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Erythropoiesis stimulating agents in chronic kidney disease

Rajeewa Dassanayake Senior Registrar in Nephrology. Erythropoiesis stimulating agents in chronic kidney disease. ESA in CKD. “ Erythropoietin is arguably the best example of the therapeutic benefits of molecular biology / biotechnology in clinical medicine ”. History.

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Erythropoiesis stimulating agents in chronic kidney disease

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  1. Rajeewa Dassanayake Senior Registrar in Nephrology Erythropoiesis stimulating agents in chronic kidney disease

  2. ESA in CKD “Erythropoietin is arguably the best example of the therapeuticbenefits of molecular biology / biotechnology in clinical medicine”

  3. History • 1906 RBC production regulated by hormones, later purified and confirmed as erythropoietin • 1970s EPO stimulates production of red cells and could lead to a treatment • 1980s clinical trial was successful • Published in NEJM in 1987 • 1985 gene identified • 1989, FDA approval • More recently newer erythropoiesis stimulating agents (ESAs)

  4. Anaemia – definition • NKF • < 12 g/dl for women • < 13.5 g/dl for men • Eur Best Prac Gdlnes for Mx of Anemia in CRF • <11.5 g/dl in women • < 13.5 g/dl in men <70 years ofage • < 12 g/dl in men > 70 years of age.

  5. Causes • Erythropoietin deficiency • Medications • ACE/ARB, metformin, fibrates, thiazolidinediones • Inflammation • mediators,such as interleukins and tissue necrosis factorblunt erythropoietin effect • Platelet dysfunction • with GI bleeding, shortens erythrocyte survival (30–60%) • Haemolysis • secondary to uremic toxins • Chronic blood loss • from phlebotomy and HD • Malnutrition • Deficiencies • of iron, folate, and vitamin B12

  6. Impact • Fatigue, dizziness, SOB • Reducedcognitive function / mental acuity and quality of life • CVS complications – LVH, CCF • With T2DM1 • Independent riskfactor for loss of kidney function. • Cardiovasculardisease • Independently increase the risk of retinopathy • Thought to hasten the progression of diabetic neuropathy • Need for blood transfusions • O'Mara NB. Diabetes Spectrum 2008

  7. Benefits of correction • Cardiac function1 • Stabilization of renal function1 • has been associatedwith treatment of the anemia of CKD • Exercise capacity • endurance, energy, mobility • Patient satisfaction • quality-of-lifescores, sexual function, cognition, less depression,and better socialization • Reduction in hospitalization and mortality2,3,4 • Silverberg DS et al. Nephrol Dialysis Transplant 2003 • Collins AJ et al. J Am Soc Nephrol2001 • Collins AJ, Ma JZ, Ebben J. SeminNephrol2000 • Regidor DL et al. J Am Soc Nephrol2006

  8. Treatment

  9. Targets • NKF K/DOQI-target Hb 11–12g/dl • FDA: 10 – 12 g/dl • “Maintaining higher hemoglobin levels in patientswith chronic kidney failure increases the risk for death andfor serious cardiovascular reactions such as stroke, heart attack,or heart failure.“ • Hb variability is common • Clinicalsignificance of transient excursions is less clear. • May be associated with worseoutcome

  10. Normal Hematocrit Study(NHS)1 • RCT of 1233 HDpts with established heart disease. • Complete correction vs partial correction • Strong trend for nonfatal MI or death in higher Hb group • Besarab A et al. N Engl J Med 1998

  11. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) Trial • 1432 pts • Hb 13.5 Vs 11.5 g/dL • Conc: Hb of 13.5 g/dL associated with cardiovascular risk and no improvement in QOL • Singh AK et al. CHOIR Investigators N Engl J Med 2006

  12. The Cardiovascular Reduction Early Anemia Treatment Epoetin Beta (CREATE) Study • 603 patients with CKD • Early (Hb 11 - 12.5 g/dL) intervention to target Hb 13 -15 g/dL • Late (Hb < 10.5 g/dL) intervention to target Hb 10.5 -11.5 g/dL • 1ry outcome – death / defined CV event • No statistically significant difference • Quality of life better with higher Hb • Recommended partial correction of anemia and not routine normalization • Drueke TB et al. CREATE Investigators. N Engl J Med 2006

  13. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) • Ongoing RCTs • May provide critical guidance for the future management of anemia and ESA safety at highertarget Hb levels • de Francisco ALMNephrol Dialysis Transplant 2009

  14. Erythropoietin • Indistinguishable from endogenous erythropoietin • Binds the dimerized erythropoietin receptor on the surface of erythroid progenitor cells. • Triggers a variety of responses by several signaling pathways • Results in cell proliferation and inhibits apoptosis of the erythroid progenitor cells • Highly effective at stimulating erythropoiesis1 • Eschbach JW et al. N Engl J Med 1987

  15. Current and future erythropoietic agents for the treatment of CKD anemia • Protein-based ESA therapy      • epoetin (alfa, beta, delta, omega)     • biosimilar EPO     • darbepoetin alfa •  CERA     •  SEP      • EPO fusion proteins          • EPO–EPO          • GM-CSF–EPO          • Fc-EPO         •  CTNO 528 • Small-molecule ESA      • peptide-based (e.g., Hematide)      • non–peptide-based • Other strategies for stimulating erythropoiesis      • prolylhydroxylase inhibitors (HIF stabilizers)      • GATA inhibitors      • HCP inhibitors      • EPO gene therapy

  16. Darbepoetin alpha • A 2nd generation ESA • 2 amino acid substitutions • Greater metabolic stability • Elimination t½ 25.3 hrs (vs 8.5 hrs) • weekly or every other week • RCT in over 500 HD pts • wkly darbepoetin alfa as effective as epoetin 3 times weekly • Nissenson AR et al. Am J Kidney Dis 2002

  17. CERA • Addition of a large polymer chain into the erythropoietin molecule • Elimination t ½ 130 hrs • (vs 8.5 hours for epoetin alpha and 25.3 hours for darbepoetin alpha) • Given 3 to 4 weekly is safe and effective

  18. Multicentre RCTs1 • long-term tight control of Hb in over 800 HD pts converted from epoetin to CERA once every 2 weeks or once monthly • Achieved irrespective of the patients' age, gender, or diabetic status • CERA once every 2 wks Vs Darbepoetin alpha in 324 non HD, ESA-naïve pts, similar response rates (97.5% Vs 96.3% • Ongoing -monthly CERA Vs darbepoetin alpha in dialysis pts • 2006 ASN Annual Meeting

  19. Erythropoietin-mimetic peptides • Hematide • in phase 2 of clinical development • Binds erythropoietin receptor • causes cell proliferation and differentiation • Stimulate erythropoiesis in multiple species, to produce a sustained increase in hemoglobin levels. • Well tolerated • A pegylated peptide • has a long duration of action that allows for once monthly dosing. • Other possible benefits • Stability at room temperature • Lack of crossreactivity with antierythropoietin antibodies

  20. Hypoxia-inducible factor (HIF) stabilizer • The first oral ESA. In phase 2 of clinical development • Stabilises HIF • a transcription factor • activates erythropoietin during hypoxic conditions • regulates iron absorption, metabolic response, and vasculogenesis • May surpass effectiveness of erythropoietin • ability to stimulate iron absorption • suppress the negative effects of proinflammatory cytokines on red blood cell production

  21. Dosage of Erythropoietin • Adult 50 to 100 Units/kg thrice a week • Children 50 Units/kg thrice a week • Increase Dose by 25% if: • Hb< 10 g/dL and not increased 1 g/dL after 4 wks • Hb decreases <10 g/dL • Reduce Dose by 25% if: • Hb approaches 12 g/dL or • Hb increases > 1 g/dL in any 2-week period • <10g/dL over12-weeks: • do not administer higher doses • lowest dose avoid recurrent transfusions • Evaluate • Discontinue if responsiveness does not improve

  22. Dosage of Darbepoetin / CERA • Darbepoetin: • Initially 0.45 mcg/kg wkly • Appr conversion is 200 IU of epoetin alpha to 1 mcg of darbepoetin alpha. Follow manufacturer recommendations • CERA: • Initially 0.6µg/kg fortnightly • Conversion: follow manufacturer recommendations • Convert to monthly dosing when Hb stable, at double the fortnightly dose • Dose adjustments as for erythropoietin • Follow manufacturer instructions for administration of all ESAs

  23. ESA resistance • Hyporesponse is common CKD • Defined as • Significant increasein dose requirement for maintenance • Significant decrease in Hb at constant dose • Failure to achieve Hb of 11 g/dl despite an ESA dose equivalent to epoetin > 500units/kg/week

  24. Causes of ESA resistance1 • The most common causes are iron deficiency and inflammatory disorders • Compliance should also be checked • Other Causes • chronic blood loss • hyperparathyroidism/osteitisfibrosa • aluminium toxicity • haemoglobinopathies (e.g. a- and b-thalassaemias,sickle cell anaemia) • vitamin deficiencies (e.g. folate or vitamin B12) • multiple myeloma, myelofibrosis, other malignancies • malnutrition • haemolysis • inadequate dialysis • adverse effects of certain drugs [e.g. cytotoxic and immunosuppressive agents, ACE/ARBs] • Nephrol Dial Transplant 2004

  25. Management of epo resistance • Iron deficiency • Absolute Fe deficiency found in 2.8% of Sri Lankan HD pts, while 44.4% had both SF and TS in range indicating risk of overload1 • Inflammation2 • Detect and treat occult infection • Optimise dialysis procedure • Optimise heart failure management • ?pentoxyfylline • ?vitamin E • Malnutrition • Herath CA, Dassanayake RT, Mendis DSN. 2007 • de Francisco ALM, Stenvinkel P, Vaulont s. NDT 2009

  26. Diabetes associated with higher ESA requirements • Low endogenous erythropoietin concentrations • Rossert J et al. Nephrol Dial Transplant 2007

  27. Adverse effects • Hypertension • Access clotting • ?Neovascularisation1 • ?enhancement of cancer growth1 • ?protection of nervoussystem, myocardium, and other tissues1 • Bunn FH. Blood 2007

  28. Syndrome of PRCA • First described in 1980s • Marrow failure with selectivereduction or absence of erythroid precursors • All epoetin molecules(epoetin-, darbepoetin, and epoetin-β) reported in inducingcases • Attributed Tween in place of human albumin as stabilizer. • Interacts with rubber, enhancing antigenicity • Modifications in the manufacturingand storage of epoetin have resulted in a dramatic (>80%)reduction • Singh AK . Clin J Am Soc Nephrol 2008

  29. Thank you!

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