Management of anemia in CKD. Masaomi Nangaku Division of Nephrology and Endocrinology the University of Tokyo Graduate School of Medicine, Japan

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1 Management of anemia in CKD Masaomi Nangaku Division of Nephrology and Endocrinology the University of Tokyo Graduate School of Medicine, Japan

2 Shiga toxin Kiyoshi Shiga Shiga toxin binds to the Gb3 receptor on intestinal epithelial cells, renal tubular epithelial cells, and endothelial cells Moake. N Engl J Med 2002

3 HUS due to Shiga toxinproducing E. coli Tarr et al. Lancet 2005

4 erythropoietin glycosylation Receptor 1 Receptor 2

5 Heart, kidney, and intestine have different tolerances for anemia cardiac μpo 2 (40 ± 6 mm Hg at baseline) decreased only in the ultimate stage of the experiment at Ht of 8.7 ± 3.5% van Bommel et al. Transl Res 2008

6 Heart, kidney, and intestine have different tolerances for anemia intestinal μpo 2 (59 ± 6 mm Hg at baseline) did not start to decrease until Ht reached 17.4 ± 7.1% van Bommel et al. Transl Res 2008

7 Heart, kidney, and intestine have different tolerances for anemia renal μpo 2 (56 ± 10 mm Hg at baseline) started to decrease at a Ht of 38.5 ± 8.6% van Bommel et al. Transl Res 2008

8 Oriental Asians tend to develop renal anemia compared with other races Observational cross-sectional study (n=5,322) Barbour et al. Kidney Int 2008

9 Chronic Kidney Disease Japan Cohort Study CKD-JAC Distribution of Hb range 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 10.1% 14.1% 33.6% 57.7% 45 GFR 30 GFR<45 15 GFR<30 GFR<15 N=297 N=1014 N=1148 N= Hb Hb<11.0 egfr (ml/min/1.73 m2 ) Akizawa et al. Clin Exp Nephrol 2011

10 The longitudinal relationship between egfr and hematocrit was steeper when baseline egfr was <45 ml/min/1.73 m 2 : AASK Chen et al. Nephrol Dial Transplant 2015

11 male sex, younger age, and higher baseline proteinuria were associated with greater hematocrit declines per unit decrease in longitudinal egfr Chen et al. Nephrol Dial Transplant 2015

12 Serum EPO concentrations and responses to anemia in patients with or without CKD This case EPO 14.1 miu/ml Log = 1.15 Hb 8.8g/dl Artunc & Risler. Nephrol Dial Transplant 2007

13 anemia Adaptation to hypoxia Hypoxia Cardiac output Tachycardia LVH Coronary flow Cardiac oxygen demand Atherosclerosis Cardiac damage

14 Poor prognosis in heart failure patients with anemia Relative risk: 8~10% per 1g/dl of Hb IN-CHF Val-HeFT Maggioni et al. J Cardiac Fail 2005

15 Fluid status, as defined by overhydration, was negatively correlated with Hb levels Hung et al. J Am Heart Assoc 2015

16 Poor prognosis in IHD patients with anemia Relative risk: 21% per 1g/dl of Hb Sabatine et al. Circulation 2005

17 Poor prognosis in CABG patients with anemia Kulier et al. Circulation 2007

18 Anemia and reduced kidney function as risk factors for new onset of atrial fibrillation (from the Ibaraki Prefectural Health Study) Xu et al. Am J Kidney Dis 2015

19 Mechanisms of EPO production and its disturbance

20 Suppression of EPO expression by indoxyl sulfate: in vitro 1.80 * EPO mrna levels Normalized by control group 1.60 EPO mrna expression levels CoCL (100μM) Indoxyl sulfate (mm) Chiang, Nangaku, Inagi et al. Lab Invest 2011

21 Oral adsorbent AST-120 potentiated the effect of ESA on Stage 5 CKD patients % of patients with Hb > 11 g/dl control group AST-120 group Wu et al. Nephrol Dial Transplant 2014

22 add-on AST-120 resulted in a positive change of egfr Wu et al. Nephrol Dial Transplant 2014

23 mortality and event rates did not differ between patients treated at facilities predominantly using DPO versus EPO in incident HD patients Quasi-experimental Cohort Study (Observational, registry-based, retrospective cohort study) Winkelmayer et al. Am J Kidney Dis 2015

24 Biosimilar recombinant EPO induces the production of neutralizing antibodies n = 30 patients with CKD treated with biosimilar Epo and who developed a sudden loss of efficacy Praditpornsilpa et al. Kidney Int 2011

25 IRON

26 NICE Anaemia Management in CKD 2011 People receiving ESA maintenance therapy should be given iron supplements to keep their: serum ferritin levels between 200 and 500 µg/l in both HD and non-hd patients, and either TSAT above 20% (unless ferritin is greater than 800 µg/l) or percentage hypochromic red cells (%HRC) less than 6% (unless ferritin is greater than 800 µg/l).

27 KDIGO Clinical Practice Guideline for Anemia in CKD 2012 For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of iron therapy if an increase in Hb concentration without starting ESA treatment is desired and TSAT is 30% and ferritin is 500 ng/ml ( 500 mg/l)

28 Kovesdy et al. CJASN 2009 Multivariable adjusted log-hazards of all-cause mortality associated with levels of natural-logtransformed serum ferritin concentration non-hd 250 ng/ml

29 Association between serum ferritin and all-cause mortality HD 800 ng/ml Kalantar-Zadeh et al. JASN 2005

30 Association between high risk of death with high serum ferritin levels HD the Nishinomiya Study 92.9 ng/ml cut-off 100 ng/ml Hasuike et al. Clin Exp Nephrol 2010

31 Association between adverse events with high serum ferritin levels (>100 ng/ml) and with high-amplitude ferritin fluctuations Treatment for Renal Anemia on Prognosis (TRAP) study HD Kuragano et al. Kidney Int 2014

32 New anemia guideline: JSDT Iron supplementation should be started in patients with serum ferritin 50 ng/ml in patients NOT treated with ESA. Iron supplementation should be started in patients with TSAT 20 % or serum ferritin 100 ng/ml in patients treated with ESA. Serum ferritin should not exceed 300 ng/ml or 500 ng/ml.

33 Target Hb

34 Epidemiological studies showed correlation between high Hb and good prognosis

35 Anemia and prognosis of CKD patients meta-analysis Volkova & Arab. AJKD 2006

36 Prospective trials showed that high Hb does not necessarily improve cardiovascular outcome

37 CREATE: primary endpoint Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) HR 0.78 [95%CI, ] Group 1: target Hb Group 2: target Hb Drueke et al. N Engl J Med 2006

38 TREAT: Composite and Component End Points Pfeffer et al. N Engl J Med 2009

39 Difference of cardiovascular events between Japan and Western countries A21 trial 秋澤忠男 et al. 腎と透析 Past history AMI (%) CABG (%) PAD (%) High Hb group Low Hb group CHOIR Past history AMI (%) CABG (%) PAD (%) High Hb group Low Hb group

40 Difference of cardiovascular events between Japan and Western countries Cardiovascular events (/1000 person year) CHOIR CREATE TREAT A Gonryo (G3-5) apoplexy (/1000 person year)

41 Renal outcome in prospective trials

42 CREATE: secondary endpoint Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) Drueke et al. N Engl J Med 2006

43 TREAT: secondary endpoint of renal outcomes Pfeffer et al. N Engl J Med 2009

44 Difference of kidney outcomes between Japan and Western countries Incident dialysis egfr (ml/min/1.73m 2 ) reason A uremia CREATE 12 USRDS 11.1 heart failure/ volume overload heart failure/ volume overload 秋澤忠男 et al. 腎と透析. 2014

45 A21 STUDY Design Multi-center, prospective, randomized, open-labeled trial Primary endponit CKD patients (Age 20) Hb <10.0 g/dl, serum Cr : 2.0~6.0 mg/dl High Hb group(target Hb11.0~13.0g/dL): treated with darbepoietin Low Hb group(target Hb 9.0~11.0g/ dl ): treated with EPO Iron is supplemented to keep transferrin saturation > 20% and ferritin > 100 ng/ml Time to doubling of serum Cr, incident dialysis, kidney transplantation, or death Tsubakihara et al. Ther Apher Dial 2012

46 Hazard ratio of renal survival Initiating serum Cr (mg/dl) Diabetes Age Female (vs Male) High Hb group (vs Low Hb group) Initiating Hb (g/dl) Hazard ratio (95% CI) Tsubakihara et al. Ther Apher Dial 2012

47 post-hoc analysis CKD stage G4 CKD stage G5 Tsubakihara et al. Ther Apher Dial 2015

48 post-hoc analysis non-diabetic diabetic Tsubakihara et al. Ther Apher Dial 2015

49 Gouva trial : primary endpoint log-rank P = Gouva et al. Kidney Int 2004

50 JSDT(2008) NICE (2011) KDIGO(2012) ERBP(2013) non- HD HD Start (9~12 according to risks ) Target 11~13 10~12 ~11.5 ~12 Upper limit Start 13 (12 for those with severe cardiovascular complications ) 10 (11 for young and active) Target 10~11 (11~12 for young and active) Upper limit 12 (13 for young and active) ~10 10 (9~12 according to risks ) 10~12 ~11.5 ~

51 New anemia guideline: JSDT Target Hb should be 11~13 g/dl for non-hd CKD patients and PD patients, and 10~12 g/dl for HD patients, respectively. Target Hb should be individualized based on the personal conditions of the patient.

52 ESA hyporesponsiveness

53 2010

54 Based on changes of Hb during the 1 st month Poor response Better response Quartile 1 Quartile 2 Quartile 3 Quartile 4 Hb change (%) <2 2 to <8 8 to <15 15 Median (g/dl) (interquartile range) -0.2 (-0.7 to 0.0) 0.5 (0.4 to 0.7) 1.2 (1.0 to 1.4) 2.0 (1.7 to 2.6)

55 Death, myocardial infarction, apoplexy, heart failure, or hospitalization due to cardiac ischemia

56 EPO hyporesponsiveness : RISCAVID study death cardiovascular events n=753 (HD patients) ESAs resistance index (ERI): the weekly ESAs dose / kgbw / Hb (g/dl) Panichi et al. Nephrol Dial Transplant 2011

57 EPO hyporesponsiveness and risk of ESRD n=194 (non-hd) ESA-R: (Hb 1 Hb 0 )/time/esa Minutolo et al. Nephrol Dial Transplant 2012

58 New anemia guideline: JSDT The definition of ESA hyporesponsiveness remains unclear. Failure of achievement of target Hb with the dose of ESA approved by the administration authorities or the government suggests ESA hyporesponsiveness. A cause of ESA hyporesponsiveness should be investigated before increasing the dose of ESA.

59 Clinical management of myelodysplastic syndromes: Japanese Society of Hematology guideline 40 60,000 U of EPO (once to three times per week) (grade A) is recommended

60 Clinical management of myelodysplastic syndromes: update of SIE, SIES, GITMO practice guidelines Fixed, rather than weight-adjusted, weekly subcutaneous doses of 60 80,000 U of EPO (once-a-week or subdivided in two doses) (grade A) or 300 μg darbepoetin (once-aweek) should be used (grade B) for at least 12 weeks, possibly more than 20 (grade B). Santini et al. Leuk Res 2010

61 ESAs are not associated with increased risk of thrombosis in patients with MDS Smith et al. Haematologica 2012

62 Anemia treatment should be individualized based on the personal conditions of the patient.

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