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Introduction
Haemolytic uraemic syndrome is a rare but severe disease that has in the past two decades generated many studies. Experimental and genetic studies have helped to decipher the pathophysiology of various forms of haemolytic uraemic syndrome, while clinical studies have better delineated the picture and improved diagnosis. These breakthroughs have paved the way for new targeted therapies. Haemolytic uraemic syndrome is a rapidly evolving field but is one of the best examples of precision medicine-ie, tailored mechanism-based treatment-and of how translational research can improve the management of a disease. In this Seminar, we discuss the definitions and classifications, pathophysiology, genetics, clinical presentation, diagnostics, and management of haemolytic uraemic syndrome subsets.
Definitions and classifications
Haemolytic uraemic syndrome belongs to a range of thrombotic microangiopathies and arises from an initial endothelial cell injury. The term thrombotic microangiopathy refers primarily to pathological features of vascular damage. In haemolytic uraemic syndrome, these features are documented mainly in the kidney as fibrin and platelet thrombi in capillaries and arterioles, endothelial cell swelling and detachment from the glomerular basement membrane, and the appearance of so-called double contours on the glomerular basement membrane. These pathological features translate clinically into a classic triad: peripheral thrombocytopenia, mechanical haemolytic anaemia, and damage to various organs, predominantly the kidney and the brain.
The pathophysiology of haemolytic uraemic syndrome is complex because several mechanisms can lead to the same pattern of endothelial cell damage and similar clinical and biological abnormalities. Additionally, several types of haemolytic uraemic syndrome might share common mechanisms of endothelial cell damage. At least seven classifications have been previously proposed, which are continually evolving as new mechanisms are discovered (appendix pp 1-3). The 2016 classification proposed by the International Haemolytic Uraemic Syndrome group1 will be used in this Seminar (figure 1).
The term haemolytic uraemic syndrome encompasses a heterogeneous group of disorders, including typical haemolytic uraemic syndrome due to an infection from shiga toxin-producing Escherichia coli (STEC), compared with atypical haemolytic uraemic syndrome during which genetic or acquired dysregulation of the complement alternative pathway is detected in 40-60% of patients.2,3 Cobalamin C (cblC)4,5 and diacylglycerol kinase ɛ (DGKE) deficiency6 are two rare genetic forms of haemolytic uraemic syndrome. Approximately 30% of atypical haemolytic uraemic...