Genetic, clinical, and pathological study of patients with severe hypertension-associated renal microangiopathy.

backgroundSevere hypertension may be a prominent manifestation of complement-mediated thrombotic microangiopathy. Furthermore, patients with severe hypertension-associated thrombotic microangiopathy may present with concurrent hematologic abnormalities that mimic complement-mediated thrombotic microangiopathy. Whether or not severe hypertension-associated thrombotic microangiopathy is associated with genetic susceptibility in complement- and/or coagulation-pathway genes remains unclear, and there is thus a need to identify clinicopathological clues to distinguish between these entities.

methodsForty-five patients with concomitant severe hypertension and thrombotic microangiopathy on kidney biopsy were identified retrospectively. Whole-exome sequencing was performed to identify rare variants in 29 complement- and coagulation-cascade genes. Clinicopathological features were compared between patients with severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension.

resultsThree patients with pathogenic variants diagnostic of complement-mediated thrombotic microangiopathy and two with anti-factor H antibody positivity were diagnosed with complement-mediated thrombotic microangiopathy with severe hypertension. Among the 40 patients with severe hypertension-associated thrombotic microangiopathy, 53 rare variants of uncertain significance were found in the analyzed genes in 34 (34/40, 85%) patients, of whom 12 patients harbored two or more variants. Compared with complement-mediated thrombotic microangiopathy patients with severe hypertension, patients with severe hypertension-associated thrombotic microangiopathy were more likely to have left ventricular wall thickening (p < 0.001), less-severe acute glomerular thrombotic microangiopathy lesions including mesangiolysis and subendothelial space widening (both p < 0.001), and less arteriolar thrombosis formation (p < 0.001).

conclusionsRare genetic variants involving complement and coagulation pathways can be found in patients with severe hypertension-associated thrombotic microangiopathy; their role needs further investigation. Cardiac remodeling and acute glomerular TMA lesions may help to differentiate between severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension.