Advertisement

Preemptive plasma therapy prevents atypical hemolytic uremic syndrome relapse in kidney transplant recipients

Published:November 30, 2019DOI:https://doi.org/10.1016/j.ejim.2019.11.007

      Highlights

      • aHUS patients are at great risk of disease relapse after kidney transplantation.
      • Preemptive plasma-therapy reduced the risk of disease relapse and improved graft survival.
      • Switch from plasma therapy to Eculizumab was necessary in 50% of patients.

      Abstract

      Background

      Atypical hemolytic uremic syndrome (aHUS) frequently leads to renal failure, and kidney transplantation bears a high risk of disease recurrence and graft loss.

      Methods

      Patients who received a kidney graft in our center were retrospectively identified using our Vienna Thrombotic Microangiopathy Cohort. Since 2005, the majority of aHUS patients received perioperative plasma exchange (PE) followed by plasma infusions (PI). Patients were switched to eculizumab in case of plasma intolerance or failure. Those with no preemptive therapy served as controls. We used proportional Cox regression and logistic regression to examine predictors of graft survival.

      Results

      19 aHUS patients received 32 grafts and had a follow-up > 1 year. Eight patients received preventive plasma therapy for eight transplants and 13 patients (including 2 patients who received plasma therapy for their last transplant) had no preventive therapy for 24 grafts. The median graft survival was 2.372 days in patients, that received preemptive therapy and 411 days in patients, that did not receive preemptive treatment (hazard ratio: 0.11; p= 0.03). Four patients were switched to eculizumab because of plasma intolerance or failure. Additionally, one patient, that was not transplanted according to the above-mentioned protocol, received eculizumab for aHUS relapse. Additionally, relapse of aHUS (p = 0.01) and year of transplantation (p<0.01) had an effect on graft failure.

      Conclusions

      This study shows that preemptive plasma therapy and eculizumab rescue in selected cases improve graft survival among kidney transplant recipients with aHUS.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Noris M.
        • Caprioli J.
        • Bresin E.
        • Mossali C.
        • Pianetti G.
        • Gamba S.
        • 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: 1844-1859
        • Le Quintrec M.
        • Zuber J.
        • Moulin B.
        • Kamar N.
        • Jablonski M.
        • Lionet A.
        • et al.
        Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.
        Am J Transplant. 2013; 13: 663-675
        • Bresin E.
        • Daina E.
        • Noris M.
        • Castelletti F.
        • Stefanov R.
        • Hill P.
        • et al.
        Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background.
        Clin J Am Soc Nephrol. 2006; 1: 88-99
        • Hirt-Minkowski P
        • Schaub S
        • Mayr M
        • Schifferli JA
        • Dickenmann M
        • Fremeaux-Bacchi V
        • et al.
        Haemolytic uraemic syndrome caused by factor H mutation: is single kidney transplantation under intensive plasmatherapy an option?.
        Nephrol Dial Transplant. 2009; 24: 3548-3551
        • Davin JC
        • Strain L
        • Goodship TH
        Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation.
        Pediatr Nephrol. 2008; 23: 1517-1521
        • Zuber J.
        • Le Quintrec M.
        • Krid S.
        • Bertoye C.
        • Gueutin V.
        • Lahoche A.
        • et al.
        Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation.
        Am J Transplant. 2012; 12: 3337-3354
        • Zuber J
        • Le Quintrec M
        • Morris H
        • Fremeaux-Bacchi V
        • Loirat C
        • Legendre C
        Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation.
        Transplant Rev (Orlando). 2013; 27: 117-125
        • Ardissino G.
        • Testa S.
        • Possenti I.
        • Tel F.
        • Paglialonga F.
        • Salardi S.
        • et al.
        Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases.
        Am J Kidney Dis. 2014; 64: 633-637
        • van den Brand J.A.
        • Verhave J.C.
        • Adang E.M.
        • Wetzels J.F
        Cost-effectiveness of eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome.
        Nephrol Dial Transplant. 2017; 32: i115-i122
        • Albertazzi V
        • Bonucchi D
        • De Amicis S
        • Americo C
        • Ghiandai G
        • Cappelli G
        A favorable 3-year outcome of kidney transplantation in atypical hemolytic uremic syndrome associated with a factor H mutation: case report.
        Transplant Proc. 2010; 42: 1352-1354
        • Davin J.C.
        • Groothoff J.
        • Gracchi V.
        • Bouts A
        Long-term renal function under plasma exchange in atypical hemolytic uremic syndrome.
        Pediatr Nephrol. 2011; 26: 1915-1916
        • Fakhouri F.
        • Zuber J.
        • Fremeaux-Bacchi V.
        • Loirat C
        Haemolytic uraemic syndrome.
        Lancet. 2017; 390: 681-696
        • Sethi S.
        • Fervenza F.C.
        Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS).
        Semin Thromb Hemost. 2014; 40: 416-421
        • Haas M
        • Loupy A
        • Lefaucheur C
        • Roufosse C
        • Glotz D
        • Seron D
        • et al.
        The Banff 2017 kidney meeting report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.
        Am J Transplant. 2018; 18: 293-307
        • Gaggl M.
        • Aigner C.
        • Csuka D.
        • Szilagyi A.
        • Prohaszka Z.
        • Kain R.
        • et al.
        Maternal and fetal outcomes of pregnancies in women with atypical hemolytic uremic syndrome.
        J Am Soc Nephrol. 2018; 29: 1020-1029
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Osborne AJ
        • Breno M
        • Borsa NG
        • Bu F
        • Frémeaux-Bacchi V
        • Gale DP
        • et al.
        Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy.
        J Immunol. 2018; 200: 2464-2478
        • Adzhubei I
        • Jordan DM
        • Sunyaev SR
        Predicting functional effect of human missense mutations using PolyPhen-2.
        Curr Protoc Hum Genet. 2013; (Chapter 7:Unit7 20)
        • Ng P.C.
        • Henikoff S
        Predicting deleterious amino acid substitutions.
        Genome Res. 2001; 11: 863-874
        • Choi Y
        • Sims GE
        • Murphy S
        • Miller JR
        • Chan AP
        Predicting the functional effect of amino acid substitutions and indels.
        PLoS ONE. 2012; 7: e46688
        • Schwarz J.M.
        • Rodelsperger C.
        • Schuelke M.
        • Seelow D
        MutationTaster evaluates disease-causing potential of sequence alterations.
        Nat Methods. 2010; 7: 575-576
        • Zuber J
        • Fakhouri F
        • Roumenina LT
        • Loirat C
        • Frémeaux-Bacchi V
        Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.
        Nature Rev Nephrol. 2012; 8: 643-657
        • Miller R.B.
        • Burke B.A.
        • Schmidt W.J.
        • Gillingham K.J.
        • Matas A.J.
        • Mauer M.
        • et al.
        Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report.
        Nephrol Dial Transplant. 1997; 12: 1425-1430
        • de Andrade LGM
        • Contti MM
        • Nga HS
        • Bravin AM
        • Takase HM
        • Viero RM
        • et al.
        Long-term outcomes of the atypical hemolytic uremic syndrome after kidney transplantation treated with eculizumab as first choice.
        PLoS ONE. 2017; 12e0188155
        • Duineveld C
        • Verhave JC
        • Berger SP
        • van de Kar N
        • Wetzels JFM
        Living donor kidney transplantation in atypical hemolytic uremic syndrome: a case series.
        Am J Kidney Dis. 2017; 70: 770-777
        • Noris M
        • Ruggenenti P
        • Remuzzi G
        Kidney transplantation in patients with atypical hemolytic uremic syndrome: a therapeutic dilemma (or not)?.
        Am J Kidney Dis. 2017; 70: 754-757
        • Zuber J.
        • Le Quintrec M.
        • Sberro-Soussan R.
        • Loirat C.
        • Fremeaux-Bacchi V.
        • Legendre C
        New insights into postrenal transplant hemolytic uremic syndrome.
        Nat Rev Nephrol. 2011; 7: 23-35
        • Levi C
        • Fremeaux-Bacchi V
        • Zuber J
        • Rabant M
        • Devriese M
        • Snanoudj R
        • et al.
        Midterm outcomes of 12 renal transplant recipients treated with eculizumab to prevent atypical hemolytic syndrome recurrence.
        Transplantation. 2017; 101: 2924-2930
        • Olie K.H.
        • Florquin S.
        • Groothoff J.W.
        • Verlaak R.
        • Strain L.
        • Goodship T.H.
        • et al.
        Atypical relapse of hemolytic uremic syndrome after transplantation.
        Pediatr Nephrol. 2004; 19: 1173-1176
        • Goodship TH
        • Cook HT
        • Fakhouri F
        • Fervenza FC
        • Fremeaux-Bacchi V
        • Kavanagh D
        • et al.
        Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney disease: improving global outcomes” (KDIGO) controversies conference.
        Kidney Int. 2017; 91: 539-551
        • Wijnsma K.L.
        • Duineveld C.
        • Wetzels J.F.M.
        • van de Kar N
        Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use.
        Pediatr Nephrol. 2018;
        • Woodroffe R.
        • Yao G.L.
        • Meads C.
        • Bayliss S.
        • Ready A.
        • Raftery J.
        • et al.
        Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.
        Health Technol Assess. 2005; 9 (iii-iv): 1-179
        • Manuelian T
        • Hellwage J
        • Meri S
        • Caprioli J
        • Noris M
        • Heinen S
        • et al.
        Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.
        J Clin Invest. 2003; 111: 1181-1190
        • Bresin E.
        • Rurali E.
        • Caprioli J.
        • Sanchez-Corral P.
        • Fremeaux-Bacchi V.
        • Rodriguez de Cordoba S.
        • et al.
        Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype.
        J Am Soc Nephrol. 2013; 24: 475-486
        • Heinen S
        • Sanchez-Corral P
        • Jackson MS
        • Strain L
        • Goodship JA
        • Kemp EJ
        • et al.
        De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome.
        Hum Mutat. 2006; 27: 292-293
        • Szarvas N.
        • Szilagyi A.
        • Csuka D.
        • Takacs B.
        • Rusai K.
        • Müller T.
        • et al.
        Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome.
        Mol Immunol. 2016; 71: 10-22
        • Herbert AP
        • Kavanagh D
        • Johansson C
        • Morgan HP
        • Blaum BS
        • Hannan JP
        • et al.
        Structural and functional characterization of the product of disease-related factor H gene conversion.
        Biochemistry. 2012; 51: 1874-1884