Quiz Page December 2010:
Severe Anemia After Kidney Transplant
Article Outline
Clinical Presentation
A 42-year-old Chinese man with end-stage renal disease from unknown glomerular disease underwent deceased donor kidney transplant 2 months after initiating peritoneal dialysis therapy. After transplant, his discharge hemoglobin level was 7.5 g/dL (75 g/L). He presented 2 months later with symptoms of dyspnea on exertion and a hemoglobin level of 5.0 g/dL (50 g/L).
The patient was blood group type A positive with β-thalassemia trait, whereas the donor's blood group type was A positive. He had never received human recombinant erythropoietin therapy. No monoclonal antibody induction was used, and immunosuppression consisted of tacrolimus, prednisolone, and mycophenolate mofetil. Other medications included acyclovir, trimethoprim-sulfamethoxazole, entecavir (for chronic hepatitis B), famotidine, folic acid, and diltiazem. Laboratory test results included estimated glomerular filtration rate of 56 mL/min/1.73 m2 (0.93 mL/s/1.73 m2), normal white blood cells and count, and bilirubin, vitamin B12, and folate levels in the reference range. Reticulocyte count was <1% of total red blood cells. Direct Coombs test was negative, and no features of thrombotic microangiopathy were evident on peripheral smear. Bone marrow study was performed (Fig 1).
Figure 1.
Low-power view of bone marrow aspirate.
■ What are the causes of anemia in the posttransplant period?
■ What evaluation is appropriate for this condition?
■ What are the findings on bone marrow examination?
■ What treatment is indicated?
Discussion
What are the causes of anemia in the posttransplant period?
As for discussing the differential diagnosis of infection or transplant dysfunction in kidney transplant recipients, a useful approach to evaluating anemia is to distinguish early (in the first 6 months) versus late (after the first 6 months) development.1
Although improvement in kidney function is expected to be accompanied by an increase in endogenous erythropoietin production and hemoglobin level, anemia in the early posttransplant period is well recognized. Causes include blood loss through surgery and venipuncture, delayed transplant function, chronic inflammation, ongoing hyperparathyroidism, and discontinuation of exogenous erythropoietin therapy. Several common medications in the posttransplant period might cause anemia, including antiproliferative drugs (azathioprine, mycophenolate mofetil, and sirolimus), trimethoprim-sulfamethoxazole (particularly in the setting of glucose-6-phosphate dehydrogenase deficiency), ganciclovir, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Rarely, calcineurin inhibitors are associated with microangiopathic hemolytic anemia. Minor blood group incompatibility, as when blood group type A recipients receive transplants from blood group type O donors, might cause self-limiting immune-mediated hemolytic anemia secondary to passenger lymphocytes.2 Other transplant-specific conditions more common in the early period of kidney transplant include acute rejection and infection-related anemia.
What evaluation is appropriate for this condition?
A rapid decrease in hemoglobin level warrants a search for gastrointestinal blood loss and bleeding from surgical sites. Another disorder that causes such a clinical picture is hemolysis; however, this patient's laboratory findings and absence of increased reticulocyte count rule out this diagnosis. However, glucose-6-phosphate dehydrogenase deficiency should be evaluated because the patient is a member of an ethnic group that has a relatively high prevalence of the disease and he was using trimethroprim-sulfamethoxazole.
In the absence of clinical evidence of drug-related anemia, infection should be excluded. Because the cardinal feature in our patient was profoundly suppressed erythropoiesis reflected by a low reticulocyte count, bone marrow evaluation was pursued.
What are the findings on bone marrow examination?
Bone marrow examination confirmed markedly decreased erythropoiesis with a striking lack of maturing erythroblasts (Fig 1), consistent with pure red cell aplasia. Because our patient had not received recombinant erythropoietin previously, the picture of acquired pure red cell aplasia most likely is a complication of parvovirus B19 infection.
The characteristic feature of giant pronormoblasts (Fig 2) with cytoplasmic vacuoles and intranuclear inclusions also was evident. A diagnosis of parvovirus B19–associated pure red cell aplasia was confirmed after detection of parvovirus B19 using nucleic acid amplification testing (polymerase chain reaction).
Figure 2.
The characteristic giant pronormoblast can be appreciated by comparing its size with that of the surrounding neutrophils and mature red blood cells.
What treatment is indicated?
This acute infectious condition is caused by a member of the Parvoviridae family, the same responsible for a highly contagious childhood exanthema (fifth disease). After gaining access to the human host, parvovirus targets erythroid precursors in bone marrow and causes abrupt cessation of red blood cell production. Failure to produce neutralizing antibodies to parvovirus B19 might occur in kidney transplant recipients and patients with an ineffective humoral or cellular immune response, culminating in protracted viral replication and prolonged erythropoiesis suppression. The incidence of symptomatic parvovirus infection in kidney transplant recipients has been estimated at 0%-12% during the first year after transplant.3
There are no data from randomized controlled trials to guide decisions about specific therapy for parvovirus B19–associated pure red cell aplasia in kidney transplant recipients. Effective antiviral agents against parvovirus B19 currently are not available. Extrapolation from observational studies supports the use of intravenous immunoglobulin, an important source of anti-B19 antibodies resulting in passive immunity.
Complete viral eradication may not be achieved with intravenous immunoglobulin therapy alone.3 A suggested explanation included the persistence of parvovirus B19 in the intracellular compartment of erythroid progenitor cells, which is not accessible to passively transferred antibodies. In addition, a temporary decrease in immunosuppressive treatment has been recommended.3, 4, 5 After changing immunosuppression therapy from tacrolimus to cyclosporine in our patient, there was only transient recovery of the aplastic crisis. This was complicated further by biopsy-proved acute cellular rejection of the kidney. The patient finally had full bone marrow recovery after cessation of the antimetabolite mycophenolate mofetil, together with judicious use of sirolimus and tacrolimus. The patient's most recent estimated glomerular filtration rate was 56 mL/min/1.73 m2 (0.93 mL/s/1.73 m2) 18 months after transplant.
Final diagnosis
Pure red cell aplasia secondary to parvovirus B19 infection.
References
- . Anemia after renal transplantation. Am J Kidney Dis. 2006;48(4):519–536
- . Immune hemolysis associated with transplantation. Semin Hematol. 2005;42(3):145–155
- . Parovirus-B19-associated complications in renal transplant recipients. Nat Clin Pract Nephrol. 2007;3(10):540–550
- . Parvovirus B19 infection causing red cell aplasia in renal transplantation on tacrolimus. Am J Kidney Dis. 1999;34(6):1132–1136
- . Relapsing severe anaemia due to primary parvovirus B19 infection after renal transplantation: a case report and review of the literature. Nephrol Dial Transplant. 2007;22(12):3660–3663
Support: None.
Financial Disclosure: The authors declare that they have no relevant financial interests.
PII: S0272-6386(10)00960-1
doi:10.1053/j.ajkd.2010.05.012
© 2010 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
