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Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene

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Abstract

Background

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available.

Case-diagnosis/treatment

We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis.

Conclusion

Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene.

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Abbreviations

aHUS:

Atypical hemolytic uremic syndrome

C3:

Complement component 3

C5:

Complement component 5

FH:

Complement factor H

FI:

Complement factor I

FB:

Complement factor B

MCP:

Membrane cofactor protein

CFHR1:

CFH-related protein 1

SCR:

Short consensus repeat domain

TMA:

Thrombotic microangiopathy

BP:

Blood pressure

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Acknowledgments

We thank Dr. Agustin Tortajada for his contribution to this work.

SRdeC is supported by the Spanish Ministerio de Economía y Competitividad [Ministry of Finance and Competition] (SAF2011-26583), the Comunidad de Madrid [Autonomous Region of Madrid] (S2010/BMD-2316), the European Union FP7 (EURENOMICS) and the Fundación Renal Iñigo Alvarez de Toledo.

PSC is supported by the Spanish Ministerio de Economía y Competitividad (PS09-00268), and the Comunidad de Madrid (S2010/BMD-2316).

MLT is supported by the Spanish Ministerio de Economía y Competitividad (PS09-00122), and the Comunidad de Madrid (S2010/BMD-2316).

Disclosures

SRdeC has received fees from Alexion Pharmaceuticals for invited lectures. This interaction has not influenced the results and interpretations in this manuscript. All other authors of this manuscript have no conflicts of interest to disclose, including sponsorship or funding arrangements relating to this research.

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Authors and Affiliations

  1. Pediatric Nephrology Unit, Hospital La Fe, Bulevar sur s/n, 46026, Valencia, Spain

    Elena Román-Ortiz & Santiago Mendizabal Oteiza

  2. Centro de Investigaciones Biológicas—Consejo Superior de Investigaciones Científicas (CIB-CSIC) [Centre for Biological Research—Spanish Scientific Research Council] and CIBER de Enfermedades Raras (CIBERER) [Centre for Biomedical Network Research on Rare Diseases], Madrid, Spain

    Sheila Pinto & Santiago Rodríguez de Cordoba

  3. Immunology Unit, CIBERER Research Unit, Hospital Universitario La Paz, Madrid, Spain

    Margarita López-Trascasa & Pilar Sánchez-Corral

Authors
  1. Elena Román-Ortiz
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  2. Santiago Mendizabal Oteiza
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  3. Sheila Pinto
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  4. Margarita López-Trascasa
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  5. Pilar Sánchez-Corral
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  6. Santiago Rodríguez de Cordoba
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Corresponding author

Correspondence to Elena Román-Ortiz.

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Supplementary Fig. 1

Summary of the genetic data in the patient (H142) and their relatives. a The H142 pedigree. The members of the pedigree are identified, and for the affected individual H142 and the other carriers of the CFH/CFHR1 hybrid gene, the levels of total plasma FH and normal FH (402Y) are indicated. Notice that H142 also inherits an aHUS risk allele from his father. b Summary of the MLPA data. Graphs illustrate the number of copies of different exons in the CFH-CFHR1 region. Notice that levels of CFH exon 23, but not CFHR1 exon 6, are decreased in the patient and three of their relatives, indicating they are carriers of a CFH/CFHR1 hybrid gene. c Diagram of the FH molecule resulting from the CFH/CHFR1 hybrid gene. The circles indicate each of the 20 SCR domain units that compose FH. The locations of the four amino acid differences found are indicated. Notice that the two changes in SCRs 15 and 16 are rare polymorphisms with no functional relevance (see [10]). (PNG 328 kb)

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Román-Ortiz, E., Mendizabal Oteiza, S., Pinto, S. et al. Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene. Pediatr Nephrol 29, 149–153 (2014). https://doi.org/10.1007/s00467-013-2591-8

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  • DOI: https://doi.org/10.1007/s00467-013-2591-8

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