Thrombotic microangiopathies (TMA) are a heterogeneous group of disorders characterized to varying degrees by mechanical hemolytic anemia, thrombocytopenia and histological microvascular occlusion. TMA can be complicated by multiple organ disorders, mainly neurological and nephrological (defining the hemolytic uremic syndrome, HUS). Classification based on disease pathophysiology has highlighted the importance of dysregulation of the alternative complement pathway in atypical (non-infection-related) HUS. However, the pathophysiology and treatment of many forms of aHUS in specific contexts (such as pregnancy, renal transplantation or hypertensive emergencies) remain poorly characterized. In this article, we review recent diagnostic and therapeutic advances in these three forms of aHUS in specific contexts. We show the specificities of these forms and describe the current and future challenges of their management. Les microangiopathies thrombotiques (MAT) sont un groupe hétérogène de pathologies caractérisées à différents degrés par une anémie hémolytique mécanique, une thrombopénie et une occlusion microvasculaire histologique. Les MAT peuvent se compliquer de multiples atteintes d’organe, principalement neurologiques et néphrologiques (définissant alors le syndrome hémolytique et urémique). La classification fondée sur la physiopathologie de la maladie a mis en évidence l’importance de la dérégulation de la voie alterne du complément dans les SHU atypiques (SHUa) (non-liés aux infections). Cependant, la physiopathologie et le traitement de nombreuses formes de SHUa dans des contextes spécifiques (tels que la grossesse, la transplantation rénale ou l’urgence hypertensive) restent mal caractérisés. Dans cet article, nous reprenons les avancées diagnostiques et thérapeutiques récentes dans ces trois formes de SHUa aux contextes spécifiques. Nous montrons les spécificités de ces formes et décrivons les enjeux actuels et futurs de leur prise en charge.

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of  ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10 years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. In contrast, it is still unclear whether self-limited complement activation, which frequently occurs in other forms of HUS, provides key mechanistic clues or results from endothelial damage. Development of novel biomarkers is underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized the management of aHUS patients, resulting in a halving of the subpopulation under chronic dialysis over the course of a few years. On the other hand, the efficacy of C5 blockade in secondary forms of HUS, as assessed by small and uncontrolled case series, is less compelling and should be investigated through properly designed prospective clinical trials. The increased risk of meningococcal infection, related to C5 inhibition, must be rigorously addressed with suitable prophylaxis. Treatment duration should be determined based on an individualized benefit/risk assessment.

Drug-induced thrombotic microangiopathy (DITMA) represents 10%-13% of all thrombotic microangiopathy (TMA) cases and about 20%-30% of secondary TMAs, just behind pregnancy-related and infection-related forms. Although the list of drugs potentially involved as causative for TMA are rapidly increasing, the scientific literature on DITMA is quite scarce (mostly as individual case reports or little case series), leading to poor knowledge of pathophysiological mechanisms and clinical management. In this review, we focused on these critical aspects regarding DITMA. We provided an updated list of TMA-associated drugs that we selected from a scientific literature review, including only those drugs with a definite or probable causal association with TMA. The list of drugs is heterogeneous and could help physicians from several different areas to be familiar with DITMA. We describe the clinical features of DITMA, presenting the full spectrum of clinical manifestations, from systemic to kidney-limited forms. We also analyze the association between signs/symptoms (i.e., malignant hypertension, thrombocytopenia) and specific DITMA causative drugs (i.e., interferon, ticlopidine). We highlighted their multiple different pathophysiological mechanisms, being frequently classified as immune-mediated (idiosyncratic) and dose-related/toxic. In particular, to clarify the role of the complement system and genetic deregulation of the related genes, we conducted a revision of the scientific literature searching for DITMA cases who underwent renal biopsy and/or genetic analysis for complement genes. We identified a complement deposition in renal biopsies in half of the patients (37/66; 57%), with some drugs associated with major deposits (i.e., gemcitabine and ramucirumab), particularly in capillary vessels (24/27; 88%), and other with absent deposits (tyrosine kinase inhibitors and intraocular anti-VEGF). We also found out that, differently from other secondary TMAs (such as pregnancy-related-TMA and malignant hypertension TMA), complement genetic pathological mutations are rarely involved in DITMA (2/122, 1.6%). These data suggest a variable non-genetic complement hyperactivation in DITMA, which probably depends on the causative drug involved. Finally, based on recent literature data, we proposed a treatment approach for DITMA, highlighting the importance of drug withdrawal and the role of therapeutic plasma-exchange (TPE), rituximab, and anti-complementary therapy.