Key words : Kidney transplant, Maintenance immunosuppression, Tacrolimus

Introduction

Acquired pure red cell aplasia (PRCA) is a rare, generally chronic condition of profound anemia characterized by a severe reduction in the number of reticulocytes in the peripheral blood and the near absence of erythroid precursors in the bone marrow. The other cell lineages are present and appear morphologically normal. Acquired pure red cell aplasia in adults is most often idiopathic, although several underlying causes can exist, mostly drug-induced.¹

The hematological toxicity of tacrolimus has been rarely stated. In a report of 2 pediatric recipients of liver transplant with anemia, both were treated with tacrolimus for 8 and 47 months, respectively, and then developed PRCA confirmed by bone marrow biopsy. The children recovered rapidly on withdrawal of tacrolimus. When the clinical profiles of these children were compared with the only other patient report in the literature with PRCA due to tacrolimus, all 3 patients had similar hematological findings.²

Anemia is common after renal transplant and has been reported in up to 40% of renal transplant recipients. It is commonly due to drugs and infections.³ In comparison, posttransplant anemia is usually due to graft dysfunction and drugs such as mycophenolate and cotrimoxazole, whereas tacrolimus is an uncommon cause. Severe anemia requiring multiple blood transfusions in the posttransplant period may also create a risk for rejection. Therefore, timely evaluation and management of anemia in these patients are crucially needed.^4,5

Case Report
Our patient was a 66-year-old-male Kuwaiti patient with end-stage renal disease secondary to diabetic nephropathy. He has had long-term diabetes mellitus and hypertension since 1992, which were controlled by insulin and calcium channel blockers plus beta-blocker. He had a history of ischemic heart disease and received percutaneous coronary intervention twice in June and December 2011. Three years before transplant, he received a coronary artery bypass graft with transcutaneous aortic valve implantation. In September 2018, he received a preemptive living unrelated donor renal transplant in China. He received his allograft from a haploidentical donor with the same blood group. He received basiliximab as an induction and then was maintained on prednisolone 5 mg per day, mycophenolate mofetil (MMF; 750 mg twice per day), and tacrolimus 3 mg twice per day.

The patient had early postoperative wound dehiscence managed by antibiotics, dressing, and secondary sutures in October 2018. His diabetes was controlled by insulin, and his blood pressure was controlled by amlodipine 10 mg/day and metoprolol 50 mg twice per day. He was kept on baby aspirin 81 mg/day. In accordance with our center’s protocol, the patient was kept on prophylaxis for cytomegalovirus (CMV; with valganciclovir) and Pneumocystis jirovecii pneumonia (with sulfamethoxazole).

The patient had stable renal graft function and was doing fine until 1 month after transplant, when he presented with low cardiac output symptoms and described easy fatigability. On examination, he was hemodynamically stable, with blood pressure of 130/82 mm Hg, regular pulse rate of 76 beats/min, afebrile, and oxygen saturation of 98% in room air. He denied any orifical bleeding or drug use other than those prescribed. He had pale sclera without jaundice and no lower limb edema. An abdominal examination was negative for organomegaly or ascites, but he had a body mass index showing obesity (32.6 kg/m²). Other systems were examined and showed unremarkable findings.

His complete blood count revealed normocytic nor-mochromic anemia with hemoglobin drop from 111 down to 69 g/L with reticulocytopenia that necessitated regular blood transfusion. Laboratory results showed white blood cell count of 8.7 × ¹⁰³/L and platelet count of 183 × 10³/L, serum creatinine level of 98 ?mol/L, acceptable tacrolimus trough level (around 6 ng/dL), international normalized ratio of 1.1, activated partial thromboplastin time ratio of 1.2%, normal iron profile transferrin saturation of 67%, normal serum folate and vitamin B12 levels, and negative hemolytic index and autoimmune screening tests. Occult blood in stool was negative, and virology screening tests for BK virus, CMV, Epstein-Barr virus, and parvovirus B19 were negative. Bone marrow biopsy revealed a remarkable absence of maturing erythroblasts yet showed giant proerythroblasts with strongly basophilic cytoplasm reticulum stain (marrow fibrosis of 0 on scale of 0 to 3). Biopsy showed normal active bi-lineage hematopoiesis (myelopoiesis and megakaryopoiesis, Figure 1). These findings confirmed posttransplant acquired PRCA, which was most likely induced by MMF and/or by tacrolimus.

Despite discontinuation of MMF for 1 month, anemia persisted, and the patient was still in need of multiple blood transfusions over 4 weeks. Our review of the literature showed several case reports of acquired PRCA as a result of tacrolimus.^9-11 Therefore, we replaced tacrolimus with cyclosporine (75 mg twice per day) with an acceptable drug level of around 100 ng/dL. Subsequent laboratory results showed that his hemoglobin steadily increased (Figure 2) without any blood transfusions.

The patient was maintained on prednisolone and cyclosporine for 8 weeks. We then resumed administration of MMF at 500 mg twice per day, which was subsequently increased to 750 mg twice per day. At follow-up, the patient has shown stable hemoglobin levels of around 140 g/L and stable renal allograft function.

Discussion
Posttransplant anemia is multifactorial, especially PRCA, which is a rare occurrence. Pure red cell aplasia is characterized by anemia with an almost complete absence of red cell precursors in the bone marrow but essentially normal granulopoiesis and megakaryopoiesis.⁶

Our patient developed normocytic normochromic anemia and reticulocytopenia that necessitated regular blood transfusions. After exclusion of secondary causes of anemia (hemorrhage, hemolysis, viral infections, deficiencies), his bone marrow biopsy revealed findings suggestive of PRCA. These diagnostic criteria agreed with those reported by Winkler and colleagues,⁶ who described transplant recipients diagnosed with PRCA based on chronic and persistent anemia without an obvious cause. These patients required blood transfusions, had normal morphologies of other cell lines except for erythrocytes, had low reticulocyte counts, and had bone marrow biopsy findings consistent with PRCA.⁶ Findings confirmed posttransplant PRCA, mostly drug-induced either by MMF and or tacrolimus.

Acquired causes of PRCA were assessed in our case, and we excluded them one by one. Immunological causes were excluded by negative autoimmune evaluations (antinuclear antibody, antineutrophil cytoplasmic antibody, complement levels, erythrocyte sedimentation rate) and negative virology evaluations (CMV, Epstein-Barr virus, parvovirus B19). Liver and kidney functions were normal. Also, leukemia was excluded by peripheral blood and bone marrow evaluation.⁷ The possibility of drug-induced PRCA was highly suspicious, especially with regard to MMF and tacrolimus, which were both included in our patient’s maintenance therapy.

Our patient did not improve spontaneously, as mentioned by Sawada and colleagues, who suggested waiting for at least 1 month before instituting specific treatment, with the rationale that 10% to 12% of patients with idiopathic PRCA have a short- and self-limited course.⁸

We started treatment by holding MMF for 1 month, but transfusion-dependent anemia persisted for over 4 weeks. We then replaced tacrolimus with cyclosporine with satisfactory response manifested as a steady increase of hemoglobin levels without any blood transfusions. The patient was maintained on prednisolone and cyclosporine for 8 weeks and then MMF was gradually increased; with these modifications, the patient has maintained stable hemoglobin of 140 g/L and stable renal allograft function.

Other reports have also found suspicion for tacrolimus. These reports concluded that the most effective immunosuppressive agent for PRCA was cyclosporine, with an overall response rate of more than 75%, especially when other therapeutic modalities failed. Patients improved after replacement of tacrolimus by cyclosporine. Cyclosporine can also be a treatment option for idiopathic PRCA.^9-11

Whether the clinical improvement was because of the therapeutic effect of cyclosporine rather than the withdrawal of tacrolimus remains unclear. Tacrolimus has also been reported to be effective in PRCA and may provide an alternative to cyclosporine, but has also been reported as a cause of PRCA.¹² Safety concerns and ethical issues prevented us from restarting tacrolimus to conclusively prove that the tacrolimus was a culprit in causing PRCA.

Conclusions

Posttransplant PRCA is a rare disorder among kidney transplant recipients, which could be induced by maintenance tacrolimus therapy. We recommend conversion to a cyclosporine-based regimen.

References:

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