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A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome

2017; Elsevier BV; Volume: 93; Issue: 2 Linguagem: Inglês

10.1016/j.kint.2017.06.022

1523-1755

Ana Huerta, Emilia Arjona, José Pórtoles, Paula López–Sánchez, Cristina Rabasco, Mario Espinosa, Teresa Cavero, Miquel Blasco, Mercedes Cao, Joaquín Manrique, Virginia Cabello-Chavez, Marta Suñer, Manuel Heras, Xavier Fulladosa, Lara Belmar, Amparo Sempere, Carmen Peralta, L. Castillo, A. Arnau, Manuel Praga, Santiago Rodrı́guez de Córdoba,

Pregnancy and preeclampsia studies

Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy-associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients. Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy-associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients. Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) associated with genetic or acquired abnormalities that result in uncontrolled complement activation, leading to kidney failure and other extrarenal complications.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar The term pregnancy-associated aHUS (P-aHUS) has been coined to refer to the TMA that result from uncontrolled complement activation during pregnancy or the postpartum period. P-aHUS is a devastating systemic disease, with high maternal mortality and morbidity rates that extends beyond the initial presentation. It is a rare condition with an incidence of 1 in every 25,000 pregnancies and accounts for 20% of all aHUS cases in women.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar, 2Fakhouri F. Roumenina L. Provot F. et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol. 2010; 21: 859-867Crossref PubMed Scopus (312) Google Scholar, 3Dashe J.S. Ramin S.M. Cunningham F.G. The long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy.Obstet Gynecol. 1998; 91: 662-668Crossref PubMed Scopus (90) Google Scholar During the last decade there has been enormous progress in the clinical and pathophysiological understanding of aHUS, which have greatly improved the management and treatment of the aHUS patients. The implementation of a complement inhibition therapy, based on the use of eculizumab, has changed the natural history of the disease, preventing in most of the patients the adverse consequences of the complement dysregulation. Characterization of the etiological factors predisposing the patient to aHUS and identification of the concurrent triggering events that result in the development of aHUS have nowadays become essential for an individualized management of the aHUS patients, including long-term treatment with eculizumab.4Laurence 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, 5Goodship 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, 6Legendre 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, 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, 8Fakhouri 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, 9George J.N. Nester C.M. Syndromes of thrombotic microangiopathy.N Engl J Med. 2014; 371: 654-666Crossref PubMed Scopus (522) Google Scholar, 10Verhave J.C. Wetzels J.F. van de Kar N.C. Novel aspects of atypical haemolytic uraemic syndrome and the role of eculizumab.Nephrol Dial Transplant. 2014; 29: iv131-iv141Crossref PubMed Scopus (71) Google Scholar Despite these advances, specific clinical data in P-aHUS, incidence of genetic predisposing factors and knowledge of the nature of complement activating triggers that may occur during pregnancy or the postpartum period are still scarce and mostly limited to the original work published by Fakhouri et al.2Fakhouri F. Roumenina L. Provot F. et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol. 2010; 21: 859-867Crossref PubMed Scopus (312) Google Scholar in 2010. In their report, the French group reported the first series of P-aHUS patients, providing novel and valuable information of this form of aHUS. Particularly relevant was their finding that up to 86% of their patients presented a complement genetic abnormality. In their series the postpartum was reported as the main period of onset of the disease and the second pregnancy that of highest risk for P-aHUS development. The prognosis in that cohort was very poor, especially from a renal point of view, with up to 62% of the patients reaching end-stage renal disease (ESRD) within the first month after aHUS onset. However, it must be emphasized that the study was performed in the preeculizumab era. Subsequently, only a small number of case reports and very small series have reported the efficacy of eculizumab in P-aHUS patients. Here we describe a Spanish cohort of P-aHUS including 22 patients to provide epidemiologic, clinical, and prognostic data of the disease. We also report the incidence of complement abnormalities in the aHUS candidate genes and discuss their role in aHUS pathogenesis. Most importantly, we report our experience with the use of plasma treatment and eculizumab in a significant number of patients within our P-aHUS cohort. These data, together with that generated from other P-aHUS cohorts should provide clues to anticipate situations of aHUS risk during pregnancy and to treat efficiently P-aHUS when it develops. A search in our Spanish aHUS database for adult women with P-aHUS (n = 242) resulted in the identification of 22 patients (9%). These patients were referred to us for genetics and molecular complement analysis from 13 different Spanish hospitals. Relevant clinical and biological data from most of these patients (n = 22) was collected by examining their medical records (Table 1). All patients were born in Spain and none presented with an autoimmune-associated disease. Median age was 33.9 years (interquartile range [IQR]: 25, 38.3). At the time of the event none of the patients had a familial history of aHUS. In 4 patients (18%), the P-aHUS was a recurrence of a previously diagnosed aHUS. One patient had chronic kidney disease of diabetic etiology and carried a combined pancreas-kidney transplant with normal functioning kidney (serum creatinine: 0.8 mg/dl) at the onset of the P-aHUS event. Notably, in 16 patients the P-aHUS occurred during the first pregnancy (73%) and, interestingly, among the 6 patients with previous pregnancies, 4 of those pregnancies ended in a successful vaginal birth without any complications and in 2 resulted in abortions.Table 1Clinical characteristicsPatientCCMDgn aHUS beforePrevious pregnancies, viaAge (yr)aTime of onsetaType of birthaHb min (g/dl)a*Plaq min (× 109/l)aLDH max (mg/dl)asCr max(mg/dl)aRenal biopsyaEculizumabaOther therapiesaOutcome1NoNoNo3711 dPPCSNANANAHDNoNoNoESRD. Lost RT due to relapse. Exitus.2NoNoNo215 dPPCS6.9302616HDNoNoFFPCR3NoYesNo247 dPPVd5.11703701.8TMANoNoESRD. RT.4NoNoNo346 wPPVd6.966934HDTMAbNoPE, CC, CPESRD. Lost 1st RT due to C3GN.Relapse in 2nd RT with response to eculizumab.5YesNoNo382 dPPCS7.52133382.3C3GNYesPECR6YesNo1FTP, Vd414 wPPCS5.3601977HDNoNoPEESRD. Lost 2 RT due to relapse.3rd RT with prophylaxis.7YesNoNo215 dPPCS5.9404162HDTMANoPEESRD. Lost RT due to relapse.8NoNoNo424 dPPCS6.3522450HDTMAYesPECR9NoNo2FTP, 2Vd281 dPPVd8.72613544.2TMANoHeparinCR10NoNo1FTP, 1Vd371 dPPCS7.5408875.5NoNoPE, FFPCR11NoNoNo351 dPPCS5.3267487HDNoYesPECR12YesYes1A3836 WGCS8.1498671.09TMA, IC-MPGNNoPECRc13NoNo1FTP, 1Vd2836 WGVd8.2414554.23TMAYesPECKD14NoNoNo3519 WG(A)8.9653401.4NoNoNoCKD15NoYesNo3232 WGVd7.8665112.9TMA, C3GNYesPERelapse.d CKD.16YesNoNo337 dPPCS4.5503373HDNoNoPEESRD. RT with prophylaxis.17NoNoNo281 dPPCS5.22071834.55NoYesPE, FFP, CCCR18YesNo2A4036 WGCS4.7532252HDTMAYesPECKD19YesYesNo2419 WGCS7.3648793.5NoYesNoRelapse.d CKD.20NoNoNo252 dPPCS7.19814073.8NoYesPECR21YesNoNo259 dPPCS51640554.3NoNoPERelapse. CKD.22YesNoNo397 dPPCS7.18026003.2TMAYesPECRA, abortion; aHUS, atypical hemolytic uremic syndrome; C3GN, C3 glomerulonephritis; CC, corticosteroids; CCM, carriers of pathogenic variants in complement of mutation; CKD, chronic kidney disease; CP, cyclophosphamide; CR, complete remission; CS, cesarean section; Dgn, diagnosis; dPP, day postpartum; ESRD, end-stage renal disease; FFP, fresh frozen plasma; FTP, full-term pregnancy; Hb, hemoglobin; HD, hemodialysis; IC-MPGN, immune complex-mediated membranoproliferative glomerulonephritis; LDH, lactic acid dehydrogenase; max, maximum; min, minimum; NA, not available; PE, plasma exchange; plat, platelets; RT, renal transplant; sCr, serum creatinine; TMA, thrombotic microangiopathy; Vd, vaginal delivery; WG, week of gestation; wPP, week postpartum.Data at the apregnancy-associated atypical hemolytic uremic syndrome event ba de novo C3GN in renal transplantation; cC3GN with normal renal function and proteinuria of 0.95 g/d; dafter eculizumab discontinuation, and the relapse was retreated with eculizumab, with response. Open table in a new tab A, abortion; aHUS, atypical hemolytic uremic syndrome; C3GN, C3 glomerulonephritis; CC, corticosteroids; CCM, carriers of pathogenic variants in complement of mutation; CKD, chronic kidney disease; CP, cyclophosphamide; CR, complete remission; CS, cesarean section; Dgn, diagnosis; dPP, day postpartum; ESRD, end-stage renal disease; FFP, fresh frozen plasma; FTP, full-term pregnancy; Hb, hemoglobin; HD, hemodialysis; IC-MPGN, immune complex-mediated membranoproliferative glomerulonephritis; LDH, lactic acid dehydrogenase; max, maximum; min, minimum; NA, not available; PE, plasma exchange; plat, platelets; RT, renal transplant; sCr, serum creatinine; TMA, thrombotic microangiopathy; Vd, vaginal delivery; WG, week of gestation; wPP, week postpartum. Data at the apregnancy-associated atypical hemolytic uremic syndrome event ba de novo C3GN in renal transplantation; cC3GN with normal renal function and proteinuria of 0.95 g/d; dafter eculizumab discontinuation, and the relapse was retreated with eculizumab, with response. In 6 patients (27%), the event occurred during the antepartum period, and in 16 patients (73%), it occurred in the postpartum period, mostly within the first week after delivery (Figure 1). Importantly, 13 patients within the postpartum group (81%) delivered their babies by cesarean section (C-section), and 3 of them were associated with severe bleeding. Seven of these patients underwent C-section for reasons related to the mechanics of delivery (e.g., podalic presentation of the fetus, cephalopelvic disproportion, failure to induce delivery). Notably, C-section was due to a suspected preeclampsia in only 3 patients. In another patient, the cause was because of vaginal hemorrhage, but interestingly, the aHUS episode in this patient occurred 4 weeks after delivery. Finally, the reason for the C-section in 2 patients was not reported. Six women had the P-aHUS episode before delivery. Three developed P-aHUS at week 36 and delivered healthy babies. One had a vaginal delivery at week 32 of an underweight (1500 g) but healthy child. Another P-aHUS case had the onset at week 19, but the pregnancy was maintained with eculizumab during 5 more weeks. She delivered a baby with very low weight (500 g) by C-section, who was hospitalized for 5 months and is today a healthy child. Finally, there was 1 case of therapeutic abortion at week 19 due to “hydrops fetalis.” Based on the information included in the medical records, alternative aHUS triggers, such as infections or drugs were excluded in all cases of P-aHUS included in this report. Nineteen patients presented with hypertension (86%). Extrarenal manifestations were also present in several patients: 7 patients had neurological complications, 4 had gastrointestinal alterations, and 3 had cardiac affectation, without peripheral vasculopathy. Nine patients (41%) required acute hemodialysis. Maximum serum creatinine among patients who did not required acute hemodialysis was 3.5 mg/dl (IQR: 2.3, 4.23), minimum hemoglobin level was 6.9 g/dl (IQR: 5.3, 7.8), minimum platelets count was 50 × 109/l (IQR: 30 × 109, 65 × 109), maximum levels of lactic acid dehydrogenase were 1977 UI/l (IQR: 879, 3338) and maximum proteinuria reached 2.5 g/d (IQR: 1.6, 4.8). All patients presented schistocytes in the blood smear and decreased haptoglobin. Microhematuria could not be assessed because of the presence of lochia. Renal biopsies were available for 11 patients and histologic lesions characteristic of thrombotic microangiopathy were described with 1 exception. An associated glomerulonephritis (GN) was also described in 3 cases (2 C3GN and 1 immune complex-mediated membranoproliferative GN). A fourth patient, who later receive a transplant, developed a de novo C3GN in the graft. Complement analysis and genetic findings in the 22 patients are depicted in Table 2 and described in the Supplementary Materials and Methods. Four patients presented decreased levels of C3. A complement abnormality in the aHUS candidate genes was detected in 9 of 22 patients (41%), which is significantly less than the 86% reported previously.2Fakhouri F. Roumenina L. Provot F. et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol. 2010; 21: 859-867Crossref PubMed Scopus (312) Google Scholar Three patients (14%) carried a mutated CFHR1 gene, another 3 (14%) had a CFH mutation, 2 had a C3 mutation (9%), and 1 (4%) had a CFI mutation. A total of 13 patients (59%) had no detected genetic defect.Table 2Complement levels, genetics, and autoantibodies in patients with postpartum aHUSPatientGenes analyzedaNGS panel (Ion Torrent) includes the CFH, CFI, MCP, C3, CFB, THBD, ADAMTS13, DGKE, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5 and CFP genes. NGS panel (Illumina) interrogates as many as 48 genes and includes all complement genes.Pathogenic variantsCFH risk haplotypeMCP risk haplotypeAnti FH/FI antibodiesC375–135 mg/dlC414–60 mg/dlFH90–302 μg/mlFI71%–115%MCP91%–109%1CFH, MCP, CFI (Sanger)NoneHom (H3, H3)HomNo1041914687ND2NGS panel (Ion Torrent)NoneNo (H2, H4b)HomNoNDND247ND1103CFH, MCP, CFI, CFB (Sanger)NoneHet (H3, H4b)NoNo9215132691004CFH, MCP, CFI, CFB, C3, THBD (Sanger)NoneHet (H3, H4a)NoNDNDNDNDNDND5NGS panel (Illumina)C3: Exon 4; c.481C>T; p.R161WHom (H3, H3)HetNo871679971006CFH, MCP, CFI (Sanger)CFI: Exon 3; c.452 A>G; p.N151SHom (H3, H3)HetNo8325199421037CFH, MCP, CFI, CFB, CFHR1 (Sanger)CFHR1: p.L290S, A296V (CFHR1:CFH hybrid gene)Hom (H3, H3)NoNo6429102100978CFH, MCP, CFI (Sanger)NoneHom (H3, H3)HomNo9432248NDND9CFH, MCP, CFI, CFB, C3, CFP, THBD (Sanger)NoneHet (H3, H5)HetNo10626197113ND10CFH, MCP, CFI, CFB, C3, CFP, THBD (Sanger)NoneHet (H3, H4a)HetNo10410105109ND11NGS panel (Illumina)NoneNo (H4a, H4a)HomNo9310138998812CFH, MCP, CFI (Sanger)CFH: Exon2; c.157C>A; p.R53SHet (H3, H2)HomNo13728242100ND13NGS panel (Ion Torrent)NoneNo (H4a, H4a)NoNo7123174939714NGS panel (Ion Torrent)NoneHet (H3, H1)NoNo82131227013015CFH, MCP, CFI, CFB, C3, CFP, THBD (Sanger)NoneHet (H3, H4a)HomNo51224511310016CFH, MCP, CFI, CFB (Sanger)CFH: Exon 16 c.2284G>T; p.E762*No (H1, H5)HetNo6330859312517CFH, MCP, CFI (Sanger)NoneNo (H1, H4a)NoNo1064214712010018NGS panel (Illumina)C3: Exon 41; c.4855A>C; p.S1619RHet (H3, H1)NoNo102401779011919NGS panel (Ion Torrent)CFHR1: p.L290S, A296V (CFHR1:CFH hybrid gene)Het (H3, H1)HomNo992099100ND20NGS panel (Ion Torrent)CFHR1: p.L290S, A296V (CFHR1:CFH hybrid gene)Het (H3, H1)NoNo911210510012321NGS panel (Illumina)CFH: Exon13; c.1707C>A; p.C569*No (H1, H7)NoNo1292722011610422NGS panel (Illumina)NoneNo (H1, H1)NoNo1413833397113aHUS, atypical hemolytic uremic syndrome; Het, heterozygote; Hom, homozygote; ND, not done; NGS, next generation sequencing.a NGS panel (Ion Torrent) includes the CFH, CFI, MCP, C3, CFB, THBD, ADAMTS13, DGKE, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5 and CFP genes. NGS panel (Illumina) interrogates as many as 48 genes and includes all complement genes. Open table in a new tab aHUS, atypical hemolytic uremic syndrome; Het, heterozygote; Hom, homozygote; ND, not done; NGS, next generation sequencing. All genetic variants detected in the patients were confirmed to be pathogenic. The product of the mutated CFHR1 gene encodes a mutant FHR-1 protein with the C-terminal region identical to that of factor H (FH). This abnormal FHR-1 protein competes the binding of FH to the cell surfaces and impairs complement regulation. Two of the CFH mutations introduce stop codons in the CFH sequence that results in FH deficiencies and the third is a missense mutation in the N-terminal of FH that impairs the cofactor and decay accelerating activities of FH. Finally, the CFI mutation is a missense mutation that impairs expression and associates with decreased levels of FI in plasma11Bresin E. Rurali E. Caprioli J. et al.for the European Working Party on Complement Genetics in Renal DiseasesCombined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype.J Am Soc Nephrol. 2013; 24: 475-486Crossref PubMed Scopus (261) Google Scholar, 12Bienaime F. Dragon-Durey M.A. Regnier C.H. et al.Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome.Kidney Int. 2010; 77: 339-349Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar and the 2 C3 mutations are known C3 pathogenic variants that have been previously described associated with aHUS and that impair binding to C3b of the complement regulators.13Roumenina L.T. Frimat M. Miller E.C. et al.A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function.Blood. 2012; 119: 4182-4191Crossref PubMed Scopus (109) Google Scholar, 14Martinez-Barricarte R. Heurich M. Lopez-Perrote A. et al.The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome.Mol Immunol. 2015; 66: 263-273Crossref PubMed Scopus (42) Google Scholar, 15Schramm E.C. Roumenina L.T. Rybkine T. et al.Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome.Blood. 2015; 125: 2359-2369Crossref PubMed Scopus (81) Google Scholar The genotypes for the at-risk MCPGGAAC and CFH-H3 haplotypes were also determined in all patients. The allele frequencies of both at-risk haplotypes were significantly elevated compared with the allele frequencies in the normal Spanish population (MCPGGAAC: 0.43 vs. 0.23; CFH-H3: 0.45 vs. 0.20). Notably, 7 of the 22 patients were homozygous for the at-risk MCPGGAAC haplotype, which exceeds slightly the expected number from the 0.43 allele frequency. Two patients presented the CFHR3-CFHR1 deletion in homozygosis, but anti-FH auto-antibodies were not detected. Interestingly, the percentage of adult aHUS patients in the whole Spanish aHUS cohort carrying complement gene alterations (39%; n = 280) is very similar to that observed in the P-aHUS cohort (41%). This is, however, much higher than the percentage of patients carrying genetic alterations among those reported by the referral physicians as secondary TMA, excluding P-aHUS (11%, n = 57). Notably, no mutations in MCP or anti-FH antibodies were detected in any of the patients, and none of the patients carried ≥1 mutation. Ten patients (45%) received eculizumab at the P-aHUS event and all of them (100%) had a positive response at both hematologic and renal levels. Eculizumab was initiated with a median time of 17 days (IQR: 8, 23) after the P-aHUS event and treatment lasted 9.8 months (IQR: 7.4, 12.3) on average, estimated by Kaplan-Meier method. In 9 of the 10 cases, eculizumab was initiated because of the lack of response to plasma therapies. The remaining case was a woman with a previous diagnosis of aHUS who had a relapse during pregnancy. No severe adverse effects were observed in the eculizumab-treated patients that forced treatment discontinuation. Seventeen patients were treated with plasmapheresis (77%), with an average of 6 sessions per patient (IQR: 5, 12). Plasma treatments were initiated with a median time of 2 days (IQR: 1, 3) after the P-aHUS event (estimated by Kaplan-Meier method). All but 2 patients underwent daily treatment during the first week and then every 48 hours. Two patients were treated every 48 hours from the beginning. Treatment lasted a median time of 7.5 days (IQR: 4, 15). In 8 patients (47%) there was a hematologic response, but only 3 (18%) had a renal response. Three patients received fresh frozen plasma (1–64 infusions). All of them had a good hematologic response, and 2 (67%) had a renal response. Additionally, 2 patients were treated with corticosteroids without response, and 1 evolved favorably after heparin treatment. Follow-up time was on average 7.9 years/patient (accumulated time: 173.2 years). One patient died 28 years after the P-aHUS episode at 65 years of age. Four of the 22 patients (18%) reached ESRD within the first month after the P-aHUS event, and at the end of the follow-up, 6 of the 22 patients (27%) required renal replacement therapy (RRT). All these patients have received a renal transplant during follow-up. Three of them (50%) lost their grafts due to recurrence of the disease (1 patient lost 2 grafts); 2 were carriers of pathogenic variants in complement components. A fourth patient, with no detected mutation, lost her first graft due to a de novo C3G, and in her second transplant had an aHUS episode that was resolved with eculizumab (Table 1). Seven patients had aHUS recurrences. The time to have a relapse was on average 240 months (IQR: 134.2, 346.6), estimated by Kaplan-Meier method. Four of them were carriers of pathogenic complement variants, but the other 3 had no detected genetic or acquired defect. In 4 of the 7 patients, the recurrence occurred after receiving a kidney transplant. The other 3 did not receive transplants and there was no clear trigger for the recurrence. Four patients had specific features of glomerulonephritis (Table 1): Patient 5, C3GN type, carries a complement gene alteration. She is currently under eculizumab treatment, with normal renal function (serum creatinine: 0.77 mg/dl) and without proteinuria. Patient 12, immune complex–mediated membranoproliferative glomerulonephritis type, carries a complement gene alteration. She was treated with plasmapheresis, has normal renal function (serum creatinine: 0.68 mg/dl), but presents proteinuria of 3.89 g/d. Patient 15, C3GN type, carries no genetic abnormalities, and she is under eculizumab treatment, presenting serum creatinine of 1.3 mg/dl and proteinuria of 0.95 g/d. Finally, patient 4, C3GN type, carries no genetic abnormalities. She developed it de novo in the transplanted kidney and this was the cause of the graft loss. Four patients had a low C3, but only 1 of them belong to this group having GN. Three of the 10 patients (30%) treated with eculizumab required hemodialysis at the time of the P-aHUS episode, but all 3 recovered renal function. None of the eculizumab-treated patients reached ESRD at the end of the follow-up. In contrast, within the group of patients who did not receive eculizumab (12 patients), 50% required hemodialysis at onset. Four of the 12 patients (33%) reached ESRD during the first month and 6 patients (50%) required RRT at the end of the follow-up (Figure 2). Eculizumab was suspended in 7 of the 10 cases after a median time of 10 months of treatment (IQR: 6, 10). Two of them were carriers of pathogenic variants. Whereas no recurrences were observed during the treatment, 2 of the patients, 1 carrying a genetic defect, had a recurrence 5 and 7 months after eculizumab discontinuation, respectively. Five additional cases received eculizumab with posterity to the P-aHUS event. In 2 cases, both carrying complement pathogenic variants, eculizumab was used as prophylaxis for a kidney transplant. None of them had a recurrence of aHUS and both patients are still receiving eculizumab. In a third case, it was used to successfully treat a relapse of aHUS after transplantation. She does not carry complement genetic or acquired defects. Eculizumab was also used to treat the recurrences after eculizumab discontinuation of the 2 P-aHUS already mentioned. At the time of writing this report they remain on treatment. In this study we describe the epidemiologic, clinical, and prognostic data of 22 P-aHUS patients from the Spanish cohort, with a median follow-up of 7.9 years/patient to illustrate that there are no significant differences between this group of patients and the non-pregnancy-related aHUS patients. We describe the complement abnormalities in the aHUS candidate genes found in 41% of our patients and discuss their role in P-aHUS pathogenesis. An interesting observation is that C-section shows an association with P-aHUS in our cohort. Finally, we report an excellent experience with the use of eculizumab compared with plasma treatments. Our findings together with those generated from other P-aHUS cohorts should improve prevention, diagnosis, and treatment of P-aHUS patients. P-aHUS is a serious condition that has been associated with an elevated morbidity for the mother and, in prepartum cases, also high morbidity or mortality or both for the fetus.16George J.N. Nester C.M. McIntosh J.J. Syndromes of thrombotic microangiopathy associated with pregnancy.Hematology Am Soc Hematol Educ Program. 2015; 2015: 644-648Crossref PubMed Scopus (68) Google Scholar In our series (n = 22), one-third of the 12 cases (33%) who were not treated with eculizumab reached ESRD during the first episode and one-half of the patients (50%) within this subgroup required RRT at the end of follow-up. This is consistent with previous data by the French group, who reported 62% of the patients reaching ESRD during the first month and 76% requiring RRT at the end of the follow-up.2Fakhouri F. Roumenina L. Provot F. et al.Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations.J Am Soc Nephrol. 2010; 21: 859-867Crossref PubMed Scopus (312) Google Scholar Our relatively reduced percentage