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Table of Contents
Vol. 35, No. 5, 2012
Issue release date: May 2012
Free Access
Am J Nephrol 2012;35:394–400
(DOI:10.1159/000337954)

Clinical Grand Rounds: Atypical Hemolytic Uremic Syndrome

Hodgkins K.S. · Bobrowski A.E. · Lane J.C. · Langman C.B.
Division of Kidney Diseases, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, and Children’s Memorial Hospital, Chicago, Ill., USA
email Corresponding Author

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.


 Outline


 goto top of outline Key Words

  • Thrombotic microangiopathy
  • Acute kidney injury
  • Eculizumab
  • Alternative complement pathway
  • Complement factor H
  • Kidney transplant
  • Pediatrics

 goto top of outline Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease of uncontrolled alternative pathway complement activation [1]. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Eculizumab (Soliris®; Alexion Pharmaceuticals, Cheshire, Conn., USA) is a humanized monoclonal anti-C5 antibody approved by the FDA for use in aHUS on September 23, 2011 [2]. Eculizumab is the first FDA-approved treatment for aHUS, a disease associated with a mortality rate as high as 25% and a 50% rate of progression to end-stage kidney disease (ESKD) [3].

aHUS is a form of thrombotic microangiopathy (TMA). TMA-based syndromes (table 1) are microvascular occlusive disorders that result from aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes, ultimately leading to organ dysfunction [4]. A more specific definition of TMA is the activation of the endothelium due to various insults followed by a cascade of pathologic responses, including, among others, platelet and/or complement activation of the terminal (C5b-9) complex, microthrombi formation, thrombocytopenia, and microangiopathic hemolytic anemia [5]. aHUS occurs in both pediatric and adult populations; severe kidney impairment is a prominent but not an essential feature of the disease.

TAB01
Table 1. TMA-based diseases

The most common cause of TMA and HUS is associated with Shiga toxin-producing infections (now termed STEC-HUS), including Escherichia coli serotype 0157:H7 and Shigella dysenteriae serotype 1, accounting for more than 90% of HUS cases [5,6]. Recently, an outbreak in adults was linked to a unique serotype of E. coli, O4:H4 [7]. New evidence points to complement activation in STEC-HUS, too [8]. The term aHUS has been used to describe cases of TMA not caused by Shiga toxin-associated microorganisms and bacterial infections in general [6,9], and in which thrombotic thrombocytopenic purpura has been excluded in the differential diagnosis by demonstrating levels of ADAMTS13 activity above 5–10% [5].

aHUS is caused by uncontrolled complement activation through the alternative pathway. In 50–60% of cases of aHUS, a genetic mutation in complement regulatory proteins and/or autoantibodies against these proteins has been found as an explanation for constitutive complement activation [6]. However, this leaves another 40–50% of patients in whom a mutation or autoantibody cannot be demonstrated, as in our case, but for whom aHUS is the diagnosis. Thus, the ultimate diagnosis of aHUS does not require a formal demonstration of its underlying genetic cause. Less than 20% of aHUS cases are familial, with both autosomal dominant and autosomal recessive inheritance reported [6]. Autosomal recessive cases tend to present in childhood while autosomal dominant cases more typically present in adulthood and prognosis is poor regardless of inheritance [3]. Identification of a genetic mutation, while not required for an individual’s diagnosis or management of aHUS, may be helpful for identifying and monitoring disease carriers and for providing genetic counseling.

Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 was of high interest as a mechanism to ameliorate the disease [1]. An existing humanized monoclonal antibody, eculizumab, which had been FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria, has been evaluated for the treatment of aHUS. Eculizumab binds to human C5 with high affinity, blocking C5 cleavage to C5a and C5b [10]. This blockage prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, responsible for cell lysis [11].

 

goto top of outline Case Presentation

Our patient is an African-American female who presented in June 2000 at 1 year of age with azotemia, microangiopathic hemolytic anemia, thrombocytopenia, schistocytosis, cardiomyopathy, and severe hypertension. C3 levels were persistently low. She was diagnosed clinically with aHUS in the face of a normal ADAMTS13 activity (78%). She had no known family history of kidney disease or aHUS. Attempted treatment with therapeutic plasma exchange failed to result in reversal of the TMA and progressive CKD. She developed ESKD and was started on peritoneal dialysis in February 2001. The patient’s course on dialysis was complicated by hypertension requiring multiple hospitalizations and episodes of peritonitis including fungal peritonitis with an interval change to hemodialysis in August 2002.

She received a deceased donor kidney transplant on March 24, 2005. Immunosuppression was initiated with CellCept and Rapamune (using a prednisone-free protocol). Postoperatively, the patient’s serum creatinine decreased from 16 mg/dl to a nadir of 0.3 mg/dl; her serum creatinine subsequently stabilized between 0.5 and 0.6 mg/dl (fig. 1). She received three sessions of prophylactic plasmapheresis on days 1 through 4 after the transplant. Her platelet count abruptly decreased to 8,000/µl on postoperative day 4 and her hemoglobin declined gradually to 7.2 mg/dl by postoperative day 7, though there were no other signs of TMA and she responded to platelet and red blood cell transfusions, respectively. Transplant kidney biopsies on postoperative days 7 and 18 showed an eosinophilic lymphocytic infiltrate that lessened between the biopsies, but neither biopsy demonstrated any evidence of TMA. C3 at the time of transplant was reduced, at 38.6 mg/dl, but normalized by 1 month after transplantation. Plasma complement factor H (CFH) level sent at the time of transplant was normal at 310 µg/ml.

FIG01
Fig. 1. Time course of selected parameters in the reported patient. The figure demonstrates the actual levels of serum creatinine (a), hemoglobin (b), and platelet count (c) for the patient from 2002 and through the latest data set in 2012. The first arrow represents the kidney transplant in 2005, and the second arrow represents the recurrence and administration of eculizumab.

The patient remained well for over 4 years following transplantation. Her nutritional status improved significantly as did her statural growth.

On September 4, 2009, she presented with a recurrence of aHUS at 10 years of age. She reported several days of nausea, vomiting, diarrhea, and fatigue prior to presentation to the hospital in oliguric acute kidney failure. Her initial laboratory studies were notable for a blood urea nitrogen of 117 mg/dl, serum creatinine of 8.5 mg/dl, platelet count of 35,000/µl, hemoglobin of 9.4 g/dl, peripheral blood smear positive for 3+ schistocytes, and C3 of 67.8 mg/dl. She received one session of plasma exchange as well as two sessions of hemodialysis through a temporary catheter. She required several blood transfusions coordinated with the dialysis sessions. A kidney ultrasound on admission showed increased size and echotexture of the transplanted kidney and elevated resistive indices within the transplant kidney. An evaluation for the cause of aHUS was completed and was unrevealing (table 2). Plasma concentrations of CFH, complement factor I (CFI), and complement factor B (CFB) were normal; expression of membrane cofactor protein (MCP) on leukocytes was normal, no anti-factor H antibodies were found, and no mutations in the genes for CFH, CFI, or MCP were identified. Due to her presentation with aHUS recurrence and acute failure of the transplant graft, and given her previous and current failed response to plasma exchange, an intravenous dose of eculizumab 900 mg was administered on September 6, 2009. The patient had received the meningococcal vaccine 1 day beforehand, in anticipation of initiating therapy with eculizumab, and she was started on penicillin prophylaxis.

TAB02
Table 2. Evaluation of complement, complement regulatory proteins, and complement regulatory genes in the patient

After the first dose of eculizumab, the oliguria reversed within hours, and she did not require subsequent hemodialysis or undergo further plasma exchange. Her platelet count remained between 30,000 and 40,000/µl but normalized by 1 week after the first dose of eculizumab. Her serum creatinine steadily trended downward until it stabilized at around 0.6 mg/dl 1 month after initiation of eculizumab. She received eculizumab infusions of 900 mg weekly for 4 weeks (days 0, 6, 12, and 19) after which she has been maintained on 1,200 mg every 2 weeks. 28 months after her presentation with recurrence of aHUS, the patient has stable kidney function on eculizumab and no further indication of recurrence of aHUS. Selected laboratory measurements for the patient from 2002 through the latest data of 2012 are shown in figure 1.

 

goto top of outline Summary of Case Reports in the Literature for Eculizumab Therapy in aHUS (table 3)

Including our patient, to date we found 21 cases reported in the literature of aHUS treated with eculizumab (table 3) [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. Patients range in age from 1 month to 50 years at the time of treatment with eculizumab. 10 cases involved aHUS occurrence in native kidneys, 8 cases involved aHUS recurrence in a transplanted kidney, and 3 cases involved prophylactic treatment after kidney transplant. In 1 case of aHUS diagnosed in an adolescent male, a single dose of eculizumab led to resolution of hematologic disease markers and transient improvement in kidney function (serum creatinine decreased from 7.8 to 5.2 mg/dl). aHUS recurred and, despite three more doses of eculizumab, the patient progressed to ESKD and eculizumab was discontinued [14]. A second case reports an adult with aHUS recurrence after a third kidney transplant who developed ESKD despite treatment with eculizumab, although the authors report that kidney function had already declined significantly by the time treatment was attempted [28]. In a third case, a female child with aHUS with ESKD for 5 months was treated with eculizumab due to the development of distal extremity ischemia and gangrene; eculizumab halted the progression of ischemia but did not reverse her ESKD [30]. The remaining 18 cases report complete or partial recovery of kidney function with no need for subsequent renal replacement therapy. The longest period of remission from literature case reports appears to be our patient, who has been treated with eculizumab for 28 months with no evidence of aHUS recurrence.

TAB03
Table 3. Description of case reports of eculizumab therapy for aHUS

In addition to the above case reports, two prospective clinical trials have been conducted to evaluate the safety and efficacy of eculizumab use in aHUS. These studies are not yet published, but their preliminary results, as reported by the FDA, are promising [34]. In one study, 17 patients with aHUS resistant to or intolerant of plasma therapy were treated with eculizumab for a minimum of 26 weeks. The median age was 28 years (range 17–68). These patients showed decreased signs of TMA activity including improvement in platelet counts and eGFR. In a second study, 20 patients with aHUS undergoing chronic plasma exchange or plasma infusion therapy were treated with eculizumab for a minimum of 26 weeks. The median age was 28 years (range 13–63). These patients also showed decreased signs of TMA activity with maintenance of platelet counts and eGFR off plasma therapy.

 

goto top of outline Discussion

aHUS is a challenging disease process to manage with a relatively poor prognosis, as many patients develop ESKD or die within the first year of diagnosis [6,9]. Mutations have been described in CFH, CFI, MCP, CFB, C3, and thrombomodulin [6,9]. In addition, autoantibodies to CFH can cause aHUS and are commonly associated with deletions of CFH-related proteins CFHR1 and CFHR3 [6].

Mutations in either CFH, CFI, MCP, thrombomodulin, and/or CFHR1/3 with autoantibodies to CFH are associated with loss of regulatory control of the alternative pathway of the complement cascade. Mutations in CFB and C3 are gain-of-function mutations leading to complement overactivation. Loss-of-function mutations in CFH are most common and have the worst prognosis based on registry data, with 60–70% of patients progressing to ESKD or death within a year of disease onset [9]. The prognosis for patients with CFI mutations appears slightly better, followed by patients with MCP mutations, of whom 20% require renal replacement therapy [9]. However, patients without demonstrated mutations have similar dire outcomes, raising the idea that the presence or absence of a given mutation may have limited prognostic value, except for the MCP mutation that may not recur after kidney transplantation.

Until recently, there have been no specific therapies for aHUS. Therapeutic plasma exchange or plasma infusion has generally been the initial approach to disease management, although there are no randomized controlled trials of plasma therapy in aHUS to establish its effectiveness [9]. Plasma exchange may only be beneficial for aHUS in the short term, since long-term kidney outcomes are uniformly poor with a varying short-term response in hematological parameters. Plasma exchange would not be expected to be effective for patients with mutations in MCP, a transmembrane protein. Patients who do respond to plasma exchange frequently become plasma dependent, requiring long-term therapy to maintain remission [9].

Kidney transplantation can be successful for patients with MCP mutations. MCP is cell membrane bound and highly expressed in the kidney; kidney transplant, then, would be expected to halt the disease process [6]. Other mutations or unknown ones have led to high relapse rates of aHUS in the transplanted kidney. CFH and CFI mutations have been studied more extensively. These circulating proteins are primarily synthesized in the liver. Not unexpectedly, aHUS recurs in 80% of patients with CFH mutations and 90% of patients with CFI mutations after an isolated kidney transplant [9]. Living-donor kidney transplantation is contraindicated in patients with aHUS due to mutations in CFH, CFI, C3, and CFB without other therapies concomitantly [35].

Combined liver-kidney transplantation has been attempted for patients with CFH and CFI mutations to address the abnormal protein synthesis in the liver and its downstream effect on the kidney. Simultaneous liver-kidney transplantation with prophylactic use of plasma therapy has been successful in patients with CFH mutations [11]. However, liver-kidney transplantation is associated with a higher mortality rate than kidney transplantation alone [20]. In the absence of a noted mutation, comprising a sizable fraction of patients with aHUS, liver-kidney transplantation should be avoided [36].

A pathophysiologic-based treatment in aHUS is available now with eculizumab, through inhibiting the formation of the common terminal complement complex (C5b-9). Its recent approval for aHUS in adults and in children represents its first approved use for pediatric patients [2]. Due to the impaired capacity for opsonization and clearance of encapsulated organisms, meningococcal disease is a risk with the use of eculizumab and has been reported among patients given eculizumab for paroxysmal nocturnal hemoglobinuria [10]. Patients must receive the meningococcal vaccine prior to treatment initiation.

Although recovery of kidney function has been variable with eculizumab, most case reports have demonstrated resolution of hematologic disease, and no mortality related to eculizumab use has been described to date [20]. Early initiation of eculizumab, prior to significant kidney injury, has been associated with improved renal outcomes [20]. Our patient, however, who presented in acute kidney failure, recovered complete transplant graft function with eculizumab.

Further, eculizumab holds potential for prevention as well as treatment of aHUS. Reports of preemptive use of eculizumab in kidney transplant recipients who suffer from aHUS show promising results with sustained aHUS remission after transplantation [31,32,33].

 

goto top of outline Conclusion

Eculizumab, recently approved for aHUS, represents the most promising new approach to the treatment of a complex, heterogeneous disease with a high rate of morbidity and mortality. Data from ongoing clinical trials of eculizumab administration in aHUS will likely provide further needed data on its effectiveness and safety. Our patient with aHUS and the absence of a genetic mutation had her transplant kidney function restored to normal and the TMA process halted now after over 2 years of eculizumab therapy.

 

goto top of outline Disclosure Statement

The authors have no conflicts of interest to disclose.


 goto top of outline References
  1. Kavanagh D, Richards A, Atkinson J: Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 2008;59:293–309.
  2. FDA News Release Sept 23, 2011. http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm272990.htm.
  3. Noris M, Remuzzi G: Hemolytic uremic syndrome. J Am Soc Nephrol 2005;16:1035–1050.
  4. Moake JL: Thrombotic microangiopathies. N Engl J Med 2002;347:589–590.
  5. Coppo P, Veyradier A: Thrombotic microangiopathies: towards a pathophysiology-based classification. Cardiovasc Hematol Disord Drug Targets 2009;9:36–50.
  6. Noris M, Remuzzi G: Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:1676–1687.
  7. Lapeyraque AL, Malina M, Frémeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P, Schaefer F: Eculizumab in severe Shiga toxin-associated HUS. N Engl J Med 2011;364:2561–2563.
  8. Stahl A, Sartz L, Karpman D: Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 2011;117:5503–5513.

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  10. Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R: FDA report: eculizumab (Soliris®) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 2008;13:993–1000.
  11. De S, Waters AM, Segal AO, Trautmann A, Harvey EA, Licht C: Severe atypical HUS caused by CFH S1191L – case presentation and review of treatment options. Pediatr Nephrol 2010;25:97–104.

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  12. Nürnberger J, Philipp T, Witzke O, Saez AO, Vester U, Baba HA, Kribben A, Zimmerhackl LB, Janecke AR, Nagel M, Kirschfink M: Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:542–544.
  13. Gruppo RA, Rother RP: Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:544–546.
  14. Mache CJ, Acham-Roschitz B, Frémeaux-Bacchi V, Kirschfink M, Zipfel PF, Roedl S, Vester U, Ring E: Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2009;4:1312–1316.
  15. Châtelet V, Frémeaux-Bacchi V, Lobbedez T, Ficheux M, Hurault de Ligney B: Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant 2009;9:2644–2645.
  16. Châtelet V, Lobbedez T, Frémeaux-Bacchi V, Ficheux M, Ryckelynck JP, Hurault de Ligney B: Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant Proc 2010;42:4353–4355.
  17. Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T: Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis 2010;55:708–711.

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  18. Larrea C, Cofan F, Oppenheimer F, Campistol JM, Escolar G, Lozano M: Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation 2010;85:976–977.
  19. Prescott HC, Wu HM, Cataland SR, Baiocchi RA: Eculizumab therapy in an adult with plasma exchange-refractory atypical hemolytic uremic syndrome. Am J Hematol 2010;5:976–977.

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  20. Al-Akash SI, Almond PS, Savell VH, Gharaybeh SI, Hogue C: Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr Nephrol 2011;26:613–619.

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  21. Lapeyraque AL, Frémeaux-Bacchi V, Robitaille P: Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome. Pediatr Nephrol 2011;26:621–624.

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  22. Tschumi S, Gugger M, Bucher BS, Riedl M, Simonetti GD: Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr Nephrol 2011;26:2085–2088.

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  23. Ohanian M, Cable C, Halka K: Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome. Clin Pharmacol 2011;3:5–12.
  24. Ohanian M, Cable C, Halka K: Reduced dose maintenance eculizumab in atypical hemolytic uremic syndrome (aHUS): an update on a previous case report. Clin Pharmacol 2011;3:45–50.
  25. Legault DJ, Boelkins MR: Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with terminal complement inhibitor eculizumab. Annual Meeting and Exposition of 51st American Society of Hematology, New Orleans 2009.
  26. Fremont OT, Gordon CA, Hand MM: Eculizumab treatment for aHUS in a child with positive family history. Renal Week 2009. 42nd Annual Meeting of the American Society of Nephrology, San Diego 2009.
  27. Häffner K, Hofer J, Zimmerhackl LB, Pohl M: Effective eculizumab therapy of familiar atypical HUS in a 4-year-old patient. 2nd International Conference HUS-MPGN-PNH: Current Diagnosis and Therapy of Thrombotic Microangiopathies: Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis and Paroxysmal Nocturnal Hemoglobinuria, Innsbruck 2010.
  28. Loos S, Lehnhardt A, van Husenl M, Klaassen I, Möller K, Kemper MJ: Rescue therapy with eculizumab fails to prevent graft loss in a renal transplant patient with factor I mutation: chronic rejection or recurrence? 2nd International Conference HUS-MPGN-PNH: Current Diagnosis and Therapy of Thrombotic Microangiopathies: Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis and Paroxysmal Nocturnal Hemoglobinuria, Innsbruck 2010.
  29. Aguirre M, Arrizabalaga B, Abarrategui C, Morteruel E, López-Trascasa M, Areses R, Quintela MJ, Ariceta G: Eculizumab pharmacokinetics and efficacy in a newborn with aHUS: an option in no-candidates to plasmaexchange. 44th Annual Scientific Meeting of the European Society for Paediatric Nephrology, Cavtat-Dubrovnik 2011.
  30. Malina M, Gulati A, Majid MA, Bagga A, Schafer F: Peripheral gangrenes in children with atypical hemolytic uremic syndrome. 44th Annual Scientific Meeting of the European Society for Paediatric Nephrology, Cavtat-Dubrovnik 2011.
  31. Zimmerhackl LB, Hofer J, Cortina G, Mark W, Würzner R, Jungraithmayr TC: Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 2010;362:1746–1748.

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  32. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S: Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol 2011;26:1325–1329.

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  33. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, Thomas C, Smith R, Brophy P: Preemptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2011;6:1488–1494.
  34. FDA Drug Product Label for Soliris (BLA) 125166, approved Sept 23, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2011/125166s172lbl.pdf.
  35. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C: New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011;7:23–35.

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  36. Saland JM, Ruggenenti P, Remuzzi G: Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 2009;20:940–949.

 goto top of outline Author Contacts

Craig B. Langman, MD
Division of Kidney Diseases, Children’s Memorial Hospital
2300 Children’s Plaza #37
Chicago, IL 60614 (USA)
Tel. +1 312 227 6160, E-Mail c-langman@northwestern.edu


 goto top of outline Article Information

Published online: April 18, 2012
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 3, Number of References : 36


 goto top of outline Publication Details

American Journal of Nephrology

Vol. 35, No. 5, Year 2012 (Cover Date: May 2012)

Journal Editor: Bakris G. (Chicago, Ill.)
ISSN: 0250-8095 (Print), eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.



 goto top of outline Author Contacts

Craig B. Langman, MD
Division of Kidney Diseases, Children’s Memorial Hospital
2300 Children’s Plaza #37
Chicago, IL 60614 (USA)
Tel. +1 312 227 6160, E-Mail c-langman@northwestern.edu


 goto top of outline Article Information

Published online: April 18, 2012
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 3, Number of References : 36


 goto top of outline Publication Details

American Journal of Nephrology

Vol. 35, No. 5, Year 2012 (Cover Date: May 2012)

Journal Editor: Bakris G. (Chicago, Ill.)
ISSN: 0250-8095 (Print), eISSN: 1421-9670 (Online)

For additional information: http://www.karger.com/AJN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Kavanagh D, Richards A, Atkinson J: Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 2008;59:293–309.
  2. FDA News Release Sept 23, 2011. http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm272990.htm.
  3. Noris M, Remuzzi G: Hemolytic uremic syndrome. J Am Soc Nephrol 2005;16:1035–1050.
  4. Moake JL: Thrombotic microangiopathies. N Engl J Med 2002;347:589–590.
  5. Coppo P, Veyradier A: Thrombotic microangiopathies: towards a pathophysiology-based classification. Cardiovasc Hematol Disord Drug Targets 2009;9:36–50.
  6. Noris M, Remuzzi G: Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:1676–1687.
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