Declining comorbidity-adjusted mortality rates in English patients receiving maintenance renal replacement therapy
Authors: Benjamin C. Storey, Natalie Staplin, Charlie H. Harper, Richard Haynes, Christopher G. Winearls, Raph Goldacre, Jonathan R. Emberson, Michael J. Goldacre, Colin Baigent, Martin J. Landray, William G. Herrington
Journal: Kidney International (2018)

We aimed to compare long-term mortality trends in end-stage renal disease versus general population controls after accounting for differences in age, sex and comorbidity. Cohorts of 45,000 patients starting maintenance renal replacement therapy (RRT) and 5.3 million hospital controls were identified from two large electronic hospital inpatient data sets: the Oxford Record Linkage Study (1965-1999) and all-England Hospital Episode Statistics (2000-2011). All-cause and cause-specific three-year mortality rates for both populations were calculated using Poisson regression and standardized to the age, sex, and comorbidity structure of an average 1970-2008 RRT population. The median age at initiation of RRT in 1970-1990 was 49 years, increasing to 61 years by 2006-2008. Over that period, there were increases in the prevalence of vascular disease (from 10.0 to 25.2%) and diabetes (from 6.7 to 33.9%). After accounting for age, sex and comorbidity differences, standardized three-year all-cause mortality rates in treated patients with end-stage renal disease between 1970 and 2011 fell by about one-half (relative decline 51%, 95% confidence interval 41-60%) steeper than the one-third decline (34%, 31-36%) observed in the general population. Declines in three-year mortality rates were evident among those who received a kidney transplant and those who remained on dialysis, and among those with and without diabetes. These data suggest that the full extent of mortality rate declines among RRT patients since 1970 is only apparent when changes in comorbidity over time are taken into account, and that mortality rates in RRT patients appear to have declined faster than in the general population. We aimed to compare long-term mortality trends in end-stage renal disease versus general population controls after accounting for differences in age, sex and comorbidity. Cohorts of 45,000 patients starting maintenance renal replacement therapy (RRT) and 5.3 million hospital controls were identified from two large electronic hospital inpatient data sets: the Oxford Record Linkage Study (1965-1999) and all-England Hospital Episode Statistics (2000-2011). All-cause and cause-specific three-year mortality rates for both populations were calculated using Poisson regression and standardized to the age, sex, and comorbidity structure of an average 1970-2008 RRT population. The median age at initiation of RRT in 1970-1990 was 49 years, increasing to 61 years by 2006-2008. Over that period, there were increases in the prevalence of vascular disease (from 10.0 to 25.2%) and diabetes (from 6.7 to 33.9%). After accounting for age, sex and comorbidity differences, standardized three-year all-cause mortality rates in treated patients with end-stage renal disease between 1970 and 2011 fell by about one-half (relative decline 51%, 95% confidence interval 41-60%) steeper than the one-third decline (34%, 31-36%) observed in the general population. Declines in three-year mortality rates were evident among those who received a kidney transplant and those who remained on dialysis, and among those with and without diabetes. These data suggest that the full extent of mortality rate declines among RRT patients since 1970 is only apparent when changes in comorbidity over time are taken into account, and that mortality rates in RRT patients appear to have declined faster than in the general population. Maintenance dialysis programs for end-stage renal disease (ESRD) began in the United Kingdom in the 1960s.1Anon. (Editorial). Profit and loss in intermittent haemodialysis.Lancet. 1965; 2: 1058-1059Google Scholar, 2Anon. (Editorial). Intermittent Haemodialysis.Lancet. 1962; 279: 2Google Scholar, 3Crowther S.M. Reynolds L.A. Tansey E.M. History of Dialysis in the UK: c. 1950-1980. Wellcome Trust Centre, London2009Google Scholar Until the 1980s, renal replacement therapy (RRT; i.e., dialysis or kidney transplantation) was restricted to ESRD patients who were considered the most economically active, and those with diabetes or other comorbidities were often not referred or treated.4Medical Services Study Group of the Royal College Of PhysiciansDeaths from chronic renal failure under the age of 50.Br Med J (Clin Res Ed). 1981; 283: 283-286Crossref PubMed Scopus (20) Google Scholar This contrasts with the situation 50 years later, when the median age of patients starting maintenance RRT is 65 years and diabetes is the leading cause of ESRD.5Caskey F. Castledine C. Dawnay A. et al.UK Renal Registry: 18th Annual Report of the Renal Association 2015.Nephron. 2016; 132Google Scholar Examining long-term temporal mortality trends helps describe past and current serious health risks. Interpreting these trends is difficult in RRT populations because comparisons between patients treated for ESRD and other populations need to take account of the substantial secular changes in the prevalence of comorbid illnesses that influence both mortality6Khan I.H. Catto G.R. Edward N. et al.Influence of coexisting disease on survival on renal-replacement therapy.Lancet. 1993; 341: 415-418Abstract PubMed Scopus (244) Google Scholar, 7Miskulin D. Bragg-Gresham J. Gillespie B.W. et al.Key comorbid conditions that are predictive of survival among hemodialysis patients.CJASN. 2009; 4: 1818-1826Crossref PubMed Scopus (60) Google Scholar, 8Davies S.J. Phillips L. Naish P.F. Russell G.I. Quantifying comorbidity in peritoneal dialysis patients and its relationship to other predictors of survival.NDT. 2002; 17: 1085-1092Google Scholar and the likelihood of receiving RRT. To date, no large study has standardized mortality rates in treated ESRD and general population cohorts to the same comorbidity as well as age and/or sex structure. Therefore, although data from ESRD registries in the United States from 1977 to 2007,9van Walraven C. Manuel D.G. Knoll G. Survival trends in ESRD patients compared with the general population in the United States.AJKD. 2014; 63: 491-499Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Europe from 1998 to 2007,10Pippias M. Jager K.J. Kramer A. et al.The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA Registry.NDT. 2016; 31: 831-841Google Scholar Australasia from 1992 to 2005,11Roberts M.A. Polkinghorne K.R. McDonald S.P. Ierino F.L. Secular trends in cardiovascular mortality rates of patients receiving dialysis compared with the general population.AJKD. 2011; 58: 64-72Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and the UK from 2002 to 20115Caskey F. Castledine C. Dawnay A. et al.UK Renal Registry: 18th Annual Report of the Renal Association 2015.Nephron. 2016; 132Google Scholar have all shown modest improvements in mortality for people with treated ESRD, it is unclear whether the magnitude of this change is comparable to that observed in the general population during the same period.12Norheim O.F. Jha P. Admasu K. et al.Avoiding 40% of the premature deaths in each country, 2010-30: review of national mortality trends to help quantify the UN sustainable development goal for health.Lancet. 17 2015; 385: 239-252Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar The Oxford Record Linkage Study (ORLS) was established in 1963 and recorded information about all hospital inpatient admissions in Oxfordshire and surrounding counties covering about 5% of England (referred to as "Oxfordshire").13Acheson E.D. The Oxford Record Linkage Study: a review of the method with some preliminary results.Proc R Soc Med. 1964; 57: 269-274PubMed Google Scholar Hospital Episode Statistics (HES) succeeded ORLS and established nationwide coverage from 1998. Both data sets have been linked to national mortality registers, so we aimed to study mortality trends among new maintenance RRT patients and controls from the general population between 1970 and 2008 using novel approaches to ensure all cohorts could correct for changes in comorbidity over time. We also consider the effects of temporal changes in the availability of transplantation on mortality trends. Between 1970 and 2008, 44,922 new ESRD patients started maintenance RRT (2192 in ORLS 1970–1996 and 42,730 from all-England HES 2000–2008), and 5,360,712 general population controls (532,019 from ORLS and 4,828,693 from HES) were identified. Indirect validation included observing closely matched numbers of kidney transplant operations recorded in HES and the UK Transplant Registry14NHS Blood and Transplant, UK Transplant Registry. Available at: http://www.odt.nhs.uk/uk-transplant-registry/. Accessed March 14, 2017.Google Scholar (Supplementary Table S1); closely matched cohort sizes, demographics and renal characteristics when HES data were compared with summary English data from the UK Renal Registry (Supplementary Table S2)15Ansell D, Feehally J, Feest TG, et al. UK Renal Registry: 10th Annual Report of the Renal Association 2007. Available at: https://www.renalreg.org/reports/2007-the-tenth-annual-report/.Google Scholar, 16Ansell D. Feehally J. Fogarty D. et al.UK Renal Registry: 11th Annual Report of the Renal Association 2008.Nephron Clin Pract. 2009; 111Google Scholar, 17Ansell D. Feehally J. Fogarty D. et al.UK Renal Registry: 12th Annual Report of the Renal Association 2009.Nephron Clin Pract. 2010; 114Google Scholar, 18Caskey F. Dawnay A. Farrington K. et al.UK Renal Registry: 13th Annual Report of the Renal Association 2010.Nephron Clin Pract. 2011; 119Google Scholar; and similar age- and sex-adjusted 3-year mortality rates for ORLS/"HES Oxford" and for Oxford Kidney Unit (Supplementary Figure S1). In Oxfordshire, the median age at start of maintenance RRT increased from 49 years (interquartile cut-offs 36–60 years) in 1970 to 1990 to 61 years (46–72 years) by 2006 to 2008. Consequently, while only one-quarter of patients starting RRT from 1970 to 1990 were aged ≥60 years, by 2006 to 2008 this proportion was more than one-half (Table 1). Of those starting RRT, the proportion who were female remained at about 40% across all time periods (Supplementary Figure S2A), but the proportion with any major comorbidity rose steeply from 1970 to 2008. In particular, diabetes prevalence among those starting RRT increased from 6.7% during 1970 to 1990 to 33.9% in 2006 to 2008, while prior vascular disease increased from 10.0% to 25.2% (Supplementary Figure S2B), constituting increases in peripheral arterial disease from 3.0% to 12.9%, major coronary disease from 2.6% to 8.3%, and admission for heart failure from 5.2% to 10.5% (Table 1). Prior cancer was recorded in 2.9% of RRT patients during 1970 to 1990 and 7.6% of patients during 2006 to 2008. The demographics and comorbidity of treated ESRD patients in Oxfordshire who started RRT between 2000 and 2008 were broadly similar to those observed in the rest of England (Table 1).Table 1Baseline characteristics of newly treated end-stage renal disease patients, by yearCharacteristicsYear groupsOxfordshireAll-EnglandOxford Record Linkage StudyHospital Episode Statistics (Oxford)Hospital Episode Statistics (All-England)1970–19901991–19962000–20022003–20052006–20082000–20022003–20052006–2008N122097270075087813,17813,60615,946Demographics Female40.2%38.0%41.1%35.9%37.7%39.5%37.9%38.5% Median age (yr)49 (36–60)59 (44–69)61 (45–72)61 (45–72)61 (46–72)61 (47–71)62 (47–72)63 (49–73)18–4030.2%18.7%18.7%18.7%15.9%15.8%14.8%13.0%40–5021.2%15.6%13.6%13.1%14.7%13.5%13.4%12.9%50–6023.5%17.2%15.4%16.4%17.1%17.8%16.6%17.2%60–7016.8%24.2%20.7%20.8%22.1%23.1%22.9%22.7%70–807.9%20.5%24.4%23.5%19.8%23.6%24.1%24.5%≥800.3%3.8%7.1%7.6%10.4%6.1%8.2%9.7% EthnicityaEthnicity only recorded in Hospital Episode Statistics (92% complete) with percentages quoted only for those with a known ethnicity., cNot used for standardization. Baseline characteristics of general population hospital controls are in Supplementary Table S3.White--86.8%86.4%84.0%82.1%81.2%79.9%Black--3.5%3.5%4.7%6.3%6.5%6.9%South Asian--7.4%6.3%7.2%8.2%8.3%8.7%Other--2.3%3.8%4.0%3.4%3.9%4.4%Unknown--13136351,694962745Comorbidities Diabetes6.7%16.8%24.4%29.2%33.9%25.7%29.9%34.3% Vascular10.0%18.3%22.3%24.7%25.2%25.2%26.5%28.3%Major coronary disease2.6%4.2%5.1%7.2%8.3%6.1%7.0%7.7%Congestive heart failure5.2%8.5%9.9%10.8%10.5%11.7%12.3%12.8%Cerebrovascular disease1.4%2.2%3.1%2.8%3.5%3.3%3.4%3.4%Peripheral arterial disease3.0%7.8%11.3%11.5%12.9%12.0%12.5%14.2% NonvascularbAlso includes hemiplegia or paraplegia.7.8%14.4%18.3%21.7%24.9%21.7%25.0%27.5%Liver disease0.5%0.4%1.7%1.1%2.3%1.6%2.0%2.8%Cancer2.9%4.6%5.3%8.9%7.6%6.4%7.8%8.3%Chronic obstructive pulmonary disease1.3%2.9%6.3%6.5%10.3%8.3%10.0%12.1%Peptic ulcer disease1.6%2.3%2.7%1.9%1.9%2.3%2.3%2.0%Connective tissue disease2.0%4.3%3.1%4.4%4.9%4.7%5.0%4.8%Renal characteristicscNot used for standardization. Baseline characteristics of general population hospital controls are in Supplementary Table S3. Initial renal replacement therapy modalityDialysis94.6%92.6%93.7%92.7%91.6%94.5%94.3%93.6%Transplant5.4%7.4%6.3%7.3%8.4%5.5%5.7%6.4% Primary renal diagnosis (presumed)Diabetic kidney disease1.6%8.4%20.0%22.5%22.1%19.1%20.1%20.4%Glomerulonephritis9.3%14.1%9.3%10.8%14.5%10.8%12.2%14.1%Polycystic kidney disease10.5%8.4%8.6%7.5%10.4%9.2%8.6%8.9%Other known diagnosis/unknown78.5%69.0%62.1%59.2%53.1%60.9%59.1%56.6%Excludes patients dying within 90 days. Data are n or % or median (interquartile range).a Ethnicity only recorded in Hospital Episode Statistics (92% complete) with percentages quoted only for those with a known ethnicity.b Also includes hemiplegia or paraplegia.c Not used for standardization. Baseline characteristics of general population hospital controls are in Supplementary Table S3. Open table in a new tab Excludes patients dying within 90 days. Data are n or % or median (interquartile range). Compared with new ESRD patients, general population controls were on average younger and more likely to be female. General population controls in the later time periods were older and had more comorbidity than general population controls from the earlier periods (Supplementary Table S3). Of the 1220 new ESRD patients starting RRT in 1970 to 1990, 267 (crude 3-year mortality rate 24.8%) died within the first 3 years. For the 878 Oxfordshire patients and 15,946 all-England patients starting RRT in 2006 to 2008, 221 (28.7%) and 4482 (38.2%) died within 3 years, respectively. Crude mortality rates—which do not take account of secular changes in age, sex, or comorbidity of those who received maintenance RRT—showed an average increase in mortality between 1970 and 1996, followed by the beginnings of a decline (Supplementary Figure S3A). After standardization by age and sex, however, a continuous decline in 3-year mortality rates from 1970 became evident (Supplementary Figure S3B), which steepened further when diabetes and other comorbidities were accounted for (Supplementary Figure S3C). On a relative scale, this corresponded to a 25-year 51% (95% confidence interval [CI], 41%–60%) decline in standardized 3-year mortality rates since about 1980 (Figure 1). Examination of 1-year, 2-year, 3-year, and 5-year mortality rates also showed steep declines in mortality rate with time (Supplementary Figure S4). Standardized 3-year all-cause mortality rates in the general population were substantially lower than for new ESRD patients, and declined somewhat less steeply: from 8.6% during 1970 to 1990 (15,158 deaths in 406,897 people) to 5.7% (3885 deaths in 79,593 people) during 2006 to 2008. On a relative scale, this represented a 25-year reduction of 34% (95% CI 31%–36%; Figure 1). All-England data from 2000 mirrored findings in Oxfordshire data from the same period (Figure 1). Kidney transplantation was introduced in Oxfordshire in 1975. The 3-year standardized mortality rate among these early transplant recipients was substantially lower than for those who remained on dialysis (15.3% vs. 41.8% during 1970–1990), and fell over time such that the 2000 to 2008 3-year standardized mortality rates for transplanted patients were 4.6% (Figure 2). Despite increased availability of transplantation over time (the proportion of patients receiving a transplant within 3 years of needing to start RRT increased from 26% to 30% between 1970–1990 and 2006–2008), 3-year mortality also substantially and continually declined among ESRD patients who remained on dialysis. The rates of improvements in mortality were similar in both the Oxfordshire and all-England data. In the general population, there were steeper reductions in mortality over time in people with diabetes (heterogeneity P < 0.0001 for Oxfordshire and P < 0.0001 for all-England). The same was not observed among treated ESRD patients in Oxfordshire over 25 years since 1980 (heterogeneity P = 0.41), but there was evidence of steeper declines in mortality rates among people with diabetes from 2000 in England (heterogeneity P = 0.01). The absolute difference in mortality rates between those with and without diabetes has therefore become substantially smaller between 1970 and 2011 (Figure 3). Among new ESRD patients, 3-year mortality rates from vascular causes fell from 12.2% between 1970 to 1990 to 7.4% by 2006 to 2008, representing a 25-year relative reduction of about 40% (95% CI 19%–60%) since 1980, which included about a 31% (95% CI 2%–60%) reduction in cardiac mortality and 55% (95% CI 28%–82%) reduction in noncardiac vascular mortality (Figure 4). In general population controls, 3-year mortality from vascular mortality declined from 4.1% in the 1970 to 1990 group to 1.9% by 2006 to 2008. This represented a relative 25-year decline in 3-year vascular mortality of 53% (95% CI 50%–56%), which included a 58% (95% CI 55%–61%) decline in cardiac and 45% (95% CI 40%–50%) decline in noncardiac vascular mortality (Figure 4). Between 1970 and 2011, declines in cardiac mortality have therefore been steeper in the general population than in new ESRD patients. Again, all-England data from 2000 to 2011 mirrored findings from Oxfordshire in 2000 to 2011. In new ESRD patients, 3-year mortality from nonvascular causes declined steeply and continuously since 1970 from 28.4% in the 1970 to 1990 group to 12.6% by 2006 to 2008 (Figure 4). On a relative scale this represented a 25-year decline of 56% (95% CI 45%–66%) since 1980. The commonest underlying nonvascular causes of death were from renal failure or its causes (e.g., deaths in which chronic, diabetic, hypertensive, and polycystic kidney diseases initiated the train of terminal events that led to death). Such mortality fell from 16.8% to 4.9% between the 1970 to 1990 and 2006 to 2008 groups, a relative decline of 71% (95% CI 61%–81%). Declines in other common nonvascular causes were more modest. These included a reduction of 27% in infectious mortality (95% CI –14% to 68%; absolute decline from 3.3% to 2.4%) and a reduction of 50% in cancer mortality (95% CI 21%–80%; absolute rates 4.2% and 2.1%; Figure 4). In general population controls, the declines in 3-year nonvascular mortality were more modest than the corresponding declines in new ESRD patients. Three-year standardized mortality rates fell from 4.6% in 1970 to 1990 to 3.8% by 2006 to 2008, which on a relative scale represents a 25-year 17% (95% CI 13%–21%) decline since 1980. This included a 25-year 26% relative reduction in death from cancer (95% CI 20%–31%; absolute decline from 2.1% to 1.6%), and 30% relative reduction in infection-related mortality (95% CI 22%–37%; absolute decline from 0.7% to 0.5%; Figure 4). In treated ESRD patients, the steeper proportional declines in nonvascular mortality compared with those in the general population (56% vs. 17%, Figure 4), and shallower declines in vascular mortality (40% vs. 53%, respectively) resulted in the proportion of all deaths ascribed to vascular disease rising from 29.9% in 1970 to 1990 to 36.8% in 2006 to 2008, while the proportion of all deaths ascribed to vascular disease in the general population fell from 47.5% to 33.3% over the same period. We have used large cohorts derived from routine hospital admission data sets established before the start of maintenance RRT programs to compare changes in cause-specific mortality among people with newly treated ESRD and contemporaneous general population controls, taking account of the major changes in age and comorbid illnesses of those selected to start RRT since 1970. Three-year absolute mortality rates from many causes have remained high among people on maintenance RRT, but on a relative scale, overall mortality has halved. This decline is substantially steeper than the one-third decline observed in the general population. As those on RRT are at much higher mortality risk than the general population, this also translates into substantially larger reductions in absolute mortality rates. An important finding from this study is that the reported reductions in mortality rates have declined faster than reported by ESRD registries in the United States from 1977 to 2007,9van Walraven C. Manuel D.G. Knoll G. Survival trends in ESRD patients compared with the general population in the United States.AJKD. 2014; 63: 491-499Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Europe 1998 to 2007,10Pippias M. Jager K.J. Kramer A. et al.The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA Registry.NDT. 2016; 31: 831-841Google Scholar Australasia 1992 to 2005,11Roberts M.A. Polkinghorne K.R. McDonald S.P. Ierino F.L. Secular trends in cardiovascular mortality rates of patients receiving dialysis compared with the general population.AJKD. 2011; 58: 64-72Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and the UK 2002 to 2011.5Caskey F. Castledine C. Dawnay A. et al.UK Renal Registry: 18th Annual Report of the Renal Association 2015.Nephron. 2016; 132Google Scholar These registry studies may have underestimated improvements in mortality by virtue of not being able to adjust for temporal changes in serious vascular and nonvascular comorbidities. Our comorbidity-adjusted estimates suggest relative mortality declines of perhaps 30% over the 10 years from the mid-1990s, which is larger than the approximately 20% declines evident from contemporaneous European registry data without such comorbidity adjustment.19ERA-EDTA Registry: ERA-EDTA Registry 2002 Annual Report. Academic Medical Center, Amsterdam, Netherlands2004Google Scholar, 20ERA-EDTA Registry: ERA-EDTA Registry Annual Report 2011. Academic Medical Center, Department of Medical Informatics, Amsterdam, Netherlands2013Google Scholar Our results from HES data were, however, almost identical to the relative declines in comorbidity-adjusted mortality rates reported by a 2002 to 2006 study that used UK Renal Registry HES-linked data.21Fotheringham J. Jacques R.M. Fogarty D. et al.Variation in centre-specific survival in patients starting renal replacement therapy in England is explained by enhanced comorbidity information from hospitalization data.Nephrol Dial Transplant. 2014; 29: 422-430Crossref PubMed Scopus (20) Google Scholar Over the last 40 years, there has been a progressive and steep increase in the proportion of people with diabetes who start RRT treatment for ESRD. We found evidence that mortality rates have fallen faster among people with diabetes both in the general population and in those on maintenance RRT, meaning the absolute gap in mortality rates between those with and without diabetes has progressively closed over the last few decades. This study includes data in the 25 years before RRT registries had complete nationwide coverage in England. Over the early period, the numbers of people undergoing RRT progressively increased, and short-to-medium mortality was still attributed in large part to renal failure or its causes. This renal mortality rate appears to have fallen by more than one-half over the last 40 years. If this is true, kidney transplantation may have been a key intervention in reducing such mortality.22Wolfe R.A. Ashby V.B. 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