C5 inhibition with eculizumab prevents thrombotic microangiopathy in a case series of pig-to-human kidney xenotransplantation
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ABSTRACT:
SUBMITTER: Jones-Carr M
PROVIDER: S-EPMC10904036 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Whether C5 blocking may improve the outcomes of patients developing chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive. Lung fibrosis is a well-known complication of bleomycin, whereas TMAs are very rare (<20 cases described). Here, we report an exceptional case of a male patient that developed acute respiratory distress syndrome and TMA following administration of bleomycin, cisplatin and etoposide . Refractoriness to plasma exchanges prompted us to use eculizumab as salvage therapy. Eculizumab led to complete remission of the TMA before Day 2. However, the patient progressed towards refractory respiratory failure, suggesting that pathophysiological mechanisms of bleomycin-induced lung fibrosis and TMA differ.
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Project description:BackgroundEculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).MethodsIn five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated.ResultsOf 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment.ConclusionsAs expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
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Project description:BackgroundGemcitabine is a broadly used chemotherapeutic agent that can cause a rare but life-threatening complication called thrombotic microangiopathy (TMA). Early recognition is crucial as therapy options are limited.Case descriptionWe report the case of a 46-year-old patient with pancreatic adenocarcinoma who presented with severe anemia and thrombocytopenia as well as acute kidney injury. A diagnosis of gemcitabine-induced TMA was made. He became rapidly transfusion and dialysis dependent. Despite discontinuation of gemcitabine and treatment with high-dose corticotherapy as well as plasmapheresis, no improvement in both renal and hematological parameters was seen. Treatment with eculizumab was initiated. One week after the first administration, the patient no longer required packed cells nor platelet transfusions and one month later, dialysis could be discontinued. After five doses, treatment with eculizumab was stopped. Four months later, his serum creatinine was 1 mg/dL.ConclusionsThis case report illustrates the promising beneficial effects of eculizumab in gemcitabine-induced TMA, both regarding transfusion dependence as well as improvement in renal function, thereby allowing further therapy options in patients with an active malignancy.
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Project description:BackgroundGemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA).MethodsThis study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016.ResultsTwelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4-44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2-22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m2 respectively in the eculizumab group and in the control group.ConclusionsThese results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.
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Project description:Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.
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Project description:The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.
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Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal posttransplant complication of hematopoietic stem cell transplantation. We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal bleeding showed poor survival, even when treated with more frequent doses. Our objective was to develop separate models in bleeding and nonbleeding patients with TA-TMA and to propose precision dosing algorithms. Eculizumab PK/PD was analyzed in 19 bleeding and 38 nonbleeding patients (0.5-29.9 years of age). A complement activation biomarker (sC5b-9) and body weight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding than in nonbleeding patients (83.8 vs 61.3 mL/h per 70 kg; P = .07). The high clearance was maintained over treatment doses in bleeding patients, whereas nonbleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time, regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for atypical hemolytic uremic syndrome had <15% probability of attaining the target concentration of >100 μg/mL eculizumab in nonbleeding patients. We identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision guideline for precision dosing to improve outcomes in children and young adults with TA-TMA.
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