Thrombotic microangiopathies (TMAs) are a heterogeneous group of disorders characterized by endothelial damage, microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia. While the initiating triggers may differ-ranging from infections and autoimmune diseases to genetic complement dysregulation-a unifying pathophysiological feature is injury to the vascular endothelium. Recent advances have highlighted the critical role of pro-inflammatory cytokines in mediating endothelial dysfunction, contributing to both the initiation and propagation of thrombotic events in TMAs. Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) have been implicated in promoting endothelial activation, increased permeability, leukocyte adhesion, and procoagulant changes. These effects contribute to the loss of vascular integrity and the formation of microthrombi. Moreover, cytokine-mediated inflammation appears to be a common feature across various TMA subtypes, including Shiga toxin-associated hemolytic uremic syndrome (HUS), atypical HUS, thrombotic thrombocytopenic purpura (TTP), and secondary TMAs. The intensity and profile of cytokine involvement may vary, but their pathological influence on endothelial health remains a shared mechanism.

This research explores complement activation products involvement and risk and protective polymorphisms in the complement alternative pathway genes in Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) pathogenesis. We analyzed the levels of complement activation products, C3a, C5a and soluble C5b-9 (sC5b-9) and plasma concentrations of Factor H (FH) and FH-related protein 1 (FHR-1) in 44 patients with STEC-HUS, 12 children with STEC-positive diarrhea (STEC-D), and 72 healthy controls (HC). STEC-HUS cases were classified as "severe" or "non-severe". Genetic analysis was performed for complement genes (CFH, CFB, MCP, C3). No significant differences in the frequency of atypical HUS (aHUS) complement risk polymorphisms were found between groups. In severe STEC-HUS, the risk haplotypes CFH-H3 and MCPggaac were identified in three patients each, all in homozygosity. Patients with STEC-HUS had significantly elevated C3a, C5a and sC5b-9 levels at admission compared to HC and STEC-D, with higher sC5b-9 levels in severe cases. Increased ratio between FHR-1 and FH (FHR-1/FH) was demonstrated in STEC-HUS vs. HC, with significantly higher FHR-1/FH ratio in severe STEC-HUS patients. Principal component analysis revealed significant changes in sC5b-9 direction and magnitude in STEC-HUS. Pearson correlation showed a significant relationship between FH and sC5b-9. Logistic regression indicated sC5b-9, leukocytosis, creatinine, and anuria duration as independent factors for severe STEC- HUS. This study highlights the significant activation of the alternative complement pathway in STEC-HUS, particularly sC5b-9 in severe cases, and suggests a limited contribution of complement risk polymorphisms in STEC-HUS. FHR-1 may represent a promising target for future investigations related to STEC-HUS pathogenesis.

Shiga toxin-producing Escherichia coli (STEC) is among the most common pathogens that cause bacterial enteritis. They can also lead to extraintestinal manifestations including hemolytic uremic syndrome (HUS), which is defined by the triad of hemolytic anemia, thrombocytopenia, and acute renal dysfunction due to Shiga toxin-mediated damage to the vascular endothelium with a subsequent inflammatory reaction and thrombotic microangiopathy. The thrombotic microangiopathy mainly affects the small blood vessels of the kidneys and brain. Neurologic involvement, especially in adults, is rare but can include nonspecific symptoms such as a decreased consciousness, altered mental status, seizures, and hyperreflexia. Although HUS is often assumed to cause isolated involvement of small vessels, in this case report, a 52-year-old woman with a STEC-HUS-encephalopathy developed multiple craniocervical dissections during the course of her disease in the absence of any trauma or cardiovascular risk factors. This case thus could possibly indicate that Shiga toxin-mediated damages are not limited to the small vessels but can also affect larger vessels.

The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.

Shiga toxin-associated hemolytic uremic syndrome (STECHUS) is the main cause of acute kidney injury in children and may be responsible for adverse outcomes despite an apparent quiescent period. To describe the medium- and long-term kidney outcomes of pediatric STECHUS in a French region. A single-center, descriptive, retrospective study of STECHUS cases that occurred at Besançon University Hospital between 1999 and 2017 in children up to 17 years of age was conducted. The primary study endpoint was the proportion of chronic kidney disease (CKD) cases at 5 years of follow-up. We included 98 consecutive patients. Among the 71 patients at the 5-year follow-up, we found 24 (34 %) patients with no adverse kidney outcome, 18 (25 %) with moderate adverse kidney outcome, and one (1.4 %) with severe adverse kidney outcome. Among the 96 patients at 1 year from the diagnosis, these figures were, respectively, 25 (26 %), 51 (53 %), and two (2 %); and among the 38 patients at 10 years, they were, respectively, nine (24 %), 12 (32 %), and one (3 %). The glomerular filtration rate level and oliguria-anuria beyond 8 days at baseline were significantly associated with more severe kidney outcomes at 10 years (p = 0.03 and 0.005, respectively). Two patients died during the acute phase. Overall, 33 patients (34 %) were lost to follow-up. Adverse kidney outcomes may appear many years after an episode of STECHUS despite an apparent quiescent period. Regular long-term monitoring is required. The challenge is to reduce the proportion of patients lost to follow-up with potentially severe adverse kidney outcomes and no evaluation or treatment.