The perfect storm

Abstract

Timmermans et al. describe 9 patients with malignant hypertension, renal thrombotic microangiopathy (TMA), and complement alternative pathway (AP) dysregulation.1Timmermans S.A.M.E.G. Abdul-Hamid M.A. Vanderlocht J. et al.Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.Kidney Int. 2017; 91: 1420-1425Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar To their list of complement gene defects, we would add a pathogenic heterozygous factor H–related protein 3 variant (CFHR3-I280KfsX6)2Abarrategui-Garrido C. Martinez-Barricarte R. Lopez-Trascasa M. et al.Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome.Blood. 2009; 114: 4261-4271Crossref PubMed Scopus (166) Google Scholar in a 30-year-old male twin presenting with a picture identical to their study population: native renal biopsy showing acute TMA (Figure 1); microangiopathic hemolytic anemia (as in 4 of 9 patients in Timmermans et al.1Timmermans S.A.M.E.G. Abdul-Hamid M.A. Vanderlocht J. et al.Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.Kidney Int. 2017; 91: 1420-1425Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) with mild thrombocytopenia, elevated lactate dehydrogenase, ADAMTS13 activity >10% and negative autoimmune serology; end-stage kidney disease (8 of 9 patients); and severe hypertension with papilledema (1 of 9 patients, with milder retinopathy in 8). Hypertension had been present for some years, and was exacerbated (with possible triggering of the AP) by recent methamphetamine use.3Jones E.S. Rayner B.L. Hypertension, end-stage renal disease and mesangiocapillary glomerulonephritis in methamphetamine users.S Afr Med J. 2015; 105: 199-201Crossref PubMed Google Scholar Timmermans et al. rightly suggest that AP dysregulation in hypertension-associated TMA may be treatable, although only 1 patient in their series received eculizumab (after 3 months’ dialysis).1Timmermans S.A.M.E.G. Abdul-Hamid M.A. Vanderlocht J. et al.Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.Kidney Int. 2017; 91: 1420-1425Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Unfortunately, in our patient, despite drug cessation, antihypertensive therapy, and eculizumab (administered within 24 hours of presentation, and for a total of 6 months), leading to prompt resolution of papilledema and microangiopathic hemolytic anemia, renal function did not recover. In patients presenting with “the perfect storm” of TMA, malignant hypertension, and dialysis-dependent renal failure, severity of renal histological injury may be the best predictor of response to complement therapy. Honoraria have been paid to the Royal Melbourne Hospital by Alexion Pharmaceuticals Australasia on behalf of TB for lectures. Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalitiesKidney InternationalVol. 91Issue 6PreviewThrombotic 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. Full-Text PDF Open ArchiveThe Authors ReplyKidney InternationalVol. 92Issue 1PreviewIt was with interest that we read the correspondence of Ruderman et al., presenting a patient who developed hypertension-associated thrombotic microangiopathy (TMA) on the background of a CFHR3 mutation and who remained dialysis dependent although eculizumab was started.1 The patient’s disease course highlights the challenging approach to patients with TMA and, in particular, the question of when to consider complement-mediated disease and initiate treatment. Full-Text PDF Open Archive