Etiology and outcomes of kidney-limited and systemic thrombotic microangiopathy.

Abstract

The syndromes of thrombotic microangiopathy (TMA) are associated with acute kidney injury and end-stage kidney disease (ESKD). TMAs typically present with thrombocytopenia and microangiopathic hemolytic anemia (i.e., systemic TMA). Kidney-limited TMA can occur, although often overlooked and undertreated. Here, we studied the etiology and outcome of kidney-limited TMA. Patients with TMA on kidney biopsy, either systemic or kidney-limited TMA, were recruited and classified as definite complement-mediated (C-)TMA (i.e., ≥1 pathogenic complement gene variant), probable C-TMA (i.e., massive ex vivo C5b9 formation without a pathogenic complement gene variant), and non (n)C-TMA (i.e., normal ex vivo C5b9 formation). Morphologic features of TMA on kidney biopsy and their clinical correlates were studied. Patients were classified as definite C-TMA (N=14, 18%), probable C-TMA (N=21, 27%), or nC-TMA (N=42, 55%), including 51 (66%) out of 77 patients with kidney-limited TMA. Patients with definite and probable C-TMA often presented with hemolysis (79% and 62% versus 34%; P=0.007), glomerular thrombosis (79% and 76% versus 43%), higher creatinine (974 and 502 versus 280 μmol/L; P=0.001), and younger age (33 and 33 versus 40 years; P=0.029) as compared to nC-TMA. Morphologic features neither defined etiology nor differed between systemic and kidney-limited TMA. Eculizumab improved kidney outcomes in patients with kidney-limited C-TMA but not in those with nC-TMA akin to patients with systemic C-TMA. Kidney outcomes were not affected by chronicity grading on kidney biopsy. Kidney-limited TMA is common in the diverse TMAs, including C-TMA. A kidney biopsy is needed to detect the TMA at the earliest possible stage of disease. Morphology does not allow for the identification of etiology and patients with kidney-limited TMA should therefore be screened for complement dysregulation, having major impact on treatment and prognosis.