Prof B. Watschinger Associate Professor of Medicine University of Vienna Medical School Vienna, Austria

 

A caucasian female patient received a first cadaveric renal transplant at age 57 (HLA Mismatch 1-1-0, PRA 2%), after 13 months on hemodialysis because of endstage polycystic kidney disease. Both donor and recipient tested positiv for CMV IgG. The patient was put on an immunosuppressive triple regimen including prednisolone, azathioprin and tacrolimus. One week after transplantation allograft rejection was treated with a steroid pulse (dexamethasone 100mg for 3 days). The serum creatinine at dismission from the hospital three weeks after transplantation was 2,0 mg/dl.

Nine weeks after transplantation the patient was readmitted to the hospital because of a rise in serum creatinine to 3,0 mg/dl. Immunosuppression consisted of tacrolimus (0,5g/kg/day), azathioprin (50mg/day) and an increased dose of prednisolon (raised from 15 to 50mg/day). A transplant biopsy revealed acute vascular rejection. After the start of antithymocyte globulin (ATG) a significant pancytopenia (erythrocytes 2,2 T/l, hemoglobin 6,5 g/dl, platelets 59 G/l, leucocytes 3.1G/l) developed. The patient was transfused with two units of packed red blood cells.

Question 1

The transplant rejection was successfully reversed with a 14-day course of antithymocyte globulin. The serum creatinine returned to values below 2 mg/dl. CMV infection, detected by de novo CMV-IgM antibodies and a rise in KBR titers, was treated with gancyclovir. As a result the hematological parameters stabilized (erythrocytes 3,0 T/l, hemoglobin 8,9 g/dl, Platelets 191 G/l, leucocytes 7,5G/l), with the exception of erythrocytes remaining on low levels. In order to improve anemia, erythropoietin was introduced.

Two subsequent rejection episodes at week 13 and 27 required two more steroid pulses. Despite the repeated rejections the kidney maintained a stable function (serum creatinine between 1,8 to 2,0 mg/dl). The rejection in week 27 was accompanied by a significant drop in the erythrocyte count and severe normocytic normochromic anemia developed in week 30. CMV IgM-antibodies were present again and thus gancyclovir was reintroduced. Two more courses of anti-CMV therapy followed (starting in weeks 39 and 50). The anemia was resistant to erythropoietin and required repetitive blood transfusions. There was no evidence for hemolysis, or signs of iron deficiency, the reticulocyte count remained in a low range (1%o). Moderate reductions in leucocyte counts 3,0G/l and platelet counts 112 G/l were observed concurrently. A bone marrow aspirate demonstrated a diminished erythropoiesis as predominant feature. Thus the diagnosis of pure-red-cell-aplasia was made.

Question 2

Of the pathomechanisms mentioned above that can lead to PRCA, drugs and viral infections are among the most suspicious causal candidates in the transplant setting. An association between PRCA and imunosuppressive drugs has been reported for azathioprine, mycophenolate mofetil and tacrolimus. Despite the cessation of azathioprin and a switch from tacrolimus to cyclosporine A in this patient, transfusion dependent anemia persisted. As all other major causes of PRCA had been ruled out, an infectious cause was the most likely assumption for the mechanisms resulting in PRCA in this patient.

Question 3

Human DNA was detected by polymerase chain reaction (PCR). Another indication for the infection with Parvovirus B19 was the presence of specific IgM-antibodies. Retrospective analysis allowed to trace Parvovirus B19 viremia back to the onset of severe anemia in week 27 post transplantation. (see Figure 1).

Question 4

Figure 1

After obtaining proof of Parvovirus B19 infection, the patient was readmitted to the hospital for treatment. On admission serum creatinine was 1,8 mg/dl, Hb 7,2 g/dl, reticulocyte count 3%o. The patient was treated with 167 IU/kg erythropoietin 4 times per week (during the 28 precedent weeks she had received 22 blood transfusions). Treatment options for Parvovirus B19 infection in transplant patients include a change in the immunosuppressive protocol (switch from tacrolimus to cyclosporine A (which had already been performed in this patient) and/or a reduction of immunosuppression (not very likely to be feasable in most of the patients) or the institiutuion of i.v. Immunoglobulins (IVIG). IVIG preaparation are the best availbale source of anti B19 antibodies, as Parvovirus B19 IgG have a high prevalence in the adult population.

Question 5

The patient was treated with 0,4 g/kg/day IVIG (no sucrose containing IVIG preparations). The original plan to continue the treatment for 10 days, was changed and IVIG discontinued after 4 days due to a rise in serum creatinine. Nevertheless this short course of IVIG resulted in a resolution of anemia (and made the cessation of erythropoietin therapy possible) and in stable hemoglobin values thereafter. No signs of a relapse of Parvovirus B19 infection were detected in the post IVIG treatment period (observation time > 3 years).

Parvovirus B19 infection should be considered in the differential diagnosis of anemia in transplant recipients. IVIG can successfully restore normal hemoglobin values in Parvovirus B19 infected patients, but kidney function should be closely monitored during IVIG treatment.

Acknowledgement: The author is indebted to Heinz Gisslinger for revising this manuscript

References:

1: Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol. 2000 Dec;111(4):1010-22. Pubmed Link

2: Geetha D, Zachary JB, Baldado HM, Kronz JD, Kraus ES. Pure red cell aplasia caused by Parvovirus B19 infection in solid organ
transplant recipients: a case report and review of literature. Clin Transplant. 2000 Dec;14(6):586-91. Pubmed Link

3: Carper E, Kurtzman GJ. Human parvovirus B19 infection. Curr Opin Hematol. 1996 Mar;3(2):111-7. Pubmed Link

4: Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev. 2002 Jul;15(3):485-505. Pubmed Link

This case was originally published in NDT:

Sturm I, Watschinger B, Geissler K, Guber SE, Popow-Kraupp T, Horl WH, Pohanka E.
Chronic parvovirus B19 infection-associated pure red cell anaemia in a kidney transplant recipient.
Nephrol Dial Transplant. 1996 Jul;11(7):1367-70.