title: Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.
abstract: Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.
authors.affiliation: Department of Nephrology and Clinical Immunology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Sjoerd A M E G
authors.initials: SAMEG
authors.lastname: Timmermans
authors.affiliation: Department of Pathology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Myrurgia A
authors.initials: MA
authors.lastname: Abdul-Hamid
authors.affiliation: Department of Transplantation Immunology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Vanderlocht
authors.affiliation: Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Jan G M C
authors.initials: JGMC
authors.lastname: Damoiseaux
authors.affiliation: Deptartment of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Reutelingsperger
authors.affiliation: Department of Nephrology and Clinical Immunology, Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address: p.vanpaassen@maastrichtuniversity.nl.
authors.forename: Pieter
authors.initials: P
authors.lastname: van Paassen
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D001794:Blood Pressure; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D017244:Complement Factor I / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000276:immunology; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D012720:Severity of Illness Index; D057049:Thrombotic Microangiopathies / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000628:therapy
chemical_list: C038245:C3 protein, human; C497857:CD46 protein, human; C493495:CFH protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D003165:Complement System Proteins; C493611:CFI protein, human; D017244:Complement Factor I
keywords: atypical hemolytic uremic syndrome; complement dysregulation; genetics; malignant hypertension; thrombotic microangiopathy