Pediatr Transplantation 2014: 18: E185–E189
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12290
Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation Ranch D, Crowther B, Arar M, Assanasen C. (2014) Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic 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 kidney transplantation in a three-yr-old child with aHUS due to complement factor H mutation, using only prophylactic eculizumab treatment prior to transplant. She developed disease exacerbation in the immediate post-operative period despite having therapeutic eculizumab concentrations and evidence for complete complement pathway blockade. The patient responded well to additional doses of eculizumab and has maintained excellent graft function and disease control in the first year post-transplantation. The optimal dosing scheme for eculizumab in the perioperative period remains to be determined. More sensitive biomarkers of early disease activity are needed to improve disease monitoring. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined.
aHUS is a disease of complement pathway dysregulation, leading to excessive complement activation and endothelial injury. This results in acute renal failure due to TMA, but can also involve other organ systems including the central nervous system. There are several known genetic mutations associated with aHUS; the most CFH is produced by the liver and plays a major role in the regulation of the alternative pathway (1). In patients with CFH deficiency, 70–80% of patients eventually develop ESRD or death. The rate of disease recurrence in renal transplant recipients is high (80–90%), and therapies such as plasma exchange and combined kidney/liver transplantation have had suboptimal outcomes (2). More recently, eculizumab, a C5 monoclonal antibody, has been shown to be
Abbreviations: aHUS, atypical hemolytic uremic syndrome; BUN, blood urea nitrogen; CFH, complement factor H; CFI, complement factor I; ESRD, end-stage renal disease; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy.
Daniel Ranch1, Barrett Crowther2, Mazen Arar1 and Chatchawin Assanasen1 1
Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA, 2 Department of Pharmacy Services, University Hospital, San Antonio, TX, USA Key words: atypical hemolytic uremic syndrome – complement factor H – eculizumab – pediatric kidney transplantation Daniel Ranch, Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl, MC 7813, San Antonio, TX 78229, USA Tel.: 210 562 5365 Fax: 210 358 2095 E-mail: [email protected] Accepted for publication 17 April 2014
effective in blocking terminal complement pathway activation and membrane attack complex formation. For patients with ESRD, it has significantly altered the disease course allowing for kidney transplantation without the risk of disease recurrence. In some instances, eculizumab has been used to treat disease recurrence after kidney transplantation in pediatric patients, but prophylactic eculizumab treatment prior to transplantation is relatively new (3–7). However, the optimal timing and duration of therapy is not yet known. We report the case of a three-yrold girl with aHUS due to a factor H mutation, who received a deceased-donor kidney transplant after prophylactic eculizumab treatment. Case
Our patient initially presented to a referring hospital as a seven-month-old baby girl with acute gastroenteritis. There she was found to have oliguric acute kidney injury due to presumed STEC HUS and was transferred to a second facility for acute dialysis. She did have documented thrombocytopenia and hemolytic anemia at that time, E185
Ranch et al.
which seemed to slowly improve. There was no documentation of bloody diarrhea, stool occult blood was negative, and there was no positive pathogenic stool culture recorded. Serum C3 and C4 were normal, and a kidney biopsy was not carried out at the time. She was maintained on peritoneal dialysis for about three wk, but did not show signs of renal function recovery, so she was transferred for further management. At our hospital, the patient was still in renal failure, with a BUN 23 mg/dL and serum creatinine 4.8 mg/dL, and a renal ultrasound showed diffusely echogenic kidneys. She was discharged home after one wk of peritoneal dialysis education and training. However, she returned a couple of weeks later with pallor and petechiae, and laboratory testing revealed severe anemia, thrombocytopenia, and schistocytes on her peripheral blood smear. Her serum C3 was mildly decreased at 69 mg/dL. No ADAMTS13 assay was done. Due to the recurrence of MAHA, mutational analysis for aHUS was carried out, which revealed a heterozygous mutation in the CFH gene (c.3572C>G, p.Ser1191Trp), resulting in impaired CFH binding (8). CFI gene analysis was normal. However, anti-CFH antibody testing was not done. She was subsequently maintained on chronic dialysis for ~2 yr, during which time she did not have laboratory evidence for ongoing intravascular hemolysis. However, she did continue to have poorly controlled hypertension, an episode of Bell’s palsy, and delayed developmental milestones. At that time, the initial reports of eculizumab for treatment of atypical HUS recurrence in pediatric renal transplant patients began to appear in the literature (3). These were followed by reports of prophylactic eculizumab treatment in pediatric renal transplant patients to prevent recurrence, with promising results (4–6). Due to concerns for the aHUS affecting her neurocognitive development in addition to her ESRD, we were able to obtain approval for eculizumab treatment and she was activated on the renal transplant waiting list after her treatments had started. The patient received meningococcal vaccination about two wk prior to eculizumab initiation. Pre-transplant treatment course
Seven months prior to renal transplant, our patient was started on eculizumab infusions, receiving 600 mg as her initial dose, followed by 300 mg one wk later, then 300 mg every two wk thereafter. Her weight at the time of drug initiation was 10 kg. She tolerated her infusions well, with no significant adverse reactions. Prior E186
to and during her treatment course, her platelets remained normal, but her serum LDH remained slightly increased until one month before transplant. Her serum haptoglobin remained within normal limits. Total complement (CH50) activity was suppressed, and serum C3 remained normal. Peri- and post-operative course
On the day of her deceased-donor renal transplant, the patient received eculizumab 300 mg a few hours prior to surgery. Her weight at the time of surgery was 13 kg. Her previous maintenance eculizumab dose of 300 mg had been given 11 days prior. She did not receive any prior plasma exchange or plasma infusion. The patient also received rabbit antithymocyte globulin 1.5 mg/kg/dose intra-operatively for transplant induction due to high panel reactive antibodies, as well as on post-operative days 1 and 2. Her intra-operative course was uneventful, and allograft urine output was good. Initial laboratory tests at two h post-surgery showed that her serum creatinine had already decreased to 2.73 mg/dL from 5.75 mg/dL preoperatively; however, her platelets had decreased from 166 000/mm3 to 83 000/mm3 in the same time period (Fig. 1). Also, her serum LDH at that time increased to 444 U/L and serum haptoglobin was undetectable. Her hemoglobin was 16.4 g/dL, which was after a blood transfusion in the OR. The next morning, approximately 12 h later, her serum creatinine improved further to 0.22 mg/dL, but platelets decreased to 73 000/mm3, LDH increased to 570 U/L, and serum C3 decreased to 56 mg/dL from 92 mg/dL pre-operatively. Her urine was clear, but she did have microscopic hematuria. Her peripheral blood smear was reviewed with the hematologist, and no schistocytes were detected. On post-operative day 2, serum creatinine was 100 lg/mL. Since her renal transplant, her kidney function has been stable and she continues on maintenance dosing of eculizumab. Subsequent laboratory testing has not revealed evidence for recurrence of MAHA, her serum eculizumab levels have remained above 100 lg/mL, and her functional C5 assay results show continued pathway blockade. Also, she has been enrolled in the aHUS registry (clinicaltrials.gov ID: NCT01522183), which collects clinical and laboratory data to assess the long-term manifestations of TMA complications of her aHUS as well as other clinical outcomes. Discussion
The advent of eculizumab for the treatment of aHUS has made kidney transplantation a viable option for patients with ESRD due to complement dysregulation. This development is especially important for affected children, as kidney transplantation provides the best long-term survival compared with chronic dialysis therapy (10, 11). In our patient, eculizumab treatment was started prior to transplant not only to prevent disease recurrence in the graft, but also due to concerns for central nervous system damage, as
it is known that genetic HUS has detrimental effects on other organ systems (12). Others have reported success with eculizumab treatment prior to kidney transplantation in pediatric patients. Nester et al. reported successful living unrelated kidney transplantation in a child with a hybrid CFH/CFHR1 gene mutation and ESRD. Their patient was treated with plasma exchange and eculizumab one wk prior to surgery and then again on the day prior to surgery. Complement C5 functional assay results showed pathway blockade, and a post-transplant kidney biopsy did not show evidence of TMA (6). Weitz et al. reported a child with CFH mutation and ESRD who was started on eculizumab without plasma therapy and received a deceased-donor kidney transplant three wk afterward. The patient did well except for increased complement activity in the second week post-transplant, attributed to BK polyoma virus infection which responded to cidofovir (5). Krid et al. reported a child with a hybrid CFH/CFHR1 gene mutation and ESRD who was maintained on biweekly plasma infusions and then received a deceased-donor kidney. He was given eculizumab two h prior to surgery and again on post-operative day 1; his last plasma infusion was two wk prior. Three posttransplant biopsies were performed for increased creatinine, and no signs of TMA were present; however, the third biopsy at day 104 revealed antibody-mediated rejection which responded to treatment (7). Additionally, Tran et al. reported a five-yr-old female with CFH mutation and ESRD, who received a deceased-donor combined liver–kidney transplant with perioperative eculizumab and plasma exchange. The patient E187
Ranch et al.
received one dose of eculizumab immediately prior to transplant and one other dose on postoperative day 0 after transplant. A six-month post-transplant protocol biopsy did not show evidence of aHUS recurrence or rejection (13). In the immediate post-operative period, our patient showed evidence for disease exacerbation despite having received eculizumab a few hours before surgery. Our patient developed prolonged thrombocytopenia, a known complication of antithymocyte globulin (14). This likely contributed to our patient’s laboratory findings; however, our patient also showed evidence for recurrence of MAHA, which was more likely due to her aHUS. Complement activation with surgical trauma is well documented, and at that time, we believed that the pre-operative eculizumab dose would prevent this (15). Xie et al. reported post-operative hemolysis in an adult kidney transplant patient treated with prophylactic eculizumab that was attributed to extravascular hemolysis due to opsonization of C3b-bearing erythrocytes (16). However, their patient did not have thrombocytopenia or schistocytes as was seen in our patient. Further studies are needed to determine the optimum dosing, timing, and/or frequency of eculizumab in the perioperative period. Our patient responded quickly to the additional dose given on post-operative day 2, with rapid improvement of her hemolysis markers and stabilization of her platelet count. A related issue is how to best detect early disease activity in these patients. Traditional markers such as platelets, LDH, and creatinine become abnormal late in the disease process, after the damage is already done. An assay for functional C5 is available, which demonstrates the mean hemolytic activity based on a validated pharmacodynamics assay that quantified the complement activity in serum by measuring the degree of hemolysis. The measure of hemolysis is the amount of hemoglobin release as determined by means of spectrophotometer (17). However, in our patient, disease exacerbation was evident despite the assay results showing pathway blockade. Also, minimal eculizumab concentrations of 50–100 lg/mL have been reported to achieve complete complement blockade (17). In our patient, random drug levels were consistently above this threshold; however, disease exacerbation still occurred. This may suggest the need for higher eculizumab levels during surgery and other strong triggers of complement activation. Thus, development of biomarkers that can detect early disease activation will be of the utmost importance in the monitoring of disease control E188
in these patients. Unpublished data suggest that serum free C5 levels may be a better marker of terminal C5 inhibition in the setting of eculizumab administration (Personal communication, Sept. 2013 and March 2014, Dr. Camille Bedrosian, Alexion Pharmaceuticals). Finally, the duration of eculizumab treatment in patients with aHUS is not known. Therapy will probably become tailored to individual mutational phenotypes in the future. Otherwise, complement dysregulation is an ongoing process in these patients, despite normal laboratory parameters. Discontinuation of the drug has resulted in disease exacerbation, and so, these patients likely will require lifelong therapy (18–20). Factors that need to be considered with chronic eculizumab treatment include potential complications, such as increased risk for meningococcal and other encapsulated bacterial infections, as well as the cost of therapy compared with other treatment modalities. However, it is known that mortality in untreated patients is high, and eculizumab offers the best option at this time. In conclusion, we report a successful case of renal transplantation in a pediatric patient with aHUS due to CFH, using prophylactic eculizumab treatment and without plasma therapy. She developed disease exacerbation from complement overactivity immediately after transplant with a rapid response to eculizumab, despite confirmation of presumed adequate dosing using traditional biomarkers. The optimal dosing scheme in the immediate pre- and post-transplant period needs to be determined. Also, biomarkers for early disease activation need to be developed to help prevent organ damage, as traditional markers may not be adequately sensitive or specific in the post-operative period. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined. Acknowledgments We would like to thank Dr. Carla Nester, University of Iowa, 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 National Experts Advisory Board Meeting held by Alexion Pharmaceuticals. MA has participated in a TMA/aHUS National Experts Advisory Board Meeting held by Alexion Pharmaceuticals. CA is on the Alexion Pharmaceuticals Speaker’s Bureau.
Eculizumab in aHUS and kidney transplantation
References 1. CAPRIOLI J, NORIS M, BRIOSCHI S, et al. Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006: 108: 1267–1279. 2. NORIS M, REMUZZI G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009: 361: 1676–1687. 3. AL-AKASH SI, ALMOND PS, SAVELL VH Jr, 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. 4. ZIMMERHACKL LB, HOFER J, CORTINA G, et al. Prophylactic eculizumab after renal transplantation in atypical hemolyticuremic syndrome. N Engl J Med 2010: 362: 1746–1748. 5. 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. 6. NESTER C, STEWART Z, MYERS D, et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2011: 6: 1488– 1494. 7. KRID S, ROUMENINA LT, BEURY D, CHARBIT M, et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant 2012: 12: 1938–1944. 8. JOSZI M, HEINEN S, HARTMAN A, et al. Factor H and atypical hemolytic uremic syndrome: Mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol 2006: 17: 170–177. 9. Alexion Pharmaceuticals. Soliris (Eculizumab) Full Prescribing Information. Cheshire, CT: Alexion Pharmaceuticals, 2012. 10. MCDONALD SP, JONATHAN CC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004: 350: 2654–2662.
11. GROOTHOFF JW. Long-term outcomes of children with endstage renal disease. Pediatr Nephrol 2005: 20: 849–853. 12. FITZPATRICK MM, WALTERS MD, TROMPETER RS, DILLON MJ, BARRATT TM. Atypical (non-diarrhea-associated) hemolyticuremic syndrome in childhood. J Pediatr 1993: 122: 532–537. 13. TRAN H, CHAUDHURI A, CONCEPCION W, GRIMM PC. Use of eculizumab and plasma exchange in successful combined liverkidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediatr Nephrol 2014: 29: 477–480. 14. BRENNAN DC, DALLER JA, LAKE KD, CIBRIK D, DEL CASTILLO D, THYMOGLOBULIN INDUCTION STUDY GROUP. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006: 355: 1967–1977. 15. MOLLNES TE, FOSSE E. The complement system in traumarelated and ischemic tissue damage: A brief review. Shock 1994: 2: 301–310. 16. XIE L, NESTER CM, REED AI, ZHANG Y, SMITH RJ, THOMAS CP. Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: A case report. Transplant Proc 2012: 44: 3037–3040. 17. LEGENDRE CM, LICHT C, MUUS P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013: 368: 2169–2181. 18. VALOTI E, ALBERTI M, NORIS M. Posttransplant recurrence of atypical hemolytic uremic syndrome. J Nephrol 2012: 25: 911–917. 19. Le QUINTREC M, ZUBER J, MOULIN B, et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013: 13: 663–675. 20. NORIS M, REMUZZI G. Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 2013: 22: 704–712.
E189
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12290
Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation Ranch D, Crowther B, Arar M, Assanasen C. (2014) Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic 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 kidney transplantation in a three-yr-old child with aHUS due to complement factor H mutation, using only prophylactic eculizumab treatment prior to transplant. She developed disease exacerbation in the immediate post-operative period despite having therapeutic eculizumab concentrations and evidence for complete complement pathway blockade. The patient responded well to additional doses of eculizumab and has maintained excellent graft function and disease control in the first year post-transplantation. The optimal dosing scheme for eculizumab in the perioperative period remains to be determined. More sensitive biomarkers of early disease activity are needed to improve disease monitoring. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined.
aHUS is a disease of complement pathway dysregulation, leading to excessive complement activation and endothelial injury. This results in acute renal failure due to TMA, but can also involve other organ systems including the central nervous system. There are several known genetic mutations associated with aHUS; the most CFH is produced by the liver and plays a major role in the regulation of the alternative pathway (1). In patients with CFH deficiency, 70–80% of patients eventually develop ESRD or death. The rate of disease recurrence in renal transplant recipients is high (80–90%), and therapies such as plasma exchange and combined kidney/liver transplantation have had suboptimal outcomes (2). More recently, eculizumab, a C5 monoclonal antibody, has been shown to be
Abbreviations: aHUS, atypical hemolytic uremic syndrome; BUN, blood urea nitrogen; CFH, complement factor H; CFI, complement factor I; ESRD, end-stage renal disease; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy.
Daniel Ranch1, Barrett Crowther2, Mazen Arar1 and Chatchawin Assanasen1 1
Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA, 2 Department of Pharmacy Services, University Hospital, San Antonio, TX, USA Key words: atypical hemolytic uremic syndrome – complement factor H – eculizumab – pediatric kidney transplantation Daniel Ranch, Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl, MC 7813, San Antonio, TX 78229, USA Tel.: 210 562 5365 Fax: 210 358 2095 E-mail: [email protected] Accepted for publication 17 April 2014
effective in blocking terminal complement pathway activation and membrane attack complex formation. For patients with ESRD, it has significantly altered the disease course allowing for kidney transplantation without the risk of disease recurrence. In some instances, eculizumab has been used to treat disease recurrence after kidney transplantation in pediatric patients, but prophylactic eculizumab treatment prior to transplantation is relatively new (3–7). However, the optimal timing and duration of therapy is not yet known. We report the case of a three-yrold girl with aHUS due to a factor H mutation, who received a deceased-donor kidney transplant after prophylactic eculizumab treatment. Case
Our patient initially presented to a referring hospital as a seven-month-old baby girl with acute gastroenteritis. There she was found to have oliguric acute kidney injury due to presumed STEC HUS and was transferred to a second facility for acute dialysis. She did have documented thrombocytopenia and hemolytic anemia at that time, E185
Ranch et al.
which seemed to slowly improve. There was no documentation of bloody diarrhea, stool occult blood was negative, and there was no positive pathogenic stool culture recorded. Serum C3 and C4 were normal, and a kidney biopsy was not carried out at the time. She was maintained on peritoneal dialysis for about three wk, but did not show signs of renal function recovery, so she was transferred for further management. At our hospital, the patient was still in renal failure, with a BUN 23 mg/dL and serum creatinine 4.8 mg/dL, and a renal ultrasound showed diffusely echogenic kidneys. She was discharged home after one wk of peritoneal dialysis education and training. However, she returned a couple of weeks later with pallor and petechiae, and laboratory testing revealed severe anemia, thrombocytopenia, and schistocytes on her peripheral blood smear. Her serum C3 was mildly decreased at 69 mg/dL. No ADAMTS13 assay was done. Due to the recurrence of MAHA, mutational analysis for aHUS was carried out, which revealed a heterozygous mutation in the CFH gene (c.3572C>G, p.Ser1191Trp), resulting in impaired CFH binding (8). CFI gene analysis was normal. However, anti-CFH antibody testing was not done. She was subsequently maintained on chronic dialysis for ~2 yr, during which time she did not have laboratory evidence for ongoing intravascular hemolysis. However, she did continue to have poorly controlled hypertension, an episode of Bell’s palsy, and delayed developmental milestones. At that time, the initial reports of eculizumab for treatment of atypical HUS recurrence in pediatric renal transplant patients began to appear in the literature (3). These were followed by reports of prophylactic eculizumab treatment in pediatric renal transplant patients to prevent recurrence, with promising results (4–6). Due to concerns for the aHUS affecting her neurocognitive development in addition to her ESRD, we were able to obtain approval for eculizumab treatment and she was activated on the renal transplant waiting list after her treatments had started. The patient received meningococcal vaccination about two wk prior to eculizumab initiation. Pre-transplant treatment course
Seven months prior to renal transplant, our patient was started on eculizumab infusions, receiving 600 mg as her initial dose, followed by 300 mg one wk later, then 300 mg every two wk thereafter. Her weight at the time of drug initiation was 10 kg. She tolerated her infusions well, with no significant adverse reactions. Prior E186
to and during her treatment course, her platelets remained normal, but her serum LDH remained slightly increased until one month before transplant. Her serum haptoglobin remained within normal limits. Total complement (CH50) activity was suppressed, and serum C3 remained normal. Peri- and post-operative course
On the day of her deceased-donor renal transplant, the patient received eculizumab 300 mg a few hours prior to surgery. Her weight at the time of surgery was 13 kg. Her previous maintenance eculizumab dose of 300 mg had been given 11 days prior. She did not receive any prior plasma exchange or plasma infusion. The patient also received rabbit antithymocyte globulin 1.5 mg/kg/dose intra-operatively for transplant induction due to high panel reactive antibodies, as well as on post-operative days 1 and 2. Her intra-operative course was uneventful, and allograft urine output was good. Initial laboratory tests at two h post-surgery showed that her serum creatinine had already decreased to 2.73 mg/dL from 5.75 mg/dL preoperatively; however, her platelets had decreased from 166 000/mm3 to 83 000/mm3 in the same time period (Fig. 1). Also, her serum LDH at that time increased to 444 U/L and serum haptoglobin was undetectable. Her hemoglobin was 16.4 g/dL, which was after a blood transfusion in the OR. The next morning, approximately 12 h later, her serum creatinine improved further to 0.22 mg/dL, but platelets decreased to 73 000/mm3, LDH increased to 570 U/L, and serum C3 decreased to 56 mg/dL from 92 mg/dL pre-operatively. Her urine was clear, but she did have microscopic hematuria. Her peripheral blood smear was reviewed with the hematologist, and no schistocytes were detected. On post-operative day 2, serum creatinine was 100 lg/mL. Since her renal transplant, her kidney function has been stable and she continues on maintenance dosing of eculizumab. Subsequent laboratory testing has not revealed evidence for recurrence of MAHA, her serum eculizumab levels have remained above 100 lg/mL, and her functional C5 assay results show continued pathway blockade. Also, she has been enrolled in the aHUS registry (clinicaltrials.gov ID: NCT01522183), which collects clinical and laboratory data to assess the long-term manifestations of TMA complications of her aHUS as well as other clinical outcomes. Discussion
The advent of eculizumab for the treatment of aHUS has made kidney transplantation a viable option for patients with ESRD due to complement dysregulation. This development is especially important for affected children, as kidney transplantation provides the best long-term survival compared with chronic dialysis therapy (10, 11). In our patient, eculizumab treatment was started prior to transplant not only to prevent disease recurrence in the graft, but also due to concerns for central nervous system damage, as
it is known that genetic HUS has detrimental effects on other organ systems (12). Others have reported success with eculizumab treatment prior to kidney transplantation in pediatric patients. Nester et al. reported successful living unrelated kidney transplantation in a child with a hybrid CFH/CFHR1 gene mutation and ESRD. Their patient was treated with plasma exchange and eculizumab one wk prior to surgery and then again on the day prior to surgery. Complement C5 functional assay results showed pathway blockade, and a post-transplant kidney biopsy did not show evidence of TMA (6). Weitz et al. reported a child with CFH mutation and ESRD who was started on eculizumab without plasma therapy and received a deceased-donor kidney transplant three wk afterward. The patient did well except for increased complement activity in the second week post-transplant, attributed to BK polyoma virus infection which responded to cidofovir (5). Krid et al. reported a child with a hybrid CFH/CFHR1 gene mutation and ESRD who was maintained on biweekly plasma infusions and then received a deceased-donor kidney. He was given eculizumab two h prior to surgery and again on post-operative day 1; his last plasma infusion was two wk prior. Three posttransplant biopsies were performed for increased creatinine, and no signs of TMA were present; however, the third biopsy at day 104 revealed antibody-mediated rejection which responded to treatment (7). Additionally, Tran et al. reported a five-yr-old female with CFH mutation and ESRD, who received a deceased-donor combined liver–kidney transplant with perioperative eculizumab and plasma exchange. The patient E187
Ranch et al.
received one dose of eculizumab immediately prior to transplant and one other dose on postoperative day 0 after transplant. A six-month post-transplant protocol biopsy did not show evidence of aHUS recurrence or rejection (13). In the immediate post-operative period, our patient showed evidence for disease exacerbation despite having received eculizumab a few hours before surgery. Our patient developed prolonged thrombocytopenia, a known complication of antithymocyte globulin (14). This likely contributed to our patient’s laboratory findings; however, our patient also showed evidence for recurrence of MAHA, which was more likely due to her aHUS. Complement activation with surgical trauma is well documented, and at that time, we believed that the pre-operative eculizumab dose would prevent this (15). Xie et al. reported post-operative hemolysis in an adult kidney transplant patient treated with prophylactic eculizumab that was attributed to extravascular hemolysis due to opsonization of C3b-bearing erythrocytes (16). However, their patient did not have thrombocytopenia or schistocytes as was seen in our patient. Further studies are needed to determine the optimum dosing, timing, and/or frequency of eculizumab in the perioperative period. Our patient responded quickly to the additional dose given on post-operative day 2, with rapid improvement of her hemolysis markers and stabilization of her platelet count. A related issue is how to best detect early disease activity in these patients. Traditional markers such as platelets, LDH, and creatinine become abnormal late in the disease process, after the damage is already done. An assay for functional C5 is available, which demonstrates the mean hemolytic activity based on a validated pharmacodynamics assay that quantified the complement activity in serum by measuring the degree of hemolysis. The measure of hemolysis is the amount of hemoglobin release as determined by means of spectrophotometer (17). However, in our patient, disease exacerbation was evident despite the assay results showing pathway blockade. Also, minimal eculizumab concentrations of 50–100 lg/mL have been reported to achieve complete complement blockade (17). In our patient, random drug levels were consistently above this threshold; however, disease exacerbation still occurred. This may suggest the need for higher eculizumab levels during surgery and other strong triggers of complement activation. Thus, development of biomarkers that can detect early disease activation will be of the utmost importance in the monitoring of disease control E188
in these patients. Unpublished data suggest that serum free C5 levels may be a better marker of terminal C5 inhibition in the setting of eculizumab administration (Personal communication, Sept. 2013 and March 2014, Dr. Camille Bedrosian, Alexion Pharmaceuticals). Finally, the duration of eculizumab treatment in patients with aHUS is not known. Therapy will probably become tailored to individual mutational phenotypes in the future. Otherwise, complement dysregulation is an ongoing process in these patients, despite normal laboratory parameters. Discontinuation of the drug has resulted in disease exacerbation, and so, these patients likely will require lifelong therapy (18–20). Factors that need to be considered with chronic eculizumab treatment include potential complications, such as increased risk for meningococcal and other encapsulated bacterial infections, as well as the cost of therapy compared with other treatment modalities. However, it is known that mortality in untreated patients is high, and eculizumab offers the best option at this time. In conclusion, we report a successful case of renal transplantation in a pediatric patient with aHUS due to CFH, using prophylactic eculizumab treatment and without plasma therapy. She developed disease exacerbation from complement overactivity immediately after transplant with a rapid response to eculizumab, despite confirmation of presumed adequate dosing using traditional biomarkers. The optimal dosing scheme in the immediate pre- and post-transplant period needs to be determined. Also, biomarkers for early disease activation need to be developed to help prevent organ damage, as traditional markers may not be adequately sensitive or specific in the post-operative period. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined. Acknowledgments We would like to thank Dr. Carla Nester, University of Iowa, 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 National Experts Advisory Board Meeting held by Alexion Pharmaceuticals. MA has participated in a TMA/aHUS National Experts Advisory Board Meeting held by Alexion Pharmaceuticals. CA is on the Alexion Pharmaceuticals Speaker’s Bureau.
Eculizumab in aHUS and kidney transplantation
References 1. CAPRIOLI J, NORIS M, BRIOSCHI S, et al. Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006: 108: 1267–1279. 2. NORIS M, REMUZZI G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009: 361: 1676–1687. 3. AL-AKASH SI, ALMOND PS, SAVELL VH Jr, 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. 4. ZIMMERHACKL LB, HOFER J, CORTINA G, et al. Prophylactic eculizumab after renal transplantation in atypical hemolyticuremic syndrome. N Engl J Med 2010: 362: 1746–1748. 5. 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. 6. NESTER C, STEWART Z, MYERS D, et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2011: 6: 1488– 1494. 7. KRID S, ROUMENINA LT, BEURY D, CHARBIT M, et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant 2012: 12: 1938–1944. 8. JOSZI M, HEINEN S, HARTMAN A, et al. Factor H and atypical hemolytic uremic syndrome: Mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol 2006: 17: 170–177. 9. Alexion Pharmaceuticals. Soliris (Eculizumab) Full Prescribing Information. Cheshire, CT: Alexion Pharmaceuticals, 2012. 10. MCDONALD SP, JONATHAN CC. Long-term survival of children with end-stage renal disease. N Engl J Med 2004: 350: 2654–2662.
11. GROOTHOFF JW. Long-term outcomes of children with endstage renal disease. Pediatr Nephrol 2005: 20: 849–853. 12. FITZPATRICK MM, WALTERS MD, TROMPETER RS, DILLON MJ, BARRATT TM. Atypical (non-diarrhea-associated) hemolyticuremic syndrome in childhood. J Pediatr 1993: 122: 532–537. 13. TRAN H, CHAUDHURI A, CONCEPCION W, GRIMM PC. Use of eculizumab and plasma exchange in successful combined liverkidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediatr Nephrol 2014: 29: 477–480. 14. BRENNAN DC, DALLER JA, LAKE KD, CIBRIK D, DEL CASTILLO D, THYMOGLOBULIN INDUCTION STUDY GROUP. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006: 355: 1967–1977. 15. MOLLNES TE, FOSSE E. The complement system in traumarelated and ischemic tissue damage: A brief review. Shock 1994: 2: 301–310. 16. XIE L, NESTER CM, REED AI, ZHANG Y, SMITH RJ, THOMAS CP. Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: A case report. Transplant Proc 2012: 44: 3037–3040. 17. LEGENDRE CM, LICHT C, MUUS P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013: 368: 2169–2181. 18. VALOTI E, ALBERTI M, NORIS M. Posttransplant recurrence of atypical hemolytic uremic syndrome. J Nephrol 2012: 25: 911–917. 19. Le QUINTREC M, ZUBER J, MOULIN B, et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013: 13: 663–675. 20. NORIS M, REMUZZI G. Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 2013: 22: 704–712.
E189
