A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab

BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). CASE-DIAGNOSIS/TREATMENT We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. CONCLUSIONS Not every patient with aHUS and uncontrolled complement activation shows optimal therapeutic response to eculizumab with the recommended or even increased dosing regimen. Reliable outcome measures to determine the efficacy of treatment have to be defined

Prevalent FHR-1 mutant protein generated by gene conversion reveals crucial role of factor H polymorphisms in atypical Hemolytic Uremic Syndrome (aHUS)

1 p. SI: XXVI ICW Kanazawa 2016Peer reviewe

Complement activation and effect of eculizumab in scleroderma renal crisis

Background: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved. Methods: Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. Results: Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab. Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. Conclusion: SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

ADAMTS13 deficiency shortens the lifespan of mice with experimental diabetes

In patients with diabetes, impaired activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the plasma metalloprotease that cleaves highly thrombogenic VWF multimers is a major risk factor of cardiovascular events. Here, using Adamts13-/- mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. We found that Adamts13-/- mice experienced shortened lifespan with their wild-type diabetic littermates. Surprisingly,animal death was not related to the occurrence of detectable thrombotic events. The lack of ADAMTS13 drastically increased the propensity to ventricular arrhythmias during dobutamine stress in diabetic mice. Cardiomyocytes of Adamts13-/- diabetic mice,exhibited an aberrant distribution of the ventricular gap junction connexin 43 (Cx43), increased phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) and consequent CaMKII-induced disturbance in Ca2+ handling, which underlie arrhythmia propensity. In vitro, thrombospondin1 (TSP1) promoted in a paracrine manner CaMKII phosphorylation in murine HL-1 cardiomyocytes and ADAMTS13 acted as an inhibitory factor for TSP1-induced CaMKII activation. In conclusion, the deficiency of ADAMTS13 may underlie the onset of lethal arrhythmias in diabetes through increased CaMKII phosphorylation in cardiomyocytes. Our findings disclose a novel function for ADAMTS13 beyond the antithrombotic activity