The use of ‘real‐time’ complement analysis to differentiate atypical haemolytic uraemic syndrome from other forms of thrombotic microangiopathies

We read with great interest the recent correspondence of Dr Cataland and colleagues (Cataland et al, 2012), who appropriately pointed out that symptoms alone cannot differentiate thrombotic thrombocytopenic purpura (TTP) from atypical haemolytic uraemic syndrome (aHUS) in patients with thrombotic microangiopathies (TMAs). The data presented (Cataland et al, 2012) indicated that alternative diagnoses to TTP, including aHUS, should be considered in TMA patients with non-deficient ADAMTS13 activity (>10%), moderate thrombocytopenia (>30 9 10/l), pronounced abnormalities of renal function, and suboptimal response to plasma exchange (PEX) (absence of a steadily declining lactate dehydrogenase level and an increase in the platelet count after 4– 5 d of daily PEX). Cataland et al (2012) concluded that, in the absence of an objective test to reliably diagnose aHUS, the combination of the above laboratory and clinical response data should help clinicians to identify patients who may benefit from therapy with the complement-inhibiting drug, eculizumab. The clinical data-based objective criteria, as described by Cataland et al (2012), seems to be valid and highly practical, however, based on our latest diagnostic experiences, we would like to suggest the use of additional, parallel ‘realtime’ complement testing in this setting. Given that ongoing pathological activation and consumption of the alternative complement pathway is the core factor in the pathophysiology of aHUS (Noris & Remuzzi, 2009), we hypothesized that functional testing of the alternative pathway and measurement of the alternative pathway components C3 and factor B, may provide valuable diagnostic information in patients with acute aHUS, and differentiate them from patients with other forms of TMA. Samples from 55 patients with an acute TMA episode [defined as microangiopathic haemolytic anaemia and thrombocytopenia (<130 9 10/l)] were consecutively referred to our research laboratory between April 2008 and February 2012, and parallel testing of ADAMTS13 activity and complement parameters were performed for all patients according to current guidelines (Ariceta et al, 2009; Taylor et al, 2010; Loirat & Fremeaux-Bacchi, 2011; Roumenina et al, 2011). Functional assessment of the alternative pathway was done with the Wieslab (Euro Diagnostica, Malmö, Sweden) alternative pathway enzyme linked immunosorbent assay kit (Seelen et al, 2005), C3 was measured by immunoturbidimetry and factor B by radial immune diffusion. Demographic and laboratory data are presented in aggregate for patients with final diagnosis of aHUS, TTP and typical (D+)HUS in Table I. The following criteria were used to establish the final diagnosis (Besbas et al, 2006; Scheiring et al, 2010): aHUS: acute renal failure, lack of bloody diarrhoea, non-deficient ADAMTS13 activity (>7%) and presence of complement genetic abnormalities (four cases with complement-factor H-related protein 1 deficiency with anti-factor H autoantibodies, two cases with complement factor H mutations, one case with membrane cofactor protein mutation, two recent cases with ongoing sequencing); TTP: presence of ADAMTS13 deficiency with ADAMTS13 inhibitors, no concomitant disease; D+HUS: sudden onset with typical