Cardiovascular events and death in Japanese patients with chronic kidney disease
The incidence of cardiovascular disease (CVD) is higher in patients with chronic kidney disease (CKD) than in the general population, and the risk of CVD increases with reductions in renal function. However, the incidence of CVD in Japanese patients with CKD has not been sufficiently investigated. To measure this we conducted the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study over four years in 2,966 Japanese patients with CKD to examine the incidence of CVD and all-cause death. These patients had an estimated glomerular filtration rate (eGFR) of 10–59 ml/min/1.73 m2, were under nephrologist care, and pooled from 17 medical institutions in Japan. At the median follow-up of 3.9 years, 69 patients had died, 217 had cardiovascular events, and 514 started maintenance dialysis therapy. The incidences of cardiovascular events were 11.9, 19.1, 25.0, and 39.4 per 1,000 person-years at eGFRs of 45–59, 30–44, 15–29, and under 15 ml/min/1.73 m2, respectively. The adjusted Cox proportional hazards models showed that the risk of cardiovascular events increased as the eGFR decreased, with a significant difference only between CKD stage G5 (eGFR: under 15 ml/min/1.73 m2) and CKD stage G3a (eGFR: 45–59 ml/min/1.73 m2) (hazard ratio 3.16, 95% confidence interval 1.28 to 7.76). Thus, the risk of CVD and all-cause death was related to the decrease in eGFR, but not necessarily elevated in proportion to progression of the CKD stage in Japanese patients with predialysis CKD under a nephrologist’s care. The incidence of cardiovascular disease (CVD) is higher in patients with chronic kidney disease (CKD) than in the general population, and the risk of CVD increases with reductions in renal function. However, the incidence of CVD in Japanese patients with CKD has not been sufficiently investigated. To measure this we conducted the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study over four years in 2,966 Japanese patients with CKD to examine the incidence of CVD and all-cause death. These patients had an estimated glomerular filtration rate (eGFR) of 10–59 ml/min/1.73 m2, were under nephrologist care, and pooled from 17 medical institutions in Japan. At the median follow-up of 3.9 years, 69 patients had died, 217 had cardiovascular events, and 514 started maintenance dialysis therapy. The incidences of cardiovascular events were 11.9, 19.1, 25.0, and 39.4 per 1,000 person-years at eGFRs of 45–59, 30–44, 15–29, and under 15 ml/min/1.73 m2, respectively. The adjusted Cox proportional hazards models showed that the risk of cardiovascular events increased as the eGFR decreased, with a significant difference only between CKD stage G5 (eGFR: under 15 ml/min/1.73 m2) and CKD stage G3a (eGFR: 45–59 ml/min/1.73 m2) (hazard ratio 3.16, 95% confidence interval 1.28 to 7.76). Thus, the risk of CVD and all-cause death was related to the decrease in eGFR, but not necessarily elevated in proportion to progression of the CKD stage in Japanese patients with predialysis CKD under a nephrologist’s care. Chronic kidney disease (CKD), an independent risk factor for end-stage renal disease (ESRD), cardiovascular disease (CVD), and all-cause mortality in the general population in Western countries1Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8984) Google Scholar, 2Keith D.S. Nichols G.A. Gullion C.M. et al.Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Crossref PubMed Scopus (1366) Google Scholar, 3Muntner P. He J. Hamm L. et al.Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States.J Am Soc Nephrol. 2002; 13: 745-753Crossref PubMed Google Scholar, 4Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar has become a worldwide public health problem. Japan is one of the countries with the highest incidence of ESRD, and the number of Japanese patients with ESRD has increased over the past 4 decades. In 2013, the number of ESRD patients on chronic dialysis exceeded 310,000.5Japanese Society of Dialysis Therapy. An overview of regular dialysis treatment in Japan. 2014. Available at: http://docs.jsdt.or.jp/overview/. Accessed December 31, 2013.Google Scholar The number of CKD patients is estimated to be 13.3 million (corresponding to 13% of the adult population) in Japan.6Imai E. Horio M. Watanabe T. et al.Prevalence of chronic kidney disease in the Japanese general population.Clin Exp Nephrol. 2009; 13: 621-630Crossref PubMed Scopus (382) Google Scholar However, patients with predialysis CKD have not been examined sufficiently because few cohort studies have been conducted. Recent population-based studies in Japan also have confirmed CKD as a significant risk for CVD and all-cause mortality, suggesting that CKD represents a major public health problem that is independent of ethnicity.7Nakayama M. Metoki H. Terawaki H. et al.Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population–the Ohasama study.Nephrol Dial Transplant. 2007; 22: 1910-1915Crossref PubMed Scopus (161) Google Scholar, 8Irie F. Iso H. Sairenchi T. et al.The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.Kidney Int. 2006; 69: 1264-1271Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 9Ninomiya T. Kiyohara Y. Kubo M. et al.Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama Study.Kidney Int. 2005; 68: 228-236Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar Nevertheless, few prospective observational studies have been conducted to investigate cardiovascular events in the CKD patient population. The Chronic Renal Insufficiency Cohort (CRIC) Study10Lash J.P. Go A.S. Appel L.J. et al.Chronic Renal Insufficiency Cohort (CRIC) study: baseline characteristics and associations with kidney function.Clin J Am Soc Nephrol. 2009; 4: 1302-1311Crossref PubMed Scopus (420) Google Scholar was conducted in the United States to examine risk factors for the progression of CKD with respect to the development of CVD in CKD patients, as well as to develop models for CVD development that could identify the high-risk subgroups. Hence, we intended to address the same challenges in a 4-year, multicenter, prospective cohort study, the Chronic Kidney Disease-Japan Cohort (CKD-JAC) Study. The design and methods of the CKD-JAC Study have been published previously.11Imai E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods.Hypertens Res. 2008; 31: 1101-1107Crossref PubMed Scopus (105) Google Scholar The incidences of coronary artery disease and stroke events among cardiovascular events differ between Western and Asian populations, and the risk of coronary artery disease is much lower in the Japanese general population.12Miura K. Nakagawa H. Ohashi Y. et al.Four blood pressure indexes and the risk of stroke and myocardial infarction in Japanese men and women: a meta-analysis of 16 cohort studies.Circulation. 2009; 119: 1892-1898Crossref PubMed Scopus (98) Google Scholar The aim of the present study was to investigate the incidence of the primary end points, cardiovascular events, and all-cause death in Japanese patients with predialysis CKD defined as an estimated glomerular filtration rate (eGFR) of 10 to 59 ml/min/1.73 m2. Patient disposition is shown in Figure 1. A total of 421 patients were lost to follow-up evaluation because they transferred to other medical institutions or stopped visiting the hospital as a result of socioeconomic reasons, and the follow-up evaluation of 514 patients was terminated because maintenance dialysis therapy was initiated. Baseline clinical and laboratory characteristics of Japanese patients with predialysis CKD by CKD stage have been published previously.13Imai E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort study: baseline characteristics and factors associated with causative diseases and renal function.Clin Exp Nephrol. 2010; 14: 558-570Crossref PubMed Scopus (83) Google Scholar Overall, 217 cardiovascular events and 69 all-cause deaths occurred, with only 17 cardiovascular deaths. The differences in the incidences of cardiovascular events among the 17 centers in the cohort are shown in Supplementary Table S1. The incidences of cardiovascular events and all-cause death were 22.8 and 7.2 per 1000 person-years, respectively, and they showed increases with decreases in eGFR (Figure 2). The incidences of cardiovascular events were increased significantly in patients with diabetes mellitus (DM) compared with patients without it (Table 1); however, the incidences of myocardial infarctions and cardiovascular death were markedly low both in patients with DM and in those without (Table 2). Significant differences (P < 0.001) were found in the incidence of cardiovascular events and primary end points (cardiovascular events plus all-cause death) with CKD stages at baseline in Japanese patients with predialysis CKD (Figure 3 and Supplementary Figure S1). The Cox proportional hazards models unadjusted for confounding factors showed significant associations between CKD stage at baseline and the primary end points (Table 2); however, these significant associations were weakened after multivariate adjustments for confounding factors (model 1, adjustment for age and sex; model 2, adjustment for covariates in model 1 plus classic cardiovascular risk factors such as body mass index, DM, current smoking, systolic blood pressure, and history of cardiovascular disease; model 3, adjustment for covariates in model 2 plus CKD-related cardiovascular risk factors such as hemoglobin, serum albumin, urine albumin, and high-sensitivity C-related protein). The risk of the primary end points was significantly different only between CKD stage G5 (eGFR, <15 ml/min/1.73 m2) and CKD stage G3a (eGFR, 45–59 ml/min/1.73 m2) (hazard ratio, 3.155; 95% confidence interval, 1.284–7.756; P = 0.012) (Table 2, model 3).Figure 2Incidences of cardiovascular events and all-cause death by chronic kidney disease (CKD) stage at baseline in Japanese patients with predialysis CKD. The incidences of cardiovascular events also are shown separately by myocardial infarction, cerebrovascular disease, congestive heart failure, others, and cardiovascular death (others included angina pectoris, sudden death, arrhythmias, chronic arteriosclerosis obliterans, and eGFR, estimated glomerular filtration Figure events and all-cause death in Japanese patients on predialysis chronic kidney disease with and without per 1000 for DM is to the incidence rate difference is of cohort = = = cohort = = = heart arteriosclerosis follow-up diabetes P for DM is to the incidence rate difference is in a Table between chronic kidney disease stage at baseline and the primary end points to 3 Cox proportional hazards models adjusted for confounding factors in Japanese patients with predialysis chronic kidney and CKD 10 ml/min/1.73 (eGFR, ml/min/1.73 (eGFR, to ml/min/1.73 (eGFR, to ml/min/1.73 (eGFR, <15 ml/min/1.73 1 was adjusted for age and sex; model 2 was adjusted for covariates in model 1 plus body mass index, diabetes current smoking, systolic blood pressure, and history of cardiovascular disease; and model 3 was adjusted for covariates in model 2 plus hemoglobin, serum albumin, urine albumin, and high-sensitivity confidence eGFR, estimated glomerular filtration in a Figure for the incidence of cardiovascular events by chronic kidney disease (CKD) stage at baseline in Japanese patients with predialysis CKD. P < of and P < death as a Figure DM, diabetes 1 was adjusted for age and sex; model 2 was adjusted for covariates in model 1 plus body mass index, diabetes current smoking, systolic blood pressure, and history of cardiovascular disease; and model 3 was adjusted for covariates in model 2 plus hemoglobin, serum albumin, urine albumin, and high-sensitivity confidence eGFR, estimated glomerular filtration between CKD stage at cardiovascular events, and the primary end points in patients with or without DM also were investigated. The incidence of both cardiovascular events and the primary end points increased significantly (P = with progression of CKD stage at baseline in DM (Figure and Supplementary Figure Significant differences (P = were found in the incidences of the primary end with CKD stage at baseline in patients without DM Figure but not in the incidences of cardiovascular events (Figure The Cox proportional hazards models adjusted for confounding factors showed significant associations between CKD stage at baseline and the primary end points only in patients with DM (Table Table 4 the of the incidences of cardiovascular disease and death among the present study, CKD of the United and of Japan and the United The incidences of both cardiovascular disease and all-cause death were lower in the present study than in and the Study of Kidney Disease and for myocardial M. S. et al.Chronic Renal Insufficiency Cohort Study overview and of J Am Soc Nephrol. PubMed Scopus Google Scholar, K. J. J. et outcomes in the Study of Kidney Disease and J Kidney 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, T. et is associated with cardiovascular outcomes among with chronic kidney Int. Full Text Full Text PDF PubMed Scopus Google between chronic kidney disease stage at baseline and the primary end points to a Cox proportional hazards model with or without adjustment for confounding factors in Japanese patients with predialysis chronic kidney disease with and without diabetes and CKD for age and eGFR 10 ml/min/1.73 G3a (eGFR, ml/min/1.73 (eGFR, ml/min/1.73 (eGFR, ml/min/1.73 G5 (eGFR, <15 ml/min/1.73 eGFR 10 ml/min/1.73 G3a (eGFR, ml/min/1.73 (eGFR, ml/min/1.73 (eGFR, ml/min/1.73 G5 (eGFR, <15 ml/min/1.73 confidence eGFR, estimated glomerular filtration in a Table of the incidences of cardiovascular disease and death among and other in the United States and 1000 heart patients 10–59 ml/min/1.73 M. S. et al.Chronic Renal Insufficiency Cohort Study overview and of J Am Soc Nephrol. PubMed Scopus Google patients ml/min/1.73 K. J. J. et outcomes in the Study of Kidney Disease and J Kidney 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, T. et is associated with cardiovascular outcomes among with chronic kidney Int. Full Text Full Text PDF PubMed Scopus Google patients ml/min/1.73 of coronary heart disease and mortality in the a follow-up of the J. Full Text PDF PubMed Scopus Google Scholar, et as a risk factor for The PubMed Scopus Google M. Y. Y. et of myocardial infarction in J. 2005; 69: PubMed Scopus Google M. Y. Y. et of myocardial infarction in J. 2005; 69: PubMed Scopus Google M. Kiyohara Y. et in the mortality, and rate of cardiovascular disease in a Japanese the Hisayama 2003; PubMed Scopus Google K. Nakagawa H. Ohashi Y. et al.Four blood pressure indexes and the risk of stroke and myocardial infarction in Japanese men and women: a meta-analysis of 16 cohort studies.Circulation. 2009; 119: 1892-1898Crossref PubMed Scopus (98) Google Study of Kidney Disease and Chronic Kidney Disease Japan Chronic Renal Insufficiency Japan of and in in a confidence eGFR, estimated glomerular filtration Study of Kidney Disease and Chronic Kidney Disease Japan Chronic Renal Insufficiency Japan of and in The CKD-JAC a prospective cohort study, showed for the first the incidences of cardiovascular events and all-cause death in Japanese patients with predialysis defined as an eGFR of 10 to 59 ml/min/1.73 m2, under care. The incidences of cardiovascular events and all-cause death increased as the eGFR decreased, but they were low at CKD stages compared with those published in studies of CKD in Western countries (Table M. S. et al.Chronic Renal Insufficiency Cohort Study overview and of J Am Soc Nephrol. PubMed Scopus Google Scholar, K. J. J. et outcomes in the Study of Kidney Disease and J Kidney 2006; Full Text Full Text PDF PubMed Scopus Google Scholar studies have shown that patients with kidney function patients with are at higher risk for cardiovascular events and death than the general population, and that the risk increases with decreases in A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8984) Google Scholar the risk of a cardiovascular or death was not necessarily in proportion to progression of the CKD stage in the present shown in Table the incidences of cardiovascular events were to be much lower in Japanese cohort such as the Japan Study and the Hisayama study, than in Western K. Nakagawa H. Ohashi Y. et al.Four blood pressure indexes and the risk of stroke and myocardial infarction in Japanese men and women: a meta-analysis of 16 cohort studies.Circulation. 2009; 119: 1892-1898Crossref PubMed Scopus (98) Google Scholar, M. Y. Y. et of myocardial infarction in J. 2005; 69: PubMed Scopus Google Scholar, M. Kiyohara Y. et in the mortality, and rate of cardiovascular disease in a Japanese the Hisayama 2003; PubMed Scopus Google Scholar, of coronary heart disease and mortality in the a follow-up of the J. Full Text PDF PubMed Scopus Google Scholar, et as a risk factor for The PubMed Scopus Google Scholar The incidences of cardiovascular events were lower in the present study than in the CKD cohort in the United States and were as low as in the studies in Japan. The incidences of death by cardiovascular events were much higher than of the of renal therapy in Western D.S. Nichols G.A. Gullion C.M. et al.Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Crossref PubMed Scopus (1366) Google Scholar but the number of patients started maintenance dialysis therapy in the study was than the number of deaths and in the present The present that the risk of ESRD is higher than that of death or CVD in Japanese patients with CKD. be one of the characteristics of Japanese patients with CKD and one of the that the number of patients on chronic dialysis is markedly in Japan. A of incidences or the risks of death and CVD after of maintenance dialysis therapy also be in this of the of the CKD-JAC Study was to a Japanese cohort for with the Study in the United States prospective cohort study risk factors for the progression of CKD and the development of cardiovascular events in patients with predialysis The Study of CKD patients with an eGFR of to ml/min/1.73 m2, and 13% of were and respectively. The incidences of cardiovascular events in the cohort were and per 1000 person-years for myocardial infarction, cerebrovascular disease, congestive heart failure, and death, the incidence of the first 3 and cardiovascular events was per 1000 M. S. et al.Chronic Renal Insufficiency Cohort Study overview and of J Am Soc Nephrol. PubMed Scopus Google Scholar The incidences of myocardial infarction, cerebrovascular disease, congestive heart failure, and cardiovascular death were and per 1000 person-years, respectively, in the the incidences of cardiovascular events and all-cause death were much lower in the CKD-JAC Study than in the Study. studies in the general population have shown that the risk of cardiovascular events, coronary artery disease, is lower in Japanese than in Western from patient characteristics between the CKD-JAC Study and the included of DM, body mass history of blood in patients with DM, and the proportion of patients or E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort study: baseline characteristics and factors associated with causative diseases and renal function.Clin Exp Nephrol. 2010; 14: 558-570Crossref PubMed Scopus (83) Google Scholar In the proportion of patients with DM in the Study was was higher than the in the CKD-JAC Study. the blood as by in patients with DM was managed in the CKD-JAC Study than in the Study A large difference also was found in between the Study and the CKD-JAC Study with a of or for of patients in the in to only in the CKD-JAC Study. The rate of or also in the Study and in the CKD-JAC Study. These differences differences in cardiovascular risk between the 2 patients in the CKD-JAC Study were under care and were managed for blood pressure, blood and other these patients also were and by with by population-based studies in Japan have confirmed CKD as a significant risk for cardiovascular M. Metoki H. Terawaki H. et al.Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population–the Ohasama study.Nephrol Dial Transplant. 2007; 22: 1910-1915Crossref PubMed Scopus (161) Google Scholar, 8Irie F. Iso H. Sairenchi T. et al.The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.Kidney Int. 2006; 69: 1264-1271Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 9Ninomiya T. Kiyohara Y. Kubo M. et al.Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama Study.Kidney Int. 2005; 68: 228-236Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar CKD represents a major public health problem that is independent of The that the incidences of cardiovascular events were as in the general population, that have the risk of cardiovascular events in patients with patients were of at the of patient be DM, an risk factor for is a major disease for ESRD in Japan. An observational cohort study of CKD patients in showed the the risk of cardiovascular events increased with the progression of CKD differences in the risk to differences in disease of CKD were and the risk was significantly higher in patients had than in patients M. T. M. et risk of cardiovascular events and mortality among chronic kidney disease patients with the Res. PubMed Scopus Google Scholar In the present study, the incidence of cardiovascular events was significantly higher in patients with DM the that blood was under The of DM in CKD patients the In the clinical of be not only to the eGFR and CKD but also to differences in the disease CKD. The present study had the was The of cardiovascular events and all-cause deaths cardiovascular were much lower than a is to the sufficiently that be associated with the primary end ESRD could be a risk factor for cardiovascular events or death because follow-up evaluation was terminated in patients started maintenance dialysis therapy in the present of the patients in the present study were were under care at major medical patients with of treatment were The number of is in and a of patients with CKD not are not managed at medical or not that they have CKD because of the of medical Hence, the from the present study not be to such These challenges to be by the in this cohort study with other The CKD-JAC Study is the first to have shown the incidences of cardiovascular events and all-cause death in Japanese patients with predialysis CKD were under care. Japanese patients with predialysis were under care with of blood pressure, and blood were at much lower risk of cardiovascular events or death than CKD patients in Western differences the or not the care of CKD patients clinical outcomes in a cohort study or an The CKD-JAC Study was as a prospective cohort study Japanese patients were at 17 medical institutions in a in the treatment of CKD patients in to in of Japan. The of the present study was published previously.11Imai E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods.Hypertens Res. 2008; 31: 1101-1107Crossref PubMed Scopus (105) Google Scholar, E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort study: baseline characteristics and factors associated with causative diseases and renal function.Clin Exp Nephrol. 2010; 14: 558-570Crossref PubMed Scopus (83) Google Scholar The were as Japanese patients in age to and a of defined as an eGFR of 10 to 59 ml/min/1.73 m2. The eGFR was the for Japanese patients with CKD. the eGFR from serum creatinine, and the = serum for S. E. Horio M. et for estimated from serum in J Kidney 2009; Full Text Full Text PDF PubMed Scopus Google Scholar The were as patients with kidney disease, or treatment the past 2 and patients have chronic and to was started in and patients were patients were because they of the and baseline was not for patients not the baseline after 59 were by the 4 were lost to follow-up evaluation because they not to the and 1 patient these patients from the were The was by the of medical and the study was conducted in with the of patients the clinical for follow-up at they were and The follow-up evaluation of patients transferred to other medical institutions or started maintenance dialysis therapy was The primary end points were cardiovascular events and all-cause death the of maintenance dialysis therapy. events and myocardial infarction, angina pectoris, sudden death, congestive heart failure, arrhythmias, cerebrovascular chronic arteriosclerosis obliterans, and were cardiovascular events were by the The of cardiovascular events are in Supplementary S1. The for the CKD-JAC Study was published previously.11Imai E. Matsuo S. Makino H. et al.Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods.Hypertens Res. 2008; 31: 1101-1107Crossref PubMed Scopus (105) Google Scholar of patient characteristics at as were compared between by of of cardiovascular events and all-cause death are as the number of events per 1000 The incidences of cardiovascular events also are shown separately by myocardial infarction, cerebrovascular disease, congestive heart failure, others, and cardiovascular death (others angina pectoris, sudden death, arrhythmias, chronic arteriosclerosis obliterans, and To differences in between DM and the model was (Table The and were to the of Japanese patients with predialysis CKD by CKD or not have DM, on that death as a J.P. A proportional hazards model for the of a Am Scopus Google Scholar A by eGFR stage was and multivariate 3 Cox proportional hazards models adjusted for confounding factors were to examine associations between CKD stage at baseline and the primary end In the or of DM, model 1 was to the adjusted for age and model 2 adjusted for DM, current smoking, and history of CVD in to model 1, and model 3 adjusted for hemoglobin, serum albumin, urine albumin, and high-sensitivity in to model The from the models are as with 95% confidence and P on the A P < was were has a from has for and a from has for and from and has and a from The other have to for of the study was conducted by at the medical Japan and also to the of the and for to the present study was by with on from Figure for the incidence of the primary end points (cardiovascular events plus all-cause death) by chronic kidney disease (CKD) stage at baseline in Japanese patients with predialysis CKD and diabetes mellitus (DM) of P = Figure for the incidence of the primary end points (cardiovascular events plus all-cause death) by chronic kidney disease (CKD) stage at baseline in Japanese patients with predialysis CKD not have diabetes mellitus (DM) of P = Figure with Table of the incidences of cardiovascular events among 17 medical with of cardiovascular events that were and