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16 p.-1 tab.-1 fig. ; Background: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available. Case-diagnosis/treatment: We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis. Conclusion: Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene. © 2013 IPNA. ; SRdeC is supported by the Spanish Ministerio de Economía y Competitividad [Ministry of Finance and Competition] (SAF2011-26583), the Comunidad de Madrid [Autonomous Region of Madrid] (S2010/BMD-2316), the European Union FP7 (EURENOMICS) and the Fundación Renal Iñigo Alvarez de Toledo. PSC is supported by the Spanish Ministerio de Economía y Competitividad (PS09-00268), and the Comunidad de Madrid (S2010/BMD-2316).MLT is supported by the Spanish Ministerio de Economía y Competitividad (PS09- 00122), and the Comunidad de Madrid (S2010/BMD-2316). ; Peer Reviewed

15 p.-8 fig.-3 tab. ; Haemolytic Uraemic Syndrome associated with Streptococcus pneumoniae infections (SP-HUS) is a clinically well-known entity that generally affects infants, and could have a worse prognosis than HUS associated to E. coli infections. It has been assumed that complement genetic variants associated with primary atypical HUS cases (aHUS) do not contribute to SP-HUS, which is solely attributed to the action of the pneumococcal neuraminidase on the host cellular surfaces. We previously identified complement pathogenic variants and risk polymorphisms in a few Hungarian SP-HUS patients, and have now extended these studies to a cohort of 13 Spanish SP-HUS patients. Five patients presented rare complement variants of unknown significance, but the frequency of the risk haplotypes in the CFH-CFHR3-CFHR1 region was similar to the observed in aHUS. Moreover, we observed desialylation of Factor H (FH) and the FH-Related proteins in plasma samples from 2 Spanish and 4 Hungarian SP-HUS patients. To analyze the functional relevance of this finding, we compared the ability of native and "in vitro" desialylated FH in: (a) binding to C3b-coated microtiter plates; (b) proteolysis of fluid-phase and surface-bound C3b by Factor I; (c) dissociation of surface bound-C3bBb convertase; (d) haemolytic assays on sheep erythrocytes. We found that desialylated FH had reduced capacity to control complement activation on sheep erythrocytes, suggesting a role for FH sialic acids on binding to cellular surfaces. We conclude that aHUS-risk variants in the CFH-CFHR3-CFHR1 region could also contribute to disease-predisposition to SP-HUS, and that transient desialylation of complement FH by the pneumococcal neuraminidase may have a role in disease pathogenesis. ; This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund from the European Union (grants PI16/00723 and PI19/00970 to PS-C). IG and EA are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; S2017/BMD-3673). IG was also supported by the Spanish Fundación Senefro (http://www.senefro.org/). The study was also supported by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the molecular biology thematic programme of the Semmelweis University, by the National Office for Innovation and Research (KH130355 to ZP), and by the MSCA-ITN (Horizon 2020) CORVOS (Grant 860044 to ZP). DC was supported by the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018). ; Peer reviewed

32 p.-4 tab-3 fig.-2 tab. suppl. ; Background and objectives Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-«, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-« gene in a cohort with atypical hemolytic uremic syndrome was analyzed. Design, setting, participants, & measurements Eighty-three patients with early-onset atypical hemolytic uremic syndrome (,2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-«. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. Results Four patients carried mutations in diacylglycerol kinase-«, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-« and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-« and C3 mutations. Conclusions Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-« mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-« and complement mutations. A comprehensive understanding of the genetic component predisposing to atypical hemolytic uremic syndrome is, therefore, critical to guide an effective treatment. ; Work in this report was funded by Spanish "Ministerio de Economía y Competitividad" Grants SAF2011-26583, PS09/00122 (to M.L.T.), SAF2012-38636 (to M.L.T.), and PI1200597 (to P.S.-C.) and Fundación Renal Inigo Alvarez de Toledo and Seventh Framework ~Programme European Union Project EURenOmics Grant 305608 (to S.R.d.C.). In addition, this work was supported by Autonomous Region of Madrid Grant S2010/BMD-2316 (to M.L.T., P.S.-C., and S.R.d.C.). ; Peer reviewed