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PRCA post renal transplant-a case and review


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PRCA post renal transplant-a case and review

  1. 1. Clinical CasePartha Choudhary/48/M LURRAR- date of transplantation 7/6/2011 Developed progressive anemic symptoms after transplantation, with chest pain on exertion. Pre Tx Hb-9.2, gradually decreasing Hb post Tx- 6.5 on discharge till 5.4g/dl one month after the DOTx. History of EPO use (iv) for 2 yrs, max 10,000U till Tx and sc after that for 3 doses. Preserved TLC and Plat with NC,NC picture and retic of 0.5%, and MCV of 82
  2. 2. Clinical Case Ferritin-790mcg/ml and TSAT-80% Stool occult blood X3-negative UGI Endoscopy-normal USG abdomen-normal No response to Vit B12 and folic acid supplementation. Mild rise of serum creat from 1.1mg% to 1.65mg% CMV DNA PCR-negative Anti-EPO antibodies-pending Parvovirus B19-positive
  3. 3. Mini reviewCJASN:193-199; 2008
  4. 4.  First recognized in 2002. Casadevall et al. N Engl J Med 346: 469–475, 2002 It was initially reported in patients who were treated with epoetin manufactured by Ortho- Biotec outside the United States (Eprex, Erypo [Ortho Biologics, LLC, Manati, Puerto Rico]) But cases have since been reported with all commercially available ESA (Epogen, Aranesp, Procrit, NeoRecormon)
  5. 5. Diagnosis of ESA induced PRCA This is characterised by progressive, severe, normocytic, normochromic anemia of sudden on-set; reticulocytopenia; and a striking, almost complete absence of erythroid precursor cells in the bone marrow. Hemoglobin levels decrease at a rate of approximately 0.1 g/dl per d (1 g/L per d), corresponding to the red blood cell lifespan. The hallmark of PRCA is the absence of erythroblasts from an otherwise normal bone marrow.
  6. 6. Diagnosis of ESA induced PRCA
  7. 7. Bone marrow in PRCA
  8. 8. Classification of Pure Red Cell Aplasia Self-limited  Transient erythroblastopenia of childhood  Transient aplastic crisis of hemolysis (acute B19 parvovirus infection) Fetal red blood cell aplasia  Nonimmune hydrops fetalis (in utero B19 parvovirus infection) Hereditary pure red cell aplasia  Congenital pure red cell aplasia (Diamond-Blackfan syndrome) Acquired pure red cell aplasia  Thymoma and malignancy  Thymoma  Lymphoid malignancies (and more rarely other hematologic diseases)  Paraneoplastic to solid tumors  Connective tissue disorders with immunologic abnormalities  Systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis  Multiple endocrine gland insufficiency  Virus  Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus, Epstein- Barr virus  Pregnancy  Drugs  Especially
  9. 9. Drugs implicated in PRCACausality may be established using the following three criteria:(1) at least five patients reported,(2) reports from at least three separate investigators, and(3) a minimum of one case of probable or higher causality using a published assessment scale.
  10. 10. Pathogenesis of ESA inducedPRCA The pathogenetic mechanism has been shown clearly to be secondary to the development of neutralizing anti-erythropoietin antibodies. These antibodies, which recognize all available ESA (epoetin alfa, epoetin beta, and darbepoetin alfa) as well as endogenous erythropoietin, block the interaction between erythropoietin and its receptor.
  11. 11. Clinical approach to PRCA suspectcase1. First thing to ascertain whether the ESA resistance is partial or severe. ESA related PRCA follows an “all or none” phenomenon, which means that if there is less than severe ESA resistance, then the cause is not ESA induced PRCA.2. Bone marrow examination to confirm the presence of severe erythroid hypoplasia.3. Anti-ESA antibodies are needed for completing the diagnostic criteria, absence makes ESA induced PRCA unlikely.4. Other causes of hypo responsiveness to ESA should also be evaluated
  12. 12. Conditions causing ESAresistance
  13. 13. Treatment Patients who are diagnosed with ESA induced PRCA should have the ESA stopped immediately but cessation alone may not cause remission. Regular blood transfusions till the antibodies disappear. In cases of PRCA induced by drugs other than ESA’s, the disease generally remits in 1-2 weeks. Patients who develop antibody-mediated PRCA in response to ESA treatment are unlikely to respond to treatment with other erythropoietic agents, because there is substantial crossreactivity among erythropoietic agents, including endogenous erythropoietin.
  14. 14. Treatment In patients with CKD and ESA-induced PRCA, immunosuppressive treatment is usually required to induce disappearance of anti- erythropoietin antibodies. Recovery rates from PRCA is 2% without immunosuppressive therapy, 52% after immunosuppressive treatment(s) outside the renal transplantation setting, and 95% after kidney transplantation. Bennett et al. Blood 106:3343– 3347, 2005 In the absence of kidney transplantation, treatment of PRCA includes oral administration of prednisone, usually at a starting dosage of 1 mg/kg per d. In patients with idiopathic PRCA, corticosteroids produce responses in approximately 50% of patients Similar response rates were reported in patients with
  15. 15. Treatment Other therapies like cyclophosphamide, cyclosporine, daclizumab and rituximab have also been tried with success. PRCA induced by parvovirus respond to IVIg but the response is poor in ESA induced PRCA Rechallenge with a different epoetin preparation should be considered with caution and only when anti-epoetin antibody levels have become undetectable.
  16. 16. Reasons for the development ofantibodies against EPREX The incidence rate rose drastically between 1998 and 2002, after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80 to avoid the risk for virus or transmission. Several hypothesis have been put forth to explain the breakage of the B cell tolerance but are not satisfactory. The presence of epoetin-loaded micelles in the stored formulation has been suggested as a
  17. 17.  It has been proposed that leachates released from rubber stoppers used only in syringes from Ortho Biotech could act as adjuvants and induce an immune response against erythropoietin, but experimental data substantiating this claim are controversial. However, the micelle hypothesis and the leachate hypothesis were not convincing due the universal presence in EPO syringes and the rarity of the condition. Another explanation that was put forward was the use of silicon in as lubricants in the Eprex syringes (NEJM 2004)
  18. 18. NEJM 2004
  19. 19. Parvovirus B19 in renal transplantrecipients Nature Reviews 2007
  20. 20. Parvovirus B19 related PRCA inrenal transplant recipients The onset of anemia after transplantation has been reported to occur from 2 weeks to 63 months, although most of the documented cases occurred within the first 3 months. Fever and flu-like symptoms can be seen at presentation. Weakness, dyspnea and orthostatic hypotension are often present, and are related to the abrupt onset of severe anemia. Arthralgias and rashes are less common manifestations because of impaired antibody
  21. 21. Parvovirus B19 related PRCA inrenal transplant recipients Nature Reviews 2007
  22. 22. THANK YOU