Cardiovascular Disease in CKD

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with CKD. Although the association between CKD and CVD is well established, the overall CVD burden, dominant cardiovascular phenotypes, and clinical outcomes vary substantially across populations. These differences are often described using racial or ethnic categories, yet emerging evidence suggests that they more closely reflect variation in cardiometabolic risk, inflammatory burden, environmental exposures, and health care access than race itself. This review synthesizes evidence from major CKD cohorts, including Chronic Renal Insufficiency Cohort (United States), German CKD, Chronic Renal Insufficiency Standards Implementation Study, and European Quality Study (Europe) and CKD Japan Cohort (Japan), Chinese Cohort Study of CKD (China), and KoreaN Cohort Study for Outcomes in Patients With CKD (Korea), to examine global patterns of cardiovascular burden and outcomes in CKD. North American and European CKD cohorts are characterized by greater inflammatory burden, more severe coronary artery calcification, and more pronounced left ventricular hypertrophy, corresponding to a clinical trajectory more heavily dominated by cardiovascular events and mortality. By contrast, East Asian cohorts show fewer overt atherosclerotic and cardiac structural abnormalities and a more kidney-dominant trajectory, in which kidney outcomes are more prominent relative to cardiovascular events. Genetic, environmental, and lifestyle-related modifiers likely contribute to these divergent cardiorenal phenotypes. Collectively, current evidence supports moving beyond race-based descriptions toward phenotype-informed and exposure-informed approaches to cardiovascular risk assessment in CKD, in which integration of imaging markers, inflammatory biomarkers, and cardiometabolic profiles may improve the precision and equity of cardiovascular prevention strategies across diverse CKD populations.

Introduction

CKD affects more than 850 million people globally, representing approximately 15%–20% of adults, and is a major public health challenge with substantial cardiovascular (CV) consequences.^1–3 cardiovascular disease (CVD) is the leading cause of death in CKD, accounting for nearly half of all mortality. Lower eGFR and higher albuminuria are each independently associated with a graded increase in cardiovascular and all-cause mortality, underscoring that CKD severity itself is a major determinant of adverse outcomes.⁴ Beyond coronary artery disease (CAD), the cardiovascular burden includes cerebrovascular disease (CeVD), peripheral artery disease, heart failure, and other vascular complications, reflecting the broad effect of CKD.⁵

Although the cardiorenal relationship is well recognized, cardiovascular risk patterns in CKD vary widely by region and race and ethnicity, shaped by a complex interplay of biological, environmental, and socioeconomic factors.^6,7 The cardiovascular–kidney–metabolic framework highlights shared mechanisms including metabolic dysregulation, chronic inflammation, and CKD-specific factors such as uremic toxin accumulation.⁸ However, the relative contribution of these pathways differs across populations, influenced by genetic background, lifestyle, health care access, and structural inequities. Building on this, growing evidence indicates that racial disparities in CKD outcomes largely reflect social determinants of health rather than intrinsic biological differences, with race and ethnicity functioning primarily as proxies for differential exposure.^9,10

In this review, we synthesize current evidence on the global burden and regional variation of CVD in CKD by integrating data from major cohorts in the United States (the Chronic Renal Insufficiency Cohort [CRIC]), Europe (the German CKD [GCKD] study, the European Quality Study [EQUAL], and the Chronic Renal Insufficiency Standards Implementation Study [CRISIS]), and East Asia (the CKD Japan Cohort [CKD-JAC], the Chinese Cohort Study of CKD [C-STRIDE], and the KoreaN Cohort Study for Outcomes in Patients With CKD [KNOW-CKD]). By integrating regional epidemiology with population-specific risk profiles, we aim to move beyond race-based descriptions toward a phenotype-informed and exposure-informed framework that may support more equitable and precise cardiovascular risk assessment and prevention in CKD.

Global Burden and Clinical Spectrum of CVD in CKD

Updated Global Burden of Disease (GBD) data show that mortality attributable to both CVD and CKD has increased steadily over the past three decades, although their temporal trends differ.¹ In absolute terms, CVD remains the dominant cause of death worldwide; however, CKD-related mortality has risen at a faster pace. Notably, age-standardized CVD mortality has declined with advances in prevention and treatment, whereas age-standardized CKD mortality has not shown a comparable reduction and continues to increase (Figure 1). These divergent trends suggest that population aging alone does not fully explain the growing CKD burden and instead highlight persistent gaps in CKD prevention and care. Despite these differences, CVD remains the leading cause of death across all stages of CKD, with many patients dying from CV complications before reaching kidney failure with replacement therapy.^11–13

Figure 1.

Global trends in CVD and CKD mortality over the past three decades. Global temporal trends in age-standardized mortality from CVD and CKD on the basis of GBD estimates from 1990 to 2023. The upper panel demonstrates a progressive decline in age-standardized CVD mortality over time, reflecting substantial advances in cardiovascular prevention and treatment. By contrast, the lower panel shows that age-standardized CKD mortality has not exhibited a comparable reduction and has continued to increase during the same period. CVD, cardiovascular disease; GBD, Global Burden of Disease.

Clinical Spectrum of CVD in CKD

The cardiovascular manifestations of CKD are broad and clinically heterogeneous, encompassing both atherosclerotic and nonatherosclerotic conditions.

CAD is highly prevalent in patients with CKD and becomes increasingly common and severe as kidney function declines. Importantly, a substantial proportion of patients with CKD experience fatal cardiovascular events before reaching kidney failure with replacement therapy.¹² Among patients with CKD G5D, CAD is often characterized by diffuse multivessel disease and extensive vascular calcification, reflecting accelerated atherosclerosis in the setting of profound disturbances in mineral metabolism.^5,14–18 Accordingly, clinical studies suggest that more than half of patients with CKD G5D have obstructive CAD, contributing substantially to cardiovascular morbidity and mortality.¹³

Heart failure is another major manifestation of CVD in CKD and a key component of the bidirectional cardiorenal interaction. While age-standardized mortality from several major CVD subtypes has declined in many regions,¹⁹ the burden of heart failure has continued to rise, with particularly rapid growth in aging populations across Asia.^20–22 Longitudinal cohort studies have shown that the cumulative incidence of heart failure reaches approximately 17%–21% among individuals with impaired kidney function.²² Importantly, heart failure not only increases mortality risk but also accelerates CKD progression, reinforcing the vicious cycle of cardiorenal syndrome.²³ Both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction are clinically relevant in CKD. Heart failure with preserved ejection fraction may be particularly important in this population, given the high prevalence of left ventricular hypertrophy (LVH), diastolic dysfunction, vascular stiffness, anemia, and chronic volume overload.^24,25 However, data on subtype-specific incidence and prevalence remain limited across major regional CKD cohorts, and cross-population comparisons should therefore be interpreted with caution.

Atrial fibrillation, the most common sustained arrhythmia in CKD, further amplifies CV risk. Approximately 15%–20% of patients receiving long-term dialysis are affected by atrial fibrillation, and its presence is independently associated with higher risks of ischemic stroke, major bleeding, and CV death.^26,27

CeVD is also a major contributor to disability and mortality in CKD. Stroke risk increases in a graded manner as eGFR declines and albuminuria increases.^28,29 Beyond overt stroke, CKD is associated with subclinical CeVD and cognitive impairment, reflecting the combined effects of traditional vascular risk factors and CKD-specific, uremia-related mechanisms linking kidney dysfunction to cerebrovascular injury.

CKD-Specific Mechanisms Amplifying CVD Risk

The relationship between kidney dysfunction and cardiovascular risk is continuous, graded, and independent of conventional risk factors. Compared with individuals with preserved kidney function, those with an eGFR below 60 ml/min per 1.73 m² face substantially higher risks of heart failure, atherosclerotic CVD, and cardiovascular death.^4,11 Although hypertension, diabetes, and dyslipidemia are prevalent in CKD, they do not fully explain the excess cardiovascular risk.^5,11,30,31 Instead, CKD-specific mechanisms, including chronic inflammation, uremia-related toxicity, endothelial dysfunction, oxidative stress, and disordered mineral metabolism, act as key amplifiers of cardiovascular injury.^5,32 At the population level, recent GBD analyses further highlight the growing global contribution of kidney dysfunction to cardiovascular mortality and disability-adjusted life years,³³ underscoring the need to address these CKD-specific drivers more explicitly in both research and clinical care.

Transition to Ethnic and Regional Variation

Taken together, these observations indicate that although CVD remains the leading cause of death across the CKD spectrum, its predominant manifestations and clinical trajectories vary substantially across populations. These differences are unlikely to be explained by kidney function alone and instead likely reflect complex interactions among CKD-specific pathophysiology, cardiometabolic risk profiles, and broader social and health care contexts. This heterogeneity underscores the importance of examining ethnic and regional variation in cardiovascular risk among CKD populations.

Ethnic and Regional Differences in CVD Risk among CKD Populations

Large contemporary CKD cohorts from different geographic regions provide an opportunity to examine how cardiovascular risk profiles and clinical trajectories vary across populations. Given the narrative nature of this review, we focused on prospective CKD cohorts with detailed cardiovascular phenotyping and longitudinal outcome data that allow structured cross-regional comparison (Figure 2). These cohorts are compared with respect to baseline characteristics, reported racial or ethnic differences where available, cardiovascular and kidney outcomes, and key limitations affecting interpretation (Tables 1–3).

Figure 2.

Global overview of major CKD cohorts and regional phenotypic patterns. This conceptual map summarizes the major CKD cohorts discussed in this review and highlights broad regional differences in cardiovascular and kidney risk profiles. North American cohorts show greater diabetes, obesity, and heart failure/AMI burden; European cohorts show high baseline CVD burden and mortality risk; and East Asian cohorts show more glomerular disease, lower overt CVD burden, and relative stroke prominence in some cohorts. Underrepresented regions highlight important gaps in prospective CKD-CVD data. AASK, African American Study of Kidney Disease and Hypertension; AMI, acute myocardial infarction; CKD-JAC, CKD Japan Cohort; CRIC, Chronic Renal Insufficiency Cohort; CRISIS, Chronic Renal Insufficiency Standards Implementation Study; C-STRIDE, Chinese Cohort Study of CKD; EQUAL, European Quality Study; GCKD, German CKD; KNOW-CKD, KoreaN Cohort Study for Outcomes in Patients With CKD.

Table 1.

Baseline characteristics of major CKD cohorts across regions

Cohort	Ethnic Composition	N	Mean Age, yr	Mean eGFR, ml/min per 1.73 m2	Albuminuria/Proteinuria	BMI, kg/m2	Diabetes Prevalence, %	CVDa Prevalence, %	CKD Etiology
Western cohorts
CRIC (US)34,35	Multiethnic (43% White, 44% Black, 13% Hispanic)	3785	58	45	UACR 44.5 mg/g	32	48	34	Unknown 48.5%, HTN 24%, DN 11%
AASK (randomized trial, US)39,91	100% Black	1094	55	46	UPCR <0.22 g/g (67%)	31	0	52	HTN nephrosclerosis only
EQUAL (Europe)56	98.4% White	1517	76	18	UACR 391 mg/g	28	42.3	40	HTN 44%, DN 24%, GN 11.2%
CRISIS (United Kingdom)50	98.9% White	1325	65	30	Protein 1.0 g/d	28	32.4	47.2	Vascular/HTN 24%, DN 20%, GN 18%
GCKD (German)49	Approximately 99% White	5217	60	47	UACR 51 mg/g	29.8	35.3	32.2	Vascular 23%, unknown 20%, GN 19%
East Asian cohorts
CKD-JAC (Japan)57	100% Japanese	2966	60	29	UACR 976 mg/g	23.5	38	23	GN 32% DN 20%, others 45%
C-STRIDE (China)59	100% Chinese	3168	48	50	Protein 0.9 g/d	24.5	22	Approximately 9.8	GN 60.6%, DN 13.9%, others 25.6%
KNOW-CKD (Korea)58,60,92	100% Korean	2238	52	55	UACR 453 mg/g	24.5	33	15	GN 38.3%, DN 29.5%, HTN 23.6%

AASK, African American Study of Kidney Disease and Hypertension; BMI, body mass index; CKD-JAC, CKD Japan Cohort; CRIC, Chronic Renal Insufficiency Cohort; CRISIS, Chronic Renal Insufficiency Standards Implementation Study; C-STRIDE, Chinese Cohort Study of CKD; CVD, cardiovascular disease; DN, diabetic nephropathy; EQUAL, European Quality Study; GCKD, German CKD; HTN, hypertension; KNOW-CKD, KoreaN Cohort Study for Outcomes in Patients With CKD; UACR, urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine ratio.

^aCVD prevalence definitions were primarily on the basis of self-report and medical records: Chronic Renal Insufficiency Cohort/African American Study of Kidney Disease and Hypertension/German CKD: history of myocardial infarction, stroke, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid endarterectomy, peripheral artery disease, or heart failure. European Quality Study: history of myocardial infarction, stroke, or revascularization, Chronic Renal Insufficiency Standards Implementation Study: history of ischemic heart disease, peripheral artery disease, or cerebrovascular disease (e.g., angina, myocardial infarction, coronary angioplasty or stent placement, coronary artery bypass grafting, cardiac arrest, stroke, or transient ischemic attack). East Asian Cohorts (CKD Japan Cohort, Chinese Cohort Study of CKD, KoreaN Cohort Study for Outcomes in Patients With CKD): Definitions were generally similar to Western cohorts (myocardial infarction, stroke, coronary artery bypass grafting, heart failure, peripheral artery disease). However, in the Chinese Cohort Study of CKD, e.g., it was more broadly defined to also include serious cardiac arrhythmia incidents in addition to myocardial infarction, hospitalization for congestive heart failure, peripheral arterial disease, or cerebrovascular events.

Table 3.

Reported cardiovascular outcome patterns across major CKD cohorts

Cohort	AMI	Stroke/CeVD	Heart Failure	AF/Arrhythmia	What Stands Out
CRIC (US)	Included in atherosclerotic events; in CRIC–CKD-JAC comparison, AMI predominated among ASCVD events in CRIC (51.7%, 13/1000 PY)	Included in atherosclerotic events; lower relative contribution than in CKD-JAC	Separate adjudicated endpoint; 551 heart failure events over median 6.6 yr; heart failure event rates higher in Black participants before full adjustment	AF not separately reported	Atherosclerotic/heart failure–enriched pattern; adjusted racial and ethnic differences in atherosclerotic and heart failure outcomes were not significant overall
GCKD (Germany)	MACE includes MI/stroke/PAD; (n=522, approximately 21/1000 PY)	Included within MACE	Heart failure hospitalization reported as separate end point (n=381, approximately 15/1000 PY)	AF not separately reported	High heart failure/metabolic risk burden; MACE and heart failure hospitalization both clinically important
CKD-JAC (Japan)	Included in composite ASCVD; in CRIC–CKD-JAC comparison, AMI less dominant than in CRIC (1.6/1000 PY)	Stroke-dominant pattern; ischemic stroke accounted for 55.6% of ASCVD in CRIC–CKD-JAC comparison (5.3/1000 PY)	Heart failure hospitalization included as separate outcome in CRIC–CKD–JAC comparison (8.6/1000 PY)	AF not separately reported	Cerebrovascular/heart failure pattern with lower overall CVD risk than CRIC
C-STRIDE (China)	CV composite includes nonfatal MI and unstable angina	CV composite includes cerebrovascular events	CV composite includes hospitalization for CHF	CV composite includes arrhythmia, including first AF/flutter episode	Kidney failure–dominant trajectory; CV subtype data reported mainly within composite outcome framework
KNOW-CKD (Korea)	Composite CV end point includes acute MI/unstable angina	Composite CV end point includes stroke	Composite CV end point includes congestive heart failure	Composite CV end point includes symptomatic arrhythmia	Lower overt baseline CVD burden; composite reporting limits subtype-specific comparison
CRISIS, EQUAL (Europe)	Subtype-specific AMI data limited in longitudinal reporting	Stroke/CeVD burden present, but not uniformly adjudicated as standalone longitudinal end point	Heart failure–specific longitudinal data limited	AF data limited	Older, high-risk populations with strong competing risk of death and CV events

For the German CKD cohort, crude rates for major adverse cardiovascular event and heart failure were manually calculated on the basis of the reported number of events (522 and 381, respectively) among 4951 participants over an estimated median follow-up of 5.9 years. AF, atrial fibrillation; AMI, acute myocardial infarction; ASCVD, atherosclerotic cardiovascular disease; CeVD, cerebrovascular disease; CHF, congestive heart failure; CKD-JAC, CKD Japan Cohort; CRIC, Chronic Renal Insufficiency Cohort; CRISIS, Chronic Renal Insufficiency Standards Implementation Study; C-STRIDE, Chinese Cohort Study of CKD; CV, cardiovascular; CVD, cardiovascular disease; EQUAL, European Quality Study; GCKD, German CKD; KNOW-CKD, KoreaN Cohort Study for Outcomes in Patients With CKD; MACE, major adverse cardiovascular event; MI, myocardial infarction; PAD, peripheral artery disease; PY, person-years.

These differences partly reflect regional variation in CKD etiology and cardiometabolic risk exposure and population composition. East Asian cohorts generally include younger patients and a higher proportion of primary glomerular diseases, whereas Western cohorts more often include patients with higher body mass index, more diabetes, and greater burdens of HTN-associated CKD and established atherosclerotic disease. However, such comparisons should be interpreted cautiously. Apparent differences in cardiovascular versus kidney event burden may also reflect variation in cohort composition, endpoint definitions, and competing risks. In particular, high cardiovascular mortality in some Western cohorts may reduce the observed incidence of kidney outcomes, whereas longer cardiovascular-free survival in East Asian cohorts may make kidney progression more prominent. Similarly, differences in kidney outcome definitions, such as dialysis initiation alone versus composite eGFR-based outcomes, further complicate direct cross-cohort comparisons.

United States (CRIC and AASK)

1. Baseline Data: In the CRIC study, the baseline prevalence of CVD was approximately 34%. The cohort is characterized by a substantial cardiometabolic burden, including a diabetes prevalence of 48% and a mean body mass index of 32 kg/m².^34–38 Notably, CKD etiology in CRIC is weighted more toward hypertensive and unknown causes than toward primary glomerular disease. This overall risk profile is consistent with the high prevalence of heart failure, atherosclerotic disease, and overall cardiovascular burden observed in US CKD cohorts.

2. Race and Ethnic Differences: The distribution of cardiovascular phenotypes varies across racial and ethnic groups within CRIC. Black participants had a higher prevalence of heart failure and stroke and a greater burden of socioeconomic and cardiometabolic risk factors than White participants.^34,39 Hispanic participants showed a distinct profile characterized by a high prevalence of diabetes, lower self-reported CAD, and a disproportionately high burden of LVH compared with non-Hispanic White participants.³⁵ Imaging studies further showed that Hispanic participants had higher odds of severe coronary artery calcification (CAC >400) and LVH after adjustment for sociodemographic factors,^40,41 suggesting that reliance on clinical history alone may underestimate subclinical cardiovascular burden. Taken together, these findings illustrate how cardiometabolic risk clustering and social determinants shape cardiovascular profiles within CKD populations.

3. Outcomes Data: Longitudinal analyses from CRIC showed a high burden of cardiovascular events and mortality relative to kidney outcomes.³⁵ As summarized in Table 2, the CV event rate in CRIC was 38.0 per 1000 person-years (PY), and the all-cause mortality rate was 31.0 per 1000 PY. Genetic factors also contribute to heterogeneity in kidney disease progression. In particular, apolipoprotein L1 high-risk variants strongly accelerate CKD progression among African American individuals.^42–44 However, data from AASK and CRIC suggest that apolipoprotein L1 high-risk genotypes do not consistently predict cardiovascular events once CKD is established.^45,46 After adjustment for kidney function and traditional risk factors, atherosclerotic cardiovascular event rates in CRIC did not differ substantially across racial and ethnic groups,³⁵ supporting the interpretation that race itself is unlikely to act as an independent biologic determinant of cardiovascular risk in established CKD.

4. Gaps in Knowledge and Limitations: Several limitations should be considered when interpreting these findings. In CRIC, CKD etiology was incompletely characterized, and recruitment patterns differed across racial and ethnic groups. For example, most Hispanic participants were recruited from a single geographic center, which may limit generalizability.³⁸ In addition, socioeconomic context, access to care, and other unmeasured structural factors may influence both baseline characteristics and observed outcomes. Another notable observation in US populations is the paradoxically lower mortality among Black patients receiving dialysis despite a higher predialysis cardiovascular burden.^35,47 Proposed explanations include selective survivor bias and differences in inflammatory, metabolic, or nutritional status.^36,48 Nevertheless, the mechanisms underlying this phenomenon remain incompletely understood and highlight the need for further research addressing both biological and social determinants of cardiovascular risk in CKD.⁴¹

Table 2.

Comparative patterns of kidney, cardiovascular, and mortality outcomes across major CKD cohorts

Cohort	Median FU, yr	eGFR Decline, ml/min per 1.73 m2	Kidney Event Rate, per 1000 PYa	Cardiovascular Event Rate, per 1000 PYb	Mortality, per 1000 PY	Key Reported Findings
Western cohorts
CRIC (US)34,35,37	6.6	−1.1	41.7	38	31	• AMI predominated ASCVD events (51.7%; 13/1000 PY) • ASCVD incidence: Black (22.5) >White (18.3) >Hispanic (17.4) per 1000 PY • Mortality: Black (24.6) >White (20.6) >Hispanic (18.4) per 1000 PY • Race not an independent predictor for CVD/death
AASK (randomized trial, US)41,42,44,91,93	4.1c	−1.6	40	33	21	• High-risk APOL1 strongly linked to faster CKD progression • No significant association with composite CV outcomes
GCKD (German)53,55	5.9	NA	Approximately 11d	Approximately 31d	Approximately 26d	• Prominent heart failure events (MACE: approximately 18/1000 PY, heart failure approximately 13/1000 PY) • Non-CV death (approximately 20/1000 PY) outpaced CV death (approximately six/1000 PY) • NT-proBNP showed strong prognostic value for heart failure and CVD
East Asian cohorts
CKD-JAC (Japan)64,94,95	3.9	NA	Approximately 85d	23	7.2	• Stroke incidence 3.3-fold higher than AMI (5.3 versus 1.6/1000 PY) • Ischemic stroke accounted for 55.6% of ASCVD
C-STRIDE (China)66	4.6	NA	31 (only KFRT)a	15	9.2	• Kidney failure markedly outpaces CV events (ratio >3) • Nonfatal stroke three times more frequent than MI
KNOW-CKD (Korea)60,96	6.0	−2.5	67.9	9	7.3	• Kidney outcomes predominated over CV events • Substantially lower CVD burden versus CRIC

Event rates and hazard ratios reflect each study's original analytic framework. Direct numerical comparisons across cohorts should therefore be interpreted cautiously and are primarily intended to highlight the relative dominance of kidney failure-driven versus cardiovascular event-driven trajectories. AASK, African American Study of Kidney Disease and Hypertension; AMI, acute myocardial infarction; APOL1, apolipoprotein L1; ASCVD, atherosclerotic cardiovascular disease; CKD-JAC, CKD Japan Cohort; CRIC, Chronic Renal Insufficiency Cohort; C-STRIDE, Chinese Cohort Study of CKD; CV. cardiovascular CVD, cardiovascular disease; FU, follow-up; GCKD, German CKD; HHF, hospitalization for heart failure; KFRT, kidney failure with replacement therapy; KNOW-CKD, KoreaN Cohort Study for Outcomes in Patients With CKD; MACE, major adverse cardiovascular event; MI, myocardial infarction; NA, not available (or not assessed); NT-proBNP, N-terminal pro-b-type natriuretic peptide; PY, person-years.

^aKidney outcome definitions were not uniform across cohorts. In the Chronic Renal Insufficiency Cohort, African American Study of Kidney Disease and Hypertension, KoreaN Cohort Study for Outcomes in Patients With CKD, and Japan CKD Initiative, renal outcomes were generally defined as composite kidney outcomes including severe kidney function decline (e.g., ≥50% decline in eGFR) and/or initiation of KRT, whereas in Chinese Cohort Study of CKD, kidney failure was defined more strictly as maintenance dialysis or kidney transplantation only.

^bCardiovascular outcome definitions varied across studies and are summarized in Table 3. In most cohorts, cardiovascular outcomes included myocardial infarction, stroke, heart failure or heart failure hospitalization, and related vascular events. In the German Chronic Kidney Disease cohort, major adverse cardiovascular events and heart failure hospitalization were analyzed separately.

^cFor African American Study of Kidney Disease and Hypertension, follow-up duration and event rates refer to the initial randomized trial phase rather than the later cohort follow-up phase.

^dFor cohorts in which precise incidence rates per 1000 person-years were not explicitly reported, approximate crude rates were estimated by the authors from published cumulative incidence, sample size, and follow-up duration and are provided for descriptive context only.

Europe

1. Baseline Data: European CKD cohorts generally show a substantial baseline burden of cardiometabolic risk and cardiovascular comorbidity. In the GCKD study, which enrolled more than 5000 patients with moderate-to-severe CKD, diabetes was present in approximately 35% of participants, and prevalent CVD was common at baseline.⁴⁹ Similarly, in the United Kingdom–based CRISIS cohort, nearly half of patients with CKD G3–5 had pre-existing CVD at study entry.⁵⁰ The multinational EQUAL study, focusing on older adults with advanced CKD, likewise reported a substantial baseline CVD burden of myocardial infarction (18.5%) and CeVD (15.5%).^51,52

2. Race and Ethnic Differences: Unlike the racially diverse US cohorts, major European CKD cohorts are composed predominantly of White participants. As a result, ethnicity-specific analyses are limited, and the reported cardiovascular profiles largely reflect the experience of White European CKD populations.

3. Outcomes Data: Longitudinal analyses from European cohorts indicate a substantial burden of cardiovascular events and death, often competing closely with progression to kidney failure. In GCKD, published analyses suggest a high incidence of cardiovascular outcomes, heart failure, and all-cause mortality, although exact event rates are not reported consistently across studies.^53–55 In the CRISIS cohort, the mortality rate (9.6 per 100 PY) exceeded the dialysis initiation rate (5.1 per 100 PY), and cardiovascular causes accounted for a substantial proportion of deaths (41%).⁵⁰ Similarly, EQUAL reported high cardiovascular event rates over relatively short follow-up periods in an older population with advanced CKD, with event rates of approximately 20%–25% within 2–4 years.⁵⁶ Overall, these findings suggest that European CKD cohorts, like US cohorts, experience a substantial burden of cardiovascular event and death.

4. Gaps in Knowledge and Limitations: Several factors complicate cross-regional comparison. First, outcome reporting was not fully harmonized across European cohorts, which limits precise cross-cohort comparison. Second, cohorts such as EQUAL specifically enrolled older adults with advanced CKD, which may inflate observed cardiovascular event rates relative to more general CKD populations. Finally, limited ethnic diversity, heterogeneous enrollment criteria, and differences in health care systems across countries further limit direct comparability.

East Asia (Japan, China, Korea)

1. Baseline Data: Baseline CVD prevalence is generally lower in East Asian CKD cohorts than in many Western cohorts. In CKD-JAC, the prevalence of CVD was approximately 23%,⁵⁷ whereas the KNOW-CKD cohort reported a lower prevalence of around 15%.⁵⁸ In C-STRIDE, baseline CVD prevalence was 9.8%, the lowest among the major cohorts discussed here.⁵⁹ Notably, within this low overall CVD prevalence, CeVD accounted for a prominent proportion in the C-STRIDE. Consistent with their younger age and higher proportion of primary glomerular disease, these cohorts also tend to show lower baseline inflammatory and metabolic burden.^60,61

2. Race and Ethnic Differences: Although within-cohort racial or ethnic comparisons are limited, cross-cohorts comparison suggest distinct cardiovascular phenotypes relative to Western populations. Subclinical imaging studies support these phenotypic differences. CAC is generally less prevalent and less severe in Korean patients with CKD than in White participants from the CRIC cohort, paralleling the lower rates of coronary events reported in East Asian populations.^60,62,63 Echocardiographic studies likewise suggest less adverse cardiac remodeling overall, with a lower prevalence of LVH and lower left ventricular mass index in the CKD-JAC cohort than in CRIC (Table 4).^64,65 Nevertheless, these markers remain prognostically important across populations, indicating that their predictive value is preserved even when the baseline burden differs.

3. Outcomes Data: Longitudinal analyses suggest that kidney outcomes are more prominent relative to cardiovascular events in East Asian cohorts. In KNOW-CKD, the annual rate of eGFR decline and the incidence of CKD progression were nearly twice those reported in CRIC despite extensive adjustment for confounders.⁶⁰ Similarly, in C-STRIDE, the incidence of kidney failure exceeded that of major cardiovascular events.⁶⁶ Despite faster kidney function decline, mortality rates in East Asian CKD cohorts have generally been lower than those reported in Western cohorts.^60,67 In line with these observed differences, a harmonized comparison between CKD-JAC and CRIC demonstrated significantly lower rates of both death and cardiovascular events in the Japanese cohort. This analysis further suggested that the excess CV risk in CRIC was not fully explained by baseline clinical covariates alone, but rather partly driven by between-cohort differences in left ventricular structure and function.⁶⁴ Furthermore, the distribution of cardiovascular events differs markedly between regions; acute myocardial infarction accounts for a greater proportion of atherosclerotic events in CRIC, whereas ischemic stroke represents a relatively larger share of the cardiovascular burden in East Asian cohorts such as CKD-JAC and C-STRIDE.⁶⁴

4. Gaps in Knowledge and Limitations: Interpretation of these cross-cohort differences requires caution. Variations in CKD etiology, demographic structure, health care systems, and cohort design may all influence observed cardiovascular patterns. Moreover, differences in endpoint ascertainment and competing risks may affect the apparent balance between kidney and cardiovascular outcomes. Harmonized multiregional studies will therefore be essential to clarify how biological, environmental, and health care factors interact to shape cardiorenal outcomes across CKD populations.

Table 4.

Selected intermediate cardiovascular phenotypes and biomarkers across CKD cohort

Parameter	Variable/Metric Definition	KNOW-CKD (Korea)60,62,65	CKD-JAC (Japan)64	CRIC (US)63	GCKD (German)97,98
CAC (Agatston score)	Any CAC >0, %	50	NA	60	NA
	CAC >100, %	22.0	NA	30a	NA
	CAC >400, %	8.3	NA	21.0	NA
Cardiac structure, function	LVMI, g/m2.7	41.9	46.6	55.7	63 (MRI)
	LVEF, %	64.2	65	54	61 (MRI)
	LVH, %	23.8	36	59	29.4 (MRI)
	Concentric	12.1	22	49	14.5
	Eccentric	11.7	15	10	5.5
Inflammation	hsCRP, mg/L	0.68	0.82	2.54	2.3

Definitions of coronary artery calcification, left ventricular hypertrophy, and cardiac geometry follow those used in each original cohort study and are not fully harmonized across cohorts. Coronary artery calcification was quantified using computed tomography–derived Agatston scores; coronary artery calcification categories (0, >100, >400) reflect thresholds commonly used in Chronic Renal Insufficiency Cohort and KoreaN Cohort Study for Outcomes in Patients With CKD. Coronary artery calcification data were not assessed in CKD Japan Cohort. Cardiac structure and function parameters (left ventricular mass index, left ventricular ejection fraction, left ventricular hypertrophy patterns) are based on study-specific echocardiographic protocols and cutoffs. Because standardized echocardiography was not feasible across the full German CKD cohort due to multicenter methodological constraints, structural cardiac parameters (left ventricular mass index, left ventricular ejection fraction, left ventricular hypertrophy) for German CKD were derived from the cardiovascular in-depth assessment in CKD cardiac magnetic resonance imaging substudy (n=290). CAC, coronary artery calcification; CKD-JAC, CKD Japan Cohort; CRIC, Chronic Renal Insufficiency Cohort; GCKD, German CKD; hsCRP, high-sensitivity C-reactive protein; KNOW-CKD, KoreaN Cohort Study for Outcomes in Patients With CKD; LVH, left ventricular hypertrophy; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; MRI, magnetic resonance imaging; NA: not available.

^aRacial/ethnic composition among CRIC participants with CAC >100: White (47.7%) >Black (29.6%) >Hispanic (17.1%)>Other (5.6%).

Emerging Data from Underrepresented Regions

Data from underrepresented populations are beginning to emerge, but remain less extensive and less systematically characterized, particularly with respect to prospective cardiovascular outcomes, than those from major established CKD cohorts. For instance, the Indian CKD study has provided an important prospective platform in South Asia, revealing unique baseline characteristics such as a younger age of onset, higher rates of chronic interstitial nephritis, and a significant proportion of CKD of unknown etiology compared with high-income country cohorts.⁶⁸ Comparative studies also suggest that cardiovascular risk profiles may differ across these populations; e.g., albuminuria may be a stronger predictor of cardiovascular mortality in South Asian populations than in Europeans.⁶⁹ In Africa, collaborative initiatives, such as the H3Africa Kidney Disease Research Network, have drawn attention to the growing burden of CKD and cardiometabolic disease.⁷⁰ However, the limited availability of harmonized, longitudinal cardiovascular outcome data in these settings underscores the need for broader global representation in future CKD–CVD research.

Taken together, these observations support a broader regional divergence in cardiovascular phenotype and clinical trajectory across CKD populations, as summarized conceptually in Figure 3.

Figure 3.

Conceptual framework of regional variation in CKD CV phenotype and trajectory. This diagram summarizes broad differences between North American/European and East Asian CKD cohorts. North American/European cohorts are characterized by greater metabolic and inflammatory burden and a more CV-dominant trajectory, whereas East Asian cohorts show lower overt cardiometabolic burden and a more kidney-dominant trajectory. These patterns interact with shared, race-neutral CKD-specific mechanisms to shape heterogeneous cardiorenal phenotypes. LVH, left ventricular hypertrophy.

Mechanistic and Contextual Determinants of Cardiovascular Risk in CKD

CVD in CKD arises from the convergence of common vascular and myocardial injury pathways with kidney-specific disturbances.⁵ Endothelial dysfunction, chronic inflammation, oxidative stress, and impaired nitric oxide signaling broadly contribute to cardiovascular injury, but these processes are further intensified in CKD by uremic toxin accumulation, anemia, activation of the renin–angiotensin–aldosterone and sympathetic nervous systems, and disturbances in mineral metabolism, including phosphate retention and fibroblast growth factor 23 excess.^71–74 Specifically, elevated fibroblast growth factor 23 may exert direct, Klotho-independent effects on cardiomyocytes that promote LVH, while the deranged mineral milieu increases serum calcification propensity (e.g., shortened T50), reflecting reduced resistance to ectopic calcification.^16,75–77 Together, these abnormalities contribute to arterial stiffening, vascular calcification, and adverse cardiac remodeling. Metabolic disturbances, including insulin resistance, obesity, and dyslipidemia, affect both kidney and cardiovascular systems, reinforcing a bidirectional cardio–kidney–metabolic axis.⁷³

Importantly, these shared pathophysiological pathways are not expressed uniformly across populations. Their clinical effect is shaped not only by inherited susceptibility but also by environmental, lifestyle, health care–related factors. Chronic inflammation and oxidative stress remain central contributors to cardiovascular injury in CKD, although the population-level contribution of individual biomarkers, such as high sensitivity C-reactive protein (hsCRP) or IL-6, is less certain.⁷⁸ Gene environment interactions are also likely to play a major role in regional phenotypic variations.⁷⁹ For example, high dietary sodium intake, traditionally observed in many East Asian populations, may drive salt-sensitive hypertension, volume-dependent cardiac remodeling, and a greater propensity for stroke.^80,81 Regional dietary patterns may also influence gut microbiome composition and thereby modulate the generation of gut-derived uremic toxins, such as trimethylamine N-oxide or indoxyl sulfate, which have been implicated in vascular calcification and systemic inflammation.^82–84

Taken together, cardiovascular risk in CKD is shaped by dynamic interactions among kidney-specific biological disturbances, metabolic and inflammatory stress, and broader genetic and environmental modifiers. These determinants do not act in isolation; rather, they interact to produce heterogeneous cardiovascular phenotypes and divergent clinical trajectories across CKD populations.

Translating Evidence to Clinical and Policy Actions

Accumulating evidence suggests that ethnic and regional differences in cardiovascular outcomes among patients with CKD are driven largely by differential exposure to inflammatory, metabolic, environmental, and structural determinants rather than fixed biological differences attributed to race. These observations support moving beyond race-based risk assumptions toward risk assessment strategies that more directly incorporate kidney measures, exposure profiles, and relevant biomarkers. In practice, this implies race-neutral, but context-sensitive management, with greater attention to kidney function, albuminuria, cardiometabolic comorbidity, inflammatory burden, and equitable guideline-directed prevention.

Biomarker-Informed Risk Stratification

Across CKD cohorts, inflammatory biomarkers, such as IL-6 and hsCRP, have been consistently associated with higher cardiovascular risk. In CRIC, higher plasma IL-6 levels were strongly associated with an increased risk of composite cardiovascular outcomes, with an approximately 40% higher risk per quintile increase.⁸⁵ Notably, this association seemed stronger in White than in Black participants, suggesting that the relationship between inflammatory burden and outcomes may differ across populations.^48,86 However, mediation analyses indicate that much of the apparent association between race and mortality is explained by intermediate factors, such as IL-6, albuminuria, diabetes, and reduced eGFR, rather than race itself as an independent determinant.^85,86 Collectively, these findings support biomarker and exposure-informed approaches to cardiovascular risk stratification and more individualized preventive strategies in CKD.⁸⁷

Bridging Gaps in Access and Equity

Global variation in CKD–CVD outcomes is amplified by inequities in access to diagnostics (e.g., albuminuria testing, CAC imaging, and inflammatory or cardiac biomarkers) and disparities in the availability of proven therapies, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and emerging anti-inflammatory interventions.¹³ Socially patterned exposures, such as poverty, structural racism, chronic stress, unhealthy diet, and environmental toxins, become biologically embedded through neurohormonal activation, chronic inflammation, endothelial dysfunction, and epigenetic change, converting social disadvantage into excess cardiovascular and kidney events.^13,88 Addressing these inequities requires delivery models that extend risk assessment and prevention beyond specialized nephrology settings and integrate them into primary care, community clinics, and public health programs.

Policy and System Implications

Effective translation of evidence on ethnic and regional variation in CKD–CVD risk into practice requires coordinated action across global, national, and health system levels. Although major international organizations (World Health Organization, International Society of Nephrology, Kidney Disease Improving Global Outcomes, and the GBD initiative) now recognize CKD as a cardiovascular risk amplifier, many health systems continue to manage CKD primarily as a specialty condition, limiting its integration into broader cardiometabolic and public health strategies. Strengthening health systems should prioritize early CKD–CVD screening, incorporation of kidney measures into national cardiovascular registries, and reimbursement models that reward prevention rather than late-stage intervention, while simultaneously addressing structural and social determinants. Ultimately, reframing CKD–CVD prevention as a population-level public health priority would catalyze investment in early detection, biomarker-guided risk stratification, digital prediction tools, and culturally tailored community interventions, supporting more equitable and sustainable prevention worldwide.

Future Directions and Research Priorities

As highlighted throughout this review, direct cross-regional comparison remains limited by methodological heterogeneity, including differences in definitions of kidney failure and cardiovascular outcomes. Future research should therefore prioritize the expansion and harmonization of multiethnic longitudinal CKD cohorts using standardized endpoint definitions, shared data models, and interoperable platforms. Such efforts will enable more consistent characterization of phenotype-specific cardiorenal trajectories, identification of high-risk inflammatory and metabolic profiles, and evaluation of population-specific treatment responses.⁸⁹

Key translational priorities include validating inflammatory biomarkers, such as IL-6 and hsCRP, as well as multimarker panels, within cardiovascular risk-prediction tools for CKD. These efforts should be paired with implementation studies examining clinical utility, cost-effectiveness, and effect on health equity. Broader inclusion of underrepresented regions through harmonized cohorts, biobanking, and digital linkage to long-term real-world outcomes will be essential to ensure global relevance. Policy-oriented research should further support the development and testing of race-neutral, biomarker-informed models for screening, prevention, and reimbursement across diverse health systems. Building on the observed regional divergence in cardiorenal phenotypes,⁹⁰ future multiethnic CKD research should also incorporate patient-reported outcomes and culturally sensitive implementation frameworks to better translate epidemiologic heterogeneity into person-centered CKD–CVD prevention.

Conclusions

CVD remains the leading cause of morbidity and mortality in patients with CKD, but its burden, clinical phenotypic expression, and underlying mechanisms vary substantially across populations. Accumulating evidence suggests that CKD–CVD risk is shaped by the interplay of inflammatory burden, cardiac remodeling, vascular calcification, metabolic dysregulation, and genetic and environmental influences, rather than by race alone. Integrating multimodal markers, including cardiac imaging phenotypes, CAC burden, inflammatory biomarkers, and kidney measures, may help move beyond uniform risk assessment toward more precise, phenotype-informed prevention strategies. Collectively, these insights support a race-neutral, but context-sensitive approach to CKD–CVD risk assessment and prevention across diverse populations.

Supplementary Material

cjasn-21-1800-s001.pdf ^{(2.7MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C789.

Author Contributions

Conceptualization: Seung Hyeok Han, Jwa-Kyung Kim.

Investigation: Seung Hyeok Han, Hyeon Chang Kim, Jung-Sun Kim, Yong-Joon Lee.

Methodology: Jwa-Kyung Kim.

Project administration: Seung Hyeok Han.

Resources: Seung Hyeok Han, Jwa-Kyung Kim.

Supervision: Seung Hyeok Han, Hyeon Chang Kim, Jung-Sun Kim.

Visualization: Seung Hyeok Han, Hyeon Chang Kim, Jwa-Kyung Kim.

Writing – original draft: Seung Hyeok Han, Hyeon Chang Kim, Hyung Woo Kim, Jung-Sun Kim, Jwa-Kyung Kim, Hee Byung Koh, Yong-Joon Lee, Cheol Ho Park.

Writing – review & editing: Seung Hyeok Han, Jwa-Kyung Kim.

Funding

None.