Excess risk of cardiovascular events in patients in the United States vs. Japan with chronic kidney disease is mediated mainly by left ventricular structure and function

Abstract

While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m2, respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74–4.89]) and death (4.69 [3.05–7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD. While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m2, respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74–4.89]) and death (4.69 [3.05–7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD. Lay SummaryCardiovascular disease is very common in patients with chronic kidney disease (CKD). Although US hemodialysis patients are more likely to develop heart disease compared with Japanese patients, no direct comparison exists for non–dialysis-dependent CKD. Using patient data from the United States and Japan, we found that US patients with CKD had higher rates of heart failure and heart attack than Japanese patients. We then aimed to clarify how this happened. Our results revealed that the enlarged hearts of US patients and their weak contractility play important roles. These features explain most of the differences in cardiovascular outcomes between the United States and Japan. Checking the heart with echocardiography may help identify high-risk patients. In addition, obesity and inflammation, which were related to each other, were associated with the enlargement of the heart. Therefore, countermeasures against obesity can protect patients with CKD from heart disease. Cardiovascular disease is very common in patients with chronic kidney disease (CKD). Although US hemodialysis patients are more likely to develop heart disease compared with Japanese patients, no direct comparison exists for non–dialysis-dependent CKD. Using patient data from the United States and Japan, we found that US patients with CKD had higher rates of heart failure and heart attack than Japanese patients. We then aimed to clarify how this happened. Our results revealed that the enlarged hearts of US patients and their weak contractility play important roles. These features explain most of the differences in cardiovascular outcomes between the United States and Japan. Checking the heart with echocardiography may help identify high-risk patients. In addition, obesity and inflammation, which were related to each other, were associated with the enlargement of the heart. Therefore, countermeasures against obesity can protect patients with CKD from heart disease. Cardiovascular disease (CVD) is an important outcome for patients with chronic kidney disease (CKD).1de Jager D.J. Grootendorst D.C. Jager K.J. et al.Cardiovascular and noncardiovascular mortality among patients starting dialysis.JAMA. 2009; 302: 1782-1789Crossref PubMed Scopus (561) Google Scholar, 2Ninomiya 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 (330) Google Scholar, 3Manjunath 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: 47-55Crossref PubMed Scopus (745) Google Scholar, 4Muntner 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, 5Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (3009) Google Scholar, 6Go 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 (9338) Google Scholar Studies have shown that dialysis patients in the United States are more likely to die or develop CVD events than their Japanese counterparts.7Stirnadel-Farrant H.A. Karaboyas A. Cizman B. et al.Cardiovascular event rates among hemodialysis patients across geographical regions—a snapshot from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Kidney Int Reports. 2019; 4: 864-872Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,8Goodkin D.A. Bragg-Gresham J.L. Koenig K.G. et al.Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS).J Am Soc Nephrol. 2003; 14: 3270-3277Crossref PubMed Scopus (647) Google Scholar However, little is known about patients with predialysis CKD due to a dearth of direct comparisons. Reports on the incidence of CVD from East Asia,9Tanaka K. Watanabe T. Takeuchi A. et al.Cardiovascular events and death in Japanese patients with chronic kidney disease.Kidney Int. 2017; 91: 227-234Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 10Yuan Q. Xie Y. Peng Z. et al.Urinary magnesium predicts risk of cardiovascular disease in chronic kidney disease stage 1–4 patients.Clin Nutr. 2021; 40: 2394-2400Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 11Ryu H. Kim J. Kang E. et al.Incidence of cardiovascular events and mortality in Korean patients with chronic kidney disease.Sci Rep. 2021; 11: 1131Crossref PubMed Scopus (8) Google Scholar the United States, and European countries12Grams M.E. Sang Y. Ballew S.H. et al.Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased glomerular filtration rate.Kidney Int. 2018; 93: 1442-1451Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar suggest that the incidence of CVD is lower in East Asian countries than in the United States and European countries. However, patient characteristics such as baseline kidney function, urinary protein, and history of CVD or diabetes mellitus (DM) varied among studies. Thus, whether there is a difference in the incidence of major clinical events between Japanese and American patients with CKD, and if so, what factors contribute to this difference, remains to be elucidated. To address this question, we need to harmonize patient-level data from each country rather than to compare aggregated data. Among the various types of CVD, a growing number of patients develop congestive heart failure (CHF) as kidney function declines.13Schefold J.C. Filippatos G. Hasenfuss G. et al.Heart failure and kidney dysfunction: epidemiology, mechanisms and management.Nat Rev Nephrol. 2016; 12: 610-623Crossref PubMed Scopus Google Scholar ventricular (LV) and function are important clinical that are predictive of studies have shown that LV mass index (LVMI) or LV is associated with CVD events in patients with M. et al.Cardiovascular mortality risk in chronic kidney comparison of and risk 2005; PubMed Scopus Google Scholar, J. et parameters are associated with cardiovascular events in patients with chronic kidney PubMed Scopus Google Scholar, et of echocardiographic with heart failure and the Chronic Renal Insufficiency J Am Soc Nephrol. 2017; 12: PubMed Scopus Google Scholar ejection fraction even in the of clinical heart shown to be associated with CVD and mortality in patients with M.J. et function and mortality in chronic kidney disease patients with Nephrol. Google Scholar Therefore, we the LV indices as of or disease that subsequent cardiovascular events and explain the differences in outcomes between the United States and Japan. We aimed to the of LVMI and EF in with CKD in Japan and the United States, the differences in the of these LV with subsequent major clinical events, and how these can for the differences between these countries using data from CKD the Chronic Renal Insufficiency Cohort (CRIC) study and the CKD Japan Cohort (CKD-JAC) The CRIC study is an cohort study of participants with CKD from clinical in the United The of the cohort are A.S. et al.Chronic Renal Insufficiency Cohort (CRIC) baseline characteristics and with kidney J Am Soc Nephrol. 2009; 4: PubMed Scopus Google The Chronic Renal Insufficiency Cohort (CRIC) and Am Soc Nephrol. 2003; 14: PubMed Google Scholar the participants from the CRIC study between and we those echocardiography those for and those CVD events echocardiography Thus, we data from 3125 participants with baseline echocardiography data. The CKD-JAC study is a cohort study across Japan. The participants were between and E. H. et al.Chronic Kidney Japan Cohort baseline characteristics and factors associated with and renal Nephrol. 14: PubMed Scopus Google Scholar from with participants were of the number of participants for echocardiographic results were echocardiography and study to the and participants baseline echocardiography. characteristics were compared between those with and echocardiography. We of participants of a of we included data from 1097 participants from the CKD-JAC study and 3125 participants from the CRIC study with baseline echocardiography data data the in both were in this The by the of each and the study the of patients the The by the at the of In the CRIC echocardiography using by the American of were to the echocardiography laboratory of were by a were to the baseline glomerular filtration and clinical characteristics of the In the CKD-JAC at each clinical participants and the were assessed by in with the of echocardiographic T. Y. et of function PubMed Scopus Google Scholar The are in the We the CVD events, atherosclerotic CVD death, and kidney We a CVD event as a of the any cardiovascular for and for We as a of and disease. and kidney failure were as and the of kidney The follow-up at kidney CVD events were by an in each The of each outcome event are in the In both clinical history and were at and laboratory parameters were from and using as The Chronic Renal Insufficiency Cohort (CRIC) and Am Soc Nephrol. 2003; 14: PubMed Google E. H. et al.Chronic Kidney Japan Cohort (CKD-JAC) and PubMed Scopus Google Scholar The in the CRIC study using an from CRIC study participants on and and et among participants in the Chronic Renal Insufficiency Cohort (CRIC) J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar the in the CKD-JAC study using the Japanese in Japanese patients with if E. M. et for from in J Kidney Dis. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar are in the We to the of laboratory and echocardiographic parameters in the differences between the CRIC and CKD-JAC studies with to cardiovascular We to the of the of mediators using a T. with Google Scholar We the of mediated on the between States and mediators included echocardiographic parameters and and laboratory parameters factor and C-reactive protein The are in the data are as the mean and median for and comparisons were for LV body mass index and levels of phosphate and across the levels of using the In we the and to compare CVD events, death, and kidney failure between the as as among We for patients with for baseline urinary ratio and using for the cohort and were to the between LV indices EF, LVMI, and LV and CVD events, for baseline a history of any CVD, and To the of or contractility in the LV on the we for EF the of LVMI, and LV with the the of EF, we for LVMI in each we obesity the number of of and to We then factor and to The hazard using We the between and outcomes in the of those with no CVD and those with We to data in the The included in were baseline as shown in and of in Med. PubMed Scopus Google Scholar We with and then the results across the using are of PubMed Scopus Google characteristics of the CRIC and CKD-JAC or of CVD data to those with CRIC to those with CRIC to those with CRIC in from CKD-JAC and from LVMI, ventricular body mass congestive heart Chronic Kidney Japan Chronic Renal Insufficiency C-reactive CVD, cardiovascular glomerular filtration left left ventricular LVMI, left ventricular mass urinary are as for and mean or median for to those with CRIC in from CKD-JAC and from in a for the of left ventricular indices with the incidence of CVD ventricular of events for for for for confidence Chronic Kidney Japan Chronic Renal Insufficiency C-reactive CVD, cardiovascular hazard left ventricular ejection LVMI, left ventricular mass left ventricular urinary for baseline diabetes history of any CVD, CRIC and EF obesity number of of and and were of events in a body mass congestive heart Chronic Kidney Japan Chronic Renal Insufficiency C-reactive CVD, cardiovascular glomerular filtration left left ventricular LVMI, left ventricular mass urinary are as for and mean or median for confidence Chronic Kidney Japan Chronic Renal Insufficiency C-reactive CVD, cardiovascular hazard left ventricular ejection LVMI, left ventricular mass left ventricular urinary for baseline diabetes history of any CVD, CRIC and EF obesity number of of and and were the of LVMI and EF with subsequent CVD events, we with the and of the of the of both and an of or The were at for LVMI and for To the of with LVMI, EF, and we with and to the levels of LVMI, EF, and and G. A to studies with J 2004; PubMed Scopus Google Scholar to the of in the with were and of than were of were using and for The characteristics of the study participants are shown in CRIC participants were and more likely to be than CKD-JAC of the the mean levels in the CRIC study were higher than those in the CKD-JAC study and in the CRIC and CKD-JAC respectively). CRIC participants were more likely to have and were more than CKD-JAC participants, as shown by the of and 24 kg/m2, However, the lower in CRIC participants than in CKD-JAC participants and respectively). or and were more among participants in the CKD-JAC and were more to participants in the CRIC The of any CVD, disease and disease higher in the CRIC In the CKD-JAC those echocardiography were had a higher had a higher of and more had a history of that CRIC participants were by with ventricular and left compared with CKD-JAC participants to LV mass are shown across the levels of in differences in or levels were observed between the CRIC and CKD-JAC participants, CRIC participants had significantly higher and phosphate levels than CKD-JAC In both a between LVMI and observed by obesity have any on EF a of the of LVMI in both cohorts. the of as in the cohort associated with LVMI and EF were by in the cohort and with a history of and had a higher LVMI by and and a lower EF by and receiving had a higher LVMI by and a lower EF by The difference in LVMI between the by the obesity and However, the difference in EF between the by a between levels and in both cohorts. a of the of higher in CRIC participants than in CKD-JAC The median were range, in the CRIC study and range, in the CKD-JAC CKD-JAC participants had a significantly lower CVD risk than CRIC participants and in a comparison by Japanese patients had the CVD by and patients. for important these results The for and death and in the CKD-JAC study in the CRIC study CKD-JAC participants were more likely to develop kidney failure in the for and the incidence of kidney failure lower among CKD-JAC participants than among CRIC LVMI, and were significantly associated with CVD events in both a and that the risk of CVD events as LVMI or EF a between these indices and the study that the CRIC study the CKD-JAC study and that high phosphate and levels were associated with subsequent CVD events for LVMI, obesity found to be associated with a lower risk of CVD EF and LVMI were significantly associated with both were significantly associated with ratio confidence for EF and for and with death for EF and for In addition, LVMI associated with kidney failure EF significantly associated with CVD events, and death and parameters mediated the difference in CVD events between the study by and laboratory parameters moderately mediated the difference by and The of echocardiographic parameters were more on than in the outcome laboratory the of phosphate were on CVD, death, and kidney failure and factor no on any The of were to those of phosphate on CVD, and a CVD history higher for CVD event and and In the results were the using between and the of in the between and CVD events the of this to be Our study of patients with predialysis CKD that CRIC participants had higher risks of CVD events, death kidney and kidney than CKD-JAC These differences in mortality were and those in CVD events were higher between Japanese and US patients with predialysis CKD than those in the studies of hemodialysis D.A. Bragg-Gresham J.L. Koenig K.G. et al.Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS).J Am Soc Nephrol. 2003; 14: 3270-3277Crossref PubMed Scopus (647) Google et of echocardiographic with heart failure and the Chronic Renal Insufficiency J Am Soc Nephrol. 2017; 12: PubMed Scopus Google Scholar US patients had a higher LVMI, a higher of and and a lower EF than Japanese patients. laboratory US patients had higher and higher phosphate which were the mediators of the difference in CVD between US and Japanese The observed differences in the of CVD, and between the were even more mediated by baseline echocardiographic These results suggest that and characteristics assessed by echocardiography play a in the of outcome events in patients with CKD. study found that the between echocardiographic parameters and outcomes across with no with Although the of these parameters the of parameters as shown in Thus, echocardiographic parameters are as a subsequent The study of in that an comparison using patient-level data from CKD cohorts. In the of between and K. L. Sang Y. et disease and left ventricular and the in Am 2017; Scopus Google Scholar, et and and with cardiovascular parameters in patients with chronic kidney J 2016; PubMed Scopus Google Scholar, Kang E. et between and cardiovascular parameters in chronic kidney results from the Nephrol. 2018; PubMed Scopus Google Scholar, K. E. et factors for left ventricular in patients with chronic kidney from the CKD-JAC Nephrol. 2019; PubMed Scopus Google Scholar, M. Y. et between kidney function and in Am Soc Nephrol. PubMed Scopus Google Scholar, T. G. et of left ventricular and function with cardiovascular and renal outcomes in with chronic kidney PubMed Scopus Google Scholar However, comparisons be of the differences in factors such as levels of and studies have compared the of EF in patients with CKD across countries or A study that the of heart failure with EF higher in Japan than in K. M. et of of and clinical characteristics of heart failure patients in from the J. PubMed Scopus Google Scholar However, to the of there have no studies on CKD patient LV a study that and were associated with CVD events, death, and kidney on these outcomes were to be than in this be by the that for for or E. L. et of left ventricular and with outcomes in patients with CKD and J Am Soc Nephrol. 2016; 11: PubMed Scopus Google Scholar We that which is observed in US patients with CKD, associated with high LVMI, with decreased is in with studies in general that associated with high J. B. et of a index with left ventricular in patients among the PubMed Scopus Google Scholar and that associated with rather than et left ventricular rather than and of J PubMed Scopus Google Scholar obesity and were associated with left ventricular associated with obesity J. PubMed Scopus Google et and a common and PubMed Scopus Google Scholar and to A. et left ventricular in obesity and PubMed Scopus Google Scholar The were due to et of on left ventricular in patients with CKD stage Nephrol. PubMed Scopus Google Scholar and H. Y. T. et of on left ventricular and indices in disease patients with 2021; PubMed Scopus (5) Google Scholar CRIC participants had a lower EF, even the normal range, to have a strong with CVD D. G.M. et fraction and a cohort study of and J 2021; PubMed Scopus Google Scholar on that patients with a history of and those with a history of had and lower EF than patients respectively the higher of and among US patients the difference in EF between the cohorts. We that the in contractility due to may to a in EF in CRIC Our revealed the of in the CRIC T. T. et al.Cardiovascular disease history and among Japanese and American patients with a study of the CRIC and CKD-JAC 2021; PubMed Scopus Google Scholar that CRIC participants had more than CKD-JAC the CRIC study that is common in patients with CKD and is associated with CVD J. K. et and outcomes of in Am Soc Nephrol. 2016; PubMed Scopus Google Scholar and are mediators between lower EF and higher incidence of These parameters were in the CKD-JAC phosphate shown to be a of kidney Our a difference in phosphate levels between the T. et study of phosphate and related parameters in chronic kidney disease between the and J Nephrol. PubMed Scopus Google Scholar and the study which associated with high LVMI and decreased EF and as strong a as phosphate the differences in CVD, and that associated with be by in US patients. The study had we were to compare the baseline and outcome events using data from CKD in the United States and Japan. in the we laboratory factor and which to important for LV study is the to on LV indices to explain the differences in the outcome events across countries. study had of the participants in the CKD-JAC echocardiography at even the that participants echocardiography. Clinical such as a history of CVD or have as an to echocardiography. Therefore, CKD-JAC participants echocardiography may have more likely to develop subsequent CVD events than those parameters for and were included in the data from Japan. of the were CVD T. T. et al.Cardiovascular disease history and among Japanese and American patients with a study of the CRIC and CKD-JAC 2021; PubMed Scopus Google Scholar However, each cohort had an event by an which to compare the outcome events in the there may be that the between and CVD events had an of the to be that the observed be by an that is associated with both and outcome by to such as high and have an that explain the between and CVD A.S. et for the and of cardiovascular 2018; Scholar, E. J. et of cardiovascular disease with a with or Engl J Med. 2018; PubMed Scopus Google Scholar, Z. et of with cardiovascular a and of cohort J Cardiol. 2018; PubMed Scopus Google Scholar, M. A. et al.Urinary and and cardiovascular Engl J Med. PubMed Scopus Google Scholar, P. P. et of and in on heart disease and the J Cardiol. 2017; PubMed Scopus Google Scholar, A. T. K. et and incidence of a Nutr. 2019; PubMed Scopus Google Scholar, P. et and levels of and in and a PubMed Scopus Google Scholar, T. J.L. et data 2017; PubMed Scopus Google Scholar In addition, for related to the may the for the of J PubMed Scopus Google Scholar Therefore, we the of on the between and CVD events to be the of with CVD events and in those a history of CVD, be even more to that have to explain this In US patients most had with a lower EF and a higher LVMI than Japanese patients. These differences in LV indices and the higher levels in the United States the higher incidence of CVD among US patients. the of with LVMI and against obesity may the CVD for echocardiographic LV indices may be to identify patients with CKD are at risk of CVD. receiving a from and receiving and from as a to and a from the of receiving a from the receiving a from the of and and Kidney no for the CRIC study a from the of and and Kidney and In addition, this in by the of at the of Clinical and of for of Clinical and of from the of the and for for Clinical and of at for Clinical and in and of of of The CKD-JAC study by the The had no in the study and of or to the for We the and participants of the CRIC study and the CKD-JAC study for their The CKD-JAC study by at the Japan and J. P. G. and L. with In and kidney are in the of chronic kidney disease. of the kidney in and with et a study to the of in the of kidney the on patients and on patients. the kidney were and in the than the be PDF parameters and cardiovascular disease in and CKD and US have chronic kidney disease clinical A compared cardiovascular outcomes in a and a chronic kidney disease cohort and found that the US cohort had cardiovascular that differences in left ventricular and function explain most of the cardiovascular outcome We and this and for and for PDF

Topics & Concepts