Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41–0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%–38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS. Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41–0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%–38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS. Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is complex to diagnose because of its heterogeneity. All forms of HUS are characterized by thrombotic microangiopathy (TMA) and are defined by the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and vital organ damage, most commonly affecting the kidney.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar, 2George J.N. Nester C.M. Syndromes of thrombotic microangiopathy.N Engl J Med. 2014; 371: 654-666Crossref PubMed Scopus (522) Google Scholar, 3Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (359) Google Scholar In at least 50% of patients, aHUS is the consequence of genetic or autoimmune abnormalities leading to dysregulation of the alternative complement pathway on the surface of the vascular endothelium.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar, 2George J.N. Nester C.M. Syndromes of thrombotic microangiopathy.N Engl J Med. 2014; 371: 654-666Crossref PubMed Scopus (522) Google Scholar, 3Loirat C. Fakhouri F. Ariceta G. et al.An international consensus approach to the management of atypical hemolytic uremic syndrome in children.Pediatr Nephrol. 2016; 31: 15-39Crossref PubMed Scopus (359) Google Scholar, 4Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar Prior to the availability of effective treatment, disease outcomes were poor and could be life-threatening. In a previous report, 29% and 56% of children and adults with aHUS, respectively, progressed to end-stage renal disease (ESRD) or death within 1 year of disease presentation. At 5 years, the proportions were 36% and 64%, respectively.5Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar Recommendations for disease management involved frequent plasma exchange or infusion.6Ariceta G. Besbas N. Johnson S. et al.Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome.Pediatr Nephrol. 2009; 24: 687-696Crossref PubMed Scopus (266) Google Scholar More recently, eculizumab, a humanized monoclonal antibody, has been shown to be effective in treating patients with aHUS.7Licht C. Greenbaum L.A. Muus P. et al.Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies.Kidney Int. 2015; 87: 1061-1073Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 8Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (999) Google Scholar, 9Greenbaum L.A. Fila M. Ardissino G. et al.Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.Kidney Int. 2016; 89: 701-711Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 10Fakhouri F. Hourmant M. Campistol J.M. et al.Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial.Am J Kidney Dis. 2016; 68: 84-93Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar These studies led to regulatory approval of eculizumab for the treatment of patients with aHUS in several regions and countries since 2011. aHUS is an ultra-rare disease with a reported incidence of approximately 0.5 per million per year,11Laurence J. Haller H. Mannucci P.M. et al.Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis.Clin Adv Hematol Oncol. 2016; 14: 2-15PubMed Google Scholar limiting the number of patients available to power clinical trials. Therefore, international patient registries are a key strategy for improving knowledge of the natural history of the disease, evaluating the effectiveness of clinical therapies, monitoring drug safety, and measuring quality of care in a real-life setting.12Gliklich R, Dreyer N, Leavy M. Registries for Evaluating Patient Outcomes: A User's Guide. 3rd ed. 2 vols. (Prepared by the Outcome DEcIDE Center [Outcome Sciences, Inc., a Quintiles company] under contract no. 290 2005 00351 TO7.) AHRQ Publication no. 13(14)-EHC111. Rockville, MD: Agency for Healthcare Research and Quality, 2014. Available at: https://effectivehealthcare.ahrq.gov/topics/registries-guide-3rd-edition/research/. Accessed April 23, 2018.Google Scholar, 13Rodwell C, Ayme S. Report on the state of the art of rare disease activities in Europe. Part I: overview of rare disease activities in Europe. European Union Committee of Experts on Rare Diseases. 2014. Available at: http://ec.europa.eu/health/rare_diseases/docs/2014report_rare_disease_activitieseu_1_en.pdf. Accessed April 23, 2018.Google Scholar The Global aHUS Registry was established to assess the natural history of aHUS irrespective of management choice or presence of potential precipitating factors. The Global aHUS Registry is the largest collection of demographic, clinical, and genetic information from patients suffering from this ultra-rare disease. The methodology, pattern of global participation, and basic demographics of patients enrolled by November 30, 2015 have been reported.14Licht C. Ardissino G. Ariceta G. et al.The global aHUS registry: methodology and initial patient characteristics.BMC Nephrol. 2015; 16: 207Crossref PubMed Scopus (46) Google Scholar The objective of the present study was to characterize ESRD-free survival, TMA rate, organ involvement, and genetic background of the patients enrolled in the Global aHUS Registry, prior to eculizumab use. In total, 851 patients were included in this analysis. Table 1 summarizes demographic characteristics at study entry, among pediatric (n = 387; 45%) and adult (n = 464; 55%) patients (categorized by age at initial presentation). A family history of aHUS was reported by 133 patients (16%) (73% of whom had affected first-degree relatives only, 12% second-degree relatives only, and 15% both first- and second-degree relatives). Initial disease presentation was often recent, occurring after 2011 in 38% of pediatric patients (n = 195) and 62% of adult patients (n = 318). Plasma exchange or infusion was more commonly used for adult than for pediatric patients with aHUS (P < 0.0001). Patient data were censored at time of eculizumab initiation and patient disposition for the analyses described herein are shown in Supplementary Figure S1.Table 1Patient demographics and clinical characteristicsCharacteristicAll (n = 851)Initial presentation in childhood (n = 387)Initial presentation in adulthood (n = 464)Age at initial disease presentation, yraPatients were categorized by age at initial aHUS presentation: pediatric (<18 years old) or adult (≥18 years old).21.4 (4.4–37.2)3.8 (1.0–7.7)35.4 (26.8–51.0)Age at study entry, yrbStudy entry was defined as follows: at enrollment for patients never treated with eculizumab or prior to eculizumab treatment initiation for patients who had ever received eculizumab.25.7 (10.2–43.1)8.8 (4.5–14.8)41.2 (30.9–53.9)Race Caucasian734 (86)313 (81)421 (91) Black37 (4)14 (4)23 (5) Asian18 (2)12 (3)6 (1) Other62 (7)48 (12)14 (3)Female468 (55)166 (43)302 (65)Family history of aHUS133 (16)75 (20)58 (13)Duration from initial disease presentation to enrollment, yr1.7 (0.3–6.6)3.1 (0.7–8.9)1.2 (0.2–5.2)Patients with initial disease presentation within 6 mo prior to study entry392 (46)149 (39)243 (52)PE/PI prior to study entry484 (57)198 (51)286 (62)Duration of PE/PI treatment, mo0.6 (0.1–2.0)1.0 (0.2–4.8)0.4 (0.1–1.4)Dialysis prior to study entry473 (56)201 (52)272 (59)Chronic dialysis (duration longer than 3 mo)209 (25)82 (21)127 (27)Patients with ESRD prior to study entry or ESRD developed up to data cutcData from n = 808 patients included in the time to ESRD analyses (see Supplementary Figure S1); ESRD was defined as a report of chronic dialysis (dialysis lasting ≥3 months) or kidney transplant.,dWhere patients had multiple transplants and ESRD only 1 event was counted.219 (27)90 (24)129 (30)Number of kidney transplants 1126 (15)42 (11)84 (18) ≥234 (4)16 (4)18 (4)aHUS, atypical hemolytic uremic syndrome; ESRD, end-stage renal disease; PE/PI, plasma exchange or infusion.Values are median (interquartile range) or n (%).a Patients were categorized by age at initial aHUS presentation: pediatric (<18 years old) or adult (≥18 years old).b Study entry was defined as follows: at enrollment for patients never treated with eculizumab or prior to eculizumab treatment initiation for patients who had ever received eculizumab.c Data from n = 808 patients included in the time to ESRD analyses (see Supplementary Figure S1); ESRD was defined as a report of chronic dialysis (dialysis lasting ≥3 months) or kidney transplant.d Where patients had multiple transplants and ESRD only 1 event was counted. Open table in a new tab aHUS, atypical hemolytic uremic syndrome; ESRD, end-stage renal disease; PE/PI, plasma exchange or infusion. Values are median (interquartile range) or n (%). Of patients with ≥5 genes tested, 119 (45%) had a mutation in ≥1 aHUS-associated gene or anti–complement factor H (CFH) antibody (Table 2). Patients presenting in childhood were significantly more likely to have membrane cofactor protein (MCP) mutations (P = 0.0009) and less likely to have complement factor I (CFI) mutations (P = 0.0036) than were patients with aHUS presentation in adulthood. The rarest mutation was in complement factor B (CFB), whereas anti-CFH antibodies were common in both pediatric and adult patients. In addition to complement abnormalities, diacylglycerol kinase ε (DGKε) mutations were observed in 8% of the 101 patients tested (all with initial presentation during childhood). The location of genetic mutations is shown in Supplementary Figure S2 and the characterization of genetic changes are summarized in Supplementary Table S1. Country-specific genetic screening patterns demonstrated there was no potential bias from unequal gene coverage between individual countries (Supplementary Table S2).Table 2Prevalence of complement abnormalitiesComplement abnormalityAge at presentation, yr, median (IQR)All patientsInitial presentation in childhoodInitial presentation in adulthoodP value (childhood vs. adulthood)n with complement abnormality/n screened (%)aPercentages are based on the number of patients who have the specific gene data available.Any identified mutationbFor “Any identified mutation or anti-CFH antibody” and “Any identified mutation” group, only patients tested for ≥5 genes (and anti-CFH antibodies where relevant) are included; for individual gene mutations and anti-CFH antibodies, all patients tested for the specific abnormality are included. If a patient has a mutation in more than one gene, data were included in data set for each gene. or anti-CFH Ab119/267 (45)58/136 (43)61/131 (47)0.5197Any identified mutationbFor “Any identified mutation or anti-CFH antibody” and “Any identified mutation” group, only patients tested for ≥5 genes (and anti-CFH antibodies where relevant) are included; for individual gene mutations and anti-CFH antibodies, all patients tested for the specific abnormality are included. If a patient has a mutation in more than one gene, data were included in data set for each gene.104/267 (39)50/136 (37)54/131 (41)0.4533CFH19.8 (1.1–30.4)100/482 (21)48/234 (21)52/248 (21)0.9020CD46 (MCP)5.3 (2.3–16.6)37/395 (9)28/196 (14)9/199 (5)0.0009CFI35.9 (21.8–48.5)26/406 (6)5/190 (3)21/216 (10)0.0036CFB6.0 (2.9–16.8)4/275 (2)3/141 (2)1/134 (1)0.6227C322.4 (2.5–32.6)21/331 (6)8/166 (5)13/165 (8)0.2536Anti-CFH Ab13.1 (6.1–31.3)86/402 (21)47/200 (24)39/202 (19)0.3053Ab, antibody; C3, complement component 3; CD, cluster of differentiation; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; IQR, interquartile range; MCP, membrane cofactor protein.a Percentages are based on the number of patients who have the specific gene data available.b For “Any identified mutation or anti-CFH antibody” and “Any identified mutation” group, only patients tested for ≥5 genes (and anti-CFH antibodies where relevant) are included; for individual gene mutations and anti-CFH antibodies, all patients tested for the specific abnormality are included. If a patient has a mutation in more than one gene, data were included in data set for each gene. Open table in a new tab Ab, antibody; C3, complement component 3; CD, cluster of differentiation; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; IQR, interquartile range; MCP, membrane cofactor protein. Overall median age at initial aHUS presentation was 21.4 years (Table 1). Male patients with aHUS were younger (median age: 10.0 years) at initial presentation than female patients (median age: 25.6 years) (Figure 1). Figure 1 demonstrates the different cumulative frequency curves observed for male and female patients at initial presentation. Age at initial presentation was independent of the presence of any identified complement abnormality (Supplementary Figure S3A and B). However, when patients with a single complement protein abnormality were analyzed individually, those with a CFI mutation were older at initial presentation of aHUS (median: 35.9 years old) than patients with other complement abnormalities in the overall population (Supplementary Figure S4A). In the pediatric population, patients with anti-CFH antibodies presented at a significantly older age (median: 6.4 years old) and those with DGKε mutations at a younger age (median: 0.6 years old) (Supplementary Figure S4B). Anti-CFH antibodies were the most common identified cause of aHUS in children aged 6 to 17 years (45% of tested patients; data not shown). A medical history of preselected precipitating factors potentially linked to the clinical manifestation of aHUS (potential complement activating conditions),15Asif A. Nayer A. Haas C.S. Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab.J Nephrol. 2017; 30: 347-362Crossref PubMed Scopus (60) Google Scholar including transplant, pregnancy, malignancy, autoimmune disease, and malignant hypertension, was noted in 121 patients (14%) (Supplementary Figure S1, Table 3). The median duration between the occurrence of a potential precipitating factor prior to diagnosis and time of aHUS diagnosis was variable, being <1 month for prior transplant, pregnancy, and malignant hypertension, and >2 years for malignancy and autoimmune disease. Genetic information was only available for 32 of 121 patients (26%) with a potential precipitating factor, and it is therefore not possible to associate these with specific mutations. In patients with none of these reported precipitating factors (n = 730), mutations were identified in 230 patients (32%) and no conclusive genetic information was available for 55% of patients.Table 3Disease characteristics according to selected potential precipitating factors prior to diagnosis of aHUSCharacteristicOverallpopulationn = 851None of the precipitating factors investigatedn = 730Prior Txn = 36Malignancyn = 36Pregnancyn = 26Autoimmune diseasen = 22Malignanthypertensionn = 10Time from last manifestation to aHUS diagnosis, median (IQR) mo0.9 (0.1–10.9)24.7 (6.6–64.9)0.2 (0.0–8.0)47 (4.4–147.9)0.0 (0.0–13.6)Age at initial presentation <18 yr (pediatric)38737165042 ≥18 yr (adult)464359303126188Any identified mutation or positive for anti-CFH AbsaAny mutation identified, regardless of number of genes tested.247230 (32)5 (14)3 (8)3 (12)3 (14)4 (40)No identified mutation and negative for anti-CFH AbsbIn patients tested for ≥5 genes.116101 (14)4 (11)4 (11)5 (19)2 (9)0 (0)No conclusive genetic or anti-CFH Ab informationcIn patients tested for <5 genes. No conclusive information includes patients where no mutation was identified but not all of the genes were screened and therefore no conclusion could be drawn, and patients tested for >5 genes, however, their genetic report was ambiguous in the description of the abnormalities.488399 (55)27 (75)29 (81)18 (69)17 (77)6 (60)Ab, antibody; aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; IQR, interquartile range; Tx, transplantation.Values are n (%), except for age at initial presentation. Autoimmune disease group includes systemic lupus erythematosus, scleroderma, antiphospholipid syndrome. Percentage based on number of patients with specific complement activating condition and genetic status/total number of patients with specific complement activating condition.a Any mutation identified, regardless of number of genes tested.b In patients tested for ≥5 genes.c In patients tested for <5 genes. No conclusive information includes patients where no mutation was identified but not all of the genes were screened and therefore no conclusion could be drawn, and patients tested for >5 genes, however, their genetic report was ambiguous in the description of the abnormalities. Open table in a new tab Ab, antibody; aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; IQR, interquartile range; Tx, transplantation. Values are n (%), except for age at initial presentation. Autoimmune disease group includes systemic lupus erythematosus, scleroderma, antiphospholipid syndrome. Percentage based on number of patients with specific complement activating condition and genetic status/total number of patients with specific complement activating condition. The Kaplan-Meier estimates for ESRD-free survival at 1 and 5 years (from initial disease presentation) showed being <18 or ≥18 years of age at initial presentation predicted ESRD risk. ESRD-free survival was 79% and 73% in pediatric patients and 69% and 51% in adult patients at 1 and 5 years, respectively (log-rank P < 0.001) (Figure 2a). ESRD-free survival probability was not different between patients when analyzed by sex and the presence or absence of a complement abnormality (log-rank P = 0.173 and P = 0.833, respectively) (Figure 2b, Supplementary Figure S5). Cox regression analysis showed a lower risk of ESRD for pediatric patients compared with adult patients; adjusted hazard ratio = 0.55 (95% confidence interval [CI]: 0.41–0.73). Sex, race, family history of aHUS, time from initial presentation to diagnosis, and potential precipitating factors were not associated with ESRD risk (Table 4). Analyses of ESRD-free survival in patients with specific complement abnormalities showed poor outcomes in patients with CFH mutations and longer ESRD survival in patients with MCP mutations compared with those tested negative for mutations in these genes (log-rank P = 0.0002 and < 0.0001, respectively) (Figure 3). Additionally, outcomes for patients with anti-CFH antibodies were marginally inferior to those without anti-CFH antibodies (log-rank P = 0.0476). A sensitivity analysis, excluding adults ≥51 years old, demonstrated that the increased risk of ESRD in adults was not related to greater frailty of elderly patients; adjusted hazard ratio = 0.49 (95% CI: 0.36–0.67). Further subanalyses assessed ESRD-free survival for patients with single identified mutations (Supplementary Figure S6). Exclusion of patients with MCP mutations from ESRD-free survival analysis had minimal impact on the overall 5-year ESRD-free survival probability (pediatric 73% vs. 70%; adults 51% vs. 50%). No difference was observed when ESRD analyses were stratified by sex and age at initial presentation (female vs. male log-rank P =0.804 and 0.744 for pediatric and adult patients, respectively).Table 4Multivariable Cox regression analysis for the association of risk factors with ESRDVariablenESRDevents, nUnadjusted HR (95% CI)Adjusted HR (95% CI)aHR adjusted for full Cox regression model, including all covariates in the table.Pediatric versus adult at initial presentation Adult4321291.001.00 Pediatric376900.54 (0.31–0.71)0.55 (0.41–0.73)Sex Female4381251.001.00 Male370940.83 (0.64–1.09)0.97 (0.74–1.29)Race White7031981.001.00 Nonwhite105210.87 (0.55–1.37)1.02 (0.64–1.61)Family history of aHUS No6791661.001.00 Yes129531.11 (0.81–1.52)1.26 (0.91–1.73)Time from initial presentation to diagnosis, d 0170671.001.00 1–14364660.81 (0.57–1.15)0.87 (0.61–1.24) 15–3096281.41 (0.90–2.21)1.32 (0.83–2.08) 31–180101291.04 (0.67–1.63)1.42 (0.73–2.75) >18077290.69 (0.44–1.07)0.69 (0.44–1.07)Any precipitating factorbTransplantation, malignancy, pregnancy, autoimmune disease, or malignant hypertension prior to aHUS presentation were included as precipitating factor. No7231991.001.00 Yes85201.49 (0.93–2.37)1.12 (0.69–1.81)aHUS, atypical hemolytic uremic syndrome; CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio.HRs and 95% CIs for genes and covariates among all patients in ESRD (n = 808). Patients with kidney transplant prior to aHUS presentation (n = 36) and those with treatment initiation at aHUS presentation (n = 7) were excluded from this analysis.a HR adjusted for full Cox regression model, including all covariates in the table.b Transplantation, malignancy, pregnancy, autoimmune disease, or malignant hypertension prior to aHUS presentation were included as precipitating factor. Open table in a new tab Figure 3End-stage renal disease (ESRD)–free survival by identification of specific complement abnormality in all patients. ESRD analysis excludes those patients with kidney transplant prior to atypical hemolytic uremic syndrome (aHUS) presentation (n = 36) and those with eculizumab initiation at aHUS presentation (n = 7). Number of patients at risk shown at initial presentation and every 2.5 years after initial aHUS presentation. Patients with multiple rare variants were excluded from this analysis. Patients were grouped by complement abnormality regardless of whether their specific rare variants were heterozygous, homozygous, or compound heterozygous. Patients with CFB, thrombomodulin (THBD), and DGKɛ variants were excluded as a variant occurred in <10 patients. Patients were censored at initiation of eculizumab. Ab, antibody; C3, complement component 3; CFH, complement factor H; CFI, complement factor I; MCP, membrane cofactor protein.View Large Image Figure ViewerDownload Hi-res image Download (PPT) aHUS, atypical hemolytic uremic syndrome; CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio. HRs and 95% CIs for genes and covariates among all patients in ESRD (n = 808). Patients with kidney transplant prior to aHUS presentation (n = 36) and those with treatment initiation at aHUS presentation (n = 7) were excluded from this analysis. Overall, 549 patients (65%) had a recent diagnosis of aHUS (diagnosed after 2011) (Supplementary Table S3). Of these, 18% reported multiple (≥2) additional TMA manifestations postdiagnosis, with a similar frequency reported for pediatric and adult patients. To assess the frequency of TMA manifestations in patients with aHUS, a subpopulation of patients with initial aHUS presentation between 2006 and 2011 and ≥6 months between presentation and study entry was analyzed (n = 190; 95 pediatric and 95 adult patients). Patients within this subgroup experienced 364 TMA manifestations (226 in pediatric and 138 in adult patients) at a rate of 47.7 per 100 person-years overall (95% CI: 42.9–52.9). The rate was 57.1 per 100 person-years in pediatric patients (95% CI: 49.9–65.1) and 37.6 per 100 person-years in adult patients (95% CI: 31.6–44.4). Any potential relationship between TMA rates and complement abnormalities could not be determined due to the limited number of patients with complete genetic information. Recently diagnosed patients were grouped by time between diagnosis and study entry (≤6 months, initial presenting phase; >6 months, chronic phase). Extrarenal manifestations reported here were more frequent in patients within the initial presenting phase (19%–38%) compared with those in the chronic phase (12%–23%) (Figure 4a). A greater proportion of pediatric patients experienced gastrointestinal manifestations than adults within the initial presenting phase (47% vs. 33%, respectively), but a lower proportion in the chronic phase (18% vs. 26%, respectively) (Figure 4b and c). A lower proportion of pediatric patients experienced pulmonary manifestations than adult patients (12% vs. 20%) irrespective of the disease phase (Figure 4b and c). Correlation of complement abnormalities and extrarenal manifestations associated with aHUS were not assessed due to insufficient genetic information. We assessed, in the largest real-world study of aHUS patients to date, the impact of age at initial presentation, sex, medical history, and identified complement abnormalities on the rate of TMA, frequency of extrarenal manifestations associated with aHUS and ESRD-free survival up to 15 years postpresentation, prior to any eculizumab treatment. This study confirms previous registry findings and provides novel insights regarding these phenotypic variables and genotypes on the clinical manifestation and progression of aHUS. Initial disease presentation occurred in adulthood for 55% of participants, and the majority of registry participants are female, supporting previous French aHUS registry data.5Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar In contrast, the Bergamo group reported initial aHUS presentation in adulthood for 41% of patients with 47% female patients,16Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar suggesting either regional variance in aHUS characteristics or, more likely, differences in patient enrollment. The large number of patients with aHUS followed in the registry allowed us to discover a sex-specific differenc