Eculizumab Rescue Therapy in ABO Incompatible Transplant- A Case Report

Introduction

ABO-incompatible (ABOi) transplant has a good outcome for recipients without ABO-compatible donors. Acute antibody-mediated rejection/thrombotic microangiopathy (ABMR/TMA) occurs more frequently early post-transplant in ABOi transplants.¹ We report a case of ABMR/TMA in ABOi transplant, rescued with Eculizumab.

Case Report

A 29-year-old male with end-stage kidney disease (cause unknown) (blood group A+) underwent ABOi kidney transplant with his mother as donor (blood group B+). CDC and flow cytometry crossmatches were negative. Anti-B titre IgG was 1:16. He underwent pretransplant desensitization with rituximab (200 mg) 2 weeks before transplant. He had low titres of donor-specific antibodies.

He received ATG induction (3 mg/kg) and triple immunosuppression (Steroid, MMF, Tacrolimus). Postoperatively, he had good urine output with a creatinine of 3.2 mg/dL on postoperative day 2 (POD2). Anti-B titer (POD2) was 1:1. On the evening of POD2, the patient developed oliguria that did not respond to fluid administration or diuretics. Labs showed thrombotic microangiopathy with graft dysfunction [Table 1]. Complement factors (C3, C4) were normal, and the direct Coomb’s test was negative. Tacrolimus was withheld for suspicion of drug-induced TMA. He received 1 session of plasmapheresis on POD3 with fresh frozen plasma replacement. He received multiple blood products for hemolysis and thrombocytopenia. There was no improvement post-plasmapheresis with continued hemodynamic instability; graft nephrectomy was considered. Eculizumab was administered at 900 mg on POD4, following which he stabilized with improvement in TMA. Graft kidney biopsy on POD8 showed acute TMA [Figure 1], 10–15% cortical necrosis with C4d positivity. Due to limited drug availability, only 600 mg of eculizumab was administered on POD11. He exhibited progressive improvement in urine output and renal function, and was discharged on POD12 with a creatinine of 2.9 mg/dL (Supplementary Figure 1). Further doses of eculizumab could not be administered due to cost constraints. At the 6-month follow-up, he remains stable with good graft function, a creatinine of 1.4 mg/dL, and a urine protein-creatinine ratio that has progressively declined from 6 to 3.5 gm/gm.

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Figure 1: (a) Periodic acid Schiff stain showing fibrin thrombi in glomerular capillary loops with capillary loop dilatation along with mesangiolysis indicating acute thrombotic microangiopathy (400x). (b) Masson’s trichrome stain highlights fibrin thrombi in capillary loops as fuschinophilic deposits (400x).

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Discussion

Our patient presented with early-onset TMA following an ABOi kidney transplant with no improvement with plasmapheresis. Following eculizumab therapy, graft function improved, and systemic manifestations of TMA resolved with only two doses of eculizumab.

Post-transplant TMA is associated with immunosuppressive drugs, ABOi transplant, ABMR, and viral infections,² and is associated with graft loss in 30–40% cases.^2,3 Antibody rejection presents as post-transplant TMA in ABOi transplants.^1,4,5 In the pre-eculizumab era, treatment was limited to plasmapheresis, which often failed to control disease activity, resulting in graft loss and graft nephrectomy. In our experience, among 250 ABOi transplants, 6 developed severe early TMA and required graft nephrectomy. This is our first graft successfully rescued with eculizumab.

The inability to administer eculizumab earlier likely contributed to cortical necrosis, although the intervention was still early enough to salvage the graft. Persistent proteinuria may reflect cortical necrosis or TMA sequelae and requires biopsy confirmation. Previous cases similarly suggest that early eculizumab improves graft outcomes, whereas delayed therapy is associated with chronic injury and graft failure.^1,5,6 Eculizumab should be available in hospitals to reduce the time between clinical diagnosis and eculizumab, but is constrained by local availability.

The optimal duration of maintenance eculizumab therapy is an evolving science, with no consensus, with some clinicians administering 4–5 doses, while others continue longer.^4,5 Financial constraints limited us to using 2 doses of eculizumab, which shows that this may be sufficient till accommodation happens and is similar to case by Khan et al.⁶ TMA typically occurs early and may be time-limited till accommodation develops in ABOi-transplant, while genetic complement mediated TMAs involve persistent complement activation, hence short term eculizumab therapy may suffice in the former, while prolonged treatment is often required in the latter.