Correspondence
Eculizumab for Atypical Hemolytic–Uremic Syndrome
N Engl J Med 2009; 360:542-544January 29, 2009
- Article
To the Editor:
Atypical hemolytic–uremic syndrome is a disease of uncontrolled complement activation associated with a high mortality rate, and most cases progress to end-stage renal disease.1 About 50% of patients with this syndrome carry mutations in genes encoding complement proteins.2 Complement inhibition has been suggested for the treatment of atypical hemolytic–uremic syndrome,3 but currently no data on this treatment option are available. We report on a case of atypical hemolytic–uremic syndrome that was successfully treated with eculizumab, a humanized monoclonal antibody that blocks complement activity by cleavage of the complement protein C5, thereby preventing the generation of the inflammatory peptide C5a and the cytotoxic membrane-attack complex, C5b-9. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria.4
End-stage renal disease due to atypical hemolytic–uremic syndrome developed in a woman at 25 years of age. At 30 years of age, after 5 years of undergoing dialysis, she received a cadaveric renal transplant. Five weeks after transplantation, atypical hemolytic–uremic syndrome recurred and led to the loss of transplant function despite 18 plasma exchanges. The patient underwent dialysis for another 7 years until she received a second cadaveric transplant at 37 years of age. Six weeks after the second transplantation, atypical hemolytic–uremic syndrome again recurred. The onset of atypical hemolytic–uremic syndrome may have been associated with the additional use of tacrolimus, which the patient received after three episodes of cellular rejection developed.
Genetic analysis revealed a novel heterozygous missense mutation in exon 10, codon 475 (Y475S), of the gene encoding complement factor H. This missense mutation leads to a substitution of a serine by a tyrosine that belongs to the highly conserved residues of the factor H protein sequence; this sequence may be responsible for the observed reduction in the plasma level of factor H to 180 μg per milliliter (normal range, 284 to 528). Furthermore, we detected a homozygous deletion comprising at least exon 2 within the CFHR1 gene.5 No mutation was found in the MCP or CFI genes. Transplant biopsy specimens showed thrombotic microangiopathy (Figure 1A through 1CFigure 1
Pathological Findings and Laboratory Values.).Since recurrent atypical hemolytic–uremic syndrome leads to graft loss in more than 90% of patients, we decided to administer a single dose of 600 mg of eculizumab after renal function worsened in this patient despite four plasma exchanges. After the administration of eculizumab, the total complement activity was completely blocked, the hemolysis resolved, and the transplant function recovered (Figure 1D). The patient's renal graft function has been stable for 8 months.
These findings show the positive effect of complement inhibition on the course of atypical hemolytic–uremic syndrome in our patient and, in our view, the use of eculizumab in atypical hemolytic–uremic syndrome warrants further investigation.
Jens Nürnberger, M.D.
Thomas Philipp, M.D.
Oliver Witzke, M.D.
Anabelle Opazo Saez, Ph.D.
Udo Vester, M.D.
Hideo Andreas Baba, M.D.
Andreas Kribben, M.D.
University Duisburg–Essen, 45122 Essen, Germany
jens.nuernberger@uni-due. de Lothar Bernd Zimmerhackl, M.D., Ph.D.
Andreas R. Janecke, M.D.
Innsbruck Medical University, A-6020 Innsbruck, AustriaMato Nagel, M.D.
Center for Nephrology and Metabolic Disorders, 02943 Weisswasser, GermanyMichael Kirschfink, D.V.M., M.D.
University of Heidelberg, 69120 Heidelberg, GermanyDr. Nürnberger reports receiving lecture fees from Novartis and Roche; Dr. Witzke, consulting and lecture fees from Novartis and Roche and lecture fees from Astellas and Wyeth; Dr. Zimmerhackl, grant support from Baxter and Novartis and lecture fees from Novartis and Roche; and Dr. Kribben, consulting and lecture fees from Novartis and Roche and lecture fees from Astellas. No other potential conflict of interest relevant to this letter was reported.
This article (10.1056/NEJMc0808527) was last updated on June 3, 2009, at NEJM.org.
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