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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 13  |  Issue : 3  |  Page : 231-233

Antibody-mediated pure red cell aplasia after treatment with darbepoetin-alpha postrenal transplantation


Department of Nephrology, Manipal Hospitals, Bengaluru, Karnataka, India

Date of Submission29-Jan-2019
Date of Decision06-Jun-2019
Date of Acceptance10-Sep-2019
Date of Web Publication17-Sep-2019

Correspondence Address:
Dr. Badarinath Vellaboina
Door Number – 12-2-302, Ashok Nagar Extn., Anantapur - 515 001, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_3_19

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  Abstract 


Pure red cell aplasia (PRCA) is a rare normochromic, normocytic anemia with a near-to-complete absence of erythroblasts in the bone marrow. Erythropoiesis-stimulating agents have been used widely to improve anemia in patients with chronic kidney disease. We present a case of a 38-year-old woman who was detected to have anemia (hemoglobin: 10 g/dl) and renal dysfunction (creatinine: 3 mg/dl) on a routine health check in December 2016. Her kidney biopsy showed chronic interstitial nephritis. She received intravenous (IV) iron and was started on darbepoetin-alpha. Her hemoglobin after 3 months of treatment was 12 mg/dl. She underwent preemptive one haplomatch renal transplantation on June 2017. She was discharged with serum creatinine of 0.9 mg/dl and hemoglobin of 8 g/dl. She was not on any Erthropoietin stimulating agents (ESA) at discharge. In the 4th week after transplant, her hemoglobin dropped to 7 g/dl, and she was restarted on darbepoetin-alpha 40 μg subcutaneously once a week. In the 6th week posttransplant, her hemoglobin dropped to 6 g/dl. Her peripheral smear showed normocytic normochromic anemia with no evidence of hemolysis. Transferrin saturation was 81%, serum ferritin levels were 1812 ng/ml, and reticulocyte count was 0.1%. Bone marrow biopsy showed suppression of erythroid precursors with myeloid-to-erythroid ratio of 8:1, adequate iron stores, and normal white blood cell and platelet precursors with no dysplastic cells. Paroxysmal Nocturnal hemoglobinuria (PNH) workup; antinuclear antibody; and screening for hepatitis B, hepatitis C, HIV, CMV, and human parvovirus B19 were negative. Anti-erythropoietin (EPO) antibody by enzyme-linked immunosorbent assay was positive. She was diagnosed to have PRCA secondary to anti-EPO antibodies. She was managed with pulse doses of methylprednisolone, adequate dose of tacrolimus, IV immunoglobulin of 125 g (2 g/kg) over 5 days, and two packed red cell transfusions. Darbepoetin-alpha was stopped. At present, her hemoglobin is 12.5 g/dl with serum creatinine of 1 mg/dl on triple immunosuppression with no requirement of ESA.

Keywords: Anti-erythropoietin antibody, darbepoetin-alpha, pure red cell aplasia, renal transplantation


How to cite this article:
Vellaboina B, Bonu R, Mukherjee T, Augustine R. Antibody-mediated pure red cell aplasia after treatment with darbepoetin-alpha postrenal transplantation. Indian J Transplant 2019;13:231-3

How to cite this URL:
Vellaboina B, Bonu R, Mukherjee T, Augustine R. Antibody-mediated pure red cell aplasia after treatment with darbepoetin-alpha postrenal transplantation. Indian J Transplant [serial online] 2019 [cited 2019 Oct 19];13:231-3. Available from: http://www.ijtonline.in/text.asp?2019/13/3/231/266946




  Introduction Top


Abstract Pure red cell aplasia is an uncommon entity esp in post transplantation scenario. Here we report a case of PRCA due to darbepoetin alpha occurring after transplantation.


  Case Report Top


We present a case of a 38-year-old woman who was detected to have anemia (hemoglobin: 10 g/dl) and renal dysfunction (creatinine: 3 mg/dl) on a routine health checkup in December 2016. Her kidney biopsy showed chronic interstitial nephritis. The initial anemia evaluation showed iron deficiency; she received intravenous (IV) ferric carboxymaltose and was started on 40 μg of darbepoetin-alpha subcutaneously (SC) once a week. Her hemoglobin after 3 months of treatment was 12 mg/dl until May 2017.

In the 1st week of June 2017, she presented with complaints of generalized weakness and easy fatiguability. There was no history of bleeding from any site or noncompliance to erythropoietin (EPO). On evaluation, she was found to have a hemoglobin of 6.2 g/dl with normal white blood cell (WBC) and platelet counts. Peripheral smear showed normocytic normochromic (NCNC) anemia with no evidence of hemolysis. Stool occult blood was negative. Iron stores and Vitamin B12 levels were sufficient. Hemolysis was ruled out (normal reticulocyte count and Lactate dehydrogenase (LDH) levels and Coombs test were negative). As the patient was planned for renal transplantation and to increase her hemoglobin prior to transplantation without packed red blood cell (PRBC) transfusion, her darbepoetin-alpha was stopped and changed to EPO-alpha 10000 units SC three times a week.

Her hemoglobin dropped by 1 g/dl/week (June 2nd week – 5.4 g/dl and June 3rd week – 4.6 g/dl). She was transfused two units of PRBC prior to renal transplantation on June 28, 2017. She underwent one haplomatch renal transplantation with her paternal uncle as a donor. There were no intraoperative and immediate postoperative complications. She was discharged on postoperative day 10 with a serum creatinine of 0.9 mg/dl and hemoglobin of 8 g/dl. She was not on any EPO supplement at discharge. Hemoglobin was stable for the first 3 weeks posttransplant (in the range of 8.5–9.5 g/dl).

In the 4th week after transplant, her hemoglobin dropped to 7.5 g/dl, and she was restarted on darbepoetin-alpha 40 mcg SC once a week. In the 6th week posttransplant, her hemoglobin dropped to 6 g/dl. She was evaluated for posttransplant anemia.

Posttransplant anemia evaluation

She was on triple immunosuppression, and there were no other drugs contributing to anemia. Complete blood counts showed low hemoglobin with normal red blood cell indices and normal WBC and platelet counts. Her peripheral smear showed NCNC anemia with low reticulocytes and no evidence of hemolysis. Transferrin saturation was 81%, serum ferritin levels were 1812 ng/ml, and reticulocyte count was low (0.1%) with normal serum LDH levels (247 ng/ml). Bone marrow biopsy showed suppression of erythroid precursors with a myeloid-to-erythroid ratio of 8:1, adequate iron stores, and normal WBC and platelet precursors with no dysplastic cells [Figure 1]. PNH workup and antinuclear antibody were negative. Screening for hepatitis B, hepatitis C, HIV, CMV, and human parvovirus B19 were negative. Anti-EPO antibody by enzyme-linked immunosorbent assay (ELISA) was positive (percentage of binding to EPO: 5.02% and normal percentage of binding to EPO: up to 4.7%). She was diagnosed to have pure red cell aplasia (PRCA) secondary to anti-EPO antibodies.
Figure 1: (a) Bone marrow with normal erythroid precursors. (b) Bone marrow without normal erythroid precursors

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Management

She was managed with pulse doses of methylprednisolone (125 mg/day for three days), followed by increased dose of oral steroids (1 mg/kg/day), adequate dose of tacrolimus with tacrolimus levels of 11–12 ng/ml, IV immunoglobulin of (2 g/kg) over 5 days, two Packed red cell transfusions were given and darbepoetin-alpha was stopped.

Her hemoglobin was 10 g/dl with increasing reticulocyte count at the 10th week posttransplantation [Figure 2]. At present, she is stable with hemoglobin of 12.5 g/dl, normal reticulocyte count, and serum creatinine of 1 mg/dl on triple immunosuppression with no requirement of iron supplements or ESA.
Figure 2: Graphical representation of hemoglobin on y-axis and time on x-axis

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  Discussion Top


PRCA is a rare normochromic, normocytic anemia with a near-to-complete absence of erythroblasts in the bone marrow.[1] The etiology of PRCA in half of cases is unknown. Hematological malignancies, thymoma, viral infections (parvovirus; hepatitis A, B, C virus; retrovirus; and EBV), drugs (immunosuppressants, antitubercular drugs, antiepileptics, Angiotensin converting enzyme (ACE) inhibitors, and ESA), and autoimmune disorders (Systemic lupus erythematosus (SLE) and rheumatoid arthritis) constitute rest half of cases.[2]

The incidence of reported cases of anti-EPO antibody-mediated PRCA between 1989 and 2004 was 1.6/10,000 patient-years. The incidence post-2005 is only 0.02–0.03/10,000 patient-years.[1] Darbepoetin-alpha is a second-generation ESA with two extra carbohydrate chains and eight extra sialic acid residues as compared with epoetin-alpha. It is suggested that these modifications make this molecule more resistant to antibody development. There are only two published case reports of PRCA related to the use of darbepoetin.[3] Diagnostic criteria for PRCA are shown in [Table 1].[4]
Table 1: Diagnosis of epoetin-induced pure red cell aplasia

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A number of validated assays are available for measuring EPO antibodies, and these include radioimmunoprecipitation assay, ELISA, surface plasmon resonance (BIAcore) assay, and bioassays.[5] Anti-EPO antibody by ELISA was positive in our case(percentage of binding to EPO: 5.02% and normal percentage of binding to EPO: up to 4.7%). One reason for the only marginal elevation of anti-EPO antibody in our patient is as she is postrenal transplant and already on triple Immunosuppression protocol (ISP). Bioassays are the only assays which measure the functional activity of EPO antibodies; they are known to be less sensitive than immunoassays, not readily available, and are difficult to standardize.[6]

Human serum albumin was removed as a stabilizer, due to concerns in Europe over the risk of Creutzfeldt–Jakob prions in blood-derived products and replaced with polysorbate-80. Polysorbate-80 forms micelle configuration on which EPO molecules are integrated. Several EPO molecules are presented to the recipient's immune system in regular intervals triggering immune reaction. It is important to note that darbepoetin also contains polysorbate-80 as the stabilizing agent and is given by subcutaneous injection.[7]

PRCA can be difficult to treat and simply withdrawing erythropoiesis-stimulating agents is not sufficient to reverse the condition. Due to the small numbers of affected patients, only retrospective data can be used to establish the most effective therapy. The largest retrospective series of patients with PRCA included 47 patients, with the most effective therapies being renal transplantation, corticosteroids (alone or in combination with IV immunoglobulin), and corticosteroids in combination with cyclophosphamide.[8] Our case demonstrates a clear temporal association between recovery and the introduction of combination of prednisolone and IV immunoglobulin.


  Conclusion Top


There are no case reports in the literature of PRCA related to the use of darbepoetin postrenal transplantation. This is the first case report of PRCA related to the use of darbepoetin postrenal transplantation. Renal transplantation is considered to be the treatment of PRCA. In our case challenging with darbepoetin postrenal transplantation caused an anamnestic antibody response leading to features of PRCA.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rossert J; Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB). Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur J Clin Invest 2005;35 Suppl 3:95-9.  Back to cited text no. 1
    
2.
Macdougall IC. Antibody-mediated pure red cell aplasia (PRCA): Epidemiology, immunogenicity and risks. Nephrol Dial Transplant 2005;20 Suppl 4:iv9-15.  Back to cited text no. 2
    
3.
Howman R, Kulkarni H. Antibody-mediated acquired pure red cell aplasia (PRCA) after treatment with darbepoetin. Nephrol Dial Transplant 2007;22:1462-4.  Back to cited text no. 3
    
4.
Rossert J, Casadevall N, Eckardt KU. Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004;15:398-406.  Back to cited text no. 4
    
5.
Thorpe R, Swanson SJ. Assays for detecting and diagnosing antibody-mediated pure red cell aplasia (PRCA): An assessment of available procedures. Nephrol Dial Transplant 2005;20 Suppl 4:iv16-22.  Back to cited text no. 5
    
6.
Swanson SJ, Ferbas J, Mayeux P, Casadevall N. Evaluation of methods to detect and characterize antibodies against recombinant human erythropoietin. Nephron Clin Pract 2004;96:c88-95.  Back to cited text no. 6
    
7.
Cournoyer D, Toffelmire EB, Wells GA, Barber DL, Barrett BJ, Delage R, et al. Anti-erythropoietin antibody-mediated pure red cell aplasia after treatment with recombinant erythropoietin products: Recommendations for minimization of risk. J Am Soc Nephrol 2004;15:2728-34.  Back to cited text no. 7
    
8.
Verhelst D, Rossert J, Casadevall N, Krüger A, Eckardt KU, Macdougall IC, et al. Treatment of erythropoietin-induced pure red cell aplasia: A retrospective study. Lancet 2004;363:1768-71.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

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