Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation, longer survival than men

Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation,... In 2018, World Kidney Day (WKD) and International Women’s Day coincide. The WKD editorial focuses on women’s kidney health. The European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015 summary provides an excellent snapshot of renal replacement therapy (RRT) epidemiology and women in Europe. The WKD editorial reports a lower incidence of RRT in women in major registries and potential limitations to women’s access to transplantation. What is the situation in Europe? In Europe, the incidence of RRT is also lower in women: 38% of incident RRT patients are women. Does it represent milder chronic kidney disease (CKD) in women or barriers to RRT access? The question arises from the higher prevalence of CKD Stages G3–G5 in women than in men. However, in some European countries, such as Spain, non-dialysis CKD Stages G4–G5 is less frequent in women than in men, recapitulating the difference in RRT incidence. In the ERA-EDTA Registry, the incidence of transplantation as a first modality on Day 1 was slightly higher for women and survival on RRT was similar for women and men in the first 3 months, but an intergender gap favouring women increased as RRT vintage increased. However, women on RRT are worse off regarding survival when compared with women in the general population than men on RRT compared with men in the general population. In conclusion, the ERA-EDTA Registry Annual Report 2015 and European epidemiology data suggest a lower incidence of end-stage kidney disease in women, no gender differences in access to transplantation and better RRT survival in women. Key words: access to health care, chronic kidney disease, dialysis inequality, epidemiology, gender, mortality, public heath, transplantation Introduction these inequalities persist in the Annual Report 2015 [3]. The Two years ago, upon publication of the European Renal incidence rates of RRT per million population (pmp) ranged Association–European Dialysis and Transplant Association from 24 (unadjusted) in Ukraine to 285 (adjusted) in Israel, a (ERA-EDTA) Registry Annual Report 2012 [1], we commented on >10-fold difference. Both extremes are bad news: RRT may not be offered to all in need in some countries and prevention of the inequalities in the incidence of renal replacement therapy (RRT) across different European countries [2]. Unfortunately, end-stage renal disease (ESRD) may be facing hurdles in others. Received: December 19, 2017. Editorial decision: December 19, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2| R. Fernandez-Prado et al. Fig. 1. Unadjusted incidence and prevalence of RRT by gender, according to the ERA-EDTA Registry Annual Report 2015. (A) Incidence of RRT (%). (B) Prevalence of RRT (%). (C) Incidence (%) of treatment modality at Day 1. (D) Incidence (%) of treatment modality at Day 91. (E) Prevalence (%) of established therapy. (C–E) Based on data from registries providing individual patient data as reported in Kramer et al. [3]. Reproduced with permission of Kramer et al. This issue of the journal also contains the editorial written by barriers to RRT access in women? Is access to transplantation an International Society of Nephrology World Kidney Day com- lower in European women than in European men? Are RRT out- mittee on women and kidney disease, in a year in which World comes different in European women and men? Kidney Day (WKD) and International Women’s Day coincide [4]. The editorial focuses on women’s issues in the context of kidney Incidence and prevalence of RRT in Europe by disease across the globe, from unique risks for kidney diseases to gender pregnancy to access to and dosing of dialysis and/or transplanta- tion. A key aspect is access to and results of RRT in women as Data on the incidence of RRT in Europe confirm African, Japanese compared with men. Specifically, it reports on the lower inci- and US Renal Data System (USRDS) 2017 data [4, 9] of a lower inci- dence of RRT in women than in men exemplified by statistics in dence of RRT in women (Figure 1A). In Europe, 38% (unadjusted) Africa and Japan [5, 6] indicating that there are no explanations of incident RRT patients in 2015 were women, while in the USA for this finding. One distinct possibility is that women are discri- 42% were women in 2016 [3, 9]. The gender distribution of unad- minated against when resources do not allow providing RRT to justed prevalence in Europe was similar to the incidence data, every person in need. Indeed, lack of access to RRT is the most with 40% of prevalent patients being women (Figure 1B). Are frequent cause of death in ESRD patients worldwide [7]. It also women discriminated against in RRT access in Europe? reports that data from the USA, France, China and India indicate Access to the more detailed information in the full ERA- that women have lower kidney transplant rates than men, are EDTA Registry Annual Report 2015 provides some additional less likely to be registered on national transplant waiting lists clues. In most individual countries, the adjusted incidence of and have longer time from dialysis initiation to listing [4]. RRT was lower in women than in men and the gap ranged from In Europe, the European Society of Paediatric Nephrology/ 48 (Denmark) to 127 (Greece) pmp (Figure 2A) [10]. The only ERA-EDTA Registry reported that girls have a 23% lower probabil- exception was Estonia, a country where a total of 114 patients ity of receiving pre-emptive transplantation than boys [4, 8]. started RRT in 2015. In relative terms, the absolute pmp gap rep- Despite a faster progression towards ESRD in girls than in boys resented 45% (Denmark) to 80% (Iceland) of the total adjusted overall, medical factors explained only 70% of the gender differ- RRT incidence in pmp, except for Estonia (Figure 2B). When ence [8]. This begs several questions. What is the situation among expressed in relative terms, the figures are quite consistent European women overall? Is the incidence of RRT different in across European countries with different cultures, socio-economic men and women in Europe? Are there country-specific differen- levels, health care systems and absolute incidence of RRT. ces? If they do exist, are they due to a decreased incidence or pro- Available data from countries not providing individualized data gression rate of chronic kidney disease (CKD) in women or to showed similar trends, with the exception of the Sfax region of Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Gender and RRT | 3 Fig. 2. Differences between men and women in incident rates of RRT at Day 1, adjusted for age and gender, according to the ERA-EDTA Registry Annual Report 2015 [10]. (A) Difference in the incidence of RRT between men and women expressed in pmp (men pmp  women pmp). (B) Difference in the incidence of RRT between men and women expressed as a percentage of the whole country (men and women) pmp {100 [(men pmp  women pmp)/(all pmp)]}. Data from countries and regions pro- viding individualized data. For countries not providing whole-country data (Spain, Belgium), the mean value of the different regions was calculated. Tunisia, where the incident rates pmp at Day 1, adjusted for age discrimination based on a woman’s age regarding access to and gender, were high and very similar for men (241 pmp) and RRT. women (231 pmp). Again, in this region the total number of per- Beyond gender-based discrimination in access to RRT, gen- sons initiating RRT was relatively low (193 persons). In adults, der differences in the prevalence and severity of CKD or the lower incidence of RRT in women is consistent across age response to therapy may also account for the lower incidence of RRT in women. As editorialized, certain kidney diseases, such ranges and countries, with only a handful of exceptions that could be related to the low number of patients in these catego- as lupus nephritis, are more common in women [4]. However, ries (n< 25 per gender and age range: Estonia, 20–44 and 65– what is known about gender differences in the overall preva- 74 years; Castilla–Leon and Northern Ireland, 20–44 years) [10]. lence of CKD in Europe? A recent manuscript collected epide- Thus gender differences on RRT incidence exist: they are consis- miological information on CKD in Europe [11]. The prevalence of CKD Stages G3–G5 was higher in European women [11], consis- tent across countries and regions with different cultures, health care systems, gross domestic product and absolute incidence of tent with worldwide data showing a higher prevalence of CKD RRT and are independent of age. In this regard, there is wide Stages G1–G5 and G3–G5 in women than in men [12]. These data variability in the differences between women and men at the may be interpreted as consistent with the existence of bias age of RRT initiation [10]. The age gap ranges from a median of against providing RRT to women. However, analysis of available 4 years older in women in French-speaking Belgium to a European data from countries with free, unlimited access to younger age in women in Scandinavian countries (Iceland, both primary and specialty care, such as Spain, provided addi- Finland, Sweden, Norway and Denmark), which is up to 3 years tional information and clues [13]. While the 2004–8 Spanish epi- younger in women than in men. The reasons for these differen- demiological study confirmed the higher prevalence of CKD ces and regional clustering in Scandinavia should be explored, Stages G3–G5 in women than in men (7.71% versus 5.88%) of the but the fact that these differences exist argue against systemic general adult population, it also showed that severe CKD, that Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4| R. Fernandez-Prado et al. Fig. 3. Prevalence of different CKD categories and incidence of RRT by gender in Spain. Prevalence of CKD categories (A) G3 and (B) G4/G5 according to the 2004–8 EPIRCE Spanish epidemiological study of the adult general population [13]. (C) Incidence of RRT in 2015 in Spain according to gender [14]. Fig. 4. Percentage of patients with first treatment modality transplantation unadjusted at Day 1, according to the ERA-EDTA Registry Annual Report 2015 [10]. The top four countries or regions with the largest differences favouring either women or men are depicted. Data from countries and regions providing individualized data. The small number of patients in some regions adds a caution note to interpretation of the data. is, Stages G4–G5, are less frequent in women (0.21% versus obtained when diabetics and non-diabetics were included and 0.39%) (Figure 3A and B) [13]. This is consistent with the reported progression from CKD Stages G3–G5 to ESRD was assessed [17]. incidence of RRT in Spain in 2015 of 82 and 167 pmp for women Autosomal dominant polycystic kidney disease is influenced by and men, respectively (Figure 3C) [14]. gender [18]. Kidney cysts and loss of kidney function progress There are several potential explanations for the divergent faster in men and liver cysts progress faster in women. In con- epidemiology of CKD Stages G3–G5, representing mainly Stage trast, there are contradictory data for gender-specific progres- G3, and of Stage G4–G5 in Spain, which should be explored. sion of diabetic kidney disease [19]. Male sex has been They include different rates of progression in women and men, associated with faster progression, although the impact is not either spontaneously or as a consequence of therapeutic inter- as strong as in non-diabetic CKD [19]. In a recent meta-analysis vention or of dietary or health habits. In this regard, gender dif- of data from >5 million persons, women had a higher risk of ferences for the rate of CKD progression have been described. A ESRD, leading the authors to assume that women may have an recent review concluded that among higher-income countries, accelerated progression of CKD [20]. gender differences in the ESRD population require further study The ERA-EDTA Registry does not provide a breakdown of [15]. This echoed a meta-analysis of 68 published studies dis- causes of RRT by gender. This is an opportunity for further research closing that men with non-diabetic CKD have a faster loss of that would allow understanding whether gender differences in glomerular filtration rate than women [16]. Similar results were RRT incidence are limited to one or several causes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Gender and RRT | 5 4.0 the general population [10]. Thus a wider margin for improve- 2009 - 2013 ment in survival exists for women than for men on RRT. 3.5 2006 - 2010 3.0 Limitations of ERA-EDTA Registry data 2.5 2.0 The ERA-EDTA Registry continues to have a number of limita- tions, including blackouts from large countries such as 1.5 Germany and large parts of Italy [2, 3]. Additionally, some coun- 1.0 tries or regions do not provide individualized data so some epi- 0.5 demiological gender-related features could not be appropriately Difference favours women 0.0 explored in those countries. The possibility of a systematic bias 0 20406080 -0.5 arises and data from countries providing individualized data Difference favours men may not apply to countries not providing those data. Thus large -1.0 Months after initiation of RRT swaths of Eastern Europe do not provide individualized data and they include some of the countries with the lowest inci- Fig. 5. Difference in survival probability between men and women expressed as dence of RRT, such as Ukraine, Russia and Belarus. a percentage survival difference over time in incident RRT patients from Day 1, adjusted for age, gender and primary renal disease, according to the ERA-EDTA Registry Annual Report 2015 [10]. Data from countries and regions providing Conclusion individualized data. In conclusion, the ERA-EDTA Registry is a key resource to Access to transplantation in Europe by gender explore potential gender differences in the incidence of and access to RRT. The lower incidence of RRT in European women In USRDS 2017 data [9], there was a slightly lower incidence of compared with men may be caused by a slower progression of transplantation as a percentage of RRT modalities in women CKD. If this is so, the contributing factors should be unraveled (2.4%) than in men (2.6%). However, the situation was as they may provide clues to improve CKD outcomes across the different in European countries providing individualized data. board. This may be related not only to sex hormones, but also to The unadjusted incidence of modality at Day 1 suggested a other factors such as compliance with diet, medication or slight predominance of women having transplantation as the healthy living standards. In support of this hypothesis, at least first modality (Figure 1C) [3]. Treatment modality at Day 1 also for Spain, the gender epidemiology of CKD Stages G4–G5 is simi- displayed large country-to-country differences. However, lar to the gender epidemiology of RRT incidence. Alternatively, among countries that provided individual data, no systematic limitations in access to RRT may exist for women. Regarding bias against transplantation first in women was apparent in access to transplantation for European countries providing indi- any specific country [10]. An assessment of individual coun- vidualized data to the ERA-EDTA Registry, and this may repre- tries or regions with the largest gender gap in the percentage sent a bias, no differences were observed in access to of patients on transplantation as a first therapy disclosed a transplantation as a first RRT modality or in the prevalence of number of regions with large gaps favouring women, ranging transplantation between men and women. Finally, despite the from a 4% difference in Norway to a 6–13% difference in the better survival of European women on RRT as compared with Spanish regions of Navarre, Basque country and Cantabria, men, RRT has a greater adverse impact on survival for women while in regions where transplantation first favoured men, the than for men and research should focus on how to improve out- difference did not exceed 2% (Figure 4). By Day 91, gender dif- comes of women on RRT. ferences in transplantation could no longer be appreciated in the whole population (Figure 1D), as was the case for the prev- alence of transplantation (Figure 1E). Funding Funding was provided by grant support from the ISCIII and Gender and survival on RRT FEDER funds (PI16/02057), Sociedad Espanola de Nefrologia, ISCIII-RETIC REDinREN RD016/009, Joan Rodes (to BFF), The WKD editorial remarks that mortality rates are similar in men and women on dialysis, but the incident rates of some Comunidad de Madrid CIFRA2 B2017/BMD-3686. dialysis-associated complications and morbidity are higher in women, including hospitalization rates, 30-day readmissions, Conflict of interest statement anaemia, nutrition and quality of life issues, while the preva- lence of arteriovenous fistula was lower among women than None declared. men on haemodialysis [3, 21–23]. Furthermore, evaluation of the dialysis dose by Kt/V may result in underdialysis in urea References women [3, 24]. Despite the negative odds associated with these 1. Pippias M, Stel VS, Abad Diez JM et al. Renal replacement features, survival for women on RRT in Europe was similar to men for the first 3 months but was higher from then on, and therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report. Clin Kidney J 2015; 8: 248–261 increasing RRT vintage was associated with a widening survival 2. Gonzalez-Espinoza L, Ortiz A. 2012 ERA-EDTA Registry gap favouring women (Figure 5)[10]. However, as compared with the general population, the gap in life expectancy between Annual Report: cautious optimism on outcomes, concern about persistent inequalities and data black-outs. Clin Kidney sexes at any age range was considerably shorter in persons on RRT. Thus survival on RRT was better in women, but women on J 2015; 8: 243–247 RRT are worse off when compared with women in the general 3. Kramer A, Pippias M, Noordzij M et al. The European Renal population than when men on RRT are compared with men in Association – European Dialysis and Transplant Association Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % survival in women – % survival in men 6| R. Fernandez-Prado et al. (ERA-EDTA) Registry Annual Report 2015: a summary. Clin 15. Carrero J-J, Hecking M, Ulasi I et al. Chronic kidney disease, Kidney J 2018; 11: 108–122 gender, and access to care: a global perspective. Semin 4. Piccoli GB, Alrukhaimi M, Liu Z-H et al. Women and kidney Nephrol 2017; 37: 296–308 16. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the disease: reflections on World Kidney Day 2018. Clin Kidney J progression of nondiabetic renal disease: a meta-analysis. 2018; 11: 7–11 J Am Soc Nephrol 2000; 11: 319–329 5. Saran R, Robinson B, Abbott KC et al. US Renal Data System 17. Tsai W-C, Wu H-Y, Peng Y-S et al. Risk factors for develop- 2016 Annual Data Report: epidemiology of kidney disease in ment and progression of chronic kidney disease: the United States. Am J Kidney Dis 2017; 69(3 Suppl 1): A7–A8 a systematic review and exploratory meta-analysis. Medicine 6. Halle MP, Takongue C, Kengne AP et al. Epidemiological pro- 2016; 95: e3013 file of patients with end stage renal disease in a referral hos- 18. Gansevoort RT, Arici M, Benzing T et al. Recommendations pital in Cameroon. BMC Nephrol 2015; 16: 59 for the use of tolvaptan in autosomal dominant polycystic 7. Ortiz A, Covic A, Fliser D et al. Epidemiology, contributors to, kidney disease: a position statement on behalf of the ERA- and clinical trials of mortality risk in chronic kidney failure. EDTA Working Groups on Inherited Kidney Disorders and Lancet 2014; 383: 1831–1843 European Renal Best Practice. Nephrol Dial Transplant 2016; 8. Hogan J, Couchoud C, Bonthuis M et al. Gender disparities in 31: 337–348 access to pediatric renal transplantation in Europe: data 19. Maric C. Sex, diabetes and the kidney. Am J Physiol Renal from the ESPN/ERA-EDTA Registry. Am J Transplant 2016; 16: Physiol 2009; 296: F680–F688 2097–2105 20. Shen Y, Cai R, Sun J et al. Diabetes mellitus as a risk factor for 9. https://www.usrds.org/2017/view/Default.aspx (7 December incident chronic kidney disease and end-stage renal disease 2017, date last accessed) in women compared with men: a systematic review and 10. https://www.era-edta-reg.org/files/annualreports/pdf/Ann meta-analysis. Endocrine 2017; 55: 66–76 Rep2015.pdf (7 December 2017, date last accessed) 21. Sehgal AR. Outcomes of renal replacement therapy among 11. Bru ¨ ck K, Stel VS, Gambaro G et al. CKD prevalence varies blacks and women. Am J Kidney Dis 2000; 35(Suppl): across the European general population. J Am Soc Nephrol S148–S152 2016; 27: 2135–2147 22. Adams SV, Rivara M, Streja E et al. Sex differences in hospi- 12. Mills KT, Xu Y, Zhang W et al. A systematic analysis of world- talizations with maintenance hemodialysis. J Am Soc Nephrol wide population-based data on the global burden of chronic 2017; 28: 2721–2728 kidney disease in 2010. Kidney Int 2015; 88: 950–957 23. Ethier J, Mendelssohn DC, Elder SJ et al. Vascular access use 13. Otero A, de Francisco A, Gayoso P et al. Prevalence of chronic and outcomes: an international perspective from the dialy- renal disease in Spain: results of the EPIRCE study. Nefrologia sis outcomes and practice patterns study. Nephrol Dial 2010; 30: 78–86 Transplant 2008; 23: 3219–3226 14. http://www.senefro.org/contents/webstructure/reerOviedo 24. Depner TA. Prescribing hemodialysis: the role of gender. Adv 2016.pdf (11 December 2017, date last accessed) Ren Replace Ther 2003; 10: 71–77 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation, longer survival than men

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Abstract

In 2018, World Kidney Day (WKD) and International Women’s Day coincide. The WKD editorial focuses on women’s kidney health. The European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015 summary provides an excellent snapshot of renal replacement therapy (RRT) epidemiology and women in Europe. The WKD editorial reports a lower incidence of RRT in women in major registries and potential limitations to women’s access to transplantation. What is the situation in Europe? In Europe, the incidence of RRT is also lower in women: 38% of incident RRT patients are women. Does it represent milder chronic kidney disease (CKD) in women or barriers to RRT access? The question arises from the higher prevalence of CKD Stages G3–G5 in women than in men. However, in some European countries, such as Spain, non-dialysis CKD Stages G4–G5 is less frequent in women than in men, recapitulating the difference in RRT incidence. In the ERA-EDTA Registry, the incidence of transplantation as a first modality on Day 1 was slightly higher for women and survival on RRT was similar for women and men in the first 3 months, but an intergender gap favouring women increased as RRT vintage increased. However, women on RRT are worse off regarding survival when compared with women in the general population than men on RRT compared with men in the general population. In conclusion, the ERA-EDTA Registry Annual Report 2015 and European epidemiology data suggest a lower incidence of end-stage kidney disease in women, no gender differences in access to transplantation and better RRT survival in women. Key words: access to health care, chronic kidney disease, dialysis inequality, epidemiology, gender, mortality, public heath, transplantation Introduction these inequalities persist in the Annual Report 2015 [3]. The Two years ago, upon publication of the European Renal incidence rates of RRT per million population (pmp) ranged Association–European Dialysis and Transplant Association from 24 (unadjusted) in Ukraine to 285 (adjusted) in Israel, a (ERA-EDTA) Registry Annual Report 2012 [1], we commented on >10-fold difference. Both extremes are bad news: RRT may not be offered to all in need in some countries and prevention of the inequalities in the incidence of renal replacement therapy (RRT) across different European countries [2]. Unfortunately, end-stage renal disease (ESRD) may be facing hurdles in others. Received: December 19, 2017. Editorial decision: December 19, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2| R. Fernandez-Prado et al. Fig. 1. Unadjusted incidence and prevalence of RRT by gender, according to the ERA-EDTA Registry Annual Report 2015. (A) Incidence of RRT (%). (B) Prevalence of RRT (%). (C) Incidence (%) of treatment modality at Day 1. (D) Incidence (%) of treatment modality at Day 91. (E) Prevalence (%) of established therapy. (C–E) Based on data from registries providing individual patient data as reported in Kramer et al. [3]. Reproduced with permission of Kramer et al. This issue of the journal also contains the editorial written by barriers to RRT access in women? Is access to transplantation an International Society of Nephrology World Kidney Day com- lower in European women than in European men? Are RRT out- mittee on women and kidney disease, in a year in which World comes different in European women and men? Kidney Day (WKD) and International Women’s Day coincide [4]. The editorial focuses on women’s issues in the context of kidney Incidence and prevalence of RRT in Europe by disease across the globe, from unique risks for kidney diseases to gender pregnancy to access to and dosing of dialysis and/or transplanta- tion. A key aspect is access to and results of RRT in women as Data on the incidence of RRT in Europe confirm African, Japanese compared with men. Specifically, it reports on the lower inci- and US Renal Data System (USRDS) 2017 data [4, 9] of a lower inci- dence of RRT in women than in men exemplified by statistics in dence of RRT in women (Figure 1A). In Europe, 38% (unadjusted) Africa and Japan [5, 6] indicating that there are no explanations of incident RRT patients in 2015 were women, while in the USA for this finding. One distinct possibility is that women are discri- 42% were women in 2016 [3, 9]. The gender distribution of unad- minated against when resources do not allow providing RRT to justed prevalence in Europe was similar to the incidence data, every person in need. Indeed, lack of access to RRT is the most with 40% of prevalent patients being women (Figure 1B). Are frequent cause of death in ESRD patients worldwide [7]. It also women discriminated against in RRT access in Europe? reports that data from the USA, France, China and India indicate Access to the more detailed information in the full ERA- that women have lower kidney transplant rates than men, are EDTA Registry Annual Report 2015 provides some additional less likely to be registered on national transplant waiting lists clues. In most individual countries, the adjusted incidence of and have longer time from dialysis initiation to listing [4]. RRT was lower in women than in men and the gap ranged from In Europe, the European Society of Paediatric Nephrology/ 48 (Denmark) to 127 (Greece) pmp (Figure 2A) [10]. The only ERA-EDTA Registry reported that girls have a 23% lower probabil- exception was Estonia, a country where a total of 114 patients ity of receiving pre-emptive transplantation than boys [4, 8]. started RRT in 2015. In relative terms, the absolute pmp gap rep- Despite a faster progression towards ESRD in girls than in boys resented 45% (Denmark) to 80% (Iceland) of the total adjusted overall, medical factors explained only 70% of the gender differ- RRT incidence in pmp, except for Estonia (Figure 2B). When ence [8]. This begs several questions. What is the situation among expressed in relative terms, the figures are quite consistent European women overall? Is the incidence of RRT different in across European countries with different cultures, socio-economic men and women in Europe? Are there country-specific differen- levels, health care systems and absolute incidence of RRT. ces? If they do exist, are they due to a decreased incidence or pro- Available data from countries not providing individualized data gression rate of chronic kidney disease (CKD) in women or to showed similar trends, with the exception of the Sfax region of Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Gender and RRT | 3 Fig. 2. Differences between men and women in incident rates of RRT at Day 1, adjusted for age and gender, according to the ERA-EDTA Registry Annual Report 2015 [10]. (A) Difference in the incidence of RRT between men and women expressed in pmp (men pmp  women pmp). (B) Difference in the incidence of RRT between men and women expressed as a percentage of the whole country (men and women) pmp {100 [(men pmp  women pmp)/(all pmp)]}. Data from countries and regions pro- viding individualized data. For countries not providing whole-country data (Spain, Belgium), the mean value of the different regions was calculated. Tunisia, where the incident rates pmp at Day 1, adjusted for age discrimination based on a woman’s age regarding access to and gender, were high and very similar for men (241 pmp) and RRT. women (231 pmp). Again, in this region the total number of per- Beyond gender-based discrimination in access to RRT, gen- sons initiating RRT was relatively low (193 persons). In adults, der differences in the prevalence and severity of CKD or the lower incidence of RRT in women is consistent across age response to therapy may also account for the lower incidence of RRT in women. As editorialized, certain kidney diseases, such ranges and countries, with only a handful of exceptions that could be related to the low number of patients in these catego- as lupus nephritis, are more common in women [4]. However, ries (n< 25 per gender and age range: Estonia, 20–44 and 65– what is known about gender differences in the overall preva- 74 years; Castilla–Leon and Northern Ireland, 20–44 years) [10]. lence of CKD in Europe? A recent manuscript collected epide- Thus gender differences on RRT incidence exist: they are consis- miological information on CKD in Europe [11]. The prevalence of CKD Stages G3–G5 was higher in European women [11], consis- tent across countries and regions with different cultures, health care systems, gross domestic product and absolute incidence of tent with worldwide data showing a higher prevalence of CKD RRT and are independent of age. In this regard, there is wide Stages G1–G5 and G3–G5 in women than in men [12]. These data variability in the differences between women and men at the may be interpreted as consistent with the existence of bias age of RRT initiation [10]. The age gap ranges from a median of against providing RRT to women. However, analysis of available 4 years older in women in French-speaking Belgium to a European data from countries with free, unlimited access to younger age in women in Scandinavian countries (Iceland, both primary and specialty care, such as Spain, provided addi- Finland, Sweden, Norway and Denmark), which is up to 3 years tional information and clues [13]. While the 2004–8 Spanish epi- younger in women than in men. The reasons for these differen- demiological study confirmed the higher prevalence of CKD ces and regional clustering in Scandinavia should be explored, Stages G3–G5 in women than in men (7.71% versus 5.88%) of the but the fact that these differences exist argue against systemic general adult population, it also showed that severe CKD, that Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4| R. Fernandez-Prado et al. Fig. 3. Prevalence of different CKD categories and incidence of RRT by gender in Spain. Prevalence of CKD categories (A) G3 and (B) G4/G5 according to the 2004–8 EPIRCE Spanish epidemiological study of the adult general population [13]. (C) Incidence of RRT in 2015 in Spain according to gender [14]. Fig. 4. Percentage of patients with first treatment modality transplantation unadjusted at Day 1, according to the ERA-EDTA Registry Annual Report 2015 [10]. The top four countries or regions with the largest differences favouring either women or men are depicted. Data from countries and regions providing individualized data. The small number of patients in some regions adds a caution note to interpretation of the data. is, Stages G4–G5, are less frequent in women (0.21% versus obtained when diabetics and non-diabetics were included and 0.39%) (Figure 3A and B) [13]. This is consistent with the reported progression from CKD Stages G3–G5 to ESRD was assessed [17]. incidence of RRT in Spain in 2015 of 82 and 167 pmp for women Autosomal dominant polycystic kidney disease is influenced by and men, respectively (Figure 3C) [14]. gender [18]. Kidney cysts and loss of kidney function progress There are several potential explanations for the divergent faster in men and liver cysts progress faster in women. In con- epidemiology of CKD Stages G3–G5, representing mainly Stage trast, there are contradictory data for gender-specific progres- G3, and of Stage G4–G5 in Spain, which should be explored. sion of diabetic kidney disease [19]. Male sex has been They include different rates of progression in women and men, associated with faster progression, although the impact is not either spontaneously or as a consequence of therapeutic inter- as strong as in non-diabetic CKD [19]. In a recent meta-analysis vention or of dietary or health habits. In this regard, gender dif- of data from >5 million persons, women had a higher risk of ferences for the rate of CKD progression have been described. A ESRD, leading the authors to assume that women may have an recent review concluded that among higher-income countries, accelerated progression of CKD [20]. gender differences in the ESRD population require further study The ERA-EDTA Registry does not provide a breakdown of [15]. This echoed a meta-analysis of 68 published studies dis- causes of RRT by gender. This is an opportunity for further research closing that men with non-diabetic CKD have a faster loss of that would allow understanding whether gender differences in glomerular filtration rate than women [16]. Similar results were RRT incidence are limited to one or several causes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Gender and RRT | 5 4.0 the general population [10]. Thus a wider margin for improve- 2009 - 2013 ment in survival exists for women than for men on RRT. 3.5 2006 - 2010 3.0 Limitations of ERA-EDTA Registry data 2.5 2.0 The ERA-EDTA Registry continues to have a number of limita- tions, including blackouts from large countries such as 1.5 Germany and large parts of Italy [2, 3]. Additionally, some coun- 1.0 tries or regions do not provide individualized data so some epi- 0.5 demiological gender-related features could not be appropriately Difference favours women 0.0 explored in those countries. The possibility of a systematic bias 0 20406080 -0.5 arises and data from countries providing individualized data Difference favours men may not apply to countries not providing those data. Thus large -1.0 Months after initiation of RRT swaths of Eastern Europe do not provide individualized data and they include some of the countries with the lowest inci- Fig. 5. Difference in survival probability between men and women expressed as dence of RRT, such as Ukraine, Russia and Belarus. a percentage survival difference over time in incident RRT patients from Day 1, adjusted for age, gender and primary renal disease, according to the ERA-EDTA Registry Annual Report 2015 [10]. Data from countries and regions providing Conclusion individualized data. In conclusion, the ERA-EDTA Registry is a key resource to Access to transplantation in Europe by gender explore potential gender differences in the incidence of and access to RRT. The lower incidence of RRT in European women In USRDS 2017 data [9], there was a slightly lower incidence of compared with men may be caused by a slower progression of transplantation as a percentage of RRT modalities in women CKD. If this is so, the contributing factors should be unraveled (2.4%) than in men (2.6%). However, the situation was as they may provide clues to improve CKD outcomes across the different in European countries providing individualized data. board. This may be related not only to sex hormones, but also to The unadjusted incidence of modality at Day 1 suggested a other factors such as compliance with diet, medication or slight predominance of women having transplantation as the healthy living standards. In support of this hypothesis, at least first modality (Figure 1C) [3]. Treatment modality at Day 1 also for Spain, the gender epidemiology of CKD Stages G4–G5 is simi- displayed large country-to-country differences. However, lar to the gender epidemiology of RRT incidence. Alternatively, among countries that provided individual data, no systematic limitations in access to RRT may exist for women. Regarding bias against transplantation first in women was apparent in access to transplantation for European countries providing indi- any specific country [10]. An assessment of individual coun- vidualized data to the ERA-EDTA Registry, and this may repre- tries or regions with the largest gender gap in the percentage sent a bias, no differences were observed in access to of patients on transplantation as a first therapy disclosed a transplantation as a first RRT modality or in the prevalence of number of regions with large gaps favouring women, ranging transplantation between men and women. Finally, despite the from a 4% difference in Norway to a 6–13% difference in the better survival of European women on RRT as compared with Spanish regions of Navarre, Basque country and Cantabria, men, RRT has a greater adverse impact on survival for women while in regions where transplantation first favoured men, the than for men and research should focus on how to improve out- difference did not exceed 2% (Figure 4). By Day 91, gender dif- comes of women on RRT. ferences in transplantation could no longer be appreciated in the whole population (Figure 1D), as was the case for the prev- alence of transplantation (Figure 1E). Funding Funding was provided by grant support from the ISCIII and Gender and survival on RRT FEDER funds (PI16/02057), Sociedad Espanola de Nefrologia, ISCIII-RETIC REDinREN RD016/009, Joan Rodes (to BFF), The WKD editorial remarks that mortality rates are similar in men and women on dialysis, but the incident rates of some Comunidad de Madrid CIFRA2 B2017/BMD-3686. dialysis-associated complications and morbidity are higher in women, including hospitalization rates, 30-day readmissions, Conflict of interest statement anaemia, nutrition and quality of life issues, while the preva- lence of arteriovenous fistula was lower among women than None declared. men on haemodialysis [3, 21–23]. Furthermore, evaluation of the dialysis dose by Kt/V may result in underdialysis in urea References women [3, 24]. Despite the negative odds associated with these 1. Pippias M, Stel VS, Abad Diez JM et al. Renal replacement features, survival for women on RRT in Europe was similar to men for the first 3 months but was higher from then on, and therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report. Clin Kidney J 2015; 8: 248–261 increasing RRT vintage was associated with a widening survival 2. Gonzalez-Espinoza L, Ortiz A. 2012 ERA-EDTA Registry gap favouring women (Figure 5)[10]. However, as compared with the general population, the gap in life expectancy between Annual Report: cautious optimism on outcomes, concern about persistent inequalities and data black-outs. Clin Kidney sexes at any age range was considerably shorter in persons on RRT. Thus survival on RRT was better in women, but women on J 2015; 8: 243–247 RRT are worse off when compared with women in the general 3. Kramer A, Pippias M, Noordzij M et al. The European Renal population than when men on RRT are compared with men in Association – European Dialysis and Transplant Association Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % survival in women – % survival in men 6| R. Fernandez-Prado et al. (ERA-EDTA) Registry Annual Report 2015: a summary. Clin 15. Carrero J-J, Hecking M, Ulasi I et al. Chronic kidney disease, Kidney J 2018; 11: 108–122 gender, and access to care: a global perspective. Semin 4. Piccoli GB, Alrukhaimi M, Liu Z-H et al. Women and kidney Nephrol 2017; 37: 296–308 16. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the disease: reflections on World Kidney Day 2018. Clin Kidney J progression of nondiabetic renal disease: a meta-analysis. 2018; 11: 7–11 J Am Soc Nephrol 2000; 11: 319–329 5. Saran R, Robinson B, Abbott KC et al. US Renal Data System 17. Tsai W-C, Wu H-Y, Peng Y-S et al. Risk factors for develop- 2016 Annual Data Report: epidemiology of kidney disease in ment and progression of chronic kidney disease: the United States. Am J Kidney Dis 2017; 69(3 Suppl 1): A7–A8 a systematic review and exploratory meta-analysis. Medicine 6. Halle MP, Takongue C, Kengne AP et al. Epidemiological pro- 2016; 95: e3013 file of patients with end stage renal disease in a referral hos- 18. Gansevoort RT, Arici M, Benzing T et al. Recommendations pital in Cameroon. BMC Nephrol 2015; 16: 59 for the use of tolvaptan in autosomal dominant polycystic 7. Ortiz A, Covic A, Fliser D et al. Epidemiology, contributors to, kidney disease: a position statement on behalf of the ERA- and clinical trials of mortality risk in chronic kidney failure. EDTA Working Groups on Inherited Kidney Disorders and Lancet 2014; 383: 1831–1843 European Renal Best Practice. Nephrol Dial Transplant 2016; 8. Hogan J, Couchoud C, Bonthuis M et al. Gender disparities in 31: 337–348 access to pediatric renal transplantation in Europe: data 19. Maric C. Sex, diabetes and the kidney. Am J Physiol Renal from the ESPN/ERA-EDTA Registry. Am J Transplant 2016; 16: Physiol 2009; 296: F680–F688 2097–2105 20. Shen Y, Cai R, Sun J et al. Diabetes mellitus as a risk factor for 9. https://www.usrds.org/2017/view/Default.aspx (7 December incident chronic kidney disease and end-stage renal disease 2017, date last accessed) in women compared with men: a systematic review and 10. https://www.era-edta-reg.org/files/annualreports/pdf/Ann meta-analysis. Endocrine 2017; 55: 66–76 Rep2015.pdf (7 December 2017, date last accessed) 21. Sehgal AR. Outcomes of renal replacement therapy among 11. Bru ¨ ck K, Stel VS, Gambaro G et al. CKD prevalence varies blacks and women. Am J Kidney Dis 2000; 35(Suppl): across the European general population. J Am Soc Nephrol S148–S152 2016; 27: 2135–2147 22. Adams SV, Rivara M, Streja E et al. Sex differences in hospi- 12. Mills KT, Xu Y, Zhang W et al. A systematic analysis of world- talizations with maintenance hemodialysis. J Am Soc Nephrol wide population-based data on the global burden of chronic 2017; 28: 2721–2728 kidney disease in 2010. Kidney Int 2015; 88: 950–957 23. Ethier J, Mendelssohn DC, Elder SJ et al. Vascular access use 13. Otero A, de Francisco A, Gayoso P et al. Prevalence of chronic and outcomes: an international perspective from the dialy- renal disease in Spain: results of the EPIRCE study. Nefrologia sis outcomes and practice patterns study. Nephrol Dial 2010; 30: 78–86 Transplant 2008; 23: 3219–3226 14. http://www.senefro.org/contents/webstructure/reerOviedo 24. Depner TA. Prescribing hemodialysis: the role of gender. Adv 2016.pdf (11 December 2017, date last accessed) Ren Replace Ther 2003; 10: 71–77 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/1/4828125 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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