Res Clin Pract. 2001;54: Pettinger WA, Lee HC, Reisch J, Mitchell HC. Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension. 1989;13: Hu B, Gadegbeku C, Lipkowitz MS, et al. Kidney function can improve in patients with hypertensive CKD. J Am Soc Nephrol. 2012;23: Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 15 No 3 March

ALLHAT RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED INTO 4 GROUPS BY BASELINE GLOMERULAR FILTRATION RATE (GFR)

ALLHAT RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED INTO 4 GROUPS BY BASELINE GLOMERULAR FILTRATION RATE (GFR) 1 RENAL DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED INTO 4 GROUPS BY BASELINE GLOMERULAR FILTRATION RATE (GFR) 6 / 5 / 1006-1 2 Introduction Hypertension is the second most common cause of end-stage