Clinical CasePartha Choudhary/48/MLURRAR- date of transplantation 7/6/2011Developed 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

Clinical CaseFerritin-790mcg/ml and TSAT-80%Stool occult blood X3-negativeUGI Endoscopy-normalUSG abdomen-normalNo response to Vit B12 and folic acid

supplementation.Mild rise of serum creat from 1.1mg% to

1.65mg%CMV DNA PCR-negativeAnti-EPO antibodies-pendingParvovirus B19-positive

Mini reviewCJASN:193-199; 2008

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)

Diagnosis of ESA induced PRCAThis 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.

Diagnosis of ESA induced PRCA

Bone marrow in PRCA

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 phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid      Erythropoietin

Idiopathic Harrison’s 17th Ed

Drugs implicated in PRCA

Causality 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.

Pathogenesis of ESA induced PRCA

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.

Clinical approach to PRCA suspect case1. 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

Conditions causing ESA resistance

TreatmentPatients 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.

TreatmentIn 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 CKD and epoetin antibody–mediated PRCA.

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.

Reasons for the development of antibodies against EPREXThe 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 possible explanation.

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)

NEJM 2004

Parvovirus B19 in renal transplant recipients

Nature Reviews 2007

Parvovirus B19 related PRCA in renal transplant recipientsThe 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 production.

Nature Reviews 2007

Parvovirus B19 related PRCA in renal transplant recipients

Nature Reviews 2007

THANK YOU