Successful Treatment of aHUS Recurrence and Arrest of Plasma Exchange Resistant TMA Post-Renal Transplantation with the Terminal Complement Inhibitor Eculizumab.

Abstract 2421

Poster Board II-398

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and acute renal failure (ARF). The prognosis for aHUS is poor as 25% of patients die during acute phases of the disease and 50% progress to end stage renal disease (ESRD). A high percentage of patients with aHUS experience recurrence and graft failure following renal transplantation. This report summarizes the successful use of a terminal complement inhibitor as a treatment for aHUS following renal transplant with demonstration of both clinical and pathological resolution of aHUS in a patient who was resistant to plasma therapy. A 34-year-old female with ESRD due to aHUS underwent living related renal transplantation. Approximately one month after renal transplantation, she presented with acute renal failure (ARF), with creatinine (Cr) increasing from 1.2 to 2.2 mg/dl. The renal biopsy showed thrombotic microangiopathy (TMA). ADAMTS-13 activity was normal. Tacrolimus was discontinued and corticosteroids were initiated. She responded to 14 sessions of every-other-day plasma exchange (PLEX), with stabilization of her creatinine at 1.5mg/dl. At month 5, she again presented with ARF with a renal biopsy showing TMA. PLEX was initiated once again (3 times per week) but her serum creatinine did not improve significantly during PLEX from month 5 to month 9 and ranged from 1.9 to 2.3 mg/dL with urine protein:creatinine ratio of 1.7 to 3.0. Elevations of Cr (2.34 to 3.65mg/dLl), modest elevations in LDH (209 to 380 IU/L) and ∼20% decrease in platelets (227 to 185 × 10⁹/L) were observed when PLEX was interrupted. Diagnostic renal biopsy during this period of PLEX dependency displayed ongoing TMA. With ongoing persistent TMA despite maximal PLEX, at month 9, treatment with eculizumab, a humanized monoclonal antibody that blocks the cleavage of the terminal complement molecule C5 and generation of pro-inflammatory C5a and C5b-9, was initiated. The patient was dosed with eculizumab 900mg weekly for 4 weeks followed by 1200mg at week 5 and 1200mg every 2 weeks thereafter. After 4 weeks of induction therapy with eculizumab and no PLEX sessions, her serum creatinine stabilized at 4.0 to 4.3 mg/dL. At month 10 post transplant, and 7 weeks after the switch from PLEX to eculizumab, renal biopsy now showed no TMA and moderate residual interstitial fibrosis. Fifteen (15) months post transplant and 6 months of eculizumab treatment, the patient continues on eculizumab maintenance therapy with no requirement for PLEX. She is experiencing her best stable renal function to date, with Cr=2.7 mg/dL, a urine protein:creatinine ratio of 2.29 as well as normal platelet counts and slightly elevated LDH (∼350 IU/L) with normal haptoglobin. These results demonstrate that PLEX following recurrent aHUS post transplant did not stabilize renal function and biopsy-proven TMA persisted despite intensive PLEX therapy post transplant. In contrast, switch of PLEX to chronic terminal complement inhibitor treatment with eculizumab resolved the TMA process, stabilized and improved the transplanted kidney function, and eliminated the need for PLEX for this patient with recurrent aHUS post transplant. Clinical trials to further investigate and confirm the efficacy of eculizumab in the treatment of aHUS are ongoing.