Differential Impact of Complement Mutations on Clinical Characteristics in Atypical Hemolytic Uremic Syndrome
Anne-Laure Sellier-Leclerc*,
Veronique Fremeaux-Bacchi,
Marie-Agnès Dragon-Durey,
Marie-Alice Macher*,
Patrick Niaudet,
Geneviève Guest,
Bernard Boudailliez,
Franois Bouissou||,
Georges Deschenes¶,
Sophie Gie**,
Michel Tsimaratos,
Michel Fischbach,
Denis Morin,
Hubert Nivet||||,
Corinne Alberti¶¶,
Chantal Loirat* for the French Society of Pediatric Nephrology
* Assistance Publique–Hôpitaux de Paris, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Université Paris VII, Faculté de Médecine Denis Diderot, Paris; Assistance Publique–Hôpitaux de Paris, Laboratoire d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris; Assistance Publique–Hôpitaux de Paris, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris; Département de Pédiatrie, Hôpital Nord, Amiens; || Service de Néphrologie Pédiatrique, Hôpital des Enfants, Toulouse; ¶ Assistance Publique–Hôpitaux de Paris, Service de Néphrologie Pédiatrique, Hôpital Trousseau, Paris; ** Service de Néphrologie, Hôpital de Pontchaillou, Rennes; Service de Néphrologie, Hôpital de la Timone, Marseille; Service de Pédiatrie, Hôpital Hautepierre, Strasbourg; Service de Pédiatrie 1, Hôpital Arnault de Villeneuve, Montpellier; |||| Service de Néphrologie, Hôpital de Clocheville, Tours; and ¶¶ Assistance Publique–Hôpitaux de Paris, Hôpital Robert Debré, Unité d'Epidémiologie Clinique, Paris, France
Correspondence: Dr. Chantal Loirat, Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, 48 Boulevard Sérurier, 75 019 Paris, France. Phone: +33-1-4003-2146; Fax: +33-1-4003-2468; chantal.loirat{at}rdb.aphp.fr
Received for publication August 1, 2006.
Accepted for publication April 12, 2007.
Mutations in factor H (CFH), factor I (IF), and membrane cofactorprotein (MCP) genes have been described as risk factors foratypical hemolytic uremic syndrome (aHUS). This study analyzedthe impact of complement mutations on the outcome of 46 childrenwith aHUS. A total of 52% of patients had mutations in one ortwo of known susceptibility factors (22, 13, and 15% of patientswith CFH, IF, or MCP mutations, respectively; 2% with CFH+IFmutations). Age <3 mo at onset seems to be characteristicof CFH and IF mutation–associated aHUS. The most severeprognosis was in the CFH mutation group, 60% of whom reachedESRD or died within <1 yr. Only 30% of CFH mutations werelocalized in SCR20. MCP mutation–associated HUS has arelapsing course, but none of the children reached ESRD at 1yr. Half of patients with IF mutation had a rapid evolutionto ESRD, and half recovered. Plasmatherapy seemed to have abeneficial effect in one third of patients from all groups exceptfor the MCP mutation group. Only eight (33%) of 24 kidney transplantationsthat were performed in 15 patients were successful. Graft failureswere due to early graft thrombosis (50%) or HUS recurrence.In conclusion, outcome of HUS in patients with CFH mutationis catastrophic, and posttransplantation outcome is poor inall groups except for the MCP mutation group. New therapiesare urgently needed, and further research should elucidate theunexplained HUS group.
Hemolytic uremic syndrome (HUS) is characterized by the triadof microangiopathic hemolytic anemia, thrombocytopenia, andacute renal failure, secondary to thrombotic microangiopathy(TMA) lesions. Postdiarrheal or typical HUS, the most frequentform in children, is caused by infection with Shiga toxin (Stx)-producingEscherichia coli. A variety of triggers for non–Stx-associatedHUS have been identified, including Streptococcus pneumoniaeand various nonenteric infections, viruses, drugs, malignancies,transplantation, or autoimmune disease.1–3 When thereis no identified preceding illness, less frequently, the diseaseis known as atypical HUS (aHUS) and can occur at any age, fromthe neonatal period to adult age, with familial and sporadiccases.4,5 In patients with aHUS, mutations were reported inthe genes of three proteins that regulate complement alternativepathway and protect host cellular surfaces from complement activation:Factor H (CFH), membrane co-factor protein (MCP or CD46), andfactor I (IF).6–9 Up to now, at least 70 complement geneticabnormalities have been reported in adults and children withaHUS.10,11 It was shown that aHUS was secondary to complementdysregulation in approximately 50% of patients.12 In addition,acquired functional CFH deficiency as a result of anti-CFH antibodieshas been reported in three children.13 The identification ofcongenital ADAMTS 13 deficiency reclassified a subgroup of aHUSas congenital thrombotic thrombocytopenic purpura (Upshaw-Schulmansyndrome).14 The aims of this study were to document the frequencyof each of these genetic complement-dependent risk factors ofaHUS among pediatric patients and to provide a comprehensivecharacterization of the clinical findings according to the geneticbackground that could help to define prognosis and therapeuticguidelines according to clinicobiological characteristics.
Complement Component Assessment and Molecular Characterization of CFH, MCP, and IF Mutations
Among the 46 children, 10 (22%) had a CFH mutation, six (13%)had an IF mutation, one (2%) had a CFH and an IF mutation, andseven (15%) had an MCP mutation. Twenty-two (48%) children hadno genetic defect either in CFH or in IF or MCP genes by directsequencing analysis of all exons of each gene and are designatedas "unexplained aHUS."
Among the 22 mutations, 13 have been reported by our group andwere associated with complement haploinsufficiency9,15–17and four were previously identified in unrelated patients withaHUS by other groups (CFH: S1191L, 1232delTAGA; IF: IVS12 +5, G243D).10,12,18 Five new mutations were identified (CFH:A161S and Q635D; IF: I398L, I415V, and H165R). All mutationswere scattered throughout the coding regions of the three genes,including CFH (Table 1). None of these mutations occurred inthe controls groups. Six mutations were homozygous (three patientswith CFH mutation, born from consanguineous parents, and threewith MCP mutations).
Table 1. Complement component assessment in previously undescribed nine patients with CFH and IF gene mutationsa
C3 levels were low in nine of the 10 patients with CFH mutation,the patient (patient 11) with CFH and IF mutation, four of thesix with IF mutation, and four of the 22 with unexplained aHUS.C3 levels were significantly different among the four groups(P = 0.002) with levels being the lowest in the CFH and IF mutationgroups (Figure 1). CFH levels were nearly undetectable in thethree patients with homozygous CFH mutation and mildly decreasedin five of the eight patients with heterozygous CFH mutation(including patient 11). IF levels were normal in all patients,including those with IF mutation. MCP expression was very lowin the three patients with homozygous MCP mutation and approximately50% of normal in the heterozygous patients.
Figure 1. C3 levels according to complement mutation. —, Lower limit of normal C3 (660 mg/L, –2 SD). Patient 11 with CFH and IF mutation not shown (C3 290 mg/L).
Clinical Characteristics Familial/Sporadic.
The gender ratio was similar among the group with or withoutcomplement mutations (Figure 2, Table 2). Fourteen patientshad familial aHUS associated with CFH, IF, or MCP mutation inthree, one, and one families, respectively. Four other familiesbelong to the unexplained group (Table 2). In two families,only one of the two siblings with the disease had either CFH(patient 4) or IF (patient 16) mutation (Tables 1 and 2). Inboth families, the sibling with the mutation (patients 4 and16) had a severe outcome, whereas the sibling without the mutation(not included in the study) had a favorable outcome.
Figure 2. Individual clinical course and genetic analysis of the 46 patients with atypical hemolytic uremic syndrome (aHUS). M, male; F, female; , HUS flare; —, native kidneys functioning; , ESRD; *, fresh frozen plasma (FFP) infusions; °, plasma exchanges (PEX); - - - -, long-term FFP treatment; +++, long-term PEX treatment. Patients 1 and 2 are first cousins. Patients 20 and 21; 28, 29, and 30; and 33 and 34 are siblings. Functional consequences of the mutations and patients have been previously reported for a, b, c, d, and e, respectively.15,6,29,12,16
Table 2. Summarized clinical course in the various subgroups of aHUSa
Onset.
Age at onset of symptoms ranged from 1 d to 16 yr, with 32 (70%)of 46 with onset before age 2 (Figure 3, Table 2). Of the eightpatients with onset before 3 mo of age, three had CFH mutation,four had IF mutation, and one had unexplained HUS. Seventy percentof the patients with CFH mutation (seven of 10) and 67% withIF mutation (four of six) had onset before age 1. No patientwith CFH, IF, or CFH+IF mutations had onset later than age 4.No patients with MCP mutation had onset before age 1. Overall,age at onset was significantly different among the four groups(P = 0.02), the youngest being in the CFH and IF mutation groups.HUS onset followed a triggering event (upper respiratory tractinfection, fever, diarrhea) in 29 (63%) patients from all subgroups.In particular, prodromic diarrhea preceded HUS in 13 (28%) patientsfrom all subgroups, including infection with 0157:H7 E. coliin patient 20 with MCP mutations (Y155D and IVS8-2), familialHUS (brother of patient 21), and subsequent nonpostdiarrhealrelapses (Figure 2).
Figure 3. Age at onset of aHUS and outcome during the year after onset of the 46 patients. H, CFH mutation; I, IF mutation; MCP, MCP mutation; ?, unexplained HUS; , ESRD or death during first year after onset; , alive with functioning kidneys 1 yr after onset.
Manifestations at the First Flare and Clinical Course.
All patients except two presented with anemia with schizocytosis(mean hemoglobin [Hb] 6.7 g/dl [3.7 to 9.0 g/dl]) and 39 (85%)of 46 with thrombocytopenia (mean platelet count 55 G/L [5 to145 G/L]). Thirty-eight (83%) of the 46 patients had acute renalfailure at first flare of aHUS (mean serum creatinine 338 µmol/L[90 to 755 µmol/L]). Eight (17%) patients presented withproteinuria and hematuria, without renal failure (mean serumcreatinine 54 µmol/L [40 to 63 µmol/L]).
Eleven (24%) of the 46 had ESRD as soon as the first episodeof the disease. Twenty-five (54%) patients had from two to ninenew episodes of HUS at intervals from 1 mo to 9 yr, with ninepatients having four episodes or more (Figure 2). The proportionof patients with relapsing HUS was not significantly differentamong the four groups (Table 2). However, overall number ofrelapses during the 10 yr after onset was significantly differentamong the four groups (P = 0.03), the highest number being inthe MCP mutation and unexplained groups. Relapse with completerecovery was common in the patients with MCP mutation and unexplainedHUS. By contrast, in the CFH mutation group, eight (80%) of10 either died or reached ESRD at first flare (n = 5) or afterrelapses (n = 3), whereas an additional patient reached ESRDafter 10 yr of follow-up. Three (50%) of the six patients withIF mutation either died or had ESRD, two of them at first flare.The patient with CFH+IF mutation had ESRD at first flare. Two(29%) of seven patients with MCP mutation had ESRD after oneto two relapses 2 to 3.5 yr after onset, and one additionalpatient reached ESRD after seven relapses of HUS 37 yr afteronset. Seven (32%) of the 22 patients with unexplained HUS eitherdied (n = 1) or had ESRD (n = 6) at first flare of HUS or withina few months. One additional patient reached ESRD 15 yr afteronset. Extrarenal involvement was uncommon. Four patients, includingone with CFH mutation and three with unexplained HUS, had cerebrovascularevents, as well as pulmonary involvement in one of the latter.
Outcome
Poor outcome, defined as death or ESRD within 1 yr after onset,was observed in 17 (37%) of the 46 patients (Figures 2 and 3,Table 2). Four (9%) of the 46 patients died within a few weeksor months after onset (from sequelae of cerebrovascular events,pulmonary hemorrhage concomitant with hemolysis and thrombocytopenia,Staphylococcus aureus septicemia, and multivisceral failurewith diffuse TMA at postmortem histology). The risk for pooroutcome (patient 11 not included) within the first year wassignificantly related to serum creatinine level at first episode.No other factors were found to be significantly linked withpoor outcome during the first year (Table 3).
Table 3. Relationships between age at onset, familial incidence of HUS, serum creatinine at first flare, and C3 level and severity of outcome at 1 yra
Overall, renal survival was significantly different among thefour groups (log-rank test, P = 0.03; Figure 4). Indeed, at1 yr after onset, it was 40.6% in the CFH mutation group, 50%in the IF mutation group, 100% in the MCP mutation group, and68% in the unexplained group. At 5 yr, the percentages were27, 50, 62, and 68%, respectively (Figure 4).
Figure 4. Renal survival, according to complement mutation, up to 10 yr of follow-up. Patient 11 with CFH and IF mutation was not included.
Plasmatherapy
Twenty-two patients received plasmatherapy, most often dailyduring 7 to 10 d, and, when successful, subsequently taperedto once every week or every 2 wk (Figure 2, Table 2). Of the22, 16 received fresh frozen plasma (FFP) infusions (10 to 20ml/kg), four received plasma exchanges (PEX; 40 to 50 ml/kgper session) with FFP for volume restitution, and two receivedboth treatments. Seven (32%) of 22 patients had a positive response,including two patients with homozygous CFH deficiency. Amongthe MCP mutation group, favorable outcome occurred in eight(89%) of nine episodes that were treated with plasmatherapyand 15 (88%) of 17 untreated episodes.
Posttransplantation Course
A total of 24 kidney transplantations were performed in 15 patients(Figure 5), with cadaveric donors in all except one. All patientsexcept one had bilateral nephrectomy before transplantation.
Sixty-six percent of patients (10 of 15) had at least one graftfailure (Figure 5). During the first year, 12 (50%) grafts failed:Eight from thrombosis between 0 to 45 d after surgery, threefrom HUS recurrence, and one from cytomegalovirus infection.Six (25%) patients had an uneventful clinical course during5 to 15 yr after transplantation. One of them (patient 8) hadhistologic TMA at graft biopsy 12 yr after transplantation.Two patients had functioning graft 2 yr after transplantationdespite HUS recurrence. Four grafts were lost subsequently,from recurrence in two patients and rejection in two other patients.
Among the five patients with CFH mutation, one of the six (16.6%)kidney grafts had an uneventful course during 12 yr after transplantation.The cause of early (<1 yr after transplantation) graft failurewas HUS recurrence (n = 1) or renal artery thrombosis (n = 2).The patient with CFH+IF mutations had an uncomplicated courseduring 5 yr. Among the two patients who had IF mutation andreceived a transplant, one had an uncomplicated course and normalgraft function 3 yr, 6 mo after transplantation. The other onehad HUS recurrence at day 15 and returned to dialysis 5.5 yrafter transplantation. The patient who had MCP mutation andreceived a transplant had an uneventful posttransplantationcourse but lost the graft after 5.6 yr from rejection as a resultof noncompliance.
Six children with unexplained aHUS received 14 renal transplants.Ten (71%) failed from early renal artery/vein thrombosis (n= 6), HUS recurrence (n = 2), rejection as a result of noncompliance(n = 1), or cytomegalovirus infection (n = 1).
This article is the first to describe the genetic susceptibilityfactors and the clinical outcome in 46 children with aHUS. Wedemonstrate that aHUS with pediatric onset is a disease of complementdysregulation in roughly half of cases. We found CFH mutationsin 22% of the patients and an equivalent percentage of IF (13%)and MCP mutations (15%). Three important clinical characteristicscan be emphasized. The first is age at onset. Onset before 3mo of age seems to be a characteristic of CFH and IF mutation–associatedaHUS. By contrast, onset before age 1 has not been observedin children with MCP mutation, whereas unexplained HUS may startat any age, from the neonatal period to adolescence. The secondis that creatinine level at first episode is significantly correlatedwith the risk for ESRD or death during the first year. The thirdimportant point is that the clinical course and prognosis werenot similar in the various subgroups. The overall rate of ESRDwas 43% (20 of 46), as reported in a series of pediatric aHUS.5As previously observed by Caprioli et al.,12 we show that themost severe prognosis was in the CFH mutation group, 70% ofwhom reached ESRD during childhood, most frequently as soonas at first episode. The clinical course of MCP mutation–associatedaHUS is clearly different: These patients have a relapsing course,but none reached ESRD at 1 yr. It is interesting that patientswith IF mutation seem to have a more variable outcome, becausehalf had rapid evolution to ESRD or death and half recovered.Patients with unexplained aHUS have a variable outcome, suggestingvarious pathophysiologic mechanisms. Familial forms accountedfor 30.4% in our series, observed within all subgroups. We identifiedtwo cases of familial aHUS that illustrate phenotypic and geneticheterogeneity between siblings. In each family, only the siblingwith either CFH or IF mutation had a severe outcome. These observationssuggest the presence of additional uncharacterized genetic abnormalities.The two CFH and IF mutations might have as-yet-unknown functionalconsequences playing the role of severity factors. However,they could also correspond to rare polymorphisms (although theyhave been identified only in patients with aHUS and never incontrol subjects).
We also observed that infectious episodes, especially gastrointestinal,appeared as triggering events of HUS in all subgroups.12 Moreover,E. coli 0157 infection was the triggering event of the firstepisode of HUS in one child with MCP mutation. Considering theseresults, diarrhea and even Stx-E. coli infection do not precludethe possibility that the underlying diagnosis is aHUS. Thisconfirms that complement anomalies are risk factors rather thanthe only cause of the disease.
Ten (22%) of the 46 patients with aHUS had CFH mutation, a proportionin agreement with that of 14 to 33% reported in the literature.12,19,20As in our patients, the majority of CFH mutations reported inthe literature are heterozygous. A total of 60% of the mutationspublished up to now are located within the C-terminal domainof the protein, particularly in SCR20, which induces a reducedability of CFH to bind to surface-bound C3b and to the polyanionsof the endothelial cells.10,11,21,22 However, in our pediatricpatients, only 30% of CFH mutations were located in SCR20. Another30% were in SCR15, and other mutations were scattered over theCFH gene. These data indicate that sequencing of CFH gene cannotbe limited to SCR16 to 20 in children with aHUS, because thismay miss 70% of CFH mutations. In addition, 72% of patientswith CFH mutation presented with quantitative CFH deficiencyas opposed to approximately 20% reported by Caprioli et al.12The proportion of 15% of our patients who were found to haveMCP mutation is in agreement with that of 10 to 15% previouslyreported.12,19 In our pediatric cohort, 13% of patients hadIF mutation. This is more than the proportions reported (between2 and 4.5%).12,19,23 The frequency of familial cases in eachcohort or the sensitivity of methods for mutation detectionmay explain the difference. For the everyday practice, our datashow that the association of early-onset aHUS and low C3 isindicative of CFH or IF mutation. However, the absence of lowC3 is not predictive of a favorable outcome. We recommend determinationof C3, CFH, IF, and MCP levels and complete genetic screeningof CFH, IF, and MCP genes in all patients with aHUS.
As reported by several authors, patients with homozygous CFHmutations were those who clearly benefited from receiving normalCFH by FFP infusions.24–26 However, the benefit of plasmatherapyis not clear for the majority of patients with aHUS. Most patientsof our series received 10 ml/kg FFP infusions that may not besufficient to change the severity of the evolution. A few casereports from the literature suggest that PEX that bring at least40 ml/kg FFP are associated with a more favorable outcome inCFH mutation–associated aHUS.27,28 Two children with IFmutation in this series and a few cases in the literature18,23seemed to respond to FFP infusions or PEX, which has some logicbecause IF is brought by plasma. In practice, recommended treatmentfor children with aHUS should be aggressive PEX therapy. Thedecision of this treatment is difficult in patients with mildrenal involvement.
The posttransplantation course analysis suggests several remarks.First, the overall success of transplantation was poor: Onlyeight (33%) of the 24 kidney grafts that were performed in 15patients were functioning at last follow-up. It is interestingthat a high proportion of failures were due to causes otherthan recurrence, mainly vascular thrombosis (eight of 16 graftfailures). This has not been previously reported and suggestsadditional risk factors to thrombosis in patients with aHUS.In our pediatric series, posttransplantation HUS recurrenceoccurred in 53% of the whole group of aHUS and in 80% of patientswith CFH mutation, a proportion similar to that of 74% reportedby Bresin et al.29 The reason that 20% of patients with CFHmutation have no recurrence is unknown. The reported risk forposttransplantation HUS recurrence in patients with IF mutationwas 100%.30 Nevertheless, among the two patients with IF mutationin our series who received a transplant and who happened tohave the same nucleotide substitution, one had HUS recurrenceand the other one had no recurrence during the 3 yr of follow-up.Amazing, the patient with both CFH and IF mutation had an uncomplicatedposttransplantation course. The only patient with MCP mutationof our cohort who received a transplant had no recurrence, asmost frequently observed in patients with MCP aHUS,30 a logicissue because one may expect that the graft brings normal MCP.Another noticeable observation is that in several patients,the posttransplantation course was less severe than that ofthe native HUS. Overall, of eight patients with posttransplantationHUS recurrence, five (62%) had preserved sufficient graft functionduring at least 1 yr, up to 5 yr. Several groups have reportedthe influence of polymorphisms of MCP and CFH in the susceptibilityto HUS.19,31,32 The reason that posttransplantation HUS recurrencemay be less severe than primary HUS could be related to theimportant role of MCP, a protein that is highly expressed inthe kidney, in the severity of the disease.
The outcome of HUS in patients with CFH mutation is catastrophic.New therapies are urgently needed. Liver or combined liver andkidney transplantation has been disappointing,33–35 untilthe recent report of one successful case under plasmatherapy.36Intensive plasmatherapy is the only therapeutic option. Theadministration of CFH concentrate to treat HUS and to preventposttransplantation recurrence ought to be an easier optionin a near future.
Definitions
HUS first episode and relapses were defined on the basis ofHb levels <10 g/dl with fragmencytosis and/or thrombocytes<150 G/L, serum creatinine >97th percentile accordingto age, and/or proteinuria >1+. Criteria for aHUS were ageof onset before 3 mo and/or absence of diarrhea and/or progressiveonset and/or relapses of HUS and/or familial HUS. Remissionwas defined by normalization of Hb and thrombocytes count andnormalization or stabilization of serum creatinine level. Thesecriteria also defined positive effect of plasmatherapy, whenobserved within 10 d of treatment. Outcome category was classifiedas death, ESRD, or functioning kidneys.
Patients
From 2002 to 2005, we studied 46 patients who had aHUS of pediatriconset (before age 16) and were known to pediatricians who wereaffiliated with the French Society of Pediatric Nephrology.Of these 46, 11 were included prospectively and 35 were patientswho previously were known to clinicians. All patients exceptfor patient 20 (see the Onset section) were negative for Stx-E.coli infection (PCR for Stx1 and Stx2 genes in stools; serumIg against LPS of 0157, 0103, 026, 0145, 091, 011, and 0128Stx-E. coli). ADAMTS 13 activity was normal in all patients.None of the 46 patients had anti-CFH autoantibodies. Four patientswere black and one was Asian. Other patients were white. Twenty-six(56%) patients were male, and 20 (44%) were female. All patientswere previously healthy, except for patient 22, who had glomerulonephritiswith C3 deposits 6 yr before HUS. Sixteen patients have beenreported previously (seven, two, and seven with CFH, IF, andMCP mutations, respectively).9,15–18
Assays for Complement Components and Genetic Screening
Informed consent for DNA analysis was obtained from parentsand children when old enough. EDTA plasma samples were stockedat –80°C. Plasma protein concentrations of C3 andCFH, IF, and MCP expression (using cytometry analysis with CD46PE antibodies) were measured as described previously.9,16,17Direct sequencing of all CFH, IF, or MCP exons was undertakenin all 46 patients. Primers have been previously described.6,12,15To determine whether a mutation was also present in a controlcollective and therefore more likely be a rare polymorphismthan a deleterious mutation, we analyzed a control populationthat consisted of 100 locally recruited white and 20 black healthysubjects.
Statistical Analyses
End point of the study was to analyze the risk factors of poorprognosis (ESRD or death). Results were expressed as numericalvalues and percentages for categorical variables and median(range) for continuous variables. Comparisons between groupswere based on nonparametric tests. An event was defined by theoccurrence of ESRD or death. Times to first event were computedbetween date of disease onset and date of first event and werecensored at 10 yr (thus eliminating two events at 18 and 36yr of follow-up). They were displayed using Kaplan-Meier curvesand were compared between mutation groups by the log-rank test.A piecewise Cox model was fit to study the relationship betweenpatient characteristics and ESRD or death within the year ofonset. Results were expressed as hazard ratio (HR) and 95% confidenceinterval (95% CI). All tests were two-sided. Patient 11 withCFH and IF mutation was excluded from statistical analysis.
This work was supported by the Délégation Régionaleà la Recherche Clinique, Assistance Publique–Hôpitauxde Paris (grants P 010709, CRC 01019, and PHRC AOM 05130).
We gratefully acknowledge the colleagues who participated inthis study: E. Berard, Hôpital de l'Archet, Nice; P. Cochat,Hôpital Edouard Herriot, Lyon; P.H. Eckart, CHU de Caen;F. Janssen, Hôpital Universitaire Reine Fabiola, Bruxelles;and M. Seligman, CH de Luxembourg.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
, HUS flare; —, native kidneys functioning; 
, ESRD; *, fresh frozen plasma (FFP) infusions; °, plasma exchanges (PEX); - - - -, long-term FFP treatment; +++, long-term PEX treatment. Patients 1 and 2 are first cousins. Patients 20 and 21; 28, 29, and 30; and 33 and 34 are siblings. Functional consequences of the mutations and patients have been previously reported for a, b, c, d, and e, respectively.
, ESRD or death during first year after onset; 
, adverse event, as indicated;