Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes.

Thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of antiphospholipid syndrome nephropathy (APSN). These lesions are at high risk of recurrence after kidney transplantation. The complement pathway is thought to be active in this process. We used eculizumab to treat three consecutive kidney transplant recipients with posttransplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies. Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all three patients and in improvement of the TMA lesions within the graft. None of these patients had TMA flares after eculizumab was withdrawn. At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b-9 and C4d depositions at the endothelial cell surface of the injured vessels. Moreover, C5b-9 colocalized with vessels exhibiting a high rate of apoptotic cells. Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared but the C5b-9 deposits persisted for several months as a footprint of the TMA. Finally, we noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN. Eculizumab seems to be an efficient method for treating severe forms of posttransplant TMA due to APSN recurrence. Terminal complement inhibition does not prevent the development of chronic APSN.

Canaud G ，Kamar N ，Anglicheau D ，Esposito L ，Rabant M ，Noël LH ，Guilbeau-Frugier C ，Sberro-Soussan R ，Del Bello A ，Martinez F ，Zuber J ，Rostaing L ，Legendre C ... -  《-》

Complement inhibition with eculizumab for thrombotic microangiopathy rescues a living-donor kidney transplant in a patient with antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome (APS) is an enigmatic heterogeneous disorder despite several revelations in its pathobiology. Renal transplantation in patients with APS has been notoriously difficult due to the high risk of development of thrombotic microangiopathy (TMA), which is often refractory to conventional treatment modalities such as aggressive anticoagulation and plasmapheresis. We describe a case of a 58-year-old male with secondary APS undergoing living unrelated renal transplantation for end-stage renal disease from lupus nephritis. Shortly after transplantation, he developed graft dysfunction from APS related TMA that was refractory to systemic anticoagulation and plasmapheresis. After becoming hemodialysis dependent, the patient was started on eculizumab, a humanized monoclonal antibody against complement factor 5, as salvage therapy. We show that this intervention successfully rescued his renal allograft and that the patient has remained dialysis free for over 20 months. Our experience adds to the limited body of literature suggesting the role of complement inhibition in facilitating renal transplantation in patients with APS spectrum of disorders, thus adding a new tool to the therapeutic armamentarium for this difficult disease. The optimal treatment schedule and long term safety data for eculizumab in complement mediated TMA is still unclear. The search for an optimal biomarker to help guide treatment duration is an area of active research.

Geethakumari PR ，Mille P ，Gulati R ，Nagalla S ... -  《TRANSFUSION AND APHERESIS SCIENCE》

Eculizumab deposits in vessel walls in thrombotic microangiopathy.

Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.

Cassol CA ，Brodsky SV ，Satoskar AA ，Blissett AR ，Cataland S ，Nadasdy T ... -  《-》

Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: Case series and review of literature.

Thrombotic microangiopathy (TMA) is a life-threatening, albeit infrequent, complication of systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). Recommendations for the treatment of SLE- and APS-related secondary TMA are currently based solely on case reports and expert opinion. Unfortunately, interventions may not yield timely results or effectively halt the progression of TMA. Since complement activation plays a key role in the pathogenesis of secondary TMA due to SLE, APS, a therapy that targets the complement pathway is an attractive intervention. Eculizumab, a recombinant, fully humanized IgG2/IgG4 monoclonal antibody inhibits C5 activation and is FDA-approved for PNH and atypical HUS (aHUS). However, limited case reports are available on its use in treatment of secondary TMA. We present the largest case series to date that includes 9 patients with SLE and/or APS who were successfully treated with eculizumab for refractory secondary TMA. In this case series, we report significant responses in hematology values, renal function and other organs following treatment with eculizumab. At 4 weeks, 75% improvement in platelet counts was observed in 78% of patients. Two-thirds of patients demonstrated >75% improvement of haptoglobin and LDH at four weeks. At 4 weeks, eGFR improved by 25% in half of the patients, and 43% had reductions in proteinuria. Two of 3 patients that required hemodialysis were able to be taken off hemodialysis. Based on these observations, we suggest that eculizumab may be a potential treatment option for acutely ill patients with secondary TMA due to SLE and/or APS who have failed standard of care. A collective approach is needed to better elucidate the role and optimal timing of eculizumab use in the management of TMA complicating SLE and/or APS.

Kello N ，Khoury LE ，Marder G ，Furie R ，Zapantis E ，Horowitz DL ... -  《-》

Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation.

Renal thrombotic microangiopathy (TMA) is a severe complication of systemic lupus erythematosus (SLE), which is associated with the presence of antiphospholipid (aPL) antibodies. In its most fulminant form, TMA leads to a rapid and irreversible end-stage renal failure. Eculizumab, an anti-C5 monoclonal antibody, is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. Here, we report the case of a 27-year-old woman, known for SLE and end-stage renal disease due to fulminant TMA. Both aPL antibodies and antinucleosome antibodies were positive. The patient underwent a living-related kidney transplantation with immediate production of urine. Although serum creatinine was remaining high, a graft biopsy, performed on day 6, demonstrated a TMA recurrence. Despite a treatment with plasma exchange, the situation got worse and dialysis was started. Eculizumab treatment was subsequently administered and renal function improved rapidly. Three months after transplantation, serum creatinine was at 100 μmol/L, without proteinuria. This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation, resistant to classical therapy.

Hadaya K ，Ferrari-Lacraz S ，Fumeaux D ，Boehlen F ，Toso C ，Moll S ，Martin PY ，Villard J ... -  《-》