Korean J Transplant 2023; 37(1): 57-62
Published online March 31, 2023
© The Korean Society for Transplantation
1Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
2Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
3Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea
4Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
5Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
Correspondence to: Kyu Ha Huh
Research Institute for Transplantation, Department of Transplant Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) that can result in end-stage renal disease. Patients with aHUS often have predisposing dysfunction in the complement pathway, and continuous activation of complement proteins can be triggered after transplantation. Here, we report the first successful case of aHUS treatment in a kidney transplant recipient with early use of a C5 inhibitor, eculizumab, in South Korea. The patient was a 32-year-old man, and the donor was his 60-year-old mother. The graft showed immediate good function. On postoperative day (POD) 3, the clinical diagnosis of TMA was made. Persistent renal dysfunction despite 10 plasma exchange (PE) sessions prompted eculizumab treatment on POD 18 under suspicion of aHUS. Next-generation sequencing reported gene mutations classified as variants of unknown significance in coagulation-associated genes. The patient was discharged after three doses of eculizumab with serum creatinine of 1.82 mg/dL. In total, 16 doses of eculizumab were administered. At the last follow-up, 21 months after eculizumab discontinuation, the graft was well functioning. De novo TMA after kidney transplantation can be caused by sustained activation of the complement pathway, and early eculizumab treatment appears important in the successful treatment of aHUS refractory to PE.
Keywords: Eculizumab, Atypical hemolytic uremic syndrome, Thrombotic microangiopathy, Kidney transplantation, Case report
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury . aHUS stems from a genetically inherited or acquired dysfunction of complement proteins, which results in the upregulation of the alternative complement pathway. aHUS is usually diagnosed as a sporadic form that is triggered by events such as pregnancy, autoimmune conditions, organ transplantation, malignancy, and the use of certain drugs .
Posttransplant TMA usually develops
This study was approved by the Institutional Review Board of Severance Hospital (IRB No. 4-2022-1091). Informed consent from the patient was taken.
A 32-year-old man with end-stage renal disease caused by immunoglobulin A nephropathy underwent preemptive robotic living donor kidney transplantation (KT). The donor was the patient’s 60-year-old mother. Preoperative complement-dependent cytotoxicity and a flow cytometric cross-match test were negative; there were no donor-specific anti-human leukocyte antigen antibodies (DSA). The transplanted kidney showed good reperfusion and functioned immediately with sufficient intraoperative urine output. Antithymocyte globulin (ATG) was used as an induction agent, along with tacrolimus, mycophenolate mofetil (MMF), and methylprednisolone.
Urine output was unremarkable between postoperative days (PODs) 0 and 2, yet the patient’s blood pressure levels were elevated, ranging from 148/97 mmHg to 184/114 mmHg; the platelet count dropped from 247×103/μL to 57×103/μL. On POD 3, a clinical diagnosis of TMA was made based on the platelet count (as low as 34×103/μL), low hemoglobin (Hb) levels of 7.9 g/dL without evidence of bleeding, highly elevated lactate dehydrogenase (LDH) levels (1,145 IU/L), decreased haptoglobin levels (<5 mg/dL), and positive schistocytes on a peripheral blood smear.
Serum creatinine (sCr) levels remained high (5.02 mg/dL) compared to a preoperative level of 7.88 mg/dL. C3 levels decreased to 67.7 mg/dL, while C4 levels were within the normal range. The tacrolimus trough level was 4.7 ng/mL, and serum DSA levels were negative. PE was immediately initiated, and laboratory analysis of a disintegrin and metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13), identification of enterohemorrhagic
Due to a partial hematological response and persistent renal dysfunction despite 10 PE sessions (sCr level of 3.25 mg/dL), eculizumab therapy (900 mg weekly) was initiated on POD 18 because of suspected aHUS. Meningococcal vaccination was performed on POD 5, in anticipation of eculizumab treatment.
On POD 22, NGS results revealed gene mutations classified as variants of unknown significance (VOUS) in coagulation-associated genes, including
At 8 months after the last dose of eculizumab, the patient’s sCr levels abruptly increased to 3.28 mg/dL from a median sCr level of 2.00 mg/dL. Maintenance immunosuppression consisted of a sirolimus level of 8.7 ng/mL, MMF, and prednisolone. The laboratory findings were inconsistent with TMA. A renal biopsy showed acute tubular injury with CD61 positivity, presumably from the previous TMA. Because of suspected chronic TMA, two cycles of PE and intravenous immunoglobulin (0.2 g/kg) were administered. sCr levels improved to 2.14 mg/dL. At the last follow-up 27 months after KT, the kidney was functioning well with an sCr level of 1.83 mg/dL. Hb, platelet, and LDH levels were all within the normal range.
In about 50% of patients with aHUS, variations in complement protein genes, such as
Regarding the time to begin eculizumab treatment in patients with
This is the first case of successful eculizumab rescue therapy for post-KT aHUS in South Korea. At the time of diagnosis, the use of eculizumab in aHUS after organ transplantation was not reimbursed by the National Health Insurance System of Korea; therefore, a detailed review was required for approval. In this case, the rapid diagnosis of aHUS enabled reimbursement approval, and early treatment led to the rescue of allograft dysfunction. In addition, the patient discontinued eculizumab successfully, maintaining graft function during long-term follow-up.
To summarize, we demonstrated a case of aHUS diagnosed after KT that was rescued by the early administration of eculizumab upon partial response to conventional therapy.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Conceptualization: EKM, KHH. Data curation: all authors. Formal analysis: SK, MJ, JSK, SHH, KHH. Methodology: SK, MJ, JSK, SHH, KHH. Project administration: EKM, HJK, KHH. Visualization: EKM, KHH. Writing–original draft: EKM. Writing–review & editing: all authors. All authors read and approved the final manuscript.
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