1. Anemia in Transplantation Yvette Talusan- Tomacruz, M.D.

2. KT HD PD

3. WHY SHOULD WE TALK ABOUT ANEMIA? Is it prevalent? Etiology? Can we do something about it?

8. ?KT

11. Anemia- Definition Mild: Mild: Males= Hgb>120 g/L and 120 g/L and <130 g/L Female= Hgb >110 g/L and 110 g/L and <120 g/L Moderate Moderate Males= Hgb>110 g/L and 110 g/L and <120 g/L Female= Hgb >100 g/L and 100 g/L and <110 g/L Severe Severe Males= Hgb <110 g/L Males= Hgb <110 g/L Female= Hgb <100 g/L Female= Hgb <100 g/L Kasiske, JASN 2000: 11 (Suppl 15)

12. 76%21%36% *Hct<30, 36% Iron profile 46% had iron supplements 40% EPO

13. Vanrenterghem, AJT 2003; 3:835 At enrollment, 38.6% were anemic, 8.5% were severely anemic,17.8% were on epo.

15. Risk factors for Anemia Non-Anemic vs Anemic VariableOdds RatioP-value Serum creatinine3.48<0.001 Age of donor(>60)1.41<0.001 ACEIn or AII1.55<0.001 MMF or AZA1.24<0.05 ADPKD0.70<0.01 Recent Infection1.36<0.001 Vanrenterghem, AJT 2003; 3:835

16. Risk factors for Anemia Non-Anemic vs Severely Anemic VariableOdds RatioP-value Serum creatinine7.54<0.001 Age of donor(>60)0.97NS ACEIn or AII1.58<0.001 MMF or AZA1.22NS ADPKD0.55<0.001 Hepatitis0.84NS Recent Infection2.12<0.001 Vanrenterghem, AJT 2003; 3:835

17. Etiology Chronic Kidney Disease Chronic Kidney Disease Iron Deficiency Iron Deficiency Drugs Drugs Immunosuppressive agents- CNI, MMF, AZA, Sirolimus Immunosuppressive agents- CNI, MMF, AZA, Sirolimus ACE In vs. ARB ACE In vs. ARB Malignancy Malignancy Infections Infections Active infections Active infections Parvovirus B19 Parvovirus B19

18. Chronic Kidney Disease in Renal Transplant Patients Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 N(%)10(2.2) 103 (22.4) 274 (59.7) 66 (14.4) 6 (1.3) GFR98.6±11.571.9±8.244.2±8.424±4.211.5±2.9 Serum creatinine 0.8±0.11.1±0.21.7±0.42.8±0.55.1±1.3 Karthikeyen, AJT 2003;4:262

19. Complications per CKD Stage Chronic Kidney Disease Stage Mean Number of complication Karthikeyan, AJT 2003;4:262-269

20. Hgb and Iron indices according to CKD Stage Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 P value Hemoglobin 14.2 ±1.6 14.0 ±1.4 13.2 ±1.5 11.8 ±1.5 11.7 ±1.1 <0.001 On erythropoietin (%) 004.42167<0.001 Hgb <11 g/d (%) 02.96.62733<0.001 Hgb <11 and on epo (%) 002233500.16 Transferrin saturation (%) 100354232250.35 Ferritin <100 ng/ml (%) 0195438500.44 Karthikeyan, AJT 2003;4:262-269

22. AR rates are down AR Immunosuppressive agents ACE In and ARB Use

23. ACE In and AII RB Post transplant erythrocytosis Post transplant erythrocytosis Direct inhibition of erythropoietin of insulin-like growth factor Direct inhibition of erythropoietin of insulin-like growth factor Indirect mechanism that improves renal perfusion followed by a subsequent decrease in oxygen consumption Indirect mechanism that improves renal perfusion followed by a subsequent decrease in oxygen consumption May have a negative effect on hematopoiesis at the bone marrow level since AII receptors on erythroid progenitors May have a negative effect on hematopoiesis at the bone marrow level since AII receptors on erythroid progenitors

24. Effect of ARB on KT without PTE Variable-3 weeksbaseline3 weeks6 weeks9 weeks12 weeks Losartan group Hgb13.5±1.213.1±1.112.9±0.712.4±1.312.3±1.012.2±1.4 Hct40.7±3.539.7±4.738.8±3.436.5±4.136.1±2.936±4.3 Creatinine1.25±0.291.22±0.261.28±0.26 Control Hgb13.8±1.513.6±1.714.1±1.614.2±1.814.6±1.914.6±1.7 Hct42.0±5.041.2±4.943±4.642.4±5.844.1±5.944.1±5.6 crea1.15±0.31.25±0.261.23±0.26 P<0.05 P<0.01

25. Sirolimus-Related Anemia Known adverse effect of sirolimus therapy Known adverse effect of sirolimus therapy Sirolimus-related anemia is concentration dependent (>15 ng/mL) Sirolimus-related anemia is concentration dependent (>15 ng/mL) Analysis of phase I/II data in 40 renal allograft recipients demonstrated 24-hour trough concentrations > 15 ng/mL associated with decreased hemoglobin Analysis of phase I/II data in 40 renal allograft recipients demonstrated 24-hour trough concentrations > 15 ng/mL associated with decreased hemoglobin Possibly secondary to inhibition of sirolimus- sensitive cytokine pathways that are essential in hematopoiesis Possibly secondary to inhibition of sirolimus- sensitive cytokine pathways that are essential in hematopoiesis Kahan BD, et al. Transplantation. 1998;66:1040-1046.

26. Risk factors for Anemia Non-Anemic vs Anemic VariableOdds RatioP-value Serum creatinine3.48<0.001 Age of donor(>60)1.41<0.001 ACEIn or AII1.55<0.001 MMF or AZA1.24<0.05 ADPKD0.70<0.01 Recent Infection1.36<0.001 Vanrenterghem, AJT 2003; 3:835

27. Hgb levels across various regimens All patientsNHemoglobinP value Tac or Cya and steroids With Aza71313.3±1.9NS Tac or Cya and steroids Without Aza75813.4±2.0NS Tac or Cya and steroids With MMF150213.1±1.9P<0.01 Tac or Cya and steroids Without MMF 75813.4±2.0P<0.01

28. Etiology Chronic Kidney Disease Chronic Kidney Disease Drugs Drugs Immunosuppressive agents- CNI, MMF, AZA, Sirolimus Immunosuppressive agents- CNI, MMF, AZA, Sirolimus ACE In vs. ARB ACE In vs. ARB Iron Deficiency Iron Deficiency Malignancy Malignancy Infections Infections Active infections Active infections Parvovirus B19 Parvovirus B19

29. Vanrenterghem, AJT 2003; 3:835

30. Iron Deficiency Highly prevalent especially in early post-transplant period. Highly prevalent especially in early post-transplant period. Not examined in routine practice Not examined in routine practice 01234 Odds Ratio Hypochromic RBC<2% Transferrin <231 Serum Iron <62 TSAT <16% Serum Ferritin <32.2 Lorenz, JASN 2002

31. Iron Use in KT IV Iron (Sodium Ferric gluconate) IV Iron (Sodium Ferric gluconate) Gillespie et all in pediatric and young adult RT Gillespie et all in pediatric and young adult RT Hgb increased from 101±16 to 114±21(p=0.0092) Hgb increased from 101±16 to 114±21(p=0.0092)

32. Etiology Chronic Kidney Disease Chronic Kidney Disease Drugs Drugs Immunosuppressive agents- CNI, MMF, AZA, Sirolimus Immunosuppressive agents- CNI, MMF, AZA, Sirolimus ACE In vs. ARB ACE In vs. ARB Iron Deficiency Iron Deficiency Malignancy Malignancy Infections Infections Active infections Active infections Parvovirus B19 Parvovirus B19

33. Erythropoietin use in Kidney transplant patients Erythropoietin use in Kidney transplant patients

34. Erythropoietin Use and KT Is it beneficial to use Epo immediately after RT? Is it beneficial to use Epo immediately after RT? Other benefits of EPO Other benefits of EPO TRESAM study shoed under-utilization of epo even in patients with severe anemia TRESAM study shoed under-utilization of epo even in patients with severe anemia 207/3969 (5.2%) were on epo 207/3969 (5.2%) were on epo Mild anemia= 44/731 (6%) Mild anemia= 44/731 (6%) Moderate anemia=55/465 (11%) Moderate anemia=55/465 (11%) Severe anemia= 61/343 (17.8%) Severe anemia= 61/343 (17.8%) Vanrenterghem,AJT 2003; 3:836

35. EPO Early after KT Anemia may occur due to blood loss, inflammatory status and defective EPO production Anemia may occur due to blood loss, inflammatory status and defective EPO production Increased risk of tissue hypoperfusion and cellular hypoxia Increased risk of tissue hypoperfusion and cellular hypoxia RCT 100 u/kg RhuEPO thrice a week as long as Hgb <12 RCT 100 u/kg RhuEPO thrice a week as long as Hgb <12 Use of EPO in the immediate post-transplant period reduces time to reach Hgb 12 but marginal, dose needed was high Use of EPO in the immediate post-transplant period reduces time to reach Hgb 12 but marginal, dose needed was high Van Biesen, Transplantation 2005;79:367-368

36. Can Epo retard progression? University of Wisconsin University of Wisconsin 2 groups: early EPO (18-294 days)(N=119) vs. late EPO (>294 days)(N=57) vs. control 2 groups: early EPO (18-294 days)(N=119) vs. late EPO (>294 days)(N=57) vs. control Becker, NDT 200217:1667

37. 6.6% 2.2%

39. Impact of Anemia on Allograft Loss and Patient Mortality

40. Retrospective cohort 626 KT patients Retrospective cohort 626 KT patients Prevalence of anemia Prevalence of anemia 1 month = 72% 1 month = 72% 3 months= 40 % 3 months= 40 % 12 months= 20.3% 12 months= 20.3% PTA cohort PTA cohort Inferior patient survival Inferior patient survival Higher CV death Higher CV death Imoagene-Oyedeji, JASN. 2006 Oct 11

41. Impact of Anemia on Allograft Loss and Mortality Risk factors for 12 month PTA Risk factors for 12 month PTA Anemia at 3 months Anemia at 3 months Donor age Donor age 3-mo creatinine 3-mo creatinine Risk factors for Mortality Risk factors for Mortality 12-mo PTA 12-mo PTA 12 mo creatinine 12 mo creatinine Age at transplantation Age at transplantation Hep C (+) Hep C (+) Imoagene-Oyedeji, JASN. 2006 Oct 11

42. Impact of Anemia on Allograft Loss and Mortality Prospective study of 825 Renal transplant patients followed for 8.2 years Prospective study of 825 Renal transplant patients followed for 8.2 years 251 patients died, 401 allografts lost 251 patients died, 401 allografts lost Anemia was associated with 25% greater risk of allograft loss Anemia was associated with 25% greater risk of allograft loss But not associated with mortality But not associated with mortality Winklemeyer, NDT, 2006 Oct 13

43. Post-Transplant Anemia PTA is prevalent and may be significant PTA is prevalent and may be significant CKD is most common cause but others need to be ruled out CKD is most common cause but others need to be ruled out Check iron parameters Check iron parameters Consider use of erythropoietin in Kidney transplant patients Consider use of erythropoietin in Kidney transplant patients *Impact on graft survival and mortality *Impact on graft survival and mortality

46. Anemia in NKTI KT Patients

47. Pre- op Anemia 14 10.3 18.4 57.4

48. Creatinine and Anemia Pre-op 8.87 9.97 11.2 10.44

49. Anemia at 1 week 13 22 20 81 Percentage

50. Creatinine and Anemia 1 week 1.35 1.01 1.12 2.01

51. Anemia at One Month 45.6 23.5 14 16.9

52. Creatinine and Anemia One Month 1.09 1.19 1.8 1.5

53. Anemia at Three Months 63.2 16.2 8.1 12.5 Percentage

54. Creatinine and Anemia Three Months 1.25 1.16 1.3 1.94

55. Anemia at Six Months 72.1 13.2 8.1 6.6 Percentage

56. Creatinine and Anemia Six months 1.33 1.44 1.31 2.05

57. Anemia at One Year 71.3 13.2 8.8 6.6 Percentage

58. Creatinine and Anemia One Year 1.24 1.40 2.49 2.38