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ecurrence of Hemolytic Uremic Syndrome Afterenal Transplantation

. Seitz, L. Albano, F. Vocila, S. Mzoughi, R. Aoudia, J. Guitard, D. Ribes, H. Vachet-Copponat,. Mourad, F. Bienaimé, P. Dahan, V. Frémeaux-Bacchi, and E. Cassuto

ABSTRACT

Non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) is a rare disease.The clinical outcome is often unfavorable: 50% of patients progress to end-stage renalfailure. Several mutations in complement regulatory genes predispose to non-Stx-HUS.Transplantation outcomes are poor among patients with either mutation in the genesencoding complement H or I factors, with 80% graft loss due to HUS recurrence. Incontrast, patients with mutation in the gene encoding MCP have no disease relapse aftertransplantation. There are no treatment guidelines for non-Stx-HUS recurrence. Hereinwe have presented 8 patients with non-Stx-HUS recurrence after transplantation duringthe last 10 years in the South of France. HUS recurrence, which occurred early aftertransplantation in all but 1 patient, was treated by plasma exchange (PE) with substitutionby fresh frozen plasma (FFP). Three patients still treated with long-term plasma therapyhave no recurrence at 15, 19, or 24 months. An international registry would help to define

new guidelines.

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EMOLYTIC UREMIC SYNDROME (HUS) is arare disease with manifestations of microangiopathic

emolytic anemia, thrombocytopenia, and renal impair-ent. In most cases, HUS, which is triggered by Shiga toxin

Stx)-producing Escherichia coli, is manifested by watery orloody diarrhea (Stx-HUS).1 Approximately half of theatients require dialysis during the acute episode, but renalunction recovers in most of them.2 There is no recurrencefter transplantation. Non-Shiga toxin-associated HUS (non-tx-HUS) affects a heterogeneous group who show biochem-

cal evidence of deficiency of or abnormalities in comple-ent regulatory proteins of the alternative pathway. About

0%, 13%, or 4% of the patients have mutations in theenes encoding factors H (CHF), MCP, or factor I (IF),espectively. Transplantation outcomes are poor amongatients with either mutation in the genes encoding com-lement H or I factor, with 80% graft loss due to HUSecurrence. In contrast, patients with mutation in the genencoding MCP have no disease relapse after transplanta-ion, because MCP is a transmembrane regulator andllografts are therefore protected by wild-type MCP.3,4 Theisease may be sporadic or familial with both autosomalnd recessive transmission.1,2 Various triggering eventsave been reported such as pregnancy, virus-like diseases,

r sepsis.5,6 Persistent and remarkably depressed levels of F

2007 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 39, 2583–2585 (2007)

he third fraction of the complement system (C3) have beenocumented.3 Non-Stx-HUS with anti-CHF antibodies haseen reported.7

We conducted a retrospective multicenter study to eval-ate the outcomes of adult renal transplant recipients withecurrence of non-Stx-HUS after transplantation. Eightatients, who underwent transplantation between 1996 and006, were included in the study.

ATERIALS AND METHODS

n each case, the initial diagnosis of HUS was documented by 1 orore episodes of microangiopathic hemolytic anemia and throm-

ocytopenia and/or microangiopathic lesions on kidney biopsy.ight patients developed definite clinical or pathologic evidence of

ecurrence in at least 1 graft. Familial non-Stx-HUS was suspectedhen 2 or more members of the same family experienced theisease, excluding exposure to a common triggering infectious

From the Hôpital Pasteur, Nice, France (B.S., L.A., F.V., S.M.,.A., P.D., E.C.); Hopital Rangueil, Toulouse (J.G., D.R.); Hopital

a Conception, Marseille (H.V.-C.); Hopital la Peyronie, Montpel-ier (G.M.); Hopital European Georges Pompidou, Paris (F.B.,.F.-B.).Address reprint requests to B. Seitz, Hôpital Pasteur, Pavillon

, 30 Avenue de la Voie Romaine, BP 69, 06002 Nice Cedex 1,

rance. E-mail: barbara.seitz@wanadoo.fr

0041-1345/07/$–see front matterdoi:10.1016/j.transproceed.2007.08.021

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2584 SEITZ, ALBANO, VOCILA ET AL

gent. There was no HIV-associated HUS. Mutation studies haveeen performed by PCR amplification or measurements by ELISAor CHF or IF, and FACS caliber examinations for MCP.8,9

ESULTSast Clinical History

e recruited 8 patients (5 women, 3 men) who received 9ransplantations and had a diagnosis of non-Stx-HUS re-urrence after transplantation. Their clinical characteristicsre summarized in Table 1. There were 6 sporadic cases ofUS. Two patients (cases 7 and 8) are cousins: Patient 7’s

ather has the same mutation. He presented membranopro-iferative glomerulonephritis but no recurrence in his graft.

is brother died on dialysis. Four patients showed low C3evels. Three patients displayed no mutation. For the oth-rs, the various mutations are listed in Table 1. More thanmutation may coexist in the same patient. No patient had

nti-factor H antibody.

US History

triggering factor was present in 4 patients: infection,regnancy, or drug administration with Ticlopidine or es-roprogestative contraceptions. Median time from diagnosiso dialysis was 10.5 months (range, 10 days to 3 years).very patient (except patient 7) with the first episodeuring pregnancy was treated with plasma infusion orxchange. Six patients presented only 1 episode beforeialysis.

ransplantation

edian dialysis time before transplantation was 34 monthsrange, 7–48 months). None of them experienced bilateralephrectomy before transplantation. Two patients have aalcineurin inhibitor (CNI)-free regimen. The recurrenceas an early event, occurring before the end of the firstonth after transplantation in all except 1 patient. Every

Table 1. Patie

1 2 3 4

utation I None MCP HH

mmunosuppression Tacro Tacro CsA Siroime from transplantationto recurrence

1 month 14 days 6 days 14 da

osttransplantationepisodes

2 1 3

reatment of recurrence PE � FFP PE PE PE �

witch to sirolimus Yes No Yes —ong-term plasmatreatment

Yes No Yes Yes

raft failure No Yes No Noollow-up (months) 15 — 19 2

Tacro, tacrolimus; CsA, cyclosporine; Siro, sirolimus; CS, corticosteroids; PE, plaetween PE.

atient was initially treated by plasma exchange (PE) usingresh frozen plasma (FFP) as replacement fluid and may beonverted to a CNI-free regimen. Patient 7 received 3llografts, and had no recurrence in the third graft at 1 year.he is still treated with a CNI. Three patients have beenecondarily switched from PE to plasma infusion every 2eeks with no recurrence at 15, 19, or 24 months. Three outf 9 grafts were lost.

ISCUSSION

t is necessary to identify the mutation before transplanta-ion to evaluate the risk of recurrence for clear informationo patients. There is no recurrence when the MCP mutations present. Living donor transplantation cannot be recom-

ended for patients with CHF or IF mutation. The risk ofosing the graft is too high.

CNIs as triggering factors for recurrence are no longerebatable: Artz et al10 showed that early use of cyclosporine

ncreased the risk, but Quan et al11 denied it. In our study,patients treated with a CNI-free regimen had a recurrencend CNI did not seem to influence the recurrence.

PE is the most important treatment for the recurrence.nitially planned daily, it is decreased to every other day asoon as the platelet count becomes normal. The LDH ratioay be a useful marker to evaluate the response to PE.ong-term plasma therapy seems to be logical because theatients have a complement factor deficiency, but the dosend timing need to be clarified. Licht et al12 found completeactor H deficiency in an infant in whom non-Stx-HUSeveloped at 8 months of age. Treated with plasma infu-ion, the factor H half-life was measured at about 6 days.12

avin et al13 reported monozygotic twins with factor H-elated non-Stx-HUS. PE benefitted them versus infusionsf plasma.13 We need a larger cohort to evaluate theenefits of plasma therapy. In our cohort, 3 patients have noecurrence with long-term plasma infusion. Liver transplan-

aracteristics

Case

5 6 7a,b 8

None None MCP MCPH H

ITacro CsA CsA Tacro Siro26 days 4 days 7 months 60 months 21 days

1 1 1 1 1

PE PE CS PE PENo Yes No No —No No No No No

No No Yes, month 10 Yes, month 60 No12 36 — — 36

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HUS RECURRENCE AFTER RENAL TRANSPLANTATION 2585

ation was attempted in 3 patients: 2/3 patients died withormal plasma levels and no recurrence.14,15

In conclusion, non-Stx-HUS is associated with a geneticredisposition and triggering events, such as pregnancy,irus-like diseases, or sepsis. Genetic studies are necessaryefore transplantation to evaluate the risk of recurrence.he outcome of transplantation is excellent, in patientsnown to have an MCP mutation. For others, it is importanto inform them about the disease and the risk of recurrence.ntil now, there is no recommendation for the treatment of

hese recurrences. A benefit of long-term plasma therapy ismerging. International collaboration is urgently needed todentify safer ways of transplanting these challenging pa-ients.

EFERENCES

1. Frémeaux-Bacchi V, Bienaime F, Loirat C, et al: Microangio-athic et contrôle de la voie alterne du complément. Flammarionédecine-sciences. Acualités Néphrologiques de l’Hôpital Necker

7, 20062. Tonshoff B, Sammet A, Sanden I, et al: Outcome and

rognosis determinants in the haemolytic uremic syndrome ofhildren. Nephron 8:83, 1994

3. Gaprioli J, Noris M, Brioschi S, et al: Genetics of HUS: thempact of MCP, CFH and IF mutations on clinical presentation,esponse to treatment and outcome. Blood 18:1267, 2006

4. Kavanagh D, Goodship TH: Membrane cofactor protein andactor I: mutations and transplantation. Semin Thromb Hemost2:155, 20065. Dlott JS, Danielson CF, Blue-Hnidy DE, et al: Drug-induced

hrombotic thrombocytopenic purpura/haemolytic uremic syndrome:

concise review. Ther Apher Dial 8:102, 1994 1

6. George JN: The association of pregnancy with thrombotichrombocytopenic purpura-hemolytic uremic syndrome. Curr Opinematol 10:339, 20037. Dragon-Durey MA, Loirat C, Cloarec S, et al: Anti-factor H

ssociated with atypical haemolytic uremic syndrome. J Am Neph-ol 16:555, 2005

8. Remuzzi G, Ruggenti P, Codazzi D, et al: Combined kidneynd liver transplantation for familial hemolytic uremic syndrome.ancet 35:1671, 20029. Frémeaux-Bacchi V, Kemp EJ, Goodship T, et al: The

evelopment of atypical haemolytic-uraemic syndrome is influ-nced by susceptibility factors in factor H and membrane cofactorrotein: evidence from two independent cohorts. J Med Genet2:852, 200510. Artz MA, Steenbergen EJ, Hoistsma AJ, et al: Renal

ransplantation in patients with haemolytic uremic syndrome: highate of recurrence and increased incidence of acute rejections.ransplantation 76:821, 200311. Quan A, Sullivan FK, Alexander SR: Recurrence of hemo-

ytic uremic syndrome after renal transplantation in children: aeport of the North American Pediatric Renal Transplant Coop-rative Study. Transplantation 72:742, 2001

12. Licht C, Weyersberg A, Heinen S, et al: Successful plasmaherapy for atypical hemolytic uremic syndrome caused by factor Heficiency owing to a novel mutation in the complement cofactorrotein domain 15. Am J Kidney Dis 45:415, 200513. Davin JC, Olie KH, Verlaak R, et al: Complement factor-associated atypical haemolytic uremic syndrome in monozygote

wins: concordant presentation, discordant response to treatment.m J Kidney Dis 47:27, 200614. Remuzzi G, Ruggenti P, Collendan M, et al: Hemolytic

remic syndrome: a fatal outcome after kidney and liver transplan-ation performed to correct factor H gene mutation. Am J Trans-lant 5:1146, 200515. Cheong HL, Lee BS, Kang HG, et al: Attempted treatment

f factor H deficiency by liver transplantation. Pediatr Nephrol

9:454, 2004