Nephrol Dial Transplant (2016) 31: 1027–1030 doi: 10.1093/ndt/gfv419 Advance Access publication 6 January 2016

Why minorities live longer on dialysis: an in-depth examination of the Danish nephrology registry Connie M. Rhee1, Kamyar Kalantar-Zadeh1 and Keith C. Norris2 1

Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California

Irvine, Orange, CA, USA and 2David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

Correspondence and offprints requests to: Connie M. Rhee; E-mail: [email protected]

© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

immigrants, which demonstrated that in Western immigrants, the survival benefit attenuated over time but remained robust among those of non-Western origin [14, 15]. Access to the Danish Nephrology Registry allows for indepth examination of the entire Danish incident dialysis population, from whom inferences can be drawn without substantial selection or survivor bias. For example, the study’s low proportion of immigrant dialysis patients (∼9%) was similar to that of the broader Danish population (∼7%), and was largely comprised of patients of Western, Arab, South and Southeast Asian and sub-Saharan African origin [14, 15]. The predominantly white population, in conjunction with the relatively low burden of diabetes as the primary cause of ESRD (23%), may account for Denmark’s decline in ESRD over the past decade [incidence rates of treated ESRD patients as of 2000 and 2013 were 132 and 117 per million, respectively, according to longitudinal international data from the United States Renal Data System (USRDS)] [1]. Another notable observation was the similar age-adjusted rates of kidney transplantation among immigrant subgroups and native Danes, which stands in contrast to other Western nations, where black and Hispanic dialysis patients are less likely to undergo transplantation [1, 5]. Given their equivalent transplant rates, it is unlikely that the diminution of healthier native Danish dialysis patients due to kidney transplantation is an explanatory factor for lower mortality risk among immigrants; in addition, competing risk methods used to address differential transplantation rates across race/ethnicity demonstrated a robust immigrant survival advantage. Direct study of the Danish dialysis population also provides a unique opportunity to dissect potential mechanisms underlying the paradoxical minority survival advantage pervasive in other Western and international ESRD populations (Figure 1). For example, Denmark provides a well-established universal health care system in which most health care is

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Epidemiological data have consistently shown that various racial and ethnic minorities, including black, Hispanic, IndoAsian and Arab-Israeli populations, have a disproportionately higher prevalence of end-stage renal disease (ESRD) compared with those of white European ancestry [1–3]. Among minorities with ESRD, numerous disparities have been observed, including less access to pre-ESRD nephrology care, poorer achievement of dialysis performance measures (e.g. hemoglobin and parathyroid hormone levels) and lower kidney transplantation rates [4–6]. Despite these inequities, population-based studies show that racial/ethnic minorities receiving dialysis have a paradoxical survival advantage compared with their white counterparts [1, 2, 5, 7–9]. While these racial/ethnic differences in ESRD survival have been well documented in US and Canadian-based populations, there have been few studies of European dialysis patients, and these have largely been restricted to populations in the UK and The Netherlands (Table 1) [3, 10–14]. Further examination of dialysis populations from other countries of the European Union are warranted, given their (i) disparate racial/ethnic compositions, (ii) lower comorbidity burden and mortality rates, (iii) differential age distributions and (iv) distinct health care delivery systems across different European Union nations. In this issue of Nephrology Dialysis Transplantation, van den Beukel et al. [14] conducted one of the largest European-based studies of race, ethnicity and survival among incident dialysis patients to date using the Danish National Registry, which has comprehensive capture of all Danish ESRD patients from 1990 onward. The investigators granularly examined the survival of various immigrant racial/ethnic populations and found that all immigrant subgroups had lower mortality risk compared with native Danes in crude and adjusted analyses. Linkage of patient-level data to Statistics Denmark, a Danish governmental organization under the Ministry for Economic and Interior Affairs, also permitted examination of the association between the duration of residence and death risk among

Table 1. Selected studies of race, ethnicity, and mortality among dialysis cohorts from the European Union Author

Country

Cohort (n)

Results

Comments

Prasad et al. (2004) [3] United Kingdom

Incident dialysis patients from a Black patients had ↓ mortality risk single center (1340) versus whites

van den Beukel et al. (2008) [10]

Netherlands

Incident dialysis patients from a Immigrant patients had ↓ mortality risk Effect modification by age: >survival single center (303) versus native Dutch patients benefit in middle and older age groups (56–70, >70 years) but not in younger age group (≤55 years)

Roderick et al. (2009) [11]

England and Wales

Incident dialysis patients from the UK Renal Registry (2495)

Kalantar-Zadeh et al. (2010) [2]

Israel

Dialysis patients from the Renal Arab-Israeli patients had ↓ mortality risk The hypothetical impact of nutritional Registry of the Israeli Society of versus Jewish-Israeli patients status was speculated Nephrology and Hypertension

van den Beukel et al. (2012) [12]

Netherlands

NECOSAD cohort (1791)

Black patients had ↓ mortality risk N/A versus white patients. Asian patients had equivalent mortality risk versus white patients

Cole et al. (2014) [13] UK

Incident hemodialysis patients from a single center (465)

Indo-Asian and Afro-Caribbean patients had equivalent mortality risk versus whites

N/A

van den Beukel et al. (2015) [14]

Danish nephrology registry (8459)

All immigrant groups had ↓ mortality risk versus native Danish patients

Immigrant groups consisted of Western countries, Arabic countries, South and Southeast Asia and sub-Saharan Africa.

Denmark

South Asians and black patients had ↓ mortality risk versus white patients

N/A

N/A

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NECOSAD, Netherlands Cooperative Study on the Adequacy of Dialysis.

F I G U R E 1 : Potential explanatory factors for paradoxical survival advantage in minority dialysis patients.

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Race, ethnicity and survival in Denmark

developing ESRD or the emigration of fitter patients from their native countries of origin may have resulted in selection bias and a healthier immigrant incident dialysis population [17, 18]. Second, while the immigrant survival advantage persisted even with adjustment for household income, it is possible that the associations may still be explained by other unmeasured socioeconomic factors (e.g. education, occupation) [19]. In addition, despite Denmark’s universal health care delivery system, other factors related to health care access (i.e. related to geographic residence and distance to health care centers) may still persist [20]. Third, the observed attenuation in survival advantage among Western immigrants with a longer duration of residence in Denmark also raises the possibility of sociocultural and lifestyle factors (dietary habits, social networks, physical activity, tobacco and alcohol use) being contributory [2]. Fourth, differential perceptions of quality of life, coping mechanisms and subsequent preferences for aggressive treatment in chronic illness and at the end of life may also play a role in racial/ethnic disparities in survival [21–23]. In addition, although some markers of comorbidity burden were accounted for using hospitalization and prescription data, the robust paradoxical racial/ethnic survival benefit suggests that other biologic factors are likely to be a factor in the Danish immigrant survival advantage. For example, past studies suggest that racial/ethnic differences in survival may be due in part to more favorable inflammatory, body anthropometry and nutritional profiles (e.g. higher serum prealbumin and creatinine as well as higher body mass index) in black versus white dialysis patients in the USA [24–26]. Lastly, it is plausible that differences in dialysis treatment characteristics may play a role in the mortality differential. While a greater proportion of native Danes received initial treatment with hemodialysis versus peritoneal dialysis, initial dialysis modality and type of vascular access among those receiving hemodialysis were not accounted for in survival analyses due to data limitations. In other Western studies, it has also been suggested that a higher likelihood of receiving activated vitamin D due to higher parathyroid hormone level distributions may partially account for the longevity of black dialysis patients [2, 4]. In conclusion, the van den Beukel et al. [14] study adds new knowledge to a growing body of evidence demonstrating lower mortality risk among immigrant dialysis patients versus native residents in European-based countries, and provides greater insight into potential explanatory factors specific to the Danish population. Future studies that test the impact of interventions upon modifiable factors (e.g. socioeconomic, dietary, physical activity, social support, pharmacologic) of the survival disparity in dialysis patients are needed. Moreover, further investigations of the racial/ethnic dialysis mortality paradox within other understudied populations and of underlying causes are urgently needed. For example, black dialysis patients have been observed to have lower hemoglobin levels than their white counterparts, and how this impacts mortality differences is largely unknown [27]. In addition, there are substantial knowledge gaps as to whether the differential expression of genetic polymorphisms [e.g. apolipoprotein 1 (APOL1), glucose 6-phosphate dehydrogenase (G6PD) and glutathione S-transferase class mu enzyme (GSTM1) gene mutations] among black versus non-black patients may contribute to survival disparities

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administered free at the point of delivery to all residents [16]. While ∼40% of residents may have complementary insurance for additional noncovered services, examination of the Danish population likely reduces confounding on the basis of differential health care access or nonuniform medical care. Furthermore, the availability of data through linkage to the Danish National Patient and Danish National Prescription Registries enabled exploration of potential causal pathway intermediates using incrementally adjusted survival models. Compared to immigrant dialysis patients, native Danes were of older age and had higher comorbidity burden (e.g. higher prevalence of cardiovascular disease and greater antihypertension medication use) as potential explanatory factors for their higher death risk in crude analyses. However, hierarchical adjustment for sociodemographic, socioeconomic and clinical covariates led to only minimal attenuation of the strong survival advantage among immigrant versus native Danish patients. It is important to highlight that point estimates of the association between race/ethnicity and mortality did not substantially differ according to underlying age (≤50 versus >50 years) in this study. This stands in contrast to multiple population-based studies conducted in the USA and Europe, in which age was found to be a critical modifier of racial/ethnic survival disparities [5, 7–10]. In a study of >1.3 million incident dialysis patients from the USRDS registry, Kucirka et al. [8] demonstrated that in older age groups (>50 years), black patients had lower mortality versus whites, whereas in younger age groups (≤50 years) they had higher mortality risk. In a subsequent study that separately considered Hispanic ethnicity, Yan et al. [9] observed that Hispanic, black and non-Hispanic white dialysis patients from the USRDS registry had the lowest, intermediate and highest mortality risks across all age strata, respectively, except within the 18–30 years age category, in which blacks had a higher mortality risk than non-Hispanic whites. Since data limitations precluded the ability to comprehensively account for differential comorbidity and metabolic profiles in these prior studies, Rhee et al. [5] reexamined the association between age, race, ethnicity and survival among >130 000 prevalent dialysis patients from a large US dialysis organization and similarly observed that, compared with white patients, black patients had a lower mortality risk in older age groups (>60 years) but a similar or higher mortality risk in younger age groups (≤60 years) [5]. It has been suggested that the observed attenuation or reversal of the minority survival advantage in younger black dialysis patients may be due to limited insurance and access to health care prior to dialysis initiation, or lack thereof, resulting in a higher comorbidity burden at the time of dialysis initiation [5, 8]. The present study’s demonstration of a persistent immigrant survival advantage across all age groups in a population with universal health care access adds support to this hypothesis [14]. The proposed mechanisms underlying the paradoxical survival advantage among immigrant minority dialysis patients in Denmark and minority dialysis patients in other countries may be due to multiple, complementary factors (Figure 1). First, although the present study did not examine data prior to the initiation of dialysis, it is possible that death of more sickly predialysis chronic kidney disease (CKD) patients prior to

[28–30]. Insights gleaned from future studies may lead to the identification of factors that can be leveraged to improve the health and survival of the broader dialysis population.

AC K N O W L E D G E M E N T S The authors are supported by the research grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, including K23-DK102903 (C.M.R.), K24-DK091419 (K.K.-Z.), P20-MD000182 (K.N.), UL1TR000124 (K.N.), P30AG021684 (K.N.), and philanthropist grants from Harold Simmons, Louis Chang, Dr Joseph Lee and AVEO.

C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared. (See related article by van den Beukel et al. Differences in survival on chronic dialysis treatment between ethnic groups in Denmark: a population-wide, national cohort study. Nephrol Dial Transplant 2016; 31: 1160–1167)

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10. van den Beukel TO, Dekker FW, Siegert CE. Increased survival of immigrant compared to native dialysis patients in an urban setting in the Netherlands. Nephrol Dial Transplant 2008; 23: 3571–3577 11. Roderick P, Byrne C, Casula A et al. Survival of patients from South Asian and Black populations starting renal replacement therapy in England and Wales. Nephrol Dial Transplant 2009; 24: 3774–3782 12. van den Beukel TO, Verduijn M, le Cessie S et al. The role of psychosocial factors in ethnic differences in survival on dialysis in the Netherlands. Nephrol Dial Transplant 2012; 27: 2472–2479 13. Cole N, Bedford M, Cai A et al. Black ethnicity predicts better survival on dialysis despite greater deprivation and co-morbidity: a UK study. Clin Nephrol 2014; 82: 77–82 14. van den Beukel TO, Hommel K, Kamper AL et al. Differences in survival on chronic dialysis treatment between ethnic groups in Denmark: a population-wide, national cohort study. Nephrol Dial Transplant 2016; 31: 1160–1167 15. Statistics Denmark. http://dst.dk/eng/Statistics/ 16. Commonwealth Fund. International Profiles of Health Care Systems. New York, NY: Commonwealth Fund, 2010 17. Mehrotra R, Kermah D, Fried L et al. Racial differences in mortality among those with CKD. J Am Soc Nephrol 2008; 19: 1403–1410 18. Razum O, Twardella D. Time travel with Oliver Twist—towards an explanation foa a paradoxically low mortality among recent immigrants. Trop Med Int Health 2002; 7: 4–10 19. Patzer RE, McClellan WM. Influence of race, ethnicity and socioeconomic status on kidney disease. Nat Rev Nephrol 2012; 8: 533–541 20. Radley DC, Schoen C. Geographic variation in access to care—the relationship with quality. N Engl J Med 2012; 367: 3–6 21. Feroze U, Martin D, Reina-Patton A et al. Mental health, depression, and anxiety in patients on maintenance dialysis. Iran J Kidney Dis 2010; 4: 173–180 22. Thomas BA, Rodriguez RA, Boyko EJ et al. Geographic variation in blackwhite differences in end-of-life care for patients with ESRD. Clin J Am Soc Nephrol 2013; 8: 1171–1178 23. Weisbord SD, Fried LF, Unruh ML et al. Associations of race with depression and symptoms in patients on maintenance haemodialysis. Nephrol Dial Transplant 2007; 22: 203–208 24. Noori N, Kovesdy CP, Dukkipati R et al. Racial and ethnic differences in mortality of hemodialysis patients: role of dietary and nutritional status and inflammation. Am J Nephrol 2011; 33: 157–167 25. Ricks J, Molnar MZ, Kovesdy CP et al. Racial and ethnic differences in the association of body mass index and survival in maintenance hemodialysis patients. Am J Kidney Dis 2011; 58: 574–582 26. Streja E, Kovesdy CP, Molnar MZ et al. Role of nutritional status and inflammation in higher survival of African American and Hispanic hemodialysis patients. Am J Kidney Dis 2011; 57: 883–893 27. Obrador GT, Ruthazer R, Arora P et al. Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. J Am Soc Nephrol 1999; 10: 1793–1800 28. Genovese G, Friedman DJ, Ross MD et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329: 841–845 29. Lin HJ, Han CY, Bernstein DA et al. Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibility. Carcinogenesis 1994; 15: 1077–1081 30. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl) 1998; 76: 581–588

Received for publication: 16.11.2015; Accepted in revised form: 17.11.2015

C.M. Rhee et al.

Why minorities live longer on dialysis: an in-depth examination of the Danish nephrology registry.

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