AUTHOR=Puraswani Mamta , Khandelwal Priyanka , Saini Himanshi , Saini Savita , Gurjar Bahadur Singh , Sinha Aditi , Shende Rajashri Pramod , Maiti Tushar Kanti , Singh Abhishek Kumar , Kanga Uma , Ali Uma , Agarwal Indira , Anand Kanav , Prasad Narayan , Rajendran Padmaraj , Sinha Rajiv , Vasudevan Anil , Saxena Anita , Agarwal Sanjay , Hari Pankaj , Sahu Arvind , Rath Satyajit , Bagga Arvind 

TITLE=Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01282

DOI=10.3389/fimmu.2019.01282

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required.</p><p><bold>Methods:</bold> Of 781 patients &lt;18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year (<italic>n</italic> = 317) were compared to before (<italic>n</italic> = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity (<italic>n</italic> = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset.</p><p><bold>Results:</bold> Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank <italic>P</italic> = 0.022). Mean anti-FH titers stayed 700–1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), <italic>P</italic> = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; <italic>P</italic> = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; <italic>P</italic> = 0.024), time to PEX ≥14 days (HR 2.09; <italic>P</italic> = 0.071) and PEX for &lt;14 days (HR 2.60; <italic>P</italic> = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; <italic>P</italic> = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; <italic>P</italic> &lt; 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively.</p><p><bold>Conclusion:</bold> Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.</p>