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American Journal of Kidney Diseases

Increasing ESKD in Diabetes in the Land Down Under: What Can Be Done, We Must Wonder

Published:January 18, 2019DOI:https://doi.org/10.1053/j.ajkd.2018.11.005
      Related Article, p. 300
      Globally, kidney disease in diabetes is the leading cause of end-stage kidney disease (ESKD) and is associated with increased morbidity and mortality due to cardiovascular complications. Since 1990, national registries such as the US Renal Data System have provided data on the alarming increases in the number of people treated for ESKD due to diabetes.
      • Collins A.J.
      • Foley R.N.
      • Chavers B.
      • et al.
      US Renal Data System 2013 annual data report.
      This has been partly due to the increasing number of individuals with type 1 and, in particular, type 2 diabetes. The number of people around the world with diabetes was estimated to be 415 million in 2015 and is expected to grow to more than 640 million people by 2040, according to the International Diabetes Federation.
      • Ogurtsova K.
      • da Rocha Fernandes J.D.
      • Huang Y.
      • et al.
      IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040.
      Although it is obvious that the number of people reaching ESKD has increased dramatically on a total population level, it has been less clear whether the incidence of ESKD has changed within the diabetic population. In this issue of AJKD, Koye et al
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Trends in incidence of ESKD in people with type 1 and type 2 diabetes in Australia, 2002-2013.
      addressed this important question using Australia’s National Diabetes Services Scheme.
      Unfortunately, the results are not much cause for optimism because the incidence of ESKD in patients with type 1 diabetes did not change from 2002 to 2013, and for all patients with type 2 diabetes, there was an increasing trend for ESKD during the same period, with an annual change of 4.5% (95% confidence interval [CI], 1.9%-7.1%). This was driven, in part, by an increase in registration rates in the indigenous population with type 2 diabetes and was particularly true in nonindigenous individuals older than 80 years and, even more concerning, in those younger than 50 years. Furthermore, the study demonstrates (in accordance with previous studies) an excess of ESKD in males compared with females (hazard ratio [HR] of 1.51 [95% CI, 1.45-1.57]), those socially disadvantaged, those living in remote areas with less access to care, and the indigenous population compared to the nonindigenous population (HR of 4.03 [95% CI, 3.68-4.41]).
      Whether the results are good or not so good is not that easy to assess. On the one hand, reaching ESKD means that the patient has survived without dying from a myocardial infarction, and previous studies from the same registries have demonstrated declining total mortality and mortality due to cardiovascular disease.
      • Harding J.L.
      • Shaw J.E.
      • Peeters A.
      • Davidson S.
      • Magliano D.J.
      Age-specific trends from 2000-2011 in all-cause and cause-specific mortality in type 1 and type 2 diabetes: a cohort study of more than one million people.
      This is in accordance with data from the United States showing a marked decline in cardiovascular complications, but only modest improvements in ESKD.
      • Gregg E.W.
      • Li Y.
      • Wang J.
      • et al.
      Changes in diabetes-related complications in the United States, 1990-2010.
      On the other hand, age at onset of ESKD was not increased; thus, patients are not getting older or delaying the onset of dialysis therapy. However, diabetes duration at the onset of ESKD was not given, and an earlier onset of type 2 diabetes could be in agreement with the delay in onset of dialysis therapy without an increase in age at dialysis. The increase in younger people with type 2 indicates early-onset or more aggressive disease. More liberal access to ESKD treatment could contribute to the increase in ESKD, particularly for those older than 80 years, but inclusion of ESKD-related deaths before ESKD treatment did not change trends, which would argue against more frequent use of dialysis in the elderly population as an explanation.
      However, the findings are disappointing in these times when there has been increased focus on the treatment of hypertension in diabetic kidney disease
      • Parving H.H.
      • Smidt U.M.
      • Hommel E.
      • et al.
      Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.
      and use of renoprotective blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
      • Parving H.H.
      • Smidt U.M.
      • Hommel E.
      • et al.
      Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      In addition to studies demonstrating the benefit on progressive loss of glomerular filtration rate in late stages of kidney disease, other studies have also demonstrated an effect on progression of albuminuria (from moderately increased to severely increased) with early treatment with RAS blockade.
      • Parving H.-H.
      • Lehnert H.
      • Brochner-Mortensen J.
      • Gomis R.
      • Andersen S.
      • Arner P.
      The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
      The extent to which renoprotection with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers was implemented is not discussed by Koye et al, but at least in other clinical settings (including the United States), the use has been suboptimal, with only 60% to 65% of patients with chronic kidney disease being treated.
      It is a strength of the current Australian study that it is based on a whole population, including more than 1.2 million individuals with diabetes and a nationwide registry for diabetes and ESKD treatment with high coverage, as well as a national death registry. As mentioned by the authors, it is an important limitation that there are no data for concomitant medications such as RAS blockade, statin treatment, etc. Also, factors relevant to kidney disease progression such as hemoglobin A1c level, arterial blood pressure, low-density lipoprotein cholesterol level, smoking habits, physical activity, and diet are not known, and thus it cannot be established to what extent the patients were reaching treatment goals recommended for this population.
      The degree to which treatment goals were achieved would be important to know to find out how to improve the findings. Multifactorial targeting of multiple risk factors with lifestyle interventions and pharmacologic interventions to lower glucose levels and blood pressure, block the RAS, lower cholesterol levels, and reduce aspirin use reduced mortality by 50% in patients with type 2 diabetes and moderately increased albuminuria after 13 years,
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      and after 21 years of follow-up, reduced ESKD or death (with an HR of 0.53 [95% CI, 0.35-0.80]) in the Steno-2 study.
      • Oellgaard J.
      • Gaede P.
      • Rossing P.
      • Persson F.
      • Parving H.H.
      • Pedersen O.
      Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits.
      Steno-2 was a small randomized study with 160 patients with type 2 diabetes and moderately increased albuminuria who were randomly assigned to standard care or intensive multifactorial risk factor control. When the multifactorial intervention was implemented in our clinic in 2002, mortality in patients with proteinuric type 1 diabetes was reduced by 50% when comparing patients followed up from 2000 to 2010 with patients followed up before 2000. This could not be explained by a single factor, but was suggested to be the result of lower blood pressure, cholesterol and glucose levels, and smoking prevalence and more use of RAS blockade.
      • Andresdottir G.
      • Jensen M.L.
      • Carstensen B.
      • et al.
      Improved prognosis of diabetic nephropathy in type 1 diabetes.
      Similar data were seen in patients with proteinuric type 2 diabetes followed up in our clinic.
      • Andresdottir G.
      • Jensen M.L.
      • Carstensen B.
      • et al.
      Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors.
      These data are from a single specialist center and thus are not representative of large unselected groups of patients. Very recent data from the National Swedish Diabetes Register covering almost all patients with diabetes in Sweden documented a low (5.6%) and declining cumulative incidence of ESKD in type 1 diabetes after 38 years of follow-up. This study included patients with duration of type 1 diabetes longer than 14 years and age at onset of diabetes of 0 to 34 years. Patients who developed ESKD were identified using the Swedish Renal Registry, a national registry of renal replacement therapy. The incidence of ESKD was lower in patients with type 1 diabetes onset from 1991 to 2001 compared with those with onset from 1977 to 1984 and 1985 to 1990, independently of diabetes duration.
      • Toppe C.
      • Mollsten A.
      • Waernbaum I.
      • et al.
      Decreasing cumulative incidence of end-stage renal disease in young patients with type 1 diabetes in Sweden: a 38-year prospective nationwide study.
      Similar data were observed in a Finnish study of a cohort that included all patients younger than 30 years with type 1 diabetes diagnosed in the country from 1965 to 2011, who were followed up until ESKD, death, or end of follow-up at the end of 2013. Patients were followed up for a median of 20 years. The cumulative risk for ESRD was 2.2% and 7.0% after 20 and 30 years, respectively, from the time of diabetes diagnosis. The relative risk for ESKD was 0.13 (95% CI, 0.08-0.22) among patients given the diagnosis in the 1995 to 2011 era compared with those given the diagnosis from 1965 to 1979.
      • Helve J.
      • Sund R.
      • Arffman M.
      • et al.
      Incidence of end-stage renal disease in patients with type 1 diabetes.
      National data for diabetic ESKD incidence from different countries are given in Table 1 and demonstrate large variability.
      Table 1Global Incidence of ESKD in Diabetes
      SettingDiabetes TypeTime PeriodCumulative Risk for ESKDESKD Incidence
      Per Million Total PopulationPer 10,000 Patient-y
      Australia
       ANZDATA
      ANZDATA, 41st Annual ANZDATA Report (2018) of Dialysis and Transplantation Activity
      The Australia and New Zealand Dialysis and Transplant Registry (ANZDATA).
      DKD201746.5
       Koye
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Trends in incidence of ESKD in people with type 1 and type 2 diabetes in Australia, 2002-2013.
      T1DM2002-2013Stable14.1
       Koye
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Trends in incidence of ESKD in people with type 1 and type 2 diabetes in Australia, 2002-2013.
      T2DM2002-2013Increasing7.0
      Sweden
       Kramer
      • Kramer A.
      • Pippias M.
      • Noordzij M.
      • et al.
      The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary.
      T1DM+T2DM2015316.2
      Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
       Toppe
      • Toppe C.
      • Mollsten A.
      • Waernbaum I.
      • et al.
      Decreasing cumulative incidence of end-stage renal disease in young patients with type 1 diabetes in Sweden: a 38-year prospective nationwide study.
      T1DM20185.6% after 38 y F/U
      Finland
       Kramer
      • Kramer A.
      • Pippias M.
      • Noordzij M.
      • et al.
      The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary.
      T1DM+T2DM2015325.0
      Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
       Helve
      • Helve J.
      • Sund R.
      • Arffman M.
      • et al.
      Incidence of end-stage renal disease in patients with type 1 diabetes.
      T1DM20182.2% after 20 y, 7.0% after 30 y
      USRDS (Collins
      • Collins A.J.
      • Foley R.N.
      • Chavers B.
      • et al.
      US Renal Data System 2013 annual data report.
      )
      DM201516417.4
      Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
      Mexico (Rosa-Diez
      • Rosa-Diez G.
      • Gonzalez-Bedat M.
      • Ferreiro A.
      • Garcia-Garcia G.
      • Fernandez-Cean J.
      • Douthat W.
      Burden of end-stage renal disease (ESRD) in Latin America.
      )
      T1DM+T2DM201247231
      Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
      Japan (Maskane
      • Masakane I.
      • Taniguchi M.
      • Nakai S.
      • et al.
      Annual Dialysis Data Report 2015, JSDT Renal Data Registry.
      )
      DM201512716.4
      Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
      Note: ESKD defined as renal replacement therapy for kidney failure, except in Japan, which includes only dialysis patients (not transplant recipients).
      Abbreviations: ANZDATA, The Australia and New Zealand Dialysis and Transplant Registry; DKD, diabetic kidney disease; DM, diabetes mellitus; ESKD, end-stage kidney disease; F/U, follow-up; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; USRDS, US Renal Data System.
      a Estimated from ESKD incidence per million population, population size, and diabetes prevalence estimates.
      In addition to the benefits of targeting multiple risk factors such as hyperglycemia, blood pressure, lipid levels, and lifestyle (as discussed), new options for reducing the progression of diabetic kidney disease going forward include the newer glucose-lowering agents for treatment of type 2 diabetes, such as the sodium/glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) agonists. In cardiovascular outcome trials designed to test the cardiovascular safety of these agents, secondary end points included progression of kidney disease. The results have been encouraging, with reduction in albuminuria progression,
      • Mann J.F.E.
      • Orsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      and for empagliflozin and canagliflozin, reduction in doubling of serum creatinine level or 40% decline in estimated glomerular filtration rate, respectively.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      We are awaiting dedicated renal trials with these agents. They have already found their way into recent guidelines for the treatment of type 2 diabetes from the European Association for the Study of Diabetes and American Diabetes Association,
      • Davies M.J.
      • D'Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      although the cost of these new agents has almost excluded them from the World Health Organization’s most recent guideline
      • Roglic G.
      • Norris S.L.
      Medicines for treatment intensification in type 2 diabetes and type of insulin in type 1 and type 2 diabetes in low-resource settings: synopsis of the World Health Organization guidelines on second- and third-line medicines and type of insulin for the control of blood glucose levels in nonpregnant adults with diabetes mellitus.
      and from reaching many patients. Another new option being tested in phase 3 studies for protecting against progression of diabetic kidney disease is increased RAS blockade with the mineralocorticoid receptor antagonist finerenone.
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      Thus, we wonder whether renal outcomes for patients with diabetes in Australia and elsewhere could be improved with more patients treated to target for all the renal and cardiovascular risk factors such as glycemia (using SGLT inhibitors or GLP1 agonists), blood pressure (with renin-angiotensin-aldosterone system [RAAS] blockade), low-density lipoprotein cholesterol level, and smoking cessation. The authors mention that since 2011, blood pressure targets were increased from 130/80 to 140/90 mm Hg in guidelines for the treatment of diabetes,
      • de Boer I.H.
      • Bangalore S.
      • Benetos A.
      • et al.
      Diabetes and hypertension: a position statement by the American Diabetes Association.
      and they express concern that this may have led to less intensive treatment of risk factors and thus contributed to insufficient management. Because clinical variables are not presented, the potential impact of this remains an important speculation.
      We acknowledge the special challenges with the indigenous population and those living in remote areas of Australia, given their high risk for ESKD. There is an urgent need to better understand their disease process, as well as focus on tools addressing the special needs of this population. However, ESKD in other populations is what is driving the overall trends in Australia.

      Article Information

      Authors’ Full Names and Academic Degrees

      Peter Rossing, MD, DMSc, Marie Frimodt-Møller, MD, PhD, and Frederik Persson, MD, DMSc.

      Support

      None.

      Financial Disclosure

      Dr Persson reports having received research grants from Astra Zeneca and lecture fees from Astra Zeneca, MSD, Janssen, Eli Lilly, Boehringer Ingelheim, Novo Nordisk, and Novartis, as well as being a consultant/advisory board member for Astra Zeneca, Bayer, Amgen, and MSD. Dr Rossing received lecture fees from Bayer and Boehringer Ingelheim and research grants from Astra Zeneca and Novo Nordisk and has served as a consultant for Astra Zeneca, Astellas, Bayer, Boehringer Ingelheim, AbbVie, and Novo Nordisk (all honoraria to his institution). He also has equity interest in Novo Nordisk. Dr Frimodt-Møller declares that she has no relevant financial interests.

      Peer Review

      Received November 6, 2018, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form November 29, 2018.

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