Optimising Access to Care for Patients with Heart and Kidney Diseases: A World Heart Federation and International Society of Nephrology White Paper

Connections between kidney disease and cardiovascular diseases

In a meta-analysis involving individual patient-level data on eGFR and urinary albumin-to-creatinine ratio from up to 27,503,140 individuals from 114 global cohorts, decreasing kidney function and increasing albuminuria were associated with myocardial infarction, HF, AF, stroke, peripheral vascular disease, and CV mortality (14). In addition to this meta-analysis, many individual studies have shown similar strong associations as detailed below. The connections between specific entities of CVD and kidney disease are therefore wide-ranging (Table 1).

In light of these patterns and the growing recognition of how cardiovascular and kidney diseases intersect, this white paper was developed to consolidate current knowledge, elevate awareness of shared risk factors, and highlight areas where coordinated action could improve patient outcomes. The goal is to support more integrated and equitable approaches to care, particularly in settings where health system capacity is limited and the burden of disease is high.

Heart failure and left ventricular hypertrophy

The Atherosclerosis Risk in Communities (ARIC) study in 14,857 middle-aged adults demonstrated that those with moderately/severely reduced kidney function (as defined by eGFR) were at high risk for developing HF (34). The incidence of HF was three-fold higher in those with eGFR <60 ml/min/1.73 m² compared to the reference group with eGFR >90 ml/min/1.73 m² (18 vs. 6 per 1000 person-years). The overall adjusted relative hazard of developing HF was 1.94 for individuals with eGFR <60 ml/min/1.73 m² compared to the reference group.

Decreasing eGFR and increasing proteinuria both increased the chance of HF in a community study of 3,971 patients in the Chronic Renal Insufficiency Cohort (35). The presence of CKD in HF, which occurs in approximately half of all HF patients, is associated with increased mortality and hospitalisation (Figure 2) (36).

Figure 2

In a study of 365,494 patients hospitalised with HF, 234,332 (64%) had eGFR <60 ml/min/1.73 m² and 18,869 (5%) were on dialysis (37). Mortality increased significantly in a graded fashion with progressively declining admission eGFR (37). Steep associations were found between admission eGFR and across ejection fraction subgroups but were stronger for HF with reduced ejection fraction (HFrEF) compared with HF with mid-range (HFmrEF) or preserved ejection fraction (HFpEF) (p interaction = 0.045) (37).

In a cohort of maintenance haemodialysis patients, seven in ten had HF, of which 81% was HFpEF and 19% was HFrEF (38). Patients with HFrEF had a greater than three-fold higher risk of CV hospitalisation and/or cardiac death compared to those without HF, with an adjusted hazard ratio (HR) of 3.24 (95% confidence interval [CI] 1.08, 9.75). The association with HFpEF did not reach statistical significance (38). The prevalence of left ventricular hypertrophy (LVH) increases in a stepwise fashion as kidney function deteriorates and 70–80% of patients with KF present with established LVH (39). In a study of African Black patients with chronic kidney failure, 95% had LVH and 85% had hypertension at first presentation (40).

Coronary heart disease

In a study of 14,971 individuals, reduced eGFR was associated with a higher risk of recurrent CHD events and mortality from CHD and all causes (41). The associations were significantly greater among those with anaemia. The adjusted relative hazards of all-cause mortality associated with moderately decreased versus normal kidney function (GFR 30–59 vs. ≥90 ml/min per 1.73 m²) were 1.7 (95% CI 1.3, 2.2) without and 3.5 (95% CI 2.4, 5.1) with anaemia (p interaction = 0.001).

Albuminuria per se, even in the setting of a normal eGFR is associated with an increased risk of IHD, which is further markedly increased in the setting of a reduced eGFR (42, 43). Indeed, the ESC 2021 guideline on CVD prevention has included albuminuria in their ABCDE screening recommendations (albuminuria, blood pressure, cholesterol, diabetes, eGFR) (44). It has also been shown that the relative risk of CV mortality increases as eGFR declines and UACR rises (18).

Acute coronary syndrome

CKD impacts outcomes in patients with acute coronary syndromes (ACS). Among 2,706 patients with acute myocardial infarction (AMI) or unstable angina, kidney disease was associated with a higher odds of death, with odds ratios (ORs) of 1.76 (95% CI 0.93, 3.33), 2.72 (95% CI 1.43, 5.15), and 6.18 (95% CI 3.09, 12.36) for mild (eGFR 60–89 mL/min/1.73 m²), moderate (eGFR 30–59 mL/min/1.73 m²), and severe (eGFR <30 mL/min/1.73 m²) kidney disease, respectively, compared to those with normal eGFR (45). The associations between kidney disease and mortality rate were similar in the AMI and unstable angina subgroups (45).

In a population based study from Alberta, Canada, the unadjusted rates of AMI were highest among those with prior myocardial infarction (18.5 per 1000 person years), followed by CKD (eGFR <60 ml/min/1.73 m²) with diabetes (12.9 per 1000 person years), CKD alone (6.9 per 1000 person years) and diabetes alone (5.4 per 1000 person years), although the associations with CKD were attenuated after adjustment for demographic and clinical factors (43). Mortality after AMI was however highest among those with CKD and diabetes, followed by CKD alone, prior AMI and diabetes alone.

Sudden death

Sudden cardiac death (SCD) is the most common cause of death in people on dialysis, and is responsible for nearly one in four deaths in this group (46). Bradyarrhythmias have been implicated as a potential cause (46). It has been postulated that the high prevalence of LVH in patients with CKD, along with the accompanying risk of cardiac rhythm disturbances, may in part explain the elevated likelihood of SCD in CKD (47, 48). Abnormal electrolyte levels could also contribute to the excess SCD risk especially in those on dialysis (48).

Valvular heart disease

CKD is a major risk factor for valvular heart disease (VHD) (49). VHD in general, and particularly mitral regurgitation and aortic stenosis, is associated with significantly reduced survival in patients with CKD (49). Approximately 2–6% of patients on chronic haemodialysis develop infective endocarditis (IE), an incidence that is 50–60 times higher than in the general population (50). In a study of patients who underwent surgery for IE, mortality rates rose with the severity of underlying CKD (51). Mortality rates at 30 days and 1 year were 5.6% and 15.5%, respectively, in patients without CKD, rising to 38.1% and 75.6%, respectively, in those on haemodialysis (51). In a study of patients who underwent surgery for IE, mortality rates rose with the severity of underlying CKD (51). Mortality rates at 30 days and 1 year were 5.6% and 15.5%, respectively, in patients without CKD, rising to 38.1% and 75.6%, respectively, in those on haemodialysis (51).

Atrial fibrillation

Also from ARIC (n = 10,328), compared to individuals with normal GFR (cystatin C-based GFR [eGFR_cys] ≥90 mL/min/1.73 m²), the HRs for AF in individuals with mildly decreased kidney function (eGFR_cys of 60–89 mL/min/1.73 m²), CKD stage 3 (30–59 mL/min/1.73 m²), and CKD stage 4 (15–29 mL/min/1.73 m²) were 1.3 (95% CI 1.1,1.6), 1.6 (95% CI 1.3, 2.1), and 3.2 (95%CI 2.0, 5.0), respectively (p for trend <0.0001) (52). Moderate albuminuria, previously called microalbuminuria (UACR 30–299 mg/g), and macroalbuminuria (UACR ≥300 mg/g) were also associated with 2.0 and 3.2 higher hazards of AF, respectively, compared to those with normal UACR levels (<30 mg/g). Participants with both CKD stage 4 and high levels of albuminuria had a particularly high AF risk, with a HR of 13.1 (95% CI 6.0, 28.6) compared to those with normal UACR levels and normal GFR (52). More recent studies indicate that AF and CKD coexist and share the same risk factors, but the direction of association is unclear (53). Using bidirectional summary-level Mendelian randomization analysis on a genome-wide association study for eGFR, involving 765,348 European individuals with CKD and 588,190 with AF, a genetic predisposition to AF was significantly associated with a reduced eGFR [for log-eGFR, beta –0.003 (standard error, 0.0005), p < 0.001] and an increased risk of CKD [beta 0.059 (0.0126), p < 0.001] (54). The reverse; however, was not observed, in that a genetic predisposition to reduced eGFR was not associated with increase AF.

Stroke

In the ARIC cohort (n = 13,716), CKD was associated with a nearly two-fold increased risk of stroke after adjustment for known risk factors (HR 1.81; 95% CI 1.26, 2.02), an effect that was particularly pronounced in the presence of anaemia (HR 5.43; 95% CI 2.04, 14.41) (55). Kidney disease, determined by eGFR, was related to incident stroke in an inverse step-wise fashion, with risk increasing by 3-, 4.1-, 5.4-, and 7.1-fold for CKD stage 3 to 5 and dialysis patients compared with the general population (56). The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a two-year follow-up of 20,386 participants, documented an incidence of stroke symptoms of 20.7% with an eGFR <45 ml/min per 1.73 m² (HR: 1.26) and 18.8% with an ACR >300 mg/g (HR 1.29, p = 0.005 for trend) (57). Also, in a 2015 meta-analysis of 63 cohort and 20 randomised controlled studies, stroke risk increased by 7% for every 10 ml/min/1.73 m² decline in eGFR and 10% per 25 mg/mol increase in ACR independent of GFR. (58)

Peripheral arterial disease

Further data from ARIC (n = 14,280) uncovered an increased risk for incident peripheral arterial disease in participants with CKD, with a multivariable adjusted relative risk of 1.56 after adjustment for CVD risk factors (95% CI 1.13, 2.14) (59). In a large meta-analysis of the CKD-Prognosis Consortium report which included more than 800,000 subjects, the risk for developing peripheral arterial disease increased by 22% when eGFR decreased from a baseline of 95 ml/min/1.73 m² to 45 ml/min/1.73 m² and by 2-fold for eGFR of 15 ml/min/1.73 m² (60).

Demographics of kidney disease

CKD is common. Pooled results of 33 population-based representative studies in 2010 revealed an age-standardised prevalence of CKD stages 1–5 in individuals aged >20 years of 10.4% among men and 11.8% among women. CKD age-standardised prevalence was lower in high-income countries: 8.6% and 9.6% in men and women, respectively compared to 10.6% and 15.5% in low and middle-income countries (61). A more recent comprehensive systematic review and meta-analysis of 100 studies involving almost 7 million participants noted a global prevalence of 13.4% for CKD stages 1–5 and 10.6% for CKD stages 3–5) (62). Similar commonality and patterns are observed for CVD, with prevalence nearly doubling from an estimated 271 million people in 1990 to 523 million by 2019 (63). Lower-middle and low-income countries had the highest age-standardized CVD prevalence rates in 2019, at 7.4% compared to 6.9% across high-income countries. Variations across cardiovascular disease subtypes exist however, with ischemic heart disease and stroke more prevalent in low- and middle-income countries, and atrial fibrillation more prevalent in high-income countries (63, 64).

A study of 11,607 US adults (mean age 48.5 years, 51.0% women) found that participants with a high cardiac, renal, and metabolic comorbidity burden were more likely to be older, male, of non-Hispanic Black race or ethnicity, unemployed, of low socioeconomic status, and without a high school degree (65).

A review of US CKD patients highlighted that the likelihood of KF was nearly four-fold higher in Blacks compared with White individuals (18), with diabetes and hypertension being the primary causes of KF among Blacks. Hispanics were nearly 1.3 times more likely to be diagnosed with KF compared to non-Hispanic individuals. Racial and ethnic minorities, including African Americans in the US, Indigenous groups in Canada and Australia, and Indo-Asians in the UK, were disproportionately affected by advanced and progressive kidney disease (66).

Sex differences have also been reported. Globally, the prevalence of CKD is higher in women but men progress more rapidly to KF (67). Global CVD prevalence and mortality rates are higher in men, however important sex differences in CV phenotypes, risk factors and care outcomes are observed for different cardiovascular disease subtypes, including a potentially higher risk of developing CKD due to hypertension in women than men (68). Female CKD patients have lower risks of CV events, CV mortality and mortality from any cause than their male counterparts—differences which could not be explained by risk factors (69). Therefore, sex impacts the interaction between CKD and CVD, although the pathophysiology is not yet well understood.

Children

Links between heart and kidney disorders have also been found in children. The Cardiovascular Comorbidity in Children with CKD Study of 6–17 year-olds with an initial eGFR of 10–60 mL/min/1.73 m² found that 26.1% had uncontrolled hypertension (n = 545), with the prevalence increasing from 24.4% in CKD stage 3 to 47.4% in CKD stage 5 (70). LVH was also more prevalent with increasing severity of CKD, from 10.6% in CKD stage 3a to 48% in CKD stage 5 (70). A study of 1,410 children with congenital heart defects found that 7.4% had congenital anomalies of the kidney and urinary tract (CAKUT) (71). There were no differences in the prevalence of CAKUT according to maternal age, sex, parity, gestational age or history of medication during pregnancy (71). The reported prevalence was substantially higher than the 0.5% observed in the general population (72). A study in mouse models found that 29% of mutations causing congenital heart disease also caused kidney anomalies (72).

Pregnancy, the kidney, and cardiovascular disease

Hypertensive disorders of pregnancy are common, affecting up to 15% of women during their reproductive lives (73). These disorders are more common in lower resource settings and have important short- and long-term impacts on maternal and foetal kidney and CV health (74). Kidney disease is a major risk factor for hypertensive disorders of pregnancy. A meta-analysis of 23 studies including 5,769,891 pregnant women found that preeclampsia was associated with an increased risk of CKD (pooled adjusted risk ratio [aRR] 2.11), KF (aRR 4.90), and kidney-related hospitalisation (aRR 2.65). Gestational hypertension was associated with 1.49-fold and 3.64-fold raised risks of CKD and KF, respectively (75).

A Swedish national cohort study of 2.2 million women with a singleton delivery found that 11,572 (0.5%) were diagnosed with CKD during 56 million person-years of follow-up (76). Within 10 years following delivery, the HR for women developing CKD was 7.12 for other hypertensive disorders, 4.38 for preeclampsia, 3.50 for preterm delivery, 3.15 for gestational diabetes, and 1.22 for those with small for gestational age infants. Risk remained significantly elevated 30–46 years after delivery. Women with more than one adverse pregnancy outcome were at even greater risk.

A meta-analysis reported that a prevalence of AKI in women with hypertensive disorders of pregnancy (HDP) in Africa of 6%, with preeclampsia and eclampsia being the most common types of HDP (77). However, the authors suggested that this may be an underestimate because many studies did not use standard diagnostic criteria, and many studies were performed by obstetricians rather than nephrologists and earlier stages of AKI may have been missed (77).

A meta-analysis of 22 studies >6.4 million women, of whom >258,000 had preeclampsia, demonstrated that preeclampsia was independently associated with an increased risk of future HF (risk ratio [RR] 4.19; 95%CI 2.09, 8.38), CHD (RR 2.50; 95%CI 1.43, 4.37), CVD death (RR 2.21; 95% CI 1.83, 2.66), and stroke (RR 1.81; 95% CI 1.29, 2.55) (78).

Mortality

Overall, 9% (1 in 10) of CVD deaths in 2019 are attributable to kidney disease—which causes 13% of deaths from IHD and 8% of deaths from stroke (79). CVD is responsible for up to 50% of the mortality risk in patients on dialysis, with the largest relative excess observed in younger patients (80). The risk of death due to CVD is 10–20 times greater in dialysis patients compared to age- and sex-matched controls in the general population (80). In the US in 1997, the National Kidney Foundation established a Task Force to investigate outcomes of CVD in the general population compared to those with CKD. Their findings revealed that the annual CV-related mortality rate among patients undergoing KRT stood at approximately 9%, a figure nearly 30 times higher than that observed in the general population. Of heightened concern was the fact that CV fatalities among KRT patients aged 25–34 were comparable to those seen in individuals in the general population aged over 85, irrespective of sex or ethnicity (81).

Life course risks

The risk of premature non-communicable diseases (NCDs) may begin during foetal life (Figure 3). This paradigm was proposed by David Barker who observed an increase in cardiovascular deaths among adults who had been of low birth weight (82). Around the same time Brenner and colleagues hypothesised that low birth weight and preterm birth are associated with a congenital reduction in nephron number, which would predispose to elevated blood pressure and a higher likelihood of kidney disease in later life (83, 84). In population-based studies, preterm birth (gestational age <37 completed weeks) and low birth weight for gestational age have been associated with increased risks of CV and kidney disorders in later life (85, 86). Over 35 million babies worldwide are born too small or too early, suggesting many children begin life at risk of heart and kidney disease (87). More specifically, low birth weight and prematurity are risk factors for hypertension, proteinuria, and CKD later in life (83, 85). High birth weight, particularly when due to maternal diabetes, is also detrimental to the heart and kidneys, with increased risks of congenital heart disorders, and obesity/metabolic syndrome, proteinuria and kidney disease in later life (83).

Figure 3

Using data (CV health albuminuria [CVH], a composite of seven metrics) from the Coronary Artery Risk Development in Young Adults Study (CARDIA), investigators demonstrated that less-than-ideal CVH in young adults aged 18 to 30 predicted premature CV morbidity and mortality three or more decades later (89). Of concern, over two-thirds had moderate-poor CVH at baseline, more prevalent among Blacks compared with Whites, who then had twice (0.9 vs. 0.5/1,000 person-years) the rates of CVD during follow-up. Poor CVH established as covert subclinical disease in young adults progresses to overt CVD morbidity and mortality in mid-to late-life (90). Conversely, an ideal CVH at this age predicted a low absolute and relative risk of premature CVD in later life (89). The mechanisms involved in the evolution of poor CVH in early adulthood culminating in CVD and CKD risk over time and causing increased morbidity and mortality in late adult life, are multiple, including early life factors, social and structural factors, and health and lifestyle (91). Obesity is a major modifier of these early risks (92, 93, 94).

Developing a model with a multisectoral approach incorporating healthcare measures and socioeconomic and health policies that promote equity, access to quality care, information, education, and healthy life-style counselling starting in childhood and adolescence are ideal strategies to reduce CVD and CKD risk throughout the life course to reduce morbidity and mortality attributed to NCDs. This unique window is often not fully harnessed in many high-income countries (HICs) (95) or even explored in LMICs.

Multimorbidity burden

Given the shared risk factors, CVD and CKD often occur together as well as with other disorders. Multimorbidity is especially common among people with kidney disease. In a population-based study adults in Alberta, Canada, patients seen by nephrologists had the highest mean number of comorbidities (4.2; 95% CI, 4.2–4.3 vs [lowest] 1.1; 95% CI, 1.0–1.1) and the highest mean number of prescribed medications (14.2; 95% CI, 14.2–14.3 vs [lowest] 4.9; 95% CI, 4.9–4.9) (96). The mean number of comorbidities in patients seen by cardiologists was 2.6 (95% CI, 2.6–2.6) with a mean number of prescribed medications of 8.7 (95% CI, 8.7–8.7).

In a study of 10,336 people from South Africa, the prevalence of multimorbidity, defined as having ≥2 health conditions, was 20.7% (95% CI 19.5, 21.9) and was higher in females (26.2%) compared to males (14.8%) (97). The most common conditions, measured using biomarkers, were hypertension (45%), anaemia (24.7%), HIV (19.6%), and diabetes (11.7%) (97). This study illustrates the high prevalence of these combined risk factors for CKD and CVD in the community. The REPORT-HF global cohort study of 18,553 patients from 358 hospitals in 44 countries on six continents found that in patients with acute HF, more than half (51%) of patients with ≥5 comorbidities (n = 4,449) had CKD (98). The highest prevalence of multimorbidity was observed in North America and Europe and the lowest in southeast Asia and the western Pacific. Fewer patients from LMICs had multimorbidity compared with patients in HICs (73% vs. 85%, p < 0.0001). The proportion of 1-year all-cause mortality risk in acute HF patients that could be explained by the presence of ≥5 comorbidities was greatest in HICs (61%), followed by LMICs (31%), and upper-middle-income countries [UMICs] (27%).

Among 11,607 US adults with a mean age of 48.5 ± 0.4 years, at least one cardiac, kidney or metabolic (CKM) condition was present in 26.3%, 8% had at least two conditions and 1.5% had at least three (65). CKD was the most prevalent CKM condition (13.9%), followed by diabetes (13.3%) and CVD (8.6%). The CKM burden was higher among non-Hispanic Black subjects and among those with lower socioeconomic status and higher unemployment.

Obesity

Obesity is associated with both progression of kidney disease and CVD. Data from the ARIC study found a consistent association between midlife obesity status (measured by BMI, waist-to-hip ratio, predicted percent fat at baseline) and development of KF in White and Black women, but not in White men (107). Among patients with glomerulopathies and proteinuria, obesity is associated with adverse cardiovascular and renal outcomes, but the association with kidney disease progression attenuates with multivariate analysis (108, 109). The association between obesity and multiple forms of CVD is strong (110). Weight loss is associated with reduction in risk factors for CVD and CKD; however, the risk of CVD has been found to be reduced after surgical but not medical weight loss (110). Bariatric surgery has also been associated with improvement in CKD risk (111). This may relate to the degree of weight loss achieved and is likely mediated by accompanying improvements in additional risk factors such as hypertension and blood glucose (110).

Epidemiological studies have shown that visceral adipose tissue (VAT) is associated with increased metabolic risk and overall mortality, whereas subcutaneous adipose tissue (SAT) ameliorates insulin sensitivity and reduces the risk of type 2 DM (112). These risks are affected by genetic, biological and lifestyle factors including physical activity, nutrition, and stress (112). An analysis of African-Americans enrolled in the Jackson Heart Study reported that abdominal VAT and SAT were both associated with adverse cardiometabolic risk factors, but VAT was more strongly associated with these risk factors (113). A study of 5,113 individuals (2,933 Inuit, 1,397 Africans, and 783 Europeans) from three studies in Greenland, Kenya, and Denmark indicated that ethnicity plays a role in the pathway from abdominal fat to selected cardiometabolic risk factors (114). Across ethnic groups and sex, a one standard deviation increase in VAT was associated with higher levels of hepatic insulin resistance (ranging from 14% to 28%), triglycerides (8% to 16%) and lower high-density lipoprotein cholesterol (–1.0 to –0.05 mmol/L) independent of BMI (114). However, VAT showed positive associations with many other cardiometabolic risk factors in Inuit and Europeans but not in Africans. SAT was mainly associated with the outcomes in Inuit and Africans (114).

The Framingham Offspring Study reported that VAT and SAT were associated with CKD when defined using cystatin C estimating equations but not when using a creatinine-based estimating equation (115).

In contrast, epidemiological studies have consistently reported reduced all-cause mortality in obese haemodialysis patients. This reverse epidemiology has been referred to as the obesity paradox among patients on hemodialysis. The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) that included 9,714 haemodialysis patients from the US and Europe reported a statistically significant inverse linear correlation between relative mortality risk and BMI (p < 0.0001). Relative mortality risk was significantly lower in both US (relative risk 0.7, p = 0.002) and European (relative risk 0.61, p = 0.01) haemodialysis patients who had a BMI ≥30 kg/m² compared to those with a BMI of 23.0–24.9 kg/m² (116). Postulated mechanisms for this survival advantage include improved haemodynamic stability, altered cytokine profiles, uraemic toxins sequestered with fat tissue, and altered endotoxin-lipoprotein response (117). An obesity paradox has also been described in CVD, potentially related to earlier diagnosis among individuals with class 1 obesity, better cardiorespiratory fitness and more physical reserve (110).

Social determinants of health

The risk of NCDs, including CVD and CKD, starts in utero and is further impacted by epigenetic factors, lifestyle choices and socioeconomic circumstances throughout the life course. The United Nations (UN) Sustainable Development Goals (SDGs) emphasise wellbeing at all ages (118) and have been noted as an opportunity to stem the tide of NCDs at the source (119). CKM particularly affects populations with poor social determinants of health (SDH), which include the economic, social, environmental, and psychosocial factors that influence health (Figure 5) (65, 120, 121). The SDH that influence CV health have been subdivided into sociopolitical and economic context, social and community context, and lived personal experience (120). The sociopolitical and economic context includes economic stability, education access and quality, neighbourhood and built environment, healthcare access and quality, and structural discrimination and racism. The social and community context encompasses the food environment, social environment and cohesion, transportation instability, financial strain, food insecurity, and housing instability. Lived personal experience refers to everyday discrimination and stigma, neighbourhood perception, health literacy, implicit bias, social needs, and perceived health status. Together these factors contribute to the biology of adversity, healthcare access, health behaviours, and CV risk.

Figure 5

The risk of progressive CKD and KF is also linked with SDH, with groups of lower socioeconomic status carrying the heaviest load (66). For example, socioeconomic status impacts on diet quality through the unavailability of nutritious foods in disadvantaged neighbourhoods (122). In addition, many countries still lack access to basic diagnostics, a trained nephrology workforce, universal access to primary healthcare, and KRT (66). To identify patients with social needs and link them to available resources, the AHA recommends systematic screening for SDH—including housing insecurity, food insecurity, education, financial resource strain, alcohol use, race, ethnicity, tobacco use and exposure, depression, exposure to violence, physical inactivity, social isolation, and stress (13).

Early detection and risk factor control

Given the strong evidence of CKD and albuminuria being independent risk factors for CVD, the AHA and the European Society of Cardiology recommend measurement of eGFR and albuminuria to identify at-risk patients who would benefit from evidence-based therapies to lower CVD and CKD risks (123). Concerningly, assessment of albuminuria is inadequate in real-world practice (<10%), even in those with CKD, DM or hypertension (124, 125). Awareness of CKD is also low, ranging from 7–20% across global populations (7). Without stronger efforts to detect kidney disease among people at risk, we will miss important opportunities to initiate and maintain therapy and save kidneys, hearts and lives (7, 126).

While the AHA advises screening for CKM risk factors across the life course to promote prevention and management (13), studies have shown that both screening and treatment of risk factors are dismally inadequate. An analysis of hypertension care in 44 LMICs found that among those with hypertension, 74% had ever had their blood pressure measured, 39% had been diagnosed with hypertension, 29% had received treatment, and 10% had controlled hypertension (127). In general, Latin American and Caribbean countries achieved the best performance relative to their predicted performance based on GDP per capita, whereas countries in sub-Saharan Africa performed the worst (127). The problem extends to HICs, as demonstrated by an analysis of 12 such nations, which found that even in the best-performing countries, treatment coverage was at most 80% and control rates were less than 70% (128).

Similarly with DM, around 6 in 10 of those with the condition are actually being diagnosed (129). In HICs, recommended targets for risk factors such as glycaemic control and blood pressure control are achieved by 50–70% of patients, with only ~20% meeting all recommended targets. LMICs fare worse, with just half of patients having good glycaemic control and one in four having reasonable blood pressure control (129). Only 12% of people living with diabetes were using statins.

Novel calculators to predict CV risk have been developed that incorporate CKD measures. Adding eGFR or eGFR and UACR improved the predictive ability of both the systemic coronary risk estimation 2 (SCORE2) and SCORE2 in older persons (SCORE2-OP) algorithms (Figure 6) (42). It is important to note that the SCORE2 predictive tool performs poorly in poor socioeconomic subgroups and certain ethnic minorities (130). This underscores the importance of validating CV risk predictive tools in low-income countries and LMICs.

Figure 6

The AHAs new CVD risk calculator, Predicting Risk of Cardiovascular Disease Events (PREVENT) encompasses kidney and metabolic diseases and is based on data from a larger and more diverse sample than prior calculators (131). The PREVENT equations permit estimation of 10- and 30-year risk for total CVD (combined atherosclerotic CVD and heart failure) among adults 30 to 79 years of age, and include eGFR as a risk predictor, adjusting also for competing risk of non-CVD death (132). Importantly, where indicated, predictive utility is enhanced in additional models by inclusion of CKM indicators (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (as reflected by the social deprivation index). This model therefore may be capturing risk more holistically.

A major barrier to implementation of risk scores in many low resource settings is access to primary care facilities and to basic diagnostic tests, especially if out of pocket payment is required. Diagnosis is a critical step prior to implementation of therapeutic strategies; therefore, primary care must be strengthened and the required essential diagnostics and essential medications, most of which are common for CVD and CKD, must be made available under universal health coverage to ensure early and equitable access to quality care.

The authors of an African position paper on CKD highlighted that while assessment of UACR is recommended by many guidelines (133), it is unaffordable in African countries, and thus the use of urine test strips to identify CKD is considered acceptable (as it is in guidelines) and encouraged (134). Other authors have reported that in sub-Saharan Africa, CKD is often diagnosed very late, with kidney failure, due to resource constraints and nonavailability or unaffordability of primary care services to permit appropriate earlier identification (135). Many patients present late to nephrology services and die within weeks to months of their diagnosis, in part because of the absence of awareness, the lack of early detection among people at risk, lack of human resources and inadequate access to treatment for those with identified disease (136).

Lifestyle changes

Lifestyle modification and weight loss are recommended by the AHA to address excess or dysfunctional adiposity and facilitate regression along CKM stages, which it defines as stage 0, no CKM risk factors; stage 1, excess or dysfunctional adiposity; stage 2, metabolic risk factors (hypertriglyceridaemia, hypertension, DM, metabolic syndrome) or moderate- to high-risk CKD; stage 3, subclinical CVD in CKM syndrome or risk equivalents (high predicted CVD risk or very high-risk CKD); and stage 4, clinical CVD in CKM syndrome (13). The CV benefits of physical activity in CKD and dialysis patients have been suggested in observational studies (138, 139). In addition, low physical activity has been significantly associated with a higher likelihood of multimorbidity (140). A meta-analysis including 104 studies and 2,755,719 participants found that higher intake of potassium and vegetables, lower intake of sodium, increased physical activity, moderate alcohol consumption, and avoidance of tobacco smoking were associated with a lower risk of incident CKD in the community (141). These findings generally align with lifestyle recommendations to prevent CVD (142). A high potassium diet is usually not recommended in advanced CKD however, therefore caution and individualisation of recommendations is advised.

Health literacy

Education is fundamental to health literacy, which enables individuals to make healthy choices (143, 144). Education should be tailored to context and a patient’s own health literacy. Poor health literacy is common in patients with CKD, especially among those with low socioeconomic status and non-White ethnicity, and has been associated with reduced kidney function, poorer blood pressure control, decreased self-management, more frequent hospitalisation, and increased mortality (144, 145). The benefits of public and professional education on kidney health were demonstrated in the ESCORT study, conducted in Thailand, in which patients with CKD received more comprehensive educational activities than the control group and health workers received training on CKD, clinical practice guidelines, and optimal diets (146).

The benefits of education extend to CVD. A study pooling six community-based cohorts in the US including 40,998 participants found that lower educational attainment was associated with lifetime CVD risk across adulthood, and higher education translated to healthy longevity (147). The authors suggested that education policies could lead to long-term health benefits, with opportunities for education in early life potentially having lasting effects in middle age and older age (147). A cluster-randomised, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka showed that an intervention that included home visits by trained government community health workers for blood pressure monitoring and counselling led to a greater reduction in blood pressure than usual care among adults with hypertension (148).

Therapeutic interventions

Renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) reduce proteinuria and GFR decline (149) and have benefits in treating hypertension, improving diabetic nephropathy and other forms of CKD, preventing or ameliorating congestive HF, and optimising prognosis after AMI (150). These agents have been the mainstay of treatment for CKD (beyond therapy for a primary kidney disease) since the 1980s (137, 151), but novel therapies are proving to be game changers as reflected in the latest KDIGO CKD guidelines (137).

Therapy with SGLT2 inhibitors, non-steroidal MRA and GLP-1a have been shown to improve cardiorenal outcomes in CKD patients with and without diabetes. A meta-analysis of 78,607 participants from 11 phase 3 placebo-controlled trials of SGLT2 inhibitors has shown a reduction in major adverse cardiac events (HR 0.91 [95% CI 0.87–0.96], p < 0.0001) in diabetes, HF and CKD patients, establishing a role of SGLT2 inhibitors in all three patient groups [I² = 0%] (152). Another meta-analysis of 13 SGLT2 inhibitor trials with 90,409 participants has shown a reduction of CKD progression (relative risk [RR] 0.63, 95% CI 0.58–0.69), AKI ([RR] 0.77, 0.70–0.84) and CV death with HF hospitalisation ([RR] 0.77, 0.74–0.81) in both patients with and without diabetes (153). In a randomised trial of 3,353 CKD patients with diabetes, GLP-1a reduced kidney disease progression [hazard ratio 0.79 (95% CI, 0.66–0.94)], death from CV causes [HR 0.71 (95% CI, 0.56–0.89)] and all cause death (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, p = 0.01) (154). Finerenone, a non-steroidal MRA, in 13,206 CKD patients with diabetes reduced kidney disease progression [HR, 0.77; 95% CI, 0.67–0.88; p = 0.0002] and CV outcomes [HR, 0.86; 95% CI, 0.78–0.95; p = 0.0018]. Hyperkalaemia led to more frequent treatment discontinuation in patients receiving finerenone (1.7%) than placebo (0.6%) (155). A meta-analysis including 3,460 patients with HF and CKD found that compared with ARBs, the angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan significantly increased eGFR and decreased blood pressure and N-terminal pro b-type natriuretic peptide (NT-proBNP), indicating that it might have CV and kidney benefits in patients with HF and CKD (156). In partnership with other international organisations, ISN is developing tools to provide the necessary therapy (e.g RAAS inhibition) and interdisciplinary care of kidney patients with heart disease across all six regions of the World Health Organization (157).

Additional new therapies have been developed for HfrEF (e.g. Omecamtiv-Mecarbil, Vericiguat, Ivabradine), which have improved mortality, CV death or hospitalisation for HF, however in general these trials have only included patients with up to CKD3B (158). Such frequent exclusion of patients with more advanced CKD leaves an important knowledge gap in the treatment of CVD in those at the highest risk and in greatest need of effective therapies.

A study by Patel et al. demonstrated that despite their elevated risks of mortality, patients with both HFrEF and kidney disease were suboptimally treated with evidence-based medical therapies, even at eGFR levels where such therapies would not be contraindicated (37). Given the very high CV burden and risk of death among patients living on dialysis or with kidney transplants, large scale trials are required to examine the safety and efficacy of these medications in these populations.

Out-of-pocket costs

High out-of-pocket costs mean that some patients cannot afford evidence-based medicines for CKD and CVD. In an analysis of the Prospective Urban Rural Epidemiology (PURE) study conducted in 18 countries, cardioprotective medicines were potentially unaffordable for one-third of LMICs and 60% of households in LICs (164). A further analysis in 163,466 participants of the PURE study found that essential CVD medicines were unavailable and unaffordable for a large proportion of communities where individuals at high CVD risk reside, particularly in LMIC and LIC (165). After accounting for sociodemographic and economic factors, education and comorbidities, the unavailability, and unaffordability of essential CVD medicines were associated with a higher risk of major adverse CV events (165). Husain and colleagues reported that the costs of one month’s antihypertensive medications were, on average, 6.0 days’ wages for brand medicines and 1.8 days’ wages for generics (166). Affordability was lower in LICs and LMICs than HICs and UMICs for both brand and generic medications (166).

Across Africa, there is significant variation in the cost of SGLT2 inhibitors, with generics imported from India and Pakistan being more affordable (135). In many cases, prices are higher than the median daily income.

Patients in HICs are not immune to the impact of medicine pricing (7). In the US, a one-month supply of an SGLT2 inhibitor costs USD 530–650, and for finerenone, USD 580–690 per month, while GLP-1 RAs cost USD 770–1300 per month, leading to insurers’ reluctance to pay (6). In addition, monthly co-payments can amount to hundreds of dollars per month for each medication, making the use of multiple drugs a massive challenge. Note that prices vary across different HICs, depending on the socio-political environment.

An analysis of 66 studies examining the effect of NCDs on household economics in LMICs reported that >60% of patient populations with NCDs experience catastrophic health expenditure (167). Such expenditure was greater in lower- compared with higher- income groups. The highest incidences of catastrophic health expenditure were found in low-income patients with CVD in Tanzania (92%), India (92%), and China (79%). A study focused on sub-Saharan Africa and defining catastrophic health expenditure as health expenditure above 5%, 10%, and 25% of total household expenditure, found that households with CVD were three times more likely to incur catastrophic health expenditure compared with households without CVD (168). When categorised by the extent of catastrophic health expenditure, households with CVD had two- and three-fold odds of incurring catastrophic health expenditure at the 5% and 10% thresholds, respectively, and four-fold odds at the 25% and 40% thresholds (168). It is estimated that ~188 million people in LMICs experience catastrophic health expenditure every year due to CKD (162).

Out-of-pocket costs are a barrier to treatment and a driver of non-adherence and discontinuation, with poorer households affected most (169). An analysis of 14 studies from HICs and LMICs found that cost adversely influenced adherence to CKD medication and dialysis treatment (169). In poorer countries, patients who did receive treatment were typically diagnosed late, under-dialysed and had high levels of mortality (169). A systematic review of how patients in LMICs deal with the healthcare costs of chronic illness reported that in addition to selling possessions and borrowing from friends and family, coping strategies included taking children out of school, stopping or delaying treatment, and seeking alternative treatment for conditions like hypertension (170). Not surprisingly, multimorbidity increases out of pocket costs and risks for catastrophic expenditure, highlighting the need for integrated care, appropriate guidelines to support rational use of medication, and most importantly universal health coverage to ensure affordable and continued access to the life-saving medications required for CVD and CKD (171, 172).

Indirect costs—unemployment

CKD and CVD also come with substantial indirect costs, including the loss of employment, mental strain, and stress. A review of 260 CKD studies from 30 countries reported that in some patients, treatment led to unemployment, and patients feared catastrophic events because of limited finances (173). Those able to continue working often had informal or temporary jobs with reduced income, while others were forced into unemployment (173). Pain, fatigue, anxiety, and depression limited the ability of patients with KF to conduct daily activities, including their paid job (173).

A study of 36,732 adults aged ≥30 years who participated in the Korean National Health and Nutrition Examination Survey between 2014 and 2021 found that patients with CKD had a two-fold odds of unemployment compared to those without CKD (174). A study in nine nephrology clinics in the Netherlands among working age (18–67 years) patients with CKD Stage G3b-G5, dialysis or transplant reported that two in three (65%) were employed but reported moderate work ability (175). Of those, 21% received disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Adjustments at work included fewer hours, working at a slower pace, changes to work tasks or schedules, and working from home.

Studies have reported employment rates of between 19% and 33% among patients on dialysis (176, 177, 178, 179). A study from India reported 60% and 64% employment rates in haemodialysis and peritoneal dialysis patients, respectively, before the initiation of treatment (179). After dialysis commenced, loss of employment was observed in 44% of haemodialysis and 51% of peritoneal dialysis patients (179). A study of 480,597 patients from the US Renal Data System (USRDS) registry initiating dialysis at various time points between 1996 and 2013 found that on average over the entire study period, 38% of patients employed six months before KF stopped working before starting dialysis (180).

Numerous studies have indicated that CVD has an impact on patients’ ability to return to work (181). Among 11,880 patients with a first-time HF hospitalisation, 68% returned to work within one year and 25% did not (182). Patients with longer/higher education were twice as likely to return to employment as those with basic school education, while those with CKD were half has likely to go back to work (182). It has also been shown that an initial return to work may be followed by leaving employment. A nationwide Danish registry study found that 91% of patients with a first-time AMI returned to work within one year, but one year after their return, 24% were detached from employment and receiving social benefits (183). High education level and high income favoured continued employment (183). Similarly, among 36,174, 30-day survivors of first-time hospitalisation for AF, 34,924 (96.5%) patients returned to work (184). Of those who returned to work, 23,905 (68.5%) left the workforce within a median of 1.5 years (184). Higher education levels were associated with a lower risk of detachment from the workforce relative to lower education levels (184).

A review of vocational reintegration of patients experiencing an ACS noted that cardiac events raised the likelihood of poorer professional conditions including reduced responsible area, part-time employment, lower salary and discharge from jobs (181). An analysis of 497 patients with acute or chronic ischaemic heart disease estimated that the mean work productivity loss was €9,673 per person (185).

Indirect costs—psychosocial aspects

Psychosocial stress—including symptoms of mental disorders and stressors such as loneliness and critical life events—is associated, in a dose-response pattern, with the development and progression of CVD, independently of conventional risk factors and sex (142). An analysis of 2,585 patients with CKD stages 2–4 but without CVD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) found that one in four had depression at baseline (186). Those with depression were more likely to be women (56% vs. 46%), non-White (68% vs. 53%), with household income <USD 20,000 (53% vs. 26%), without a high school degree (31% vs. 15%), uninsured (13% vs. 7%), with lower eGFR (42 vs. 46 mL/min/1.73 m²), and with higher UACR (90 vs. 33 mg/g) compared to patients without depression. In multivariate analyses, depression was associated with a 29% increased risk of developing CVD (186). Data from Finland, France, Sweden, and the UK have shown that work stress, which refers to job strain or effort-reward imbalance at work, indicated that in men with cardiometabolic disease, age-standardised mortality rates were substantially higher in those with job strain (149.8 per 10,000 person-years) compared to those without (97.7 per 10,000 person-years; mortality difference 52.1 per 10,000 person-years; multivariable-adjusted HR 1.68, 95%CI 1.19, 2.35) (187).

Cost and cost-effectiveness for health systems

A study of patient payments for services in the public and private sectors in Kenya found that NCD screening costs ranged from USD 4 to 36 (195). Annual hypertension medication costs ranged from USD 26 to 234 and USD 418 to 987 in public and private facilities, respectively (195). Stroke admissions (USD 1,874 vs. 16,711) and dialysis for CKD (USD 5,338 vs. 11,024) were among the most expensive treatments (195). The study reported that a large proportion of Kenyans aged 15 to 49 years do not have health insurance, making NCD services unaffordable for many considering the high cost of services relative to income (in 2013, the estimated average household expenditure per adult was USD 413; USD 721 in urban areas and USD 272 in rural settings) (195). Case-finding and early treatment of CKD in high-risk populations has been found to be cost effective in some high and upper middle-income countries. This has not been studied in lower resource settings but should be presumed to be cost-effective until proved otherwise (196, 197, 198).

A review of the literature published in 2020 indicated that approaches to control hypertension can be a cost-effective way to prevent premature CVD in LMICs across a variety of population, clinical, and health system contexts (199). Most interventions that reported cost per averted disability-adjusted life-year (DALY) were cost-effective using national income thresholds, with costs per averted DALY not exceeding the average GDP per capita of LMICs (199). A cost analysis of the WHO HEARTS programme for hypertension control and CVD prevention in Ethiopia reported that the estimated annual cost per adult primary care user was USD 5.3 for hypertension control and USD 19.3 for integrated CVD risk management (200). The estimated cost of medication per person treated for hypertension was USD 9.0, whereas treating DM and high cholesterol would cost USD 15.4 and USD 15.3 per person, respectively. More than one-third (37%) of the total cost of the hypertension control programme was attributable to medications.

In the US and UK settings, the risk of CV morbidity and the costs and bed days associated with its management increased substantially with CKD severity (201). Additional costs and bed days were largely driven by high levels of albuminuria and increased severity of CKD (201). For example, patients with stage 5 CKD and UACR values >300 required an estimated additional 803 and 1,017 bed days per 1,000 patient-years for the management of CV morbidity in the US and UK, respectively, versus stage 1 (or without) CKD, and normoalbuminuria (201).

A secondary analysis of 28,261 years of data from the Study of Heart and Renal Protection (SHARP) randomised trial, conducted in 7,246 patients from Europe, North America, and Australasia, reported that annual hospital costs in CKD patients without DM or vascular disease ranged from £403 in CKD stages 1–3b to £525 in CKD stage 5 (not on dialysis) (202). Non-fatal major vascular events increased annual costs in the year of the event by £6,133 for patients on dialysis and by £4,350 for those not on dialysis and incurred additional costs in subsequent years (202).

[BOX] Case study: UK statistics on heart and kidney diseases

In 2024, 7.6 million people have heart and circulatory diseases in the UK which is twice as many as cancer and Alzheimer’s combined; and half of the population develop a heart or circulatory condition during their lifetime. Heart and circulatory diseases cause 27% of all deaths in the UK; 170,000 deaths every year, 480 every day, and 1 every 3 minutes. Heart failure is a major concern affecting over one million people. Heart and circulatory diseases cost £10 billion each year for healthcare and total cost to the economy is £25 billion/year (203).

In 2023, 7.2 million people are living with kidney disease in the UK; 30,000 adults and children are on dialysis. Dialysis costs £34,000 per year. The number of people requiring dialysis could rise to 143,000, and the number requiring transplantation could be as high as 12,000/year by 2033. The cost of kidney disease in the UK is £7.0 billion, with £6.4 billion being direct costs to the NHS—about 3.2% of the NHS budget. In addition, missed work by patients with CKD and their care givers contributes to an annual productivity loss of £372 million. (204)

Recognize kidney disease as an important contributor to the global burden of disease

As discussed above, progress has been made in improving outcomes for people living with CVDs, but the age-standardised prevalence and death rates for CKD and DM continue to rise. Similarly, data from the ARIC study, heavily quoted here, and a more recent meta-analysis (14), highlight the close interconnection between heart and kidney diseases that has been known for two decades but has only recently become part of the more mainstream discourse. A major contributor to this fact is that people with kidney disease have been historically excluded, or significantly underrepresented, in CVD studies (205). This needs to change. Many barriers exist to achieving the goal of early detection and timely treatment for all with kidney and CV diseases. Strategies to close these gaps are highlighted below (Table 2).