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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2017  |  Volume : 28  |  Issue : 2  |  Page : 388-391
Eculizumab experience in an adult patient with atypical hemolytic uremic syndrome


1 Department of Nephrology, Antalya Training and Research Hospital, Antalya, Turkey
2 Department of Hematology, Antalya Training and Research Hospital, Antalya, Turkey

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Date of Web Publication23-Mar-2017
 

   Abstract 

Atypical hemolytic-uremic syndrome is a disease characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal failure. In this study, we present a case of a patient with atypical hemolytic-uremic syndrome treated successfully with eculizumab. A 20-year-old female was admitted with clinical signs of atypical hemolytic syndrome. The laboratory findings were as follows: hemoglobin 9.2 g/dL, platelet count 18 × 103/μL, creatinine 4.69 mg/dL, schistocytes were in peripheral blood smear, lactate dehydrogenase 2080 U/L, and emergency plasmapheresis procedure with fresh frozen plasma were initiated. The patient was anuric within 12 h of her admittance. ADAMTS13 activity was normal. Her mother’s cousin developed acute rejection immediately after receiving a renal transplant and died two months later. As she did not respond to the treatment and considering her family history, eculizumab was initiated which resulted in platelet counts starting to rise on day 5, and the patient no longer needed dialysis after 22 days.

How to cite this article:
Sari F, Inci A, Karakus V, Yilmaz B, Sarikaya M, Olmaz R, Kurtoglu E. Eculizumab experience in an adult patient with atypical hemolytic uremic syndrome. Saudi J Kidney Dis Transpl 2017;28:388-91

How to cite this URL:
Sari F, Inci A, Karakus V, Yilmaz B, Sarikaya M, Olmaz R, Kurtoglu E. Eculizumab experience in an adult patient with atypical hemolytic uremic syndrome. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Jun 27];28:388-91. Available from: http://www.sjkdt.org/text.asp?2017/28/2/388/202783

   Introduction Top


Hemolytic-uremic syndrome (HUS) is generally classified as typical HUS (diarrhea +HUS or Stx-HUS) and atypical HUS.[1] Typical HUS is associated with infections caused by bacteria, such as enterohemorrhagic Escherichia coli or Shigella dysenteriae, that produce Shiga-like toxins (Stx), and it is the most common type. Typical Stx HUS mostly occurs in children, but can be seen in a wide age range during epidemics.[2] In children, HUS cases associated with neuraminidase producing Streptococcus pneumonia at 5% have been reported.[3]

Atypical HUS (aHUS) is a rare, severe, and life-threatening disease. It is characterized by microangiopathy, hemolytic anemia, reduced kidney function, and other organ failures. Annual incidence of aHUS in adults and under the age of 18 are 2/1,000,000 and 3.3/1,000,000, respectively.[4],[5] Frequent relapses are seen in aHUS, and its prognosis is much worse than typical HUS.[6],[7] In 50% of children and in the majority of adults, dialysis treatment is needed in the first attack. While mortality after the first attack occurs more in children, progression to end-stage renal failure occurs more in adults.[8] In most of these cases, specific mutations are detected in the alternative pathway of the complement cascade. Most commonly, complement factor H (CHF)-associated mutations were detected. Until 2009, plasma exchange or plasma infusion has been the only treatment method for aHUS. Eculizumab is a monoclonal antibody that binds with high affinity to C5 and inhibits the generation of inflammatory, prothrombotic, and lytic terminal complement components. Eculizumab was first approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab has successfully been used in patients with aHUS, and is becoming the first-line treatment.


   Case Report Top


A 20-year-old female was admitted to the emergency service with complaints of abdominal pain and headache. However, the patient did not complained of fever, nausea, vomiting, or diarrhea. She had stable vital signs and had no history of chronic disease or drug use. Physical examination revealed no abnormalities except for peripheral edema. Laboratory findings revealed hemoglobin (Hb) = 9.2 g/dL, platelet = 18×103/μL, creatinine = 4.69 mg/dL, lactate dehydrogenase (LDH) = 2080 U/L, and schistocytes in peripheral blood smear and Coombs test were negative. The findings were consistent with thrombotic microangiopathy (TMA). Emergency plasmapheresis treatment was started. Computed tomography (CT) scans of the brain done in view of the headache revealed no abnormalities. The patient was anuric within 12 h of her admission and dialysis was started. ADAMTS13 activity was normal (81%). C3 was low and C4 was within normal limits. Anti-nuclear antibody, anti-ds DNA, anti-neutrophil cytoplasmic antibody, hepatic panel, HIV, and anti-scl-70 were all negative. In renal ultrasonography, kidney sizes were 122 mm × 41 mm, with parenchymal thickness of 11 mm in the right side; 124 × 48 mm, and parenchymal thickness of 12 mm in the left side. Parenchymal echo was increased.

Her mother’s cousin was diagnosed with renal failure 18 years ago and received a kidney transplant, in which acute rejection developed immediately and the patient died within two months of transplantation.

After the second plasmapheresis, schistocytes in peripheral blood smear and LDH levels increased, and platelet levels did not improve. Considering the patient’s family history, eculizumab was initiated on the 5th day of the treatment. Meningococcal and pneumococcal vaccines were administered prior to eculizumab treatment. Since we need to start treatment immediately, prophylactic ampicillinsulbactam was given for 14 days in consultation with infectious diseases department. Eculizumab was administered at 900 mg dose once a week for the first four weeks. After the first administration, the patient developed severe headache, but a repeat brain CT scan remained normal. After the initiation of eculizumab treatment, platelet level started to rise on day 5, and the patient became dialysis independent on the 22nd day. After four weeks, eculizumab was given at 1200 mg dose for every two weeks. After the 10th administration, the values were determined as follows: creatinine: 0.79 mg/dL, LDH: 143 U/L, Hb: 13.2 g/dL, and platelet: 162,000/μL.


   Discussion Top


aHUS is a chronic disease, characterized by episodic attacks and has a poor prognosis due to lack of effective treatment.[8] Plasmapheresis is recommended in acute HUS exacerbations, but there is no consensus about the long-term treatment. Plasmapheresis therapy is not generally very well tolerated; plasma in high volumes is used, a central vascular access is needed, and there is a risk of allergic reaction, thrombosis, and infection.[9],[10] In our case with TMA findings, plasmapheresis was started immediately with no response.

Eculizumab is a monoclonal, humanized, anti-C5 antibody, which blocks the activation of the terminal complement pathway by binding to the complement C5. Eculizumab was first approved for the treatment of patients with PNH.[11] Since 2009, eculizumab has also been used in patients with aHUS. It was first used successfully in aHUS recurrence in transplant patients, in whom plasmapheresis treatment was not effective.[12],[13]

In a case series, in which 11 children and 13 adult patients treated with eculizumab, all the patients showed hematologic remission, and 80% of children and 31% of adults showed the full recovery of renal function. Early initiation of eculizumab treatment leads to more rapid recovery in renal functions. A significant recovery of renal functions with eculizumab use was reported even in patients who underwent dialysis treatment for several months.[14] Prospective clinical studies evaluated the use of eculizumab in adults (median age of 28 years) who were either resistant to plasma therapy (17) or required chronic plasma therapy (20). Hematologic remission was achieved in all the patients of chronic plasma therapy group with eculizumab and in 87% of patients in plasma resistance group. Initial dialysis was performed in 30% of patients in plasma resistance group and in 8% of patients in chronic plasma therapy group. After eculizumab treatment, 80% of plasma-resistant patients required no dialysis treatment. In both studies, the median duration of treatment was 62–64 weeks.[15] In our case, eculizumab was initiated on the 5th day of treatment, and on the 22nd day, the dialysis treatment was no longer required. After 6th day administration of eculizumab, our patient’s creatinine value was within normal limits.

Unlike children, it is more difficult to diagnose aHUS in adults because many diseases should be excluded in the differential diagnosis. TMA associated with ADAMTS 13 deficiency, pregnancy, cancer, drugs, infections, and with systemic diseases should be excluded.[15] Genetic mutations are detected in approximately 60% of the patients. CFH-related mutations were detected most commonly. The treatment should be initiated quickly after diagnosis without waiting for the genetic tests due to long period of time and costs.[16] In our patient’s family, there was a patient with acute rejection developed following transplantation. Genetic analysis was requested for our patient but no mutation has been detected yet.

Infectious risk with encapsulated bacteria increases during eculizumab treatment because it inhibits the generation of last components of the complement cascade system. Neisseria meningitidis prophylaxis is important. Meningococcal vaccine should be administered 14 days before the treatment or antibiotic prophylaxis should be performed concomitantly with vaccine if the treatment should be initiated immediately. Neisseria infection risk with eculizumab occurs in 4 cases per 1000 patient-years. Sexually active patients should be advised against disseminated gonococcal infections. S. pneumonia and Haemophilus influenza vaccinations are recommended particularly in children.[15] Our patient received meningococcal and pneumococcal vaccinations prior to eculizumab treatment and was given antibiotics for 14 days.

The cost of eculizumab treatment is high and cost-effectiveness has not been studied yet. However, with classical therapy, end-stage renal disease develops in the majority of the patients, and relapse is common after transplantation. For these reasons, eculizumab when afforded has become the first-line treatment in patients with aHUS.

Conflict of interest:

None declared

 
   References Top

1.
Besbas N, Karpman D, Landau D, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 2006;70:423-31.  Back to cited text no. 1
    
2.
Tarr PI, Gordon CA, Chandler WL. Shigatoxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005;365: 1073-86.  Back to cited text no. 2
    
3.
Copelovitch L, Kaplan BS. Streptococcus pneumoniae – Associated hemolytic uremic syndrome: Classification and the emergence of serotype 19A. Pediatrics 2010;125:e174-82.  Back to cited text no. 3
    
4.
Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: Causes and short-term course. Am J Kidney Dis 2004;43:976-82.  Back to cited text no. 4
    
5.
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.  Back to cited text no. 5
    
6.
Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59.  Back to cited text no. 6
    
7.
Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007;18:2392-400.  Back to cited text no. 7
    
8.
Bresin E, Daina E, Noris M, et al. Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: Prognostic significance of genetic background. Clin J Am Soc Nephrol 2006;1:88-99.  Back to cited text no. 8
    
9.
Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009;24:687-96.  Back to cited text no. 9
    
10.
Rizvi MA, Vesely SK, George JN, et al. Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Transfusion 2000; 40:896-901.  Back to cited text no. 10
    
11.
Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 2009;373:759-67.  Back to cited text no. 11
    
12.
Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011;6:60.  Back to cited text no. 12
    
13.
Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361: 1676-87.  Back to cited text no. 13
    
14.
Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V; French Study Group for aHUS/CG. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643-57.  Back to cited text no. 14
    
15.
Fakhouri F, Frémeaux-Bacchi V, Loirat C. Atypical hemolytic uremic syndrome: From the rediscovery of complement to targeted therapy. Eur J Intern Med 2013;24:492-5.  Back to cited text no. 15
    
16.
Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol 2014;36: 399-420.  Back to cited text no. 16
    

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Correspondence Address:
Ayça Inci
Department of Nephrology, Antalya Training and Research Hospital, Antalya
Turkey
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DOI: 10.4103/1319-2442.202783

PMID: 28352025

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    Abstract
   Introduction
   Case Report
   Discussion
    References
 

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