Erythropoetin - From Bench to Bedside

Anemia in Chronic Kidney disease is a fascinating area of study both for the Basic scientist and Practising Nephrologist . In this talk , both areas are highlighted with emphasis on erythropoietin .

1. K.Sampath kumar,MD,DM,FRCP Meenakshi Mission Hospital Madurai,India “Erythropoietin – From Bench to Bedside "

2. Focus of my talk Biology of Erythropoietin [EPO] Why EPO should come from Kidneys? Why not Lungs ? Practical aspects of usage of EPO in clinic Major clinical trials Use / Abuse of EPO Conclusion

3. .The mature hormone is composed of 165 amino acids EPO biology

4. Bioengineered EPO possible only with mammalian cell lines due to addtion of Sugar moiety [Unlike Insulin for which bacteria can be utilised ]

5. Native EPO versus Synthetic Darbopoietin

6. Focus of my talk Biology of Erythropoietin [EPO] Why EPO is produced in Kidneys Practical aspects of usage of EPO in clinic Major clinical trials Cautionary notes Conclusion

7. Oxygen sensing at Kidney rather than Lungs > 20% of cardiac output goes to Kidneys Richest blood supply per gram of tissue Blood supply independent of metabolic demand 10% of oxygen supply only is utilised by Kidneys

8. Kidney is a biological critmeter 45 % Hematocrit is not a random Number. It is optimises tissue Oxygen delivery with correct viscosity And fluidity Normal hematocrit Of 45 %

9. Oxygen sensor EPO Production O2 content RBC mass Serum EPO Na Reabsorption Tissue 02

10. Critmeter at Cortico medullary junction – S3 seg of PCT

11. Prolyl OHase Ubiq . Ligase VHL Proteosome degrades Hypoxia EPO HIF -2 a HIF -2 a HIF -2b Oxygen increases HIF 2 alpha Destruction by Proteosome . Hypoxia blocks this pathway Paves way for EPO gene activation Erythropoiesis

12. Practice Points in anemia management of CKD

13. Percentage of Patients With Anemia (%) N=1658 Develops early and worsens as CKD progresses Anemia of CKD

14. Obrador , J Am Soc Nephrol 1999, 10:1793-1800 131,484 patients who began dialysis between 4/1/95 and 6/30/97 Mean 27.9 +/- 5.4 Median 27.9 Anemia: At Onset of RRT

15. Why Anemia should be corrected in CKD Why should we use EPO? Anemia correction benefits in CKD

16. Anemia is Associated with Poor Survival of Patients with CKD Dynamic, retrospective cohort study among 8761 patients with CKD at Kaiser Permanente Northwest 2 Assessment of outcomes 2 Death Cardiovascular (CV) hospitalization End-stage renal disease (ESRD) 1. Fishbane S. Heart Fail Clin 2008;4:401–410; 2. Thorp ML et al. Nephrology 2009;14:240–246; 3. Kovesdy CP et al. Kidney Int 2006;69:560–564; 4. Hörl WH et al. Nephrol Dial Transplant 2007;22(suppl 3):iii2–6; 5. Gouva C et al. Kidney Int 2004;66:753–760 Due to the negative effects of anemia, 1–3 early diagnosis and treatment in patients with CKD is recommended 4,5 25.0 9.4 Rate per 100 patient-years Mean hemoglobin (g/dL) per decile 10.0 5.0 11.0 11.8 12.3 12.8 13.2 13.5 13.9 14.5 15.8 4.0 0.0 20.0 15.0 2.6 1.3 1.3 1.0 0.8 0.5 0.4 0.4 0.3 14.5 9.6 7.6 7.4 5.9 6.2 5.3 4.8 6.5 23.4 15.5 12.6 11.6 10.3 11.3 8.5 9.0 10.1 8.9 17.4 Death CV hospitalization ESRD

17. Levin, Am J Kid Dis 1999, 34:125-134 Unit RR 95% CI Hemoglobin 0.5 g/dl Decrease 1.32 1.11 – 1.59 Systolic BP 5 mm Hg Increase 1.11 1.02 – 1.21 LV Mass Index 10 g/sq. m. Decrease 0.85 0.76 – 0.96 Anemia is an Important Predictor of CVD Longitudinal study of 246 patients with 1 year FU

18. NORMAL RBC PARAMETERS RBC PARAMETER ADULT MEN ADULT FEMALE HB 15 +/- 1.5 13+/- 1.5 HEMATOCRIT 46 40 RBC COUNT 5.2 4.6 RETICULOCYTES 1.6% 1.4% MCV fl 88 88 MCH pg 30.4 30.4 MCHC 34.4 34.4 RDW 13 % 13%

19. Diagnosis of Anemia

20. Learning Point 1 Renal Anemia develops when GFR falls below 30 ml/min.

21. Point 2 Exception – Diabetics develop anemia early – 45 ml/min In CKD 1,2,3 renal anemia is rare. Rule out other causes

22. Point 3 Pure Renal anemia is Normocytic Normochromic Either a low[Fe] or high MCV[B12,F] Low MCH or MCHC strongly suggest other contributory factors [ Iron def or hemoglobinopathy ]

23. Investigation

24. Spl situations

25. Iron status

26. Anemia in CKD: Iron Replacement All CKD patients + renal anemia requiring EPO should be given supplemental iron to reach targets. Route: IV or oral in pre-dialysis -CKD or PD-CKD The preferred route is IV in CKD-HD K-DOQI 2006

27. Functional Fe Def HEPCIDIN

28. Features Iron Dextran Iron Sucrose Ferric Gluconate Nature Dextran complex covering iron core Sucrose covering iron oxide core Iron bound with 1 gluconate + 4 sucrose Mol. Wt 96-265 kd 34 – 60 kd 289 – 440 kd Direct Iron Transfer No No No Half life 40-60 hours 6 hrs 1 hrs Vol. Distribution 6 Liter 3.2 – 7.3 liter 6 liter Renal Excret . Negligible < 5 % Nil Parenteral forms of Iron

29. Point 4 Retics of > 100 x 10 9 /L suggests active BM but enhanced blood loss due to hemolysis or bleed

30. ERA OF ESAs Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115 Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130 Darbepoetin t 1 / 2 25–72 hours Epoetin d Epoetin a t 1 / 2 6–24 hours Methoxy PEG- epoetin b (CERA) t 1 / 2 130 hours Epoetin b t 1 / 2 6–24 hours 1989 2002 2007 1990 Biosimilar epoetins HX575 and SB309

31. Point-5 ***** Trigger Hb for initiating ESA therapy should be between 9 or 10 G/ dL Target Hb LEVEL 10-12 G/ dL Why not a normal hematocrit be targetted in CKD? Crux of controversy

32. Normal Hematocrit study

33. Choir Study

34. CHOIR STUDY

35. CREATE STUDY

36. CREATE STUDY

37. DIVERSITY

38. Point -6 Caution while using EPO ! Active malignancy History of Stroke CAD/CCF Uncontrolled HT

39. EPO: Routes of administration S.C. I.V. Bioavailability 48.8% 100% t 1/2 19-25 hrs 5-11 hrs Effectiveness More less Dose requirement Less More Besarab A, et al. Am J Kidney Dis 2002; 40: 439–446

40. Darbepoetin Alpha Long-acting protein 2 more carbohydrate chains and up to 8 more sialic acid residues Bind to same receptor as EPO Same mechanism of action as EPO Super- silation prolong in-vitro activity Clinical efficacy and Safety profile similar

41. Darbepoetin in Anemia: Correction Phase Dialysis patients SC/IV 0.45 μg/kg once weekly Non- Dialysis patients 0.45 μg/kg once weekly (or ) 0.75 μg/kg once every two weeks (or) 1.5 μg/kg once monthly If  in Hb is < 1 g/ dl in 4 wks ,  the dose by 25 %. Dose  not more frequently than once in four weeks If the  Hb is > 2 g/dl in 4 wks  the dose by 25%. If the Hb > 12 g/ dl, a dose reduction should be made.

42. Darbepoetin in CKD: EPO Comparison Significantly faster increase in Hb * p<0.0001 Lullo , et al. Cardiorenal Med 2012;2:18–25

43. Hemoglobin variability and its impact on survival A longitudinal survey of HD patients showing fluctuations in Hb with its impact on survival

44. Hemoglobin variability worsens survival. Long acting EPO like Darbopoietin and CERA reduce this phenomenon.

45. Conclusion Do not assume every anemia in CKD is EPO responsive Look for clues for secondary causes Do not overcorrect hematocrit in CKD Know your patient profile well before EPO therapy Start low and go slow Long acting EPO like DarboP is preferable