Eculizumab: Safety and Efficacy After 17 Months of Treatment in a Renal Transplant Patient With Recurrent Atypical Hemolytic-Uremic Syndrome: Case Report

doi:10.1016/j.transproceed.2010.09.125

Transplantation Proceedings

Volume 42, Issue 10, December 2010, Pages 4353-4355

https://doi.org/10.1016/j.transproceed.2010.09.125 Get rights and content

Abstract

In a recent study, eculizumab, a humanized monoclonal antibody which targets complement factor C5, appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome. We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation. After 17 months of eculizumab treatment, and without concomitant plasma therapy, renal function was maintained, the need for blood transfusions reduced, and acute thrombotic microangiopathy and hemolysis controlled. These data suggested that eculizumab should be considered to be a permanent treatment for this patient.

Section snippets

Patients and Methods

Herein we have described the long-term use of 17 months of eculizumab treatment in the previously reported patient.⁴ The patient, a 42-year-old woman with familial aHUS, had a heterozygous gain of function mutation (R570Q) in the C3 gene.⁵ She developed end-stage renal disease at the age of 30 years. Kidney transplantation was performed at age 34, with aHUS recurrence 5 months later as inaugurated by diarrhea, leading to graft loss after 2 years. She underwent a second transplantation in 2004

Results

After 17 months of eculizumab treatment, and without concomitant PT, the schistocytes had decreased, haptoglobin had increased to within normal limits, creatinine levels had stabilized, and there were no further episodes of diarrhea (Fig 1). Blood transfusions were delivered owing to metrorrhagia after discontinuation of contraception but stopped 4 months after continued eculizumab treatment. Two lapses in the eculizumab dosing regimen were temporally associated with an increase in

Discussion

Complement dysregulation in aHUS has been shown to cause subendothelium exposure and activation of platelets resulting in a chronic proinflammatory and prothrombotic state. Eculizumab is a humanized monoclonal antibody treatment which specifically binds to the complement protein C5, preventing its cleavage, thereby halting the complement cascade and preventing the formation of terminal complement proteins. It is comprised of murine complementarity-determining regions within a human antibody

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Cited by (49)

Successful 7-Year Eculizumab Treatment of Plasmapheresis-Resistant Recurrent Atypical Hemolytic-Uremic Syndrome due to Complement Factor H Hybrid Gene: A Case Report
2018, Transplantation Proceedings
Citation Excerpt :
In our patient, the remission of aHUS induced by eculizumab has lasted for 7 years. Long-term favorable course in patients with aHUS recurrence after KTx under the eculizumab treatment has been described in only a few cases so far [4,6–8]. The longest published experience of successful therapy of recurrent aHUS by eculizumab is 5 years [8].
Atypical hemolytic-uremic syndrome (aHUS) is an extremely rare disease, and up to 70% of the patients have a genetic mutation in the encoding components of complement activation or anti-complement factor H autoantibodies. The risk of recurrence after kidney transplantation is 10% to 80%. Eculizumab, a monoclonal antibody that binds complement protein C5, has shown to be highly effective in patients with aHUS; however, there are only few reports on the efficacy and safety of long-term eculizumab treatment in children with recurrent aHUS. Only 3 case reports regard treatment in patients with complement factor H (CFH/CFHR1/CFHR3) hybrid gene. This report presents the efficacy and safety of long-term eculizumab treatment in a child with recurrent aHUS who has been successfully treated with eculizumab for more than 7 years. The patient presented as a 9-year-old with aHUS due to CFH/CFHR1/CFHR3 hybrid gene and received deceased donor kidney transplantation. After the transplantation, he experienced recurrence of aHUS 2 months later. Daily plasma exchanges were ineffective in the transplanted kidney; the patient became anuric and hemodialysis was needed. Eculizumab was started as therapy and led to complete remission of aHUS including restoration of diuresis. Eculizumab has been given as therapy for 7 years. The young patient is in a sustained remission without any adverse events. This patient is only the sixth patient reported with recurrent aHUS due to CFH/CFHR1/CFHR3 hybrid gene and is the patient with the longest remission of recurrent aHUS ever published.
Novel biomarker and easy to perform ELISA for monitoring complement inhibition in patients with atypical hemolytic uremic syndrome treated with eculizumab
2016, Journal of Immunological Methods
Citation Excerpt :
We thus analyzed complement activity by determining the TCC capacity in patients receiving eculizumab via a q2w or q3w dosing interval. A q2w maintenance dosing schedule was described as sufficient for blocking terminal complement activation (Legendre et al., 2013), and delayed next dosing was associated with hemolysis and deterioration of renal function in one patient (Chatelet et al., 2010). Earlier reports already indicated that termination of treatment can lead to TMA recurrence (Nurnberger et al., 2009; Legendre et al., 2013).
Atypical hemolytic uremic syndrome (aHUS) is a devastating disease characterized by thrombus formation in the microvasculature and is associated with complement dysregulation. The recommended treatment is eculizumab, an humanized monoclonal antibody, which binds complement protein C5 and thereby preventing the assembly of the terminal complement complex (TCC, soluble C5b-9) and the generation of C5a, an anaphylatoxin.
The objective of the study was to identify a reliable biomarker, which estimates the degree of complement inactivation under normal and pathophysiological conditions, such as an infection. Here we report on serial measurements of the soluble form of C5b-9, measured in plasma and the TCC capacity (soluble C5b9 after ex-vivo activation, measured in serum) in seven patients with aHUS who were treated with eculizumab. By measuring the latter we were able to assess the maximum possible soluble C5b-9 production under a potent complement trigger. Patients were followed up over a median duration of 3.8 years either on biweekly (q2w) or a three-weekly (q3w) maintenance therapy interval.
As expected, eculizumab treatment resulted in a profound decrease of TCC capacity (median 55, IQR 44–88 AU/ml) compared to baseline (1249, 529–1806 AU/ml, p < 0.0001) and there was no significant difference in TCC capacity measurements on q2w vs. q3w maintenance dosing schedule. However, during q3w maintenance significantly more single measurements of TCC capacity above the lower cut-off level were detected (50% on q3w vs. 5% on q2w maintenance, p < 0.045). Higher TCC capacity levels were associated with lower eculizumab levels.
The TCC capacity may represent a novel and easy to perform parameter to determine level of complement inhibition in patients treated with eculizumab, especially because it identifies the residual capacity of inhibition at pathophysiological stages.
Complement—here, there and everywhere, but what about the transplanted organ?
2016, Seminars in Immunology
The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed “complement” by Ehrlich to reflect its complementarity to antibodies having previously been described as “alexine” (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ.
We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment.
An update for atypical haemolytic uraemic syndrome: Diagnosis and treatment. A consensus document
2015, Nefrologia
Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterises HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterised. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27–45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.
El síndrome hemolítico urémico (SHU) es una entidad clínica definida por la tríada anemia hemolítica no inmune, trombocitopenia e insuficiencia renal aguda, en la que las lesiones subyacentes están mediadas por un proceso de microangiopatía trombótica (MAT) sistémico. Distintas causas pueden desencadenar el proceso de MAT que caracteriza el SHU. En este documento consideramos SHU atípico (SHUa) como el subtipo de SHU en el que los fenómenos de MAT son fundamentalmente consecuencia del daño producido en el endotelio de la microvasculatura renal y de otros órganos por desregulación de la actividad del sistema del complemento. En los últimos años se han identificado diversas mutaciones en genes del sistema del complemento asociados a SHUa, que explicarían aproximadamente el 60% de los casos de SHUa, y se han caracterizado funcionalmente numerosas mutaciones y polimorfismos asociados a SHUa que han permitido determinar que la patología se produce como consecuencia de la deficiente regulación de la activación del complemento sobre las superficies celulares y que lleva al daño endotelial mediado por la activación del C5 y de la vía terminal del complemento. Eculizumab es un anticuerpo monoclonal humanizado que inhibe la activación del C5, bloqueando la generación de la molécula proinflamatoria C5a y la formación del complejo de ataque de membrana. En estudios prospectivos en pacientes con SHUa su administración ha demostrado la interrupción rápida y sostenida del proceso de MAT, con una mejora significativa de la función renal a largo plazo y una reducción importante de la necesidad de diálisis y el cese de la terapia plasmática. En función de las evidencias científicas publicadas y la experiencia clínica acumulada, el Grupo Español de SHUa publicamos un documento de consenso con recomendaciones para el tratamiento de la enfermedad (Nefrología 2013;33(1):27–45). En la presente versión online del documento se actualizan los contenidos sobre la clasificación etiológica de las MAT, la fisiopatología del SHUa, su diagnóstico diferencial y su manejo terapéutico.
Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: A report of 10 cases
2014, American Journal of Kidney Diseases
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.
Complement therapy in atypical haemolytic uraemic syndrome (aHUS)
2013, Molecular Immunology
Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the ‘gold-standard’ for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.

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Case reportEculizumab: Safety and Efficacy After 17 Months of Treatment in a Renal Transplant Patient With Recurrent Atypical Hemolytic-Uremic Syndrome: Case Report

Abstract

Section snippets

Patients and Methods

Results

Discussion

Am J Transplant

Blood

Case report
Eculizumab: Safety and Efficacy After 17 Months of Treatment in a Renal Transplant Patient With Recurrent Atypical Hemolytic-Uremic Syndrome: Case Report