Timmermans SAMEG, et al. - As hypertensive emergency can cause thrombotic microangiopathy (TMA) in the kidneys with high rates of end-stage renal disease (ESRD) and vice versa, researchers here focussed on the conundrum of hypertension as the cause of TMA or consequence of TMA on the background of defects in complement regulation. They examined patients with hypertensive emergency and TMA on kidney biopsy for ex vivo C5b9 development on the endothelium and rare variants in complement genes to recognize complement-mediated TMA. Eighteen (69%) out of 26 cases exhibited massive ex vivo C5b9 formation on resting endothelial cells at the presentation, these included 9 patients who carried at least one rare genetic variant. Progression to ESRD was observed in 13 (72%, N = 18) and 3 (38%, N = 8) patients with massive and normal ex vivo complement activation, respectively. In contrast to BP control, inhibition of C5 activation led to ESRD prevention in 5 (83%, N = 6) patients with massive ex vivo complement activation. Seven (47%, N = 15) donor kidneys exhibited TMA-related graft failure that was linked to genetic variants. Categorization of patients with hypertensive emergency and TMA into different groups with potential therapeutic and prognostic implications could be done via assessment of both ex vivo C5b9 formation and screening for rare variants in complement genes. An algorithm is thus proposed to identify patients at the highest risk for defects in complement regulation.