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Nephrol Dial Transplant (2011) 0: 13

doi: 10.1093/ndt/gfr436

Exceptional Case

Three kidneys, two diseases, one antibody?

Nolwenn Lorcy1, Nathalie Rioux-Leclercq2, Marie-Laure Lombard3, Patrick Le Pogamp1 andCecile Vigneau1,4

1Service de Nephrologie, CHU Pontchaillou, Rennes, France, 2Service danatomopathologie, CHU Pontchaillou, Rennes, France,3Service de Nephrologie, AUB Saint-Malo, Saint-Malo, France and 4CNRS UMR 6061, IFR 140, Universite de Rennes 1, Rennes,

France

Correspondence and offprint requests to: Cecile Vigneau; E-mail: cecile.vigneau@chu-rennes.fr

AbstractAnti-factor H antibody has been recently described as respon-sible for thrombotic microangiopathies (TMA) as well as

membranoproliferative glomerulonephritis (MPGN). We re-port here, for the first time, the case of a woman with an anti-factor H antibody, who developed MPGN on native kidney,rapid recurrence on first graft, and TMA on second graftdespite immunosuppressive therapy and plasma exchanges.This case supports the hypothesis that MPGN and TMA areclosely linked by common pathogenic mechanisms and theneed for complete explorationof complementpathway includ-ing factor H activity and autoantibody in front of any MPGN.

Keywords: anti-factor H antibody; complement alternative pathway;membranoproliferative glomerulonephritis; thombotic microangiopathies

Background

Anti-factor H antibody has been recently described asbeing responsible for atypical haemolytic and uraemic syn-drome (aHUS) [1, 2] as well as being implicated in thedevelopment of membranoproliferative glomerulonephritis(MPGN) [3]. We report the case of a woman with an anti-factor H antibody, who developed MPGN on her nativekidney and first graft and aHUS on her second graft.

Case report

A 36-year-old female was hospitalized in December 1998 for

acute renal failure (ARF) (creatininaemia 370 lmol/L) withnephrotic syndrome (proteinuria >3 g/day, albuminaemia20 g/L) and haematuria in the second month of her third

pregnancy. Kidney biopsy showed MPGN with crescentformation on 40% of the glomeruli. Subendothelial depositsof C3 and few C1q and IgG were detected by immunofluor-escence. Serum complement (C3, C4, CH50) levels werenormal. A bilateral maxillary sinusitis was considered asthe cause of MPGN. Despite corticosteroids and cyclophos-

phamide (after therapeutic pregnancy interruption), she com-menced haemodialysis in April 1999.

The first renal transplantation occurred in January 2004.Immunosuppressive therapy consisted of basixilimab, cy-closporine and mycophenolate mofetil (MMF) and no cor-

ticosteroids. The creatininaemia at J5 was at 114 lmol/L.On the 26th day post-transplantation, she presented ARF

(creatininaemia 350 lmol/L) and nephritic syndrome (protei-nuria 2 g/day andmacroscopic haematuria).TheC3 fraction ofthe complement was reduced (430 mg/L normal 6601250mg/L), while the C4 fraction was normal (110 mg/L normal93380 mg/L) (Table 1). Kidney biopsy showed MPGNthough no crescents or acute rejection was observed. Immu-nofluorescence was not performed. Since this presentationsuggested early recurrence of initial disease, immunosuppres-sive treatment wasincreasedwith high dose of corticosteroids,four injections of rituximab 375 mg/m2, 12 plasma exchangesand cyclosporine to tacrolimus switch. Following this, crea-tininaemiadecreased to 106lmol/Land proteinuriadecreased

to 0.31 g/24 h.In December 2005, a kidney graft biopsy was performed

following creatininaemia increase (130 lmol/L) and neph-rotic syndrome (proteinuria 2.83 g/L, albuminaemia 30 g/Land haematuria).She was treated withtacrolimusand azathio-

prine (in substitution of MMF because of intestinal disorder).Biopsy showed recurrence of MPGN and few lesions result-ing from tacrolimus toxicity though no acute rejection. Com-

plement was normal. Irbesartan was started for proteinuriaand hypertension. Immunosuppressive regimen was notmodified. Proteinuria and microscopic haematuria persisted.Renal function progressively decreased. The final renal

biopsy in August 2007 reported lobular MPGN with suben-dothelial deposits of C3 and C1q, similar to initial glomeru-lonephritis (Figure1). Peritubularcapillary C4d wasnegative.She had to resume haemodialysis.

In November 2007, she received a second renal transplan-tation with thymoglobulins, corticosteroids, cyclosporineandsodic mycofenolate. Creatininaemia nadir was 84 lmol/L. InApril 2008, she was hospitalized for increased creatininaemia(159 lmol/L) and proteinuria (1 g/day). Graft biopsy didnot indicate any acute rejection but could not exclude earlyendocapillar nephritis. Peritubular capillary C4d was nega-tive. She was treated by high doses of corticosteroids,

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NDT Advance Access published August 3, 2011

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cyclophosphamide and 14 plasma exchanges without any ben-efit. In June 2008, creatininaemia was 258 lmol/L and protei-nuria 2 g/day. Haemoglobin was 12.6 g/dL, without red cellfragmentation, and platelets 295 000/mm3. Graft biopsyshowed chronic and acute thrombotic microangiopathies(TMA) and tubulointerstitial lesions without any inflammatoryinfiltrate (Figure 1). Immunofluorescence showed few suben-dothelial C1q deposits and vascular C3 deposits. Peritubularcapillary C4d was negative. Electron microscopy showed glo-merular basement membrane damage as well as cell fragmentsinside the capillaries confirming chronic TMA. She resumedhaemodialysis 8 months after the second transplantation.

Confrontedwiththisclinicalfeature,acompleteexplorationofcomplement system proteins was performed on recent and pre-vious sera (Table 1). Retrospectively, we found that, just beforethe second transplantation, there was an anti-factor H antibody,which disappeared in July 2008, after plasma exchanges.

Discussion

Factor H deficiency has been reported in several cases ofaHUS or MPGN. Anti-factor H antibody has been identified

as the culprit for aHUS [1, 2] but implicated in one caseof MPGN [3]. Several clinical cases have already describedthe occurrence of the two diseases in the same patient withfactor H deficiency [4] though none involved anti-factorH antibody.

The case described here is exceptional as this patient pre-sented an anti-factor H autoantibody and both diseases onthree different kidneys: MPGN on the native kidney, recur-ring in the same pattern on the first kidney graft, and aHUSon the second graft. We were able to identify anti-factor Hantibody on sera prior to and after the second kidney trans-

plantation. Unfortunately, we could not retrospectively as-

sess the antibody levels at the time of initial disease nor at thetime of first renal transplantation due to a lack of sera. How-ever, rapid recurrence on the first graft in the absence ofimmunosuppressive preparation therapy and the initial re-sponse to immunosuppressive intensification by plasma ex-changes and rituximab are main arguments for antibodies-linked pathogenesis. Usual triggers such as pregnancy orinfection were ruled out [5]. In the literature, two differentautoantibodies have been described, suggesting different

pathogenesis: the factor H C-terminal surface-binding regionwould be the target of aHUS autoantibodies, while

Table 1. Retrospective complement exploration on sera during first (January 2004) and second (the 16th November 2007)renal transplantationa

CH50 C3 Ag C4 Ag FB Ag FH Ag FI Ag Ac anti-FH C3Nef

70130%6601250mg/L

93380mg/L

30320mg/L 65140% 70130%

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miniautoantibodies targeting the factor H N-terminal reg-ulatory domain would be involved in MPGN [6]. The firstwould promote endothelial cell damage by affecting surfaceregulatory functions of factor H. The second scenario has

been described in only one patient [3] in which IgG lambda-chain dimers would affect factor H regulatory function in thefluid phase. Our case, however, suggests that the same auto-antibody will disturb factor H activity and according to theenvironment will result in either MPGN or aHUS.

This case underlines the need for complete exploration ofcomplement pathway, especially in relation to the major reg-ulator protein factor H when confronted with cases of bothMPGN and aHUS. In our case, plasma exchanges finallyallowed us to suppress anti-factor H antibody though thiswas performed too late to save the second transplant. How-ever, in theory, plasma exchanges and rituximab therapy [7]or even the use of eculizimab (humanized monoclonal anti-C5 antibody) [8], before and during the second transplanta-tion, might have blocked the development of aHUS on thesecond renal graft. Finally, this case supports the hypothesisthat MPGN and aHUS are closely linked by common patho-genic mechanisms, with a central role for the dysregulation ofthe complement alternative pathway [6].

Acknowledgements. Many thanks to Stuart Fraser for English corrections.

Conflict of interest statement. None declared.

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Received for publication: 9.5.11; Accepted in revised form: 27.6.11

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