Essentials Molecular diagnostics has improved the differentiation of acute thrombotic microangiopathys (TMAs). Atypical hemolytic uremic syndrome may have features mimicking thrombotic thrombocytopenic purpura. We identified novel complement mutations and a high incidence of CD46, with favorable long term outcomes. Complement mutation analysis in TMA where the diagnosis is unclear and ADAMTS‐13 activity is >10%. SummaryBackgroundDifferentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS‐13 activity. The identification of alternative complement pathway abnormalities in atypical hemolytic uremic syndrome (aHUS), along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS.ObjectivesWe describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs.Patients/methodsFourteen consecutive aHUS patients were screened for mutations in C3,CD46,CFH,CFI, and CFB, as well as factor H (FH) antibodies. All aHUS patients had ADAMTS‐13 activity > 10%.ResultsOf 14 aHUS patients, 11 (79%) had platelet counts < 30 × 109/L during the acute phase. Median presenting creatinine level was 295 μmol L−1, while five (36%) of 14 presented with a serum creatinine level < 200 μmol L−1. Alternative complement pathway mutations were detected in 9 (64%) of 14 patients, including CD46 mutations in five (36%) of 14 patients. Patients were identified with novel mutations in CFB and C3 that have not been previously reported.ConclusionsWe demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations which may mimic TTP. ADAMTS‐13 activity > 10% in a patient with a TMA should necessitate genetic screening for complement abnormalities.

We present a case of haemolytic uraemic syndrome (HUS) triggered by Shigella flexneri. Of the Shigella species, only S. dysenteriae type 1 is said to produce Shiga toxin and consequently cause HUS. Investigation of the complement system in this patient revealed a CD46 mutation. In individuals with mutations in complement genes incomplete penetrance of atypical HUS (aHUS) is seen, suggesting that a trigger, such as infection, is required for disease to manifest. In an era of complement modulatory therapy for aHUS it is important to be alert to unusual presentations of diarrhoeal-associated disease.

Introduction and Aims: C3 glomerulonephritis (C3GN) is a pathology characterised by the predominance of C3 deposition. Electron microscopy shows sub-endothelial and/or sub-epithelial deposits, an appearance distinct from the laminar dense electron deposits found in dense deposit disease (DDD). Histological examination of cases of C3GN can reveal a heterogeneous pattern of glomerular injury that includes membranoproliferative glomerulonephritis (MPGN). Together, C3GN and DDD are part of an overall group of diseases called C3 glomerulopathy (C3G) that are thought to be due to disruption of complement regulation, deposition and degradation leading to renal disease. The prognosis with individuals with C3GN is variable and recurrence in transplant recipients is common. We describe and characterise a genetic variant in C3 found in a patient with recurrent C3GN in a renal transplant. Methods: We report a 17 yr old boy who presented with nephrotic syndrome, low C3 and a biopsy demonstrating MPGN1 (C3GN by C3G consensus report, 2013). He progressed to ESRF within 2 yrs and underwent renal transplantation. He developed proteinuria and progressive renal failure requiring renal replacement therapy within 3 years post transplant. A biopsy of the transplant graft demonstrated recurrent C3GN. The patient was screened for acquired and genetic complement abnormalities identifying a C3 genetic variant. To test the functional significance of the C3 genetic variant, recombinant wild type (C3 WT ) and mutant (C3 T788M ) C3 were expressed in 293T cells. Surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA) was used to test binding of the complement regulators FH and CD46 to C3 WT and C3 T788M . Fluid phase cofactor assays were used to assess the resistance to regulation by the C3 variant. Results: The patient's C3 levels have consistently remained low since presentation. Tests for C3 Nephritic factor (C3Nef ) and FH autoantibody were negative. Genetic analysis revealed a rare genetic variant in C3 (c.2363C>T; p.T788M). In addition, the patient was homozygous for the CFH MPGN risk haplotype. Functional assessment of recombinant C3 genetic variant (C3 T788M ) was undertaken. Using ELISA and SPR, C3 T788M bound less well to the surface regulatory protein MCP. Assessment of the binding of C3 T788M to the fluid phase regulator FH also showed altered kinetics. Kinetic fluid phase cofactor assays demonstrated impaired regulation of C3 T788M with both MCP and FH. Conclusions: We present a patient with recurrent C3GN in a renal transplant. Genetic analysis demonstrated a rare genetic variant in C3. Functional analysis has confirmed the resistance to complement regulation of the mutant C3 which will result in over activation of the complement system. With a diagnosis of MPGN or C3GN, the presence of a consistently low C3 level in the absence of a C3Nef should prompt genetic analysis. This will highlight those at risk of recurrent disease.