International Differences in Dialysis Mortality Reflect Background General Population Atherosclerotic Cardiovascular Mortality

Abstract

Existing national, racial, and ethnic differences in dialysis patient mortality rates largely are unexplained. This study aimed to test the hypothesis that mortality rates related to atherosclerotic cardiovascular disease (ASCVD) in dialysis populations (DP) and in the background general populations (GP) are correlated. In a cross-sectional, multinational study, all-cause and ASCVD mortality rates were compared between GP and DP using the most recent data from the World Health Organization mortality database (67 countries; 1,571,852,000 population) and from national renal registries (26 countries; 623,900 population). Across GP of 67 countries (14,082,146 deaths), all-cause mortality rates (median 8.88 per 1000 population; range 1.93 to 15.40) were strongly related to ASCVD mortality rates (median 3.21; range 0.53 to 8.69), with Eastern European countries clustering in the upper and Southeast and East Asian countries in the lower rate ranges. Across DP (103,432 deaths), mortality rates from all causes (median 166.20; range 54.47 to 268.80) and from ASCVD (median 63.39 per 1000 population; range 21.52 to 162.40) were higher and strongly correlated. ASCVD mortality rates in DP and in the GP were significantly correlated; the relationship became even stronger after adjustment for age (R² = 0.56, P < 0.0001). A substantial portion of the variability in mortality rates that were observed across DP worldwide is attributable to the variability in background ASCVD mortality rates in the respective GP. Genetic and environmental factors may underlie these differences.

Mortality rates within dialysis populations (DP) remain excessive worldwide. Striking differences in overall (¹) and cardiovascular mortality in DP have been observed among the United States, Europe, and Japan, which persist after adjustment for standard risk factors (²) such as age, serum albumin concentration (³), and dosage of dialysis (⁴). Higher mortality rates in the US DP have been explained by the inferiority of national standards of care (^4–9); an absence of patient selection leading to inclusion of more “sick” patients; a higher prevalence of patients with diabetes (¹⁰); an excess of inner-city, low economic class population; or differences in practice patterns (^11–15). However, wide differences in mortality exist even within the United States, where black, Hispanic, and Asian patients have significantly better survival than white patients (^16,17). It seems that results within the United States less likely are explained by differences in practice patterns or selection factors.

It is likely that the variability of atherosclerotic cardiovascular diseases (ASCVD) that is seen in the general population (GP) is antecedent to the CVD in the respective DP. Therefore, we hypothesized that mortality rates in different DP, particularly those as a result of ASCVD, are related to the background ASCVD mortality in their respective GP. In collaboration with a large number of national dialysis registries worldwide, the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry and the Dialysis Outcomes and Practice Patterns Study (DOPPS), we have composed a comprehensive database of cause-specific mortality rates in DP for comparison with the World Health Organization (WHO) mortality database for GP.

Materials and Methods

We performed a cross-sectional, multinational, ecologic study to investigate the relationship between all-cause and ASCVD mortality rates in each DP and its respective background GP.

Data Sources

GP.

National population estimates of cause-specific mortality from 75 countries were obtained from the official WHO mortality database (¹⁸). Because of incomplete data, Brazil, Dominican Republic, Ecuador, El Salvador, Nicaragua, Paraguay, Peru, and South Africa were excluded from analysis. The final data set represented 67 countries from Western Europe, Eastern Europe, Middle East, Central Asia, Southeast and East Asia, Australasia, North America, and Central and South America, with a total estimated GP of 1,571,852,000 (Table 1). Information that included all ages were collected from the most updated data set available at the time of analysis and were from the year 2000 (33 countries; 49.3%), 1999 (22 countries; 32.8%), or earlier years (12 countries; 17.9%).

Causes of death were coded according to the 9th or 10th revision (^19,20) of the International Classification of Disease (ICD) coding system. ICD-9 was used by 28 (41.8%) and ICD-10 by 39 (58.2%) of all 67 countries.

DP.

Data on point prevalence of DP counts including total number of deaths and causes of death for the most updated year were provided by national renal registries (n = 16) either directly or via the ERA-EDTA Registry (n = 7) and investigators of the Euro-DOPPS (²¹) (n = 5), representing a total prevalent DP of 623,900 from 28 different countries (Table 2). Entry years for these data varied from 1998 to 2003. Data for Belgium were supplied from the Dutch-speaking and the French-speaking registries, which were combined to represent the country’s total counts. Euro-DOPPS is considered a representative sample of all in-center hemodialysis (HD) patients in five large European countries: France, Germany, Italy, Spain, and the United Kingdom (²²). Because national registry data from China were not available, data from the city registry of Shanghai (²³) were used. Coding systems that were used for declaration of causes of death included ICD-9/-10, ERA-EDTA codes (²⁴), or individually defined codes.

Causes of Death.

ASCVD was defined by three categories. “Ischemic heart disease” includes acute myocardial infarction and other ischemic heart diseases. “Other forms of heart disease” includes entities such as cardiac arrest and heart failure, which may be associated with atherosclerotic but also nonatherosclerotic diseases, such as valve disorders, pericarditis, endocarditis, and pulmonary embolism. These causes could not be differentiated when coding systems other than ICD-10 were used. However, in the countries that used ICD-10, non–atherosclerosis-related diseases accounted for only 3.9% of the total cardiac death count. “Cerebrovascular disease” was reported by all countries without further specification and therefore contains some diseases that may not be related directly to atherosclerosis, such as cerebral hemorrhage.

Statistical Analyses

All-cause and ASCVD mortality rates were computed as the total number of specified deaths reported for one calendar year divided by the total prevalent GP or DP of the respective country for the same year. Pearson correlation and regression analyses were used to assess the ordinary least squares (OLS) relationship between ASCVD mortality rates and all-cause mortality rates in the DP and the background GP of the respective countries. In addition, a weighted least squares (WLS) regression analysis was performed to assess the relationship between ASCVD mortality rates and all-cause mortality rates using population size as weighting factor (²⁵). This was done to give more weight to data points from larger countries, which should reflect smaller error variance. The square of the correlation coefficient (R²) estimates the decimal fraction of the variability of outcome variable that is explained by the predictor variable. Regression analysis using an interaction term was used to test for differences in regression slope between DP and GP. All analyses were carried out using SPSS version 13.0 (SPSS, Chicago, IL).

Adjustments for Population Age Structure.

Adjustments for differences in the age structure of GP and DP among countries were possible only for 21 countries for which age data for both populations were available. The DP age structure was defined by the overall median mean age (60.4 yr); the GP age structure was defined by the overall median percentage of the population that was 65 yr and older (15.8%). The use of different age measures for the two populations was necessary because of data availability. However, a test in a limited number of countries from DOPPS, where both age measures were available for DP, found that the age measure used (mean age versus percentage of population 65 yr and older) for comparison with GP did not affect the results.

Results

GP

Data on GP all-cause and ASCVD mortality were available for 67 countries from eight geographic regions (Western Europe, Eastern Europe, Middle East, Central Asia, Southeast and East Asia, Australasia, North America, and Central and South America), representing a total GP of 1,571,852,000 (Table 1). Mortality rates differed widely between countries, ranging from 1.93 to 15.40 per 1000 population (median 8.88; mean 8.63 ± 3.03) for all-cause mortality and from 0.53 to 8.69 per 1000 population (median 3.21; mean 3.52 ± 1.89) for ASCVD mortality. ASCVD mortality rates accounted for 18.4 to 69.5% of all-cause mortality rates in individual countries and significantly correlated with all-cause mortality rates (OLS r = 0.92, R² = 0.84, P < 0.0001; Figure 1). The estimate of the correlation on the basis of WLS regression was r = 0.95 (R² = 0.90, P < 0.001). The correlation between ASCVD mortality rates and non-ASCVD mortality rates was r = 0.58 (P < 0.001). The OLS slope value for ASCVD mortality rates regressed onto all-cause mortality rates was 0.57 (WLS slope = 0.61). Countries from geographic regions formed mortality clusters, with Eastern European countries clustering at the upper right and Southeast and East Asian countries and Central and South American countries clustering at the lower left.

DP

Twenty-six countries from the same geographic regions as mentioned previously provided data for point-prevalence and cause-specific mortality rates of their DP, representing a total prevalent DP of 623,900. For two countries, Poland and Slovenia, cause-specific death counts were not available. Mortality rates again differed widely between countries, ranging from 54.5 to 268.8 per 1000 population (median 166.22; mean 166.19 ± 60.82) for all-cause mortality and from 21.5 to 129.1 per 1000 population (median 63.29; mean 70.33 ± 34.41) for ASCVD mortality (Table 2). ASCVD mortality accounted for 21.3 to 60.4% of all-cause mortality across countries, and in every country, ASCVD mortality rates were much higher than in the relative GP. Again, there was a strong correlation between ASCVD mortality rates and all-cause mortality rates (r = 0.81, R² = 0.66, P < 0.0001), with a similar geographic distribution as found for GP (Figure 2). The WLS estimate of the correlation was r = 0.98 (R² = 0.96, P < 0.0001). The regression slopes for DP (OLS 0.45; WLS 0.44) did not differ significantly from the respective slopes that were obtained for GP, even after restricting the comparison of the regression slopes to those 23 countries that provided complete data sets for their DP as well as their GP populations (OLS: DP 0.38, GP 0.45, P = 0.96; WLS: DP 0.44, GP 0.53, P = 0.85).

The relationship for all-cause mortality rates between GP and DP from 25 countries, excluding Turkey, Malaysia, and Shanghai, for which no data were available from the WHO database, is shown in Figure 3A (OLS r = 0.70, R² = 0.49, P < 0.0001; WLS r = 0.63, R² = 0.40 P = 0.001). Because the correlation of DP mortality rates with GP mortality rates may be influenced by countries with a relatively low mean age for both GP and DP, adjustments for GP and DP age were made for 21 countries for which data on age structure were available for both GP and DP (Table 3). After adjustment for age by use of the overall median DP mean age (60.4 yr) and the overall median percentage of GP 65 yr and older (15.8%), the correlation between DP and GP all-cause mortality became even stronger (OLS r = 0.83, R² = 0.69, P < 0.0001; Figure 3B).

ASCVD mortality rates in DP were significantly correlated with background ASCVD mortality rates in the GP (unadjusted: OLS r = 0.59, R² = 0.35, P = 0.002; WLS r = 0.83, R² = 0.69, P < 0.001 [Figure 4A]; age-adjusted: OLS r = 0.75, R² = 0.56, P < 0.0001 [Figure 4B]). A similar pattern of regional clustering was observed as for GP, with Southeast and East Asian countries clustering at the lower end and Western European countries clustering at the upper end. The only Eastern European country that provided data for DP ASCVD mortality rates, the Czech Republic, is located at the upper end of the graph. Thus, on the basis of the squares of the OLS correlation coefficients, approximately 35 to 56% of the variability in ASCVD mortality rates among DP can be explained by the variability in ASCVD mortality rates among the respective GP.

Discussion

CVD are the major cause of mortality in dialysis patients. Cardiovascular mortality rates of the US DP compared with the US GP are amplified by a factor of 5 to 500 depending on the age group (²⁶). However, for unexplained reasons, dialysis mortality rates differ largely among the United States, Europe, and Japan, and these differences remain significant even after adjustments for demographics and the presence and the severity of comorbid conditions, including preexisting CVD (²¹). The data presented in this report contribute to a better understanding of the reasons for these mortality differences by demonstrating that ASCVD mortality rates that were observed in DP strongly correlate with those found in the respective background GP. According to our analysis, nearly half of the variability in ASCVD mortality rates in DP across countries can be explained by differences that exist among the GP. Because age is the single most important factor for ASCVD mortality, we attempted to adjust for age in the GP and the DP. Although for only 21 countries data on age structure were available for both GP and DP, adjustment for age strengthened the correlation between DP and GP ASCVD mortality (Figure 4B).

Differences in GP cardiovascular mortality rates among selected countries have been described previously (²⁷). The major reason for including the GP without corresponding dialysis information is to support the relation of geographic regions (ethnic groups) to overall mortality related to cardiovascular mortality. It has been shown that despite a similar prevalence of traditional cardiovascular risk factors (²⁸), the relative risk for coronary heart disease (CHD) events is significantly smaller in Chinese compared with white US individuals. Similarly, age-adjusted CHD mortality rates associated with hypertension, diabetes, and hypercholesterolemia were reported to be significantly higher in the United States than in Japan and Mediterranean countries (²⁹). In accordance with those reports, Southeast and East Asian countries in our study showed lower all-cause and ASCVD mortality rates than Northern American and European countries.

All-cause and ASCVD mortality rates were significantly higher in each DP compared with the respective background GP. Although differences in data quality between the major dialysis registries that provided epidemiologic information could not be excluded, consistency largely is present between countries that were defined by geographic groups. Our data stress the importance of CVD in DP worldwide and at the same time support our hypothesis that the prevalence of ASCVD mortality in DP for each country is closely related to the frequency of this disease entity in the respective background population.

Our data also are relevant to ethnic and racial mortality differences that were observed within US DP, where Asian and Hispanic individuals have substantially lower mortality rates than US white individuals despite similar treatment characteristics and no measurable differences in dialysis practice patterns (³⁰). A survival advantage for Hispanic individuals also has been observed in the US GP despite lower socioeconomic status, higher poverty rates, less education. and less health insurance coverage (³¹), and it has been suggested that similar factors that are associated with Hispanic survival benefit in the GP also may be operative in the DP (³²). Similarly, differences in the dialysis mortality among US white individuals and US Asian individuals clearly reflect differences that were found for DP mortality between the United States and Japan, and these differences have been related to dissimilarities in the background populations rather than to differences in dialysis treatment itself (³³). Although cultural factors may play an important role, acculturation to an American lifestyle does not seem to reverse the Asian survival advantage. The cardiovascular mortality risk of Japanese patients who have ESRD and reside in the United States is increased in comparison with DP that live in Japan but still lower than for US white DP (³³).

The variations in cardiovascular mortality rates among GP of different races can hardly be explained by different risk profiles. The INTERHEART Study recently indicated that traditional cardiovascular risk factors account for >90% of CHD risk throughout the world and that their relative contribution to total risk is similar across countries and continents (³⁴). Despite the similarity of risk factors for myocardial infarction, cardiovascular mortality rates differ strikingly between countries and may be a reflection of ethnic and racial differences in disease susceptibility. The latter may be governed by genetic factors, dietary habits, socioeconomic status, and environmental conditions. The prospective Multi-Ethnic Study of Atherosclerosis (MESA) in a cohort of 6110 individuals who were free of clinical CVD and treated diabetes provides evidence for significant differences in coronary artery calcium (CAC) by race (³⁵). For women, white women had the highest percentiles and Hispanic women generally had the lowest CAC, with Chinese and black women being intermediate. For men, white men consistently had the highest CAC score and Hispanic men had the second highest; black men were lowest at the younger ages, and Chinese men were lowest at the older ages. A growing number of gene polymorphism involved in atherosclerosis has been described (³⁶), some of which, such as apolipoprotein E, angiotensin-converting enzyme, and methylenetetrahydrofolate reductase C667T and 5-LO-activating protein (FLAP) (³⁷) are associated with CVD. Thus, gene polymorphisms may explain a large part of ethnic and racial mortality differences among DP.

Diet is an important factor that differs between continents and may explain differences in disease susceptibility and cardiovascular mortality. Hispanic immigrants in the United States represent a good model to study the effects of a change in dietary habits on mortality. Over time, these immigrants adapt to the different cultural environment by increasing fat and lower fruit and vegetable intake compared with their original diet (³⁸). Nevertheless, even after dietary acculturation and the acceptance of disadvantageous dietary habits, US Hispanic individuals still have a lower mortality risk than white Americans (³⁹), suggesting that dietary customs alone do not explain international differences in cardiovascular mortality among GP and probably also DP.

There may be other reasons for an increased cardiovascular mortality rate in the American DP. The prevalence of CVD in incident patients with ESRD has been found to be higher in the United States (71.8%) compared with Europe (range 52.5 to 65.8% [R.P., F.K.P., unpublished data, May 28, 2005). This could be explained either by better survival of pre-ESRD patients with ASCVD into ESRD or by earlier dialysis initiation. Selection criteria for renal replacement therapy are not different among the United States, Japan, and most Western European countries, where patient acceptance into dialysis programs is almost unlimited (^16,40). Transplantation rates also may affect CVD prevalence among DP, with lower transplantation rates, as in Japan, resulting in a larger reservoir of more healthy HD patients. Nevertheless, even assuming a similar transplantation rate in Japan as in the United States (approximately 5%) and superior survival in patients who receive a transplant, this would not explain the mortality differences between the countries. Conversely, in countries with high transplantation rates, such as Norway, where 70 to 75% of the ESRD population have a functioning transplant kidney (¹⁶), the DP may represent a “negative selection of untransplantables” with a higher mortality rate.

Differences in dialysis practice patterns have been proposed as an explanation for international survival differences. The DOPPS had been initiated to compare practice patterns among the United States, Europe, and Japan. In particular, significant differences have been reported for anemia management and type of vascular access. Anemia management is significantly better in the United States and Europe compared with Japan (¹⁴), and, as a consequence, mean hemoglobin levels are significantly lower in Japan. Use of a native fistula is much more common in Japan and Europe than in the United States, where more tunneled catheters and polytetrafluoroethylene (PTFE) grafts more frequently are used.

Our study has its strengths and its limitations. The study is unique with respect to the combination of DP data that were accrued from 26 countries worldwide. This reflects concerted efforts of a large fraction of the international dialysis community to respond to the high cardiovascular mortality of patients. At the same time, the compilation of data sets from different renal registries and international organizations introduces some limitations to the study and its interpretation. The databases are limited with respect to the breadth and the specificity of their information, and the validity of cross-national comparisons may be disputed because of possible variations in coding practices. Cardiovascular deaths may be assigned to these codes because of insufficient clinical information at the time of death, local medical diagnostic practices, or simply error. However, among the countries included, the relationship of outcome of DP and GP as shown in these studies has a strong internal consistency and is similar for all-cause mortality.

Whereas most national dialysis registries cover HD and peritoneal DP, the National Kidney Foundation of Singapore and DOPPS data include only HD patients, who in Germany, France, Italy, and Spain represent 90% and in the United Kingdom approximately 70% of all DP. However, overall and cardiovascular mortality rates are not materially different between these two treatment regimens. Finally, we recognize that “race” is an inadequate descriptor of genetic variation that has been influenced by natural selection and interaction with specific environments.

Conclusion

All-cause and ASCVD mortality rates vary considerably among DP worldwide. According to our data, a substantial portion of the differences in ASCVD mortality rates among DP are reflective of ASCVD mortality rates in the background GP and, therefore, of variations in CVD susceptibility among ethnic and racial groups. This study suggests the importance of genetic and environmental factors for explaining the differences in and mortality associated with ASCVD in patients with ESRD worldwide. Further studies into genetic predisposition for development and progression of CVD are highly warranted. Because background GP mortality seems to explain nearly half of the variations in DP mortality, a substantial portion of the remaining variability may be modifiable by optimizing of dialysis treatment strategies, which should remain a major focus of dialysis practice in individual countries.

Figure 1: Relationship between atherosclerotic cardiovascular disease (ASCVD) mortality rates and all-cause mortality rates per 1000 population in the general populations (GP) of 67 countries: Western Europe (), Mediterranean countries (France, Greece, Italy, and Spain; (⋄), Eastern Europe (□), North America (▵), Central and South America (▴), Middle East (—), Central Asia (Æ), Southeast and East Asia (○), and Australasia (+). Ordinary least squares (OLS) regression R ² = 0.84, P < 0.0001; weighted least squares (WLS) regression R ² = 0.90, P < 0.0001.

Figure 2: Relationship between ASCVD mortality rates and all-cause mortality rates per 1000 population in dialysis populations (DP) of 26 countries: Western Europe (), Mediterranean countries (⋄), Eastern Europe (□), Middle East (—), North America (▵), Central America (▴), Southeast and East Asia (○), and Australasia (+). OLS R ² = 0.66, P < 0.0001; WLS R ² = 0.96, P < 0.0001.

Figure 3: Relationship of all-cause mortality rates per 1000 population between GP and DP. (A) Unadjusted relationship among 25 countries identified by region: Western Europe (), Mediterranean countries (⋄), Eastern Europe (□), North America (▵), Central America (▴), Southeast and East Asia (○), and Australasia (+). OLS R ² = 0.49, P < 0.0001; WLS R ² = 0.40, P = 0.0001. (B) Relationship among 21 countries after adjustment for age in DP (overall median mean age [60.4 yr]) and GP (overall median percentage of population aged ≥65 yr [15.8%]). OLS R ² = 0.69, P < 0.0001.

Figure 4: Relationship of ASCVD mortality rates per 1000 population between GP and DP. (A) Unadjusted relationship among 23 countries identified by region: Western Europe (), Mediterranean countries (⋄), Eastern Europe (□), North America (▵), Central America (▴), Southeast and East Asia (○), and Australasia (+). OLS R ² = 0.35, P = 0.002; WLS R ² = 0.69, P < 0.001. (B) Relationship among 21 countries after adjustment for age in DP (overall median mean age [60.4 yr]) and GP (overall median percentage of population aged ≥65 yr [15.8%]). OLS R ² = 0.56, P < 0.0001.

Table 1: Populations studied, years of registration, population size, and all-cause and ASCVD mortality rates in GPa

Table 2: Populations studied, years of registration, population size, and all-cause and ASCVD mortality rates in DPa

Table 3: Data from 21 countries on the age distribution and age-adjusted ASCVD mortality in the GP and DP

These data were presented in part at the annual meeting of the American Society of Nephrology; October 29 through November 1, 2004; St. Louis, MO.

We thank Brenda Gillespie, PhD (Professor of Biostatistics, University of Michigan) and Charlotte Arrington, MPH (epidemiologist, University Renal Research and Education Association) for statistical advice, Laura Rosales, MD (Renal Research Institute) for Spanish translations, Paul van Dijk (ERA-EDTA Registry) for EDTA data coordination, and Adeera Levin, MD (University of British Columbia, Vancouver, BC, Canada) and Kim Badovinac (Canadian Organ Replacement Register) for critically reviewing the manuscript.