Prophylactic eculizumab for kidneytransplantation in a child with atypicalhemolytic uremic syndrome due tocomplement factor H mutation

Ranch D, Crowther B, Arar M, Assanasen C. (2014) Prophylacticeculizumab for kidney transplantation in a child with atypicalhemolytic uremic syndrome due to complement factor H mutation.Pediatr Transplant, 18: E185–E189. DOI: 10.1111/petr.12290.

Abstract: We present a case of successful deceased-donor kidneytransplantation in a three-yr-old child with aHUS due to complementfactor H mutation, using only prophylactic eculizumab treatment priorto transplant. She developed disease exacerbation in the immediatepost-operative period despite having therapeutic eculizumabconcentrations and evidence for complete complement pathwayblockade. The patient responded well to additional doses of eculizumaband has maintained excellent graft function and disease control in thefirst year post-transplantation. The optimal dosing scheme foreculizumab in the perioperative period remains to be determined. Moresensitive biomarkers of early disease activity are needed to improvedisease monitoring. Finally, the duration of eculizumab therapy inpatients with aHUS remains to be determined.

Daniel Ranch1, Barrett Crowther2, MazenArar1 and Chatchawin Assanasen11Department of Pediatrics, University of TexasHealth Science Center, San Antonio, TX, USA,2Department of Pharmacy Services, UniversityHospital, San Antonio, TX, USA

Key words: atypical hemolytic uremic syndrome –complement factor H – eculizumab – pediatrickidney transplantation

Daniel Ranch, Division of Pediatric Nephrology,Department of Pediatrics, University of Texas HealthScience Center, San Antonio, 7703 Floyd Curl, MC7813, San Antonio, TX 78229, USATel.: 210 562 5365Fax: 210 358 2095E-mail: ranch@uthscsa.edu

Accepted for publication 17 April 2014

aHUS is a disease of complement pathway dys-regulation, leading to excessive complement acti-vation and endothelial injury. This results inacute renal failure due to TMA, but can alsoinvolve other organ systems including the cen-tral nervous system. There are several knowngenetic mutations associated with aHUS; themost CFH is produced by the liver and plays amajor role in the regulation of the alternativepathway (1). In patients with CFH deficiency,70–80% of patients eventually develop ESRDor death. The rate of disease recurrence in renaltransplant recipients is high (80–90%), and ther-apies such as plasma exchange and combinedkidney/liver transplantation have had subopti-mal outcomes (2). More recently, eculizumab, aC5 monoclonal antibody, has been shown to be

effective in blocking terminal complement path-way activation and membrane attack complexformation. For patients with ESRD, it has sig-nificantly altered the disease course allowing forkidney transplantation without the risk of dis-ease recurrence. In some instances, eculizumabhas been used to treat disease recurrence afterkidney transplantation in pediatric patients, butprophylactic eculizumab treatment prior totransplantation is relatively new (3–7). However,the optimal timing and duration of therapy isnot yet known. We report the case of a three-yr-old girl with aHUS due to a factor H mutation,who received a deceased-donor kidney trans-plant after prophylactic eculizumab treatment.

Case

Our patient initially presented to a referring hos-pital as a seven-month-old baby girl with acutegastroenteritis. There she was found to have oli-guric acute kidney injury due to presumed STECHUS and was transferred to a second facility foracute dialysis. She did have documented throm-bocytopenia and hemolytic anemia at that time,

Abbreviations: aHUS, atypical hemolytic uremic syn-drome; BUN, blood urea nitrogen; CFH, complement fac-tor H; CFI, complement factor I; ESRD, end-stage renaldisease; LDH, lactate dehydrogenase; MAHA, microangio-pathic hemolytic anemia; STEC, Shiga toxin-producingEscherichia coli; TMA, thrombotic microangiopathy.

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Pediatr Transplantation 2014: 18: E185–E189 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric TransplantationDOI: 10.1111/petr.12290

which seemed to slowly improve. There was nodocumentation of bloody diarrhea, stool occultblood was negative, and there was no positivepathogenic stool culture recorded. Serum C3 andC4 were normal, and a kidney biopsy was notcarried out at the time. She was maintained onperitoneal dialysis for about three wk, but didnot show signs of renal function recovery, so shewas transferred for further management.At our hospital, the patient was still in renal

failure, with a BUN 23 mg/dL and serum creati-nine 4.8 mg/dL, and a renal ultrasound showeddiffusely echogenic kidneys. She was dischargedhome after one wk of peritoneal dialysis educa-tion and training. However, she returned a cou-ple of weeks later with pallor and petechiae, andlaboratory testing revealed severe anemia,thrombocytopenia, and schistocytes on herperipheral blood smear. Her serum C3 wasmildly decreased at 69 mg/dL. No ADAMTS13assay was done. Due to the recurrence ofMAHA, mutational analysis for aHUS was car-ried out, which revealed a heterozygous mutationin the CFH gene (c.3572C>G, p.Ser1191Trp),resulting in impaired CFH binding (8). CFI geneanalysis was normal. However, anti-CFH anti-body testing was not done. She was subsequentlymaintained on chronic dialysis for ~2 yr, duringwhich time she did not have laboratory evidencefor ongoing intravascular hemolysis. However,she did continue to have poorly controlled hyper-tension, an episode of Bell’s palsy, and delayeddevelopmental milestones.At that time, the initial reports of eculizumab

for treatment of atypical HUS recurrence in pedi-atric renal transplant patients began to appear inthe literature (3). These were followed by reportsof prophylactic eculizumab treatment in pediatricrenal transplant patients to prevent recurrence,with promising results (4–6). Due to concerns forthe aHUS affecting her neurocognitive develop-ment in addition to her ESRD, we were able toobtain approval for eculizumab treatment andshe was activated on the renal transplant waitinglist after her treatments had started. The patientreceived meningococcal vaccination abouttwo wk prior to eculizumab initiation.

Pre-transplant treatment course

Seven months prior to renal transplant, ourpatient was started on eculizumab infusions,receiving 600 mg as her initial dose, followedby 300 mg one wk later, then 300 mg everytwo wk thereafter. Her weight at the time of druginitiation was 10 kg. She tolerated her infusionswell, with no significant adverse reactions. Prior

to and during her treatment course, her plateletsremained normal, but her serum LDH remainedslightly increased until one month before trans-plant. Her serum haptoglobin remained withinnormal limits. Total complement (CH50) activitywas suppressed, and serum C3 remained normal.

Peri- and post-operative course

On the day of her deceased-donor renal trans-plant, the patient received eculizumab 300 mg afew hours prior to surgery. Her weight at thetime of surgery was 13 kg. Her previous mainte-nance eculizumab dose of 300 mg had been given11 days prior. She did not receive any priorplasma exchange or plasma infusion. The patientalso received rabbit antithymocyte globulin1.5 mg/kg/dose intra-operatively for transplantinduction due to high panel reactive antibodies,as well as on post-operative days 1 and 2. Herintra-operative course was uneventful, and allo-graft urine output was good.Initial laboratory tests at two h post-surgery

showed that her serum creatinine had alreadydecreased to 2.73 mg/dL from 5.75 mg/dL pre-operatively; however, her platelets had decreasedfrom 166 000/mm3 to 83 000/mm3 in the sametime period (Fig. 1). Also, her serum LDH atthat time increased to 444 U/L and serum hap-toglobin was undetectable. Her hemoglobin was16.4 g/dL, which was after a blood transfusionin the OR. The next morning, approximately12 h later, her serum creatinine improved furtherto 0.22 mg/dL, but platelets decreased to73 000/mm3, LDH increased to 570 U/L, andserum C3 decreased to 56 mg/dL from 92 mg/dLpre-operatively. Her urine was clear, but she didhave microscopic hematuria. Her peripheralblood smear was reviewed with the hematologist,and no schistocytes were detected. On post-oper-ative day 2, serum creatinine was <0.1 mg/dL;however, her platelets decreased further to57 000/mm3, and her hemoglobin decreased to15.4 g/dL. Also, her serum LDH had increased to854 U/L, C3 was slightly decreased at 64 mg/dL,and review of her blood smear that morning didreveal some schistocytes. It was decided at thattime to provide another 300 mg dose of ecu-lizumab. Over the next four days, her hemolysislaboratory parameters improved, and her allo-graft function remained excellent throughout. Shewas discharged on post-operative day 7 and seenin the clinic the next day. Because of knownincreased requirements stemming from comple-ment activation following surgical procedures, wedecided to restart her eculizumab induction,giving 600 mg that day, 600 mg one wk later,

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and then resuming her maintenance scheduleof 300 mg every two wk (Personal communica-tion, Oct. 2012, Dr. Camille Bedrosian, AlexionPharmaceuticals, 9). Results of her functionalC5 assays drawn during the post-operative per-iod returned later, suggesting complete pathwayblockade, and her random serum eculizumablevels were persistently >100 lg/mL. Since herrenal transplant, her kidney function has beenstable and she continues on maintenance dosingof eculizumab. Subsequent laboratory testinghas not revealed evidence for recurrence ofMAHA, her serum eculizumab levels haveremained above 100 lg/mL, and her functionalC5 assay results show continued pathway block-ade. Also, she has been enrolled in the aHUSregistry (clinicaltrials.gov ID: NCT01522183),which collects clinical and laboratory data toassess the long-term manifestations of TMAcomplications of her aHUS as well as otherclinical outcomes.

Discussion

The advent of eculizumab for the treatment ofaHUS has made kidney transplantation a viableoption for patients with ESRD due to comple-ment dysregulation. This development is espe-cially important for affected children, as kidneytransplantation provides the best long-term sur-vival compared with chronic dialysis therapy (10,11).In our patient, eculizumab treatment was

started prior to transplant not only to preventdisease recurrence in the graft, but also due toconcerns for central nervous system damage, as

it is known that genetic HUS has detrimentaleffects on other organ systems (12). Others havereported success with eculizumab treatment priorto kidney transplantation in pediatric patients.Nester et al. reported successful living unrelatedkidney transplantation in a child with a hybridCFH/CFHR1 gene mutation and ESRD. Theirpatient was treated with plasma exchange andeculizumab one wk prior to surgery and thenagain on the day prior to surgery. ComplementC5 functional assay results showed pathwayblockade, and a post-transplant kidney biopsydid not show evidence of TMA (6). Weitz et al.reported a child with CFH mutation and ESRDwho was started on eculizumab without plasmatherapy and received a deceased-donor kidneytransplant three wk afterward. The patient didwell except for increased complement activity inthe second week post-transplant, attributed toBK polyoma virus infection which responded tocidofovir (5). Krid et al. reported a child with ahybrid CFH/CFHR1 gene mutation and ESRDwho was maintained on biweekly plasma infu-sions and then received a deceased-donor kidney.He was given eculizumab two h prior to surgeryand again on post-operative day 1; his lastplasma infusion was two wk prior. Three post-transplant biopsies were performed for increasedcreatinine, and no signs of TMA were present;however, the third biopsy at day 104 revealedantibody-mediated rejection which responded totreatment (7). Additionally, Tran et al. reporteda five-yr-old female with CFH mutation andESRD, who received a deceased-donor combinedliver–kidney transplant with perioperative ecu-lizumab and plasma exchange. The patient

Fig. 1. Laboratory values andeculizumab dosing (arrows)during the first month afterkidney transplantation.

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received one dose of eculizumab immediatelyprior to transplant and one other dose on post-operative day 0 after transplant. A six-monthpost-transplant protocol biopsy did not showevidence of aHUS recurrence or rejection (13).In the immediate post-operative period, our

patient showed evidence for disease exacerba-tion despite having received eculizumab a fewhours before surgery. Our patient developedprolonged thrombocytopenia, a known compli-cation of antithymocyte globulin (14). Thislikely contributed to our patient’s laboratoryfindings; however, our patient also showedevidence for recurrence of MAHA, which wasmore likely due to her aHUS. Complement acti-vation with surgical trauma is well documented,and at that time, we believed that the pre-oper-ative eculizumab dose would prevent this (15).Xie et al. reported post-operative hemolysis inan adult kidney transplant patient treated withprophylactic eculizumab that was attributed toextravascular hemolysis due to opsonization ofC3b-bearing erythrocytes (16). However, theirpatient did not have thrombocytopenia or schis-tocytes as was seen in our patient. Furtherstudies are needed to determine the optimumdosing, timing, and/or frequency of eculizumabin the perioperative period. Our patientresponded quickly to the additional dose givenon post-operative day 2, with rapid improve-ment of her hemolysis markers and stabilizationof her platelet count.A related issue is how to best detect early dis-

ease activity in these patients. Traditional mark-ers such as platelets, LDH, and creatininebecome abnormal late in the disease process,after the damage is already done. An assay forfunctional C5 is available, which demonstratesthe mean hemolytic activity based on a validatedpharmacodynamics assay that quantified thecomplement activity in serum by measuring thedegree of hemolysis. The measure of hemolysis isthe amount of hemoglobin release as determinedby means of spectrophotometer (17). However,in our patient, disease exacerbation was evidentdespite the assay results showing pathway block-ade. Also, minimal eculizumab concentrations of50–100 lg/mL have been reported to achievecomplete complement blockade (17). In ourpatient, random drug levels were consistentlyabove this threshold; however, disease exacerba-tion still occurred. This may suggest the need forhigher eculizumab levels during surgery andother strong triggers of complement activation.Thus, development of biomarkers that can detectearly disease activation will be of the utmostimportance in the monitoring of disease control

in these patients. Unpublished data suggest thatserum free C5 levels may be a better marker ofterminal C5 inhibition in the setting of ecu-lizumab administration (Personal communica-tion, Sept. 2013 and March 2014, Dr. CamilleBedrosian, Alexion Pharmaceuticals).Finally, the duration of eculizumab treatment

in patients with aHUS is not known. Therapywill probably become tailored to individualmutational phenotypes in the future. Otherwise,complement dysregulation is an ongoing processin these patients, despite normal laboratoryparameters. Discontinuation of the drug hasresulted in disease exacerbation, and so, thesepatients likely will require lifelong therapy(18–20). Factors that need to be considered withchronic eculizumab treatment include potentialcomplications, such as increased risk for menin-gococcal and other encapsulated bacterial infec-tions, as well as the cost of therapy comparedwith other treatment modalities. However, it isknown that mortality in untreated patients ishigh, and eculizumab offers the best option atthis time.In conclusion, we report a successful case of

renal transplantation in a pediatric patient withaHUS due to CFH, using prophylacticeculizumab treatment and without plasmatherapy. She developed disease exacerbationfrom complement overactivity immediatelyafter transplant with a rapid response toeculizumab, despite confirmation of presumedadequate dosing using traditional biomarkers.The optimal dosing scheme in the immediatepre- and post-transplant period needs to bedetermined. Also, biomarkers for early diseaseactivation need to be developed to help pre-vent organ damage, as traditional markers maynot be adequately sensitive or specific in thepost-operative period. Finally, the duration ofeculizumab therapy in patients with aHUSremains to be determined.

Acknowledgments

We would like to thank Dr. Carla Nester, University ofIowa, and Dr. Camille Bedrosian, Alexion Pharmaceuticals,for their valuable insight into the care of this patient.

Conflict of interests

DR has participated in a TMA/aHUS NationalExperts Advisory Board Meeting held by Alex-ion Pharmaceuticals. MA has participated in aTMA/aHUS National Experts Advisory BoardMeeting held by Alexion Pharmaceuticals. CA ison the Alexion Pharmaceuticals Speaker’sBureau.

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