NDT Advance Access originally published online on March 8, 2008
Nephrology Dialysis Transplantation 2008 23(6):2088-2090; doi:10.1093/ndt/gfn063
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Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome
1 Pediatric Nephrology, Hôpital Robert Debré 2 Department of Immunology, Hôpital Européen Georges Pompidou 3 Department of Pathology, Hôpital Robert Debré 4 Department of Immunology, Hôpital Européen Georges Pompidou 5 Pediatric Nephrology, Hôpital Robert Debré, Paris, France
Correspondence and offprint requests to: Theresa Kwon, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, 48 boulevard Serurier 75019, Paris, France. Tel: +33-0140034006; Fax: +33-0140032468; Email: theresa.kwon{at}rdb.aphp.fr
Keywords: anti-CFH autoantibodies; atypical HUS; plasma exchanges; renal transplantation; rituximab
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Introduction |
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Atypical haemolytic uraemic syndrome (aHUS) is known to be associated with mutations involving regulatory proteins of the complement alternative pathway, including factor H (CFH), factor I and MCP, in
50% of patients [1,2]. Eight patients have been reported with an acquired CFH deficiency because of the presence of anti-CFH autoantibodies [3,4]. These autoantibodies have been shown to influence the binding of CFH to the C3bBb convertase, thereby compromising CFH activity in vivo [3,4]. We now report the pre-transplant therapeutic management and post-transplant course of one of these patients. |
Case report |
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A previously healthy 10-year-old girl (patient 1 in reference [4]) was seen after 4 days of bloody diarrhoea. On examination, the patient had an oral temperature of 38.2°C, a blood pressure of 140/90 mmHg and generalized oedema. Laboratory evaluation demonstrated anaemia (haemoglobin 5.1 g/dl), thrombocytopaenia (51 000 platelets/mm3), elevated serum creatinine concentration (creatinine 1218 µmol/l) and proteinuria (9 g/l). The urinary sediment contained more than one million red cells/mm3. Erythrocyte fragments were seen on a blood smear (schistocytosis 13%). Search for Shiga toxin-producing Escherichia coli (STEC) using PCR in faecal sample and detection of serum antibodies against STEC O serotypes were negative [5]. Plasma C3 level was decreased (460 mg/l; normal range 660– 1250 mg/l) as well as factor B (68 mg/l; normal range 90–320 mg/l) while C4 was normal (130 mg/l; normal range 93–380 mg/l) suggesting the alternative complement pathway activation. Antigenic CFH was normal (91%; normal range 65–140%). ADAMTS13 activity [6] and plasma homocystein level were in the normal range. During the next month, the child required haemodialysis for persistent anuria, and experienced extra renal complications such as cytolytic hepatitis, pancreatitis, pericarditis and recurrent pseudoseptic episodes. Diuresis was re-established after 1 month and dialysis could be transiently discontinued. Nevertheless, the child developed end-stage renal failure within 2 months after onset. Bilateral nephrectomy for severe hypertension was performed at Month 7 after onset. Histology showed severe glomerular and arteriolar microangiopathy lesions without deposits on immunofluorescence staining. Further investigation of the complement system showed a fluctuating C3 level while CFH level remained normal. CFH activity was below 10% (normal range 70–130%) and anti-CFH autoantibodies were retrospectively detected [4] at a rate of 2323 arbitrary units/ml in serum samples collected at first admission by using an ELISA method as previously described. Briefly, diluted plasma samples were incubated in ELISA plates coated with purified human FH. After washing, the antigen–IgG complexes were revealed by using a labelled anti-human IgG antibody. Optical density above the mean +2 standard deviations of those obtained in 50 individual healthy donors plasma was considered as positive. Titres of positive samples were expressed as arbitrary units per ml (AU/ml) calculated with a reference-positive plasma given an arbitrary titre of 1000 AU/ml. Patient samples were then prospectively tested. The first one was collected before any treatment comprising any infusion of blood-derived products, indicating that these antibodies were not developed in a context of an alloimmunization.
Gene sequencing of CFH did not find any mutation. Low C3 and high anti-CFH IgG (824 AU/ml) levels persisted after 18 months of haemodialysis (Figure 1). In order to clear off the anti-CFH antibodies, as preparation to renal transplantation, prednisone (1.5 mg/kgBW/day) and azathioprine (1 mg/kgBW/day) treatment was started by Month 20 but failed to decrease anti-CFH IgG levels after 3 months (1000 AU/ml). By Month 23, a series of plasma exchanges (PE) with fresh frozen plasma (FFP) (6 sessions over 15 days; 50 ml/kg/session) allowed to normalize the C3 plasma level while anti-CFH IgG became undetectable. However, anti-CFH IgG rose up again to 700 AU/ml 1 month following PE cessation, and expectedly decreased to low levels (200 AU/ml) after an additional run of seven PE. Rituximab (375 mg/m2/week x 4 weeks) during Month 27 led to a complete B cell depletion and appeared to maintain a sustained low level of anti-CFH IgG and a normal C3 level during the next 4 months. A renal transplantation from a cadaveric donor was then performed by Month 32. A PE program (50 ml/kg/session with FFP for substitution) was started immediately before surgery, continued on a daily basis during the first week and then gradually tapered off within 4 months. The immunosuppressive regimen included basiliximab, prednisone, cyclosporine (switched to tacrolimus at Month 18 post-transplantation due to severe hypertrichosis) and mycophenolate mofetil. During the 2 years of follow-up, HUS did not recur. Graft biopsy at Month 6 post-transplantation neither showed thrombotic microangiopathy nor rejection, creatinine level remained normal, and anti-CFH IgG was barely detectable while plasma C3 levels increased up to 1460 mg/l.
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Discussion |
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TopIntroductionCase reportDiscussionReferences |
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In two studies, an association between aHUS and anti-CFH antibodies was reported in 6 [4] to 10% [3] of the study population. We report the first patient with anti-CFH antibody-associated HUS who underwent renal transplantation. In preparation for renal transplantation, PE allowed a transient decrease of anti-CFH antibodies circulating level. Therefore, rituximab was added, which appeared to maintain a sustained low level of autoantibodies during the subsequent 4 months, allowing for a renal transplantation with a limited risk of recurrence. At last follow-up, 24 months after renal transplantation, graft function is normal and no anti-CFH antibodies have re-emerged. As a matter of fact, PE treatment with rituximab, had it been undertaken at disease onset, would probably have slowed down renal destruction. This case report points out the need for early detection of anti-CFH antibodies, particularly in patients with uncertain diagnosis of post-diarrhoeal HUS, and those with decreased C3, in order to undertake appropriate immunosuppressive therapy. Most probably, patients with anti-CFH antibodies have an increased risk of post-transplant HUS recurrence. Therefore, close and sustained monitoring of antibody level is necessary. As far as we know, no other patient with anti-CFH antibody-associated HUS has been transplanted. We thereby report the treatment that apparently allowed for a successful transplantation, and at last follow up, without an HUS recurrence. In conclusion, close monitoring of the anti-CFH antibodies and intensive immunosuppressive treatment, including PE and rituximab, allowed a safe transplantation procedure and should be considered for patients with anti-CFH autoantibody-associated atypical HUS, as early as possible.
Conflict of interest statement. None declared.
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References |
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TopIntroductionCase reportDiscussionReferences |
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- Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, et al. The interactive factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and factor I mutations with structural models. Hum Mutat (2007) 28:222–234.[CrossRef][Web of Science][Medline]
- Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood (2006) 108:1267–1279.
[Abstract/Free Full Text] - Jozsi M, Strobel S, Dahse HM, et al. Anti-factor H autoantibodies block H-terminal recognition function of factor H in hemolytic uremic syndrome. Blood (2007) 110:1516–1518.
[Abstract/Free Full Text] - Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol (2005) 16:555–563.
[Abstract/Free Full Text] - Decludt B, Bouvet P, Mariani-Kurkdjian P, et al. Haemolytic uraemic syndrome and Shiga toxin-producing Escherichia coli infection in children in France. The Societe de Nephrologie Pediatrique. Epidemiol Infect (2000) 124:215–220.[CrossRef][Medline]
- Ferrari S, Scheiflinger F, Rieger M, et al. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood (2007) 109:2815–2822.
[Abstract/Free Full Text]
Accepted in revised form: 25. 1.08
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