Critical appraisal of eculizumab for atypical hemolytic uremic syndrome

Figures & data

Table 1 Criteria for response to eculizumab in prospective trials

Inhibition of “complement-mediated TMA” (progressive TMA trial)^Citation30	TMA event-free status (longstanding TMA trial)^Citation31
Normal platelet count and normal LDH level sustained for at least two consecutive measurements over a period of at least 4 weeks	No decrease in platelet count of >25%, no plasma exchange or infusion use, no initiation of dialysis, and normalization of hematologic values (a normal platelet count and LDH level, sustained for at least two consecutive measurements over a period of at least 4 weeks)
Secondary end points included measures of renal function, changes in health-related quality of life, pharmacokinetics and pharmacodynamics, and safety and tolerability	Secondary end points included measures of kidney function, changes in health-related quality of life, pharmacokinetics and pharmacodynamics, and safety and tolerability

Abbreviations: LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.

Table 2 Anecdotal case reports using eculizumab in aHUS in adults

Author (year)	Population and complement-amplifying condition	Number of patients treated with eculizumab	Outcome with eculizumab
Sevinc et al (2015)^Citation46	Woman aged 32 years with plasma-resistant aHUS and infection	1	Hematologic recovery; stopped dialysis after 3 months
Thajudeen et al (2013)^Citation47	Man aged 51 years with eculizumab first-line treatment and trauma	1	Hematologic recovery; stopped dialysis after 2.5 months
Sengul Samanci et al (2015)^Citation45	Man aged 51 years with plasma-resistant aHUS and severe hypertension	1	Hematologic recovery; remained dialysis dependent
Rafiq et al (2015)^Citation42	Woman aged 59 years with recurrent TMA and accelerated hypertension/illicit drug use	1	Noncompliant and lost to follow-up
Nguyen et al (2014)^Citation39	Man aged 62 years with CKD3, DM2, and biopsy with IgA vasculitis relapse of TMA despite 14 days of PE and 1 month of rituximab	1	Hematologic recovery; remained dialysis dependent
Rigothier et al (2015)^Citation43	Adult with distal angiopathy and ESRD	1	Remission of distal angiopathy; hematologic recovery; successful kidney transplantation
Ohanian et al (2011)^Citation40	Woman aged 50 years with ischemic colitis and neurologic impairment	1	Renal and neurologic improvement after third dose; hematologic improvement after sixth dose
Salem et al (2013)^Citation44	Woman aged 66 years with shigatoxin-negative bloody diarrhea, seizures, and coma	1	Stopped dialysis after third dose; neurologic recovery at week 7
Povey et al (2014)^Citation41	Woman aged 21 years with neurologic involvement (PRES) and past history of TMA	1	Neurologic and hematologic recovery; stopped dialysis after 3.5 months
David et al (2013)^Citation36	Woman aged 23 years with SRD and TMA unresponsive to PE and steroids and third trimester of pregnancy	1	Hematologic and kidney recovery; complete resolution of SRD, and eyes remained stable at 2-month follow-up
Ardissino et al (2013)^Citation34 Mussoni et al (2014)^Citation38	Woman aged 26 years with relapse of TMA after 39 sessions of PE during pregnancy and strong family history of aHUS	1	Eculizumab infused at 26th week of pregnancy with hematologic and kidney recovery; patient delivered a healthy baby girl at 38th week with no signs of TMA
Zschiedrich et al (2013)^Citation49	Woman aged 31 years with plasma-resistant postpartum aHUS	1	Eculizumab started at day 18 after diagnosis with full clinical resolution and creatinine 1.0 mg/dL
Tsai and Kuo (2014)^Citation48	aHUS was defined by MAHA, thrombocytopenia, and renal failure with plasma ADAMTS13 activity >10%. Other causes of the syndrome of MAHA and thrombocytopenia, such as DIC, systemic autoimmune disorders, lupus anticoagulants, metastatic neoplasms, shigatoxin, or neuraminidase-associated HUS, were excluded Case 1: patient presented with bloody diarrhea negative for shigatoxins Case 2: patient presented 3 months after undergoing autologous HSCT for advanced multiple myeloma Case 3: patient had recurrent episodes of severe hypertension accompanied by mild renal insufficiency and MAHA for 4.5 years before he was found to have aHUS Case 4: patient presented at 22 weeks of her third pregnancy and was initially assumed to have preeclampsia; however, her disease persisted after termination of pregnancy Case 5: patient had kidney biopsy performed for renal failure at 3 weeks after her seventh triweekly course of chemotherapy with gemcitabine and carboplatin for metastatic cholangiocarcinoma	5	After eculizumab infusion, platelet count began to exhibit steady increase within 3 days in each of the 5 courses in cases 1–4 No increase in platelet count occurred in case 5 while she was being treated with eculizumab LDH normalized by day 14 in cases 3 and 4 and by day 70 in case 2; it did not normalize by day 21 in case 1 and by day 84 in case 5 Improvement of renal function by 1 stage was observed: By day 14 in case 4 By day 63 in case 3 By day 378 in case 2 (with further improvement by 1 stage by day 483)
Fakhouri et al (2014)^Citation37	19 patients who had received four or more weekly 900 mg infusions of eculizumab were identified through a query sent to all nephrology centers in France aHUS was defined as three or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 μmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of TMA features in a kidney biopsy specimen For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab	19	Median time between aHUS onset and eculizumab therapy initiation was 6 days (range, 1–60 days), and median time to platelet count normalization after eculizumab therapy initiation was 6 days (range, 2–42 days). At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent CKD, and 7 had normalized kidney function. At last follow-up (range, 4–22 months), 3 patients remained dialysis dependent, 7 had nondialysis-dependent CKD (estimated glomerular filtration rate, 17–55 mL/min/1.73 m^2), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls
Ardissino et al(2014)^Citation35	Three cases of patients with aHUS and CKD (case 3 post-kidney transplant) who developed skin lesions that completely recovered when disease-specific treatment was established One patient responded to plasma therapy, and 2 also received eculizumab	2	Complete recovery of active skin lesions and hematologic parameters after eculizumab treatment

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; CKD3, chronic kidney disease stage 3; DIC, disseminated intravascular coagulation; DM2, type 2 diabetes mellitus; ESRD, end-stage renal disease; HSCT, hematopoietic stem cell therapy; HUS, hemolytic uremic syndrome; IgA, immunoglobulin A; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; PE, plasma exchange; PRES, posterior reversible encephalopathy syndrome; SRD, serous retinal detachment; TMA, thrombotic microangiopathy.

Table 3 Anecdotal case reports of use of eculizumab in children and adolescents with aHUS

Author (year)	Case presentation and complement-amplifying condition	Number of patients treated with eculizumab	Outcome with eculizumab
Diamante Chiodini et al (2014)^Citation60	Boy aged 8 years with shigatoxin-negative bloody diarrhea and severe neurologic impairment resistant to plasma therapy	1	Eculizumab started on day 37 with complete recovery of neurologic and hematologic parameters and improvement in kidney function (stopped dialysis after first dose)
Coppo et al (2015)^Citation58	Girl aged 4 years with lupus nephritis resistant to conventional therapy and features of aHUS	1	Prompt remission of vasculitis, proteinuria, and hematuria; normalization of renal function; 2 attempts to withdraw eculizumab followed by severe relapses and rescued by reinstating treatment; received eculizumab treatment for >17 months without relevant side effects.
Vaisbich et al (2013)^Citation77	Boy aged 14 months with aHUS, hypertension, and proteinuria	1	Hematologic improvement; stopped dialysis after second dose of eculizumab
Hisano et al (2015)^Citation65	Boy aged 4 years with aHUS, nonoliguric kidney injury, macrohematuria, and anti-factor H antibodies	1	Macrohematuria disappeared after second dose; discharged with complete hematologic and kidney resolution
Noone et al (2012)^Citation71	Boy aged 13 years with post-kidney transplant TMA, AMR, and aHUS	1	Kidney function recovery with AMR treatment and eculizumab; graft lost due to BK (polyomavirus) nephropathy
Cullinan et al (2015)^Citation59	Girl aged 8 months with aHUS and multiple TMA relapses treated with 212 sessions of PE; mother has aHUS	1	Patient treated with eculizumab for 52 months with complete remission and no relapses
Mache et al (2009)^Citation68	Boy aged 17.8 years with plasma-resistant aHUS	1	Hematologic recovery and partial kidney function improvement; eculizumab used only on relapses and progressed to ESRD
Belingheri et al (2014)^Citation54	Young male, first presentation at 6 months, remained with CKD until age 7 years, when PI was started because of relapses; remained with CKD, proteinuria, and hypertension	1	Eculizumab started at age 11 years with no more relapses; decrease in proteinuria, and no need for dialysis
Christmann et al (2014)^Citation57	Girl aged 5.5 months with aHUS and severe hypertension	1	Hematologic improvement on day 3; stopped dialysis 2 weeks after first dose
Dorresteijn et al (2012)^Citation61	Girl aged 6 years with aHUS treated initially with PE for 3 weeks, followed by PI; developed relapse during upper respiratory infection, and PE did not improve renal function despite platelet count normalization	1	Renal function started to improve 48 hours after first eculizumab dose; complete remission achieved until last follow-up 9 months later
Bekassy et al (2013)^Citation53	Girl aged 12 years with aHUS and kidney failure since age 20 months; bilateral nephrectomy and a lost graft due to aHUS; at 10 years of age, transient ischemic attack and occlusion of carotid arteries	1	Started eculizumab without overt TMA and despite being anephric. She received a successful kidney transplant and did not have progression of carotid lesions
Hu et al (2014)^Citation66	19-month-old girl with severe neurologic involvement and cardiomyopathy	1	Eculizumab infused 12 hours after admission. Normal echocardiography on day 15, stopped dialysis on day 18, and was discharged with mild hemiparesis, but completely alert
Tschumi et al (2011)^Citation76	Girl aged 9 years with plasma-dependent aHUS	1	Eculizumab started on day 126; PE was stopped and there were no relapses in 24 months of follow-up. Mild CKD due to fibrosis
Michaux et al (2014)^Citation70	Neonate aged 11 days with severe aHUS (myocardial impairment, respiratory failure, acute kidney disease requiring hemodiafiltration)	1	Early treatment with eculizumab as first-line therapy and completely recovered within 5 days. With >24 months of follow-up, renal function remains normal
Ohta et al (2015)^Citation72	Boy aged 4 months who developed aHUS; repeated plasma infusions and 9 sessions of plasmapheresis were ineffective. The patient initially required continuous hemodiafiltration and thereafter peritoneal dialysis	1	Eculizumab started on day 48 of diagnosis with improvement in hypertension, and dialysis was stopped on day 117. CKD2 at 17 months of follow-up
Ariceta et al (2012)^Citation51	Boy aged 28 days with plasma-resistant aHUS. He developed multiple intestinal perforations and leg skin necrosis due to systemic TMA	1	Within 48 hours of first eculizumab infusion, the patient recovered from acute kidney failure, with complete hematologic remission 2 weeks later
Al-Akash et al (2011)^Citation50	Boy aged 15 years with aHUS since age 16 months, ESRD and two failed kidney transplants	1	Eculizumab used as rescue of aHUS after the third kidney transplant with complete recovery of renal function 3 weeks after the first dose
Roman-Ortiz et al (2014)^Citation73	Boy aged 9 years presented with aHUS at age 3; irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite 5 hypotensive agents and bilateral nephrectomy	1	Kidney transplant performed with prophylactic eculizumab; after 3 years of continuous use, hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis
Cayci et al (2012)^Citation56	Girl aged 10 years with negative-culture bloody diarrhea and plasma-resistant aHUS	1	Eculizumab started on day 15 with diuresis improvement in 24 hours and complete hematologic and kidney recovery in 2 weeks
Lapeyraque et al (2011)^Citation67	Girl aged 7 years with aHUS. Weekly PI with short-term intensified PI during aHUS exacerbations was effective for 4.3 years; progressive mild renal failure (stage 2) and aHUS exacerbation unresponsive to intensified PI	1	Eculizumab was started with complete reversal of TMA after 1 week; no relapses and normal kidney function after 12 months of follow-up
Vilalta et al (2012)^Citation78	Girl aged 4 years with multiple severe clinical manifestations including acute kidney injury, dilated cardiomyopathy, and cardiorespiratory arrest; intense PE did not halt TMA manifestations	1	The initial single dose of eculizumab only temporarily improved the clinical symptoms of TMA; sustained improvement of renal, hematologic, and cardiac values were achieved only upon institution of chronic treatment with eculizumab (2.5 years)
Azukaitis et al (2014)^Citation52	Boy with first manifestation of aHUS at age 2 months and a relapse at age 10 months leading to ESRD despite PI. Remained hypertensive in dialysis and had convulsions at age 5.5 years, when stenosis of left carotid artery and bilateral middle cerebral arteries was diagnosed	1	At age 6.5 years received a kidney transplant under prophylactic eculizumab with no signs of post-transplant aHUS; evolved with seizures and cerebral ischemia on the fourth postoperative day, leading to death
Sharma et al (2015)^Citation75	Girl aged 28 days presented with plasma-resistant aHUS with gross hematuria and hypertension	1	After 1 dose of eculizumab, dialysis was discontinued and her hematologic parameters improved; after 11 months of follow-up, she remains on eculizumab and penicillin without recurrence of aHUS or any infectious complications
Besbas et al (2013)^Citation55	Newborn aged 5 days with aHUS and full renal and hematologic remission after PI. The patient was discharged with FFP infusions but subsequently developed 3 life-threatening disease recurrences at 1 month, 3 months, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions	1	Five days following the first dose of eculizumab, renal and hematologic parameters returned to normal range and blood pressure normalized; FFP infusions were gradually decreased and stopped; at the time of the report, the patient was 20 months of age and currently on eculizumab treatment every other week with completely normal renal and hematologic parameters
Giordano et al (2012)^Citation62	Boy aged 8 months with aHUS resistant to 21 PI and 15 PE treatments	1	Eculizumab first dose at age 12 months with hematologic improvement in 1 week and dialysis cessation in 5 days; no relapses and no PE/PI needed
Schalk et al (2015)^Citation74	Boy aged 3 years with aHUS and frequent relapses requiring PI	1	Started eculizumab and continued presenting relapses despite complement blockade; the authors decided to administer the medication immediately in times of immunologic triggers, such as immunizations or infections; at the time of report, the patient had been in a stable condition with an eGFR of 90 mL/min/1.73 m^2 and no further TMA events for more than a year
Gulleroglu et al (2013)^Citation64	Girl aged 11 years developed aHUS and was treated immediately with PE/PI. Although initial improvement in renal function was seen, patient showed progressing TMA despite daily PE, and neurologic manifestations developed after 1 month Girl aged 6 years developed cerebral TMA (seizures, vision loss, and nystagmus) 6 days after initial presentation and remained unresponsive to PE/PI	2	Treatment with eculizumab achieved complete control of neurologic symptoms within 24 hours and gradually normalized hematologic and renal parameters in both children
Malina et al (2013)^Citation69	Girl aged 4 years developed gangrene of the fingertips 2 days after initial presentation of aHUS. Renal function continued to decline despite daily PE, and she was started on peritoneal dialysis 5 days after admission. The distal tips of the left hand remained gangrenous with a line of demarcation. Three weeks later, she did not return for follow-up and died at home because of dialysis-related complications Another girl developed ESRD due to aHUS in the fourth month after birth. At age 9 months, she suddenly developed ischemic changes in fingers of both hands and several toes. The lesions progressed, and several fingertips became gangrenous despite intense PE therapy	1	Eculizumab was started on the second case and all non-necrotic digits rapidly regained perfusion. The 3 already gangrenous fingers healed with loss of the end phalanges; during maintenance, eculizumab aHUS activity subsided completely, and some late recovery of renal function was observed
Baskin et al (2015)^Citation22	Retrospective analysis of 15 children diagnosed with aHUS, which was defined as HUS negative for STEC Three patients had relapses, and 7 had a new diagnosis. Nine children had oliguria or anuria, and 8 required dialysis. Hypertension was observed in 6 patients. Neurologic involvement developed in 6 patients.	10	Ten were resistant to, or dependent on, plasma therapy and treated with eculizumab; following the start of eculizumab treatment, all patients achieved full recovery of renal function and hematologic parameters.
Gruppo and Rother (2009)^Citation63	Congenital aHUS: first manifestation at 8 days of life treated with PI; relapses at 3 months, 9 months, and 11 months of age; all treated with PI with good response after 2 weeks; fourth relapse at 18 months unresponsive to PE.	1	Eculizumab was initiated at day 35 of the fourth relapse with improvement in hemolysis in 48 hours and complete remission in 10 days (with no PE/PI)

Abbreviations: aHUS, atypical hemolytic uremic syndrome; AMR, antibody-mediated rejection; CKD, chronic kidney disease; CKD2, chronic kidney disease stage 2; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FFP, fresh frozen plasma; PE, plasma exchange; PI, plasma infusion; STEC, shigatoxin-producing Escherichia coli; TMA, thrombotic microangiopathy.

Table 4 Summary of case reports describing eculizumab both prior to and post-transplant to prevent TMA complications

Author (year)	Mutation status	Patient history	Transplant and post-transplant course	Eculizumab dosing	Outcome after starting eculizumab
Zimmerhackl et al (2010)^Citation98 Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79 Legendre et al^Citation30	CFH mutation	The patient was diagnosed with aHUS at age 4 years and treated with intermittent followed by continuous PD. Rapid deterioration of renal function at age 9 years required switch to HD.	First transplant from DD at age 9 years with daily PE on days 0–9. Good graft function with high urine output and normalization of SCr reported within 48 hours post-transplant.	Eculizumab 600 mg Q2W starting post-transplant on day 10 (ongoing).	No TMA complications reported over the next year with normalization of C3 levels, platelets, and haptoglobin. SCr of 46 μmol/L reported at last follow-up of 39 months.
Weitz et al (2011)^Citation96 Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH mutation	The patient was diagnosed with aHUS at age 6 months. Sudden presentation of TMA resulted in progression to ESRD within 2 months despite PE. The patient was maintained on dialysis for 7 years.	First transplant from DD at age 7 years without PE. Good graft function reported with SCr and urea rapidly falling to normal levels.	Eculizumab 600 mg on days −17, 0, and 1. Eculizumab 600 mg was administered 3 more times to suppress elevated C5b-9 levels. Maintenance with eculizumab 300 mg QW, then Q2W (ongoing).	No TMA complications reported over the following 7 months with normal SCr levels and no evidence of hemolysis. SCr of 44 μmol/L reported at last follow-up of 23 months.
Nester et al (2011)^Citation91 Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH/CFHR1 hybrid	The patient initially presented with aHUS at age 8 years and progressed to ESRD. Biopsy-confirmed TMA complications occurred 25 months after first transplant, and the patient initiated PE and HD.	Second transplant from LNRD at 12 years old with PE sessions on days −7 and −1. Graft function was established within hours of transplantation.	Eculizumab 900 mg on days −7 and −1 (after PE) and post-transplant on days 7 and 14. Maintenance with 900 mg Q2W thereafter (ongoing).	No TMA complications reported over the following 4 months with continuously declining SCr and normalization of hemolytic markers. SCr of 70 μmol/L reported at last follow-up of 16 months.
Krid et al (2012)^Citation88 Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH/CFHR1 hybrid	The patient initially presented with aHUS at age 4 years and rapidly progressed to ESRD despite PE.	First transplant from DD at age 7.5 years without PE/PI. Graft function was established within hours of transplantation with rapid normalization of SCr, platelets, and Hb.	Eculizumab 600 mg 2 hours before surgery and on day 1. Subsequent 600 mg doses administered QW for the first month and Q2W thereafter (ongoing).	Mixed rejection reported at 3 months post-transplant with biopsy-proven resolution at 15 months post-transplant. No TMA complications reported over the following 16 months with normal SCr levels.
Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	Complex CFH/CFHR1 hybrid	Patient diagnosed with aHUS at age 17 years and had no prior transplant history.	First transplant from DD at age 18 years with 6 PE sessions from days 0 to 5.	Eculizumab (dose not reported) started day 5 (ongoing).	No TMA complications and SCr of 87 μmol/L reported at last follow-up of 14 months.
Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	C3 mutation	The patient was diagnosed with aHUS at age 10 months and had no prior transplant history.	First transplant from DD at age 6.4 years without PE/PI.	Eculizumab (dose not reported) started at time of renal transplant (ongoing).	No TMA complications and SCr of 44 μmol/L reported at last follow-up of 4.5 months.
Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH mutation	The patient was diagnosed with aHUS at age 1 year and had no prior transplant history.	First transplant from DD at age 9 years without PE/PI.	Eculizumab (dose not reported) started at time of renal transplant (ongoing).	No TMA complications and SCr of 58 μmol/L reported at last follow-up of 4 months. CH50 remained below detection level with Q2W eculizumab maintenance.
Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH mutation	The patient was diagnosed with aHUS at age 3 years. One previous transplant was lost to aHUS.	Second transplant from DD at age 18 years with 1 PE session before the first eculizumab dose.	Eculizumab (dose not reported) started at time of renal transplant (discontinued).	Early arterial thrombosis occurred on day 1, and the graft was lost at day 3 post-transplant. This patient was ultimately successfully retransplanted under peritransplant eculizumab therapy.
Zuber et al (2012)^Citation82 Noris and Remuzzi (2013)^Citation79	CFH mutation	The patient was diagnosed with aHUS at age 33 years. Two previous transplants were lost to aHUS.	Third transplant from DD at age 41 years without PE/PI.	Eculizumab (dose not reported) started at time of renal transplant (ongoing).	Mixed rejection at 6 weeks post-transplant with biopsy-proven resolution 15 days later. No TMA complications and SCr of 176 μmol/L reported at last follow-up of 2 months.
Xie et al (2012)^Citation97	CFH mutation	The patient was diagnosed with aHUS at age 30 years and progressed to ESRD despite PE/PI.	First transplant from LNRD at age 31 years with PE on days −7 and −1. Graft function was established promptly after transplantation and SCr decreased from 10.8 mg/dL to 0.8 mg/dL at day 4.	Eculizumab 900 mg on day −7 and 1,200 mg on day −1 after PE. Post-transplant dosing was 900 mg QW for 2 weeks followed by 900 mg Q2W (ongoing).	No TMA complications reported with SCr of 0.88 mg/dL at last follow-up of 1 year.
Ažukaitis et al (2014)^Citation52	C3 mutation	The patient initially presented with aHUS at age 2 months. 10 months later a second TMA complication resulted in ESRD despite PI, and the patient started on PD. The patient experienced a stroke at age 5.5 years associated with suspected Moyamoya syndrome. The stroke resolved, and no neurologic complications were reported over the next year.	First transplant from DD at age 6.5 years without PE/PI. SCr decreased rapidly following transplant with no evidence of TMA.	Eculizumab 600 mg 5 hours before transplant, 300 mg 16 hours later, and 300 mg 5 days later.	Seizures occurred 4 days post-transplant, with massive irreversible ischemic lesions in the middle cerebral arteries. Neurologic status worsened and the patient died on post-transplant day 9 with well-functioning kidney grafts and no evidence of TMA. Author’s comment: “Whether the arterial stenoses could have been prevented by the initiation of eculizumab treatment at diagnosis of aHUS and the long-term maintenance of treatment is an open question.”
Parikova et al (2015)^Citation92	CFH mutation	The patient was diagnosed with aHUS at age 43 years and progressed to ESRD despite PE.	First transplant from LNRD at age 45 years without PE. Graft function was established immediately after transplant with rapid decrease in SCr from 10.6 mg/dL to 1.9 mg/dL by post-transplant day 4.	Eculizumab 900 mg QW initiated 2 months prior to transplant for 5 weeks, followed by 1,200 mg Q2W thereafter. 1,200 mg administered on the day of surgery prior to reperfusion and 900 mg 24 hours post-transplant. Induction with 900 mg QW for 4 weeks was repeated on post-transplant day 14 due to evidence of microangiopathic hemolysis and increased blood pressure. Maintenance with 1,200 mg Q2W (ongoing).	The patient had marked improvements in mental status and blood pressure after initiating eculizumab. No TMA complications reported with stable SCr of 1.7 mg/dL at 18 months post-transplant.
Ranch et al (2014)^Citation94	CFH mutation	The patient presented with aHUS at age 7 months and was maintained on chronic dialysis for 2 years.	First transplant from DD at age 3 years without PE/PI. Graft function was established post-transplant with good urine output and SCr decreasing from 5.75 mg/dL to 2.73 mg/dL at 2 hours post-transplant.	Eculizumab initiated 7 months prior to transplant, with 600 mg initial dose followed by 300 mg 1 week later and 300 mg Q2W thereafter. 300 mg administered a few hours prior to surgery and 2 days post-transplant. Induction with 600 mg QW for 2 weeks was repeated on post-transplant day 8 due to surgery-associated complement activation. Maintenance with 300 mg Q2W (ongoing).	Stable allograft function and complete terminal complement blockade with no evidence of TMA complications were reported at last follow-up.
Alasfar and Alachkar (2014)^Citation87	CFH mutation	The patient presented at age 25 years with aHUS and biopsy-confirmed TMA. Despite PE/PI, the patient progressed to ESRD and became HD-dependent.	First transplant from LNRD at age 28 years without PE/PI. Graft function was established immediately post-transplant with SCr decreasing to 1.0 mg/dL.	Eculizumab 1,200 mg initiated 24 hours prior to transplant. Induction with 900 mg QW for 4 weeks followed by maintenance with 1,200 mg Q2W starting week 5 (ongoing).	Stable allograft function and no evidence of TMA complications at last follow-up.
Alasfar and Alachkar (2014)^Citation87	Mutations in two CFHR genes	The patient presented at age 23 years with aHUS. Despite PE/PI, the patient progressed to ESRD and became dialysis-dependent. First transplant from LNRD was lost 2 years post-transplant due to TMA complications despite PE/PI.	Second transplant from DD at age 33 years without PE/PI. No evidence of hemolysis at time of transplant.	Eculizumab 1,200 mg 24 hours prior to transplant. Induction with 900 mg QW for 4 weeks followed by maintenance with 1,200 mg Q2W starting week 5 (ongoing).	Excellent allograft function and SCr of 0.5 mg/dL reported at last follow-up of 6 months.
Tran et al (2014)^Citation95	CFH mutation	The patient presented at age 11 months with aHUS and progressed to ESRD despite PE/PI. The patient experienced a cerebrovascular event with neurodevelopmental devastation and multiple episodes of peritonitis while on PD and was intolerant to HD.	Liver–kidney transplant performed at age 5 years from DD. PE was administered prior to surgery. Both organs functioned immediately post-transplant with decrease in SCr from 7.3 mg/dL to 2 mg/dL.	Eculizumab (dose not specified) prior to, and following, surgery (ongoing).	Biopsy performed 6 months post-transplant showed no evidence of rejection or TMA complications. SCr was reported stable between 0.5 mg/dL and 0.7 mg/dL with 19 month follow-up.
Matar et al (2014)^Citation90	No identified mutation	The patient progressed to ESRD due to aHUS diagnosed at age 45 years. The patient received a prior kidney transplant from a DD, which was lost to aHUS.	Second kidney transplant from LRD at age 51 years without PE/PI.	Eculizumab (dose not specified) started 24 hours prior to surgery and continued for 6 months (discontinued).	The patient maintained allograft function and had no reported TMA complications with 34 months of follow-up. SCr was 1 mg/dL and eGFR was 58 mL/min/1.73 m^2 at 1 year post-transplant.
Matar et al (2014)^Citation90	No identified mutation	The patient progressed to ESRD due to aHUS diagnosed at age 37 years.	First kidney transplant from LRD at age 38 years without PE/PI.	Eculizumab (dose not specified) started 24 hours prior to surgery and continued for 6 months (discontinued).	The patient maintained allograft function and had no reported TMA complications with 26 months of follow-up. SCr was 1.1 mg/dL and eGFR was 80 mL/min/1.73 m^2 at 1 year post-transplant.
Matar et al (2014)^Citation90	No identified mutation	The patient progressed to ESRD due to FSGS diagnosed at age 13 years. The patient received a prior kidney transplant from an LRD, which was lost after 9 years to aHUS.	Second kidney transplant from LNRD at age 40 years without PE/PI.	Eculizumab (dose not specified) started 24 hours prior to surgery and continued for 6 months (discontinued).	The patient maintained allograft function and had no reported TMA complications with 21 months of follow-up. SCr was 1.3 mg/dL and eGFR was 45 mL/min/1.73 m^2 at 1 year post-transplant.
Matar et al (2014)^Citation90	2 CFH mutations	The patient progressed to ESRD due to aHUS diagnosed at age 10 months. The patient received 3 prior kidney transplants, which were all lost to aHUS. The first allograft from a DD failed after 2 years, the second allograft from an LRD failed after 4 years, and the third allograft from an LRD failed after 5 years.	Fourth kidney transplant from LNRD at age 27 years without PE/PI.	Eculizumab (dose not specified) started 24 hours prior to surgery and continued as lifelong therapy (ongoing).	The patient maintained allograft function and had no reported TMA complications with 21 months of follow-up. SCr was 0.9 mg/dL and eGFR was 80 mL/min/1.73 m^2 at 1 year post-transplant.
Akchurin et al (2015)^Citation86	CFH	The patient presented at age 5 years and progressed to ESRD by the age of 6. While on dialysis, the patient experienced severe hypertension, seizures, PRES, pulmonary edema, and cardiac complications.	The patient received a nonrelated living donor kidney at the age of 10 years.	600 mg for 7 days and 1 day prior to transplant (induction dose for body weight between 20 kg and 30 kg). The third and fourth doses were given 1 week and 2 weeks post-transplant, after which dosing was transitioned to every other week.	The patient maintained allograft function and had no reported TMA complications with 9 months of follow-up. The patient had urine output immediately after the transplant, and by post-transplant day 2 the serum creatinine was 53.04 μmol/L.
Roman-Ortiz et al (2014)^Citation73	CFH/CFHR1 hybrid gene	The patient presented with aHUS at age 3 years with irreversible renal failure, uncontrolled hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite 5 hypotensive agents and bilateral nephrectomy.	Deceased donor kidney transplant was performed at age 6.	600 mg eculizumab pretransplant and a second dose within 24 hours of transplantation. Four additional weekly doses followed by fortnightly doses thereafter.	The patient maintained allograft function and had no reported TMA complications with 36 months of follow-up. The dose was adjusted for body weight to 900 mg per fortnight.
Mallett et al (2015)^Citation89	Unknown	Patient presented with a history of aHUS and previous graft loss to aHUS.	Second transplant with LRD.	Dosing with eculizumab 900 mg/wk for 4 weeks followed by 1,200 mg fortnightly ongoing were added to standard treatment with prednisolone, tacrolimus, and mycophenolate.	The patient maintained allograft function and had no reported TMA complications with 29 months of follow-up (creatinine 116 μmol/L).
Pelicano et al (2013)^Citation93	CFH	Patient aged 24 years was diagnosed with aHUS in April 2008. PE and corticosteroids were used with no improvement in kidney function, and HD was initiated 1 month later. The patient had inherited the CFH mutation from her asymptomatic mother, but her father had no relevant aHUS risk factors. Therefore, he was selected as a suitable living kidney donor.	In September 2011, the patient received a living-related donor kidney transplant.	Eculizumab 900 mg was given 1 week before the surgery with a further dose of 1,200 mg administered during the post-transplant period. Eculizumab continued at 900 mg/week for 4 weeks (the first dose on the day after the procedure). In the fifth week, the dose and interval were increased to 1,200 mg eculizumab every 2 weeks.	The patient maintained allograft function and had no reported TMA complications with 15 months of follow-up The recipient continues to receive maintenance treatment with eculizumab (1,200 mg) every 2 weeks.
Bekassy et al(2013)^Citation53	CFB CFI	Patient aged 12 years developed renal failure at the age of 20 months. She underwent bilateral nephrectomy and renal transplantation but lost the transplant due to recurrences. She was on hemodialysis for 7 years. At age 10 years, she developed a TIA and eculizumab was subsequently initiated.	The patient underwent a successful kidney transplant 9 months later.	600 mg/wk for 3 weeks followed by 600 mg every other week. On this treatment, the patient underwent a successful DD kidney transplant 11 months after the TIA without recurrence of HUS 1 year later. Current eculizumab dose is 900 mg every other week adjusted for the patient’s weight.	The patient maintained allograft function and had no reported TMA complications with 12 months of follow-up. No progression of vascular occlusion was noted within 1 year after the TIA by repeated imaging.

Abbreviations: aHUS, atypical hemolytic uremic syndrome; CFB, complement factor B; CFH, complement factor H; CFHR, complement factor H-related; CFI, complement factor I; DD, deceased donor; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FSGS, focal segmental glomerulosclerosis; Hb, hemoglobin; HD, hemodialysis; HUS, hemolytic uremic syndrome; LNRD, living nonrelated donor; LRD, living related donor; PD, peritoneal dialysis; PE, plasma exchange; PI, plasma infusion; PRES, posterior reversible encephalopathy syndrome; QW, once per week; Q2W, once every 2 weeks; SCr, serum creatinine; TIA, transient ischemic attack; TMA, thrombotic microangiopathy.

Table 5 Summary of case reports describing interrupted eculizumab use

Author (year)	Mutation status	Patient history	Transplant and post-transplant course	Time from TMA to eculizumab	Eculizumab dosing	Post-eculizumab course
Nurnberger et al (2009)^Citation83	CFH and CFHR1 mutations	The patient developed ESRD due to aHUS and received 5 years of dialysis. At age 25 years, the patient underwent DD kidney transplant, which was lost due to TMA complications presenting 5 weeks post-transplant, despite PE. Dialysis was resumed for 7 years.	Second renal transplant from DD at age 37 years. TMA complications presented 6 weeks post-transplant following 3 episodes of cellular rejection requiring additional tacrolimus. Platelet counts and renal function worsened despite 4 PE sessions. SCr prior to eculizumab was 1.49 mg/dL.	5 days	Eculizumab 600 mg (single dose).	Haptoglobin normalized after 8 days, platelet counts and SCr improved. Renal function reported stable at 8-month follow-up. After eculizumab discontinuation, TMA complications presented at 21 months, resulting in graft loss.
Larrea et al (2010)^Citation106 Loirat et al (2016)^Citation11	No identified mutation	The patient presented postpartum at age 20 years with biopsy-confirmed aHUS and progressed to ESRD and HD dependence.	First renal transplant from DD at age 22 years. The patient presented 12 days post-transplant with elevated SCr, thrombocytopenia, hemolytic anemia, and biopsy evidence of TMA, despite daily PE. SCr prior to eculizumab was 4.69 mg/dL.	9 days	Eculizumab 600 mg (single dose).	Hemolysis and platelets improved 36 hours after first dose, with normalization of renal function and platelet counts at 4 days. TMA complications presented at 11.5 months, and eculizumab was reinitiated with resolution of manifestations. Graft was lost after second eculizumab cessation following humoral rejection.
Alachkar et al (2012)^Citation99	No identified mutation	The patient presented at age 27 years with acute kidney injury, thrombocytopenia, and hemolytic anemia. Despite PE and high-dose corticosteroids, the patient progressed to ESRD and started on HD. Two years later, the patient received LRD transplant that was lost to aHUS 2 months post-transplant, despite PE.	Second renal transplant from living donor at age 32 years. Proteinuria developed at 28 days post-transplant, and biopsy showed evidence of TMA 10 weeks later. Renal function and hematologic parameters deteriorated despite PE. Oliguria and fluid overload developed, and HD was initiated.	2 weeks	Eculizumab 900 mg QW followed by 1,200 mg Q2W with 600 mg supplemental dose after each PE session (8 months).	Steady renal improvement and discontinuation of HD. Laboratory and clinical parameters normal over 8 months of treatment. TMA complications reported 5 months after discontinuation. Eculizumab restarted with improvement in SCr and Hb. Tubular necrosis developed 2 weeks later due to complications of an endovascular procedure, and graft was lost at 2 years post-transplant.
Zuber et al (2012)^Citation82	No identified mutation	The patient presented postpartum with aHUS. One previous kidney transplant lost to aHUS.	Second renal transplant received at age 43 years. TMA complications presented 8 days post-transplant. SCr prior to eculizumab was 1.99 mg/dL.	1 day	Eculizumab 900 mg QW followed by 1,200 mg Q2W (5 months). Restarted at a frequency of every other month (ongoing).	Hematologic parameters normalized, and SCr progrey2ssively improved. 3 months after eculizumab discontinuation, TMA complications presented following influenza vaccination. Eculizumab was resumed every other month. SCr was 1.39 mg/dL with 14 months of follow-up.
Chandran et al (2011)^Citation101	No identified mutation (no testing performed)	The patient progressed to ESRD secondary to diabetes mellitus and remained on dialysis for 3.5 years.	Combined pancreatic and renal transplant received at age 34 years. TMA complications presented 8 days post-transplant with worsening renal function despite daily PE. Biopsy showed features of AMR and TMA. SCr prior to eculizumab was ∼5 mg/dL.	6 days	Eculizumab 1,200 mg followed by a 900 mg dose 1 week later (2 doses).	Platelet count, LDH, and renal function improved rapidly within 2 days of starting eculizumab, and HD was discontinued. Normal LDH, platelets, and Hb reported at 4-month follow-up with SCr of 0.71 mg/dL.
Wilson et al (2011)^Citation108	No identified mutation	The patient had ESRD due to diabetic nephropathy.	Combined pancreatic and renal transplant received from DD at age 46 years. Evidence of renal dysfunction reported 26 days post-transplant. Biopsies showed borderline rejection on days 21 and 25, and evidence of TMA seen on day 41. Renal function continued to deteriorate despite 18 cycles of PE over 3 weeks.	3 weeks	Eculizumab 900 mg QW for 4 weeks (4 doses).	Platelet count and Hb increased within 24 hours of starting eculizumab. Renal function reportedly improved with 1 year of follow-up.
Matar et al (2014)^Citation90	CFH mutation	The patient progressed to ESRD due to aHUS diagnosed at age 36 years. The patient received 2 prior kidney transplants, both lost to aHUS. The first allograft from a DD never functioned post-transplant, and the second allograft from an LRD was lost after 6 months.	Third kidney transplant from LRD at age 38 years without PE/PI. TMA complications occurred at 6 years and 7 years post-transplant following bacterial infections.	Not reported	Eculizumab (dose not specified) was administered with PE/PI after each TMA complication. Lifelong therapy was initiated after the second TMA complication (ongoing).	Both TMA complications responded to eculizumab with restoration of graft function and normalization of laboratory parameters. The patient maintained allograft function and no further TMA complications were reported. SCr was 0.9 mg/dL and eGFR was 91 mL/min/1.73 m^2 at 1-year follow-up.
Matar et al (2014)^Citation90	No identified mutation	The patient progressed to ESRD due to aHUS diagnosed at age 28 years. The patient received 1 prior kidney transplant from LRD that was lost to aHUS after 1 year.	Second kidney transplant from LNRD at age 33 years without PE/PI. TMA complications occurred at 3 months and 17 months post-transplant.	Not reported	Eculizumab (dose not specified) was administered with PE/PI after each TMA complication (discontinued).	Both TMA complications responded to eculizumab. Allograft was lost at 23 months due to contrast nephropathy and acute tubular injury. SCr was 2.1 mg/dL and eGFR was 27 mL/min/1.73 m^2 at 1-year follow-up.
Matar et al (2014)^Citation90	2 CFH mutations	The patient progressed to ESRD due to an unclear primary diagnosis with hypertension.	First kidney transplant from DD at age 57 years without PE/PI. TMA complications occurred at 3 months post-transplant.	Not reported	Eculizumab (dose not specified) was administered with PE/PI (discontinued).	The patient did not recover allograft function and the graft was lost after 7 months.
Kransdorf et al (2014)^Citation105	No identified mutation	aHUS after heart transplantation in a woman aged 40 years.	Preoperative laboratory studies showed normal renal function, normal platelet count, and mild anemia (Hb 10.6 g/dL). After a 10-hour surgery, the patient returned to the intensive care unit, where she was noted to have TMA.	4 days	900 mg followed by 3 additional doses of eculizumab on a weekly basis, then every 2 weeks.	Renal function improved and renal replacement therapy was discontinued on POD 18. She was discharged home on POD 22. At 14 months post-transplant she developed acute kidney injury and underwent a renal biopsy to exclude recurrent aHUS. Histopathology showed moderate tubular injury without evidence of TMA. Eculizumab infusions were discontinued at that time. She had no further evidence of aHUS.
Pu and Sido (2014)^Citation107	Not identified	Patient aged 85 years with TMA after diarrhea with Pseudomonas aeruginosa but shigatoxin negative. She was aggressively treated with systemic antibiotics but developed mental status changes with seizure activity requiring protective intubation and acute renal failure needing HD.	NA	Not described	Eculizumab was administered 2 weeks after patient received meningococcal vaccine.	Her mental status, seizure activity, and kidney function dramatically improved after several doses of eculizumab. She was extubated and stopped HD after 2 weeks and 4 weeks of starting eculizumab therapy, respectively. Twelve weeks after receiving eculizumab therapy, she developed sepsis originating from a urinary tract infection. She was treated with intravenous antibiotics, and her eculizumab was discontinued. She has been off eculizumab for 12 months with a normal CBC profile, mental status, and kidney function.
Kourouklaris et al (2014)^Citation104	Not performed	31-week-pregnant young woman (aged 23 years), free of previous medical history, was admitted for an urgent cesarean section due to preeclampsia and presented with postpartum TMA. Intensive PE treatment was initiated (twice daily for 22 days) in parallel with dialysis, and her clinical condition transiently improved. Four months later, her renal function deteriorated again and aHUS was diagnosed.	NA	Not described	900 mg weekly eculizumab for 4 weeks, followed by 1 dose of 1,200 mg. A 6-week interruption of eculizumab treatment occurred due to drug accessibility, and the patient was managed with dialysis. Three months later, eculizumab was reinstated at 1,200 mg Q2W.	Following 2 doses of eculizumab, the patient presented with pneumonia), cardiac failure, and hypertensive crisis. She received treatment with antibiotics, diuretics, and antihypertensives, and eculizumab treatment was discontinued again due to patient’s decision. During this period, her anemia worsened, schistocytes were observed on the peripheral blood smear, LDH increased twofold, and renal function was compromised (creatinine 5.5 mg/dL). Eculizumab was reintroduced (4-dose induction phase followed by 1,200 mg every 2 weeks). Her creatinine and LDH levels decreased rapidly to normal ranges while her thrombocytopenia was also reversed until her last follow-up 2 years later.
De Sousa Amorim et al (2015)^Citation102	Homozygous carrier for CFH and MCP risk haplotypes	Patient aged 41 years was admitted 4 days after her first childbirth (uneventful pregnancy) for generalized edemas and asthenia. She presented with TMA, and renal replacement therapy was started 4 days later with diagnosis of postpartum aHUS. Daily PE with fresh frozen plasma was started on day 7 for 5 days, with an initial hematologic response without renal improvement.	NA	12 days	Induction schedule at a dose of 900 mg IV per week for 4 weeks, with discontinuation of PE.	Four days later, renal function improved and the patient remained dialysis free. A renal biopsy was performed on day 19, revealing TMA lesions. The patient was discharged and eculizumab was continued at a dose of 900 mg twice weekly, with complete recovery of renal function and no signs of hemolysis by week 4 of treatment. After 11 months, eculizumab was discontinued and close monitoring was performed. One year after eculizumab discontinuation, the patient remains well with normal renal function, no need for antihypertensive drugs, and no signs of aHUS recurrence.
Cañigral et al (2014)^Citation100	No identified mutation	Pregnant woman aged 32 years without relevant medical history presented at delivery with anemia, thrombocytopenia, and renal failure. After cesarean section, she developed severe bleeding that forced hysterectomy. An interstitial pattern up to middle lung fields was observed in the chest radiography leading to noninvasive mechanical ventilation. Treatment was started with PE and corticosteroids at a dose of 2 mg/kg per day with no response. ADAMTS13 activity was completely normal and the patient was diagnosed as having aHUS.	NA	Not described	Eculizumab was administered following an induction schedule at a dose of 900 mg IV per week for 4 weeks, followed by maintenance at a dose of 1,200 mg every 2 weeks. Apheresis was discontinued before the first dose of eculizumab.	In the first week, after initial induction dose, the platelet count increased above 150×10^3/μL. Creatinine and anemia diminished progressively. In outpatient follow-up, complete remission with normalization of creatinine levels was obtained after 2 doses of maintenance treatment. Eculizumab was discontinued after 6 months of treatment. One year after diagnosis, the patient remained in complete remission.
Gilbert et al (2013)^Citation103	Heterozygous mutation in CFB	A previously well female infant born to healthy, nonconsanguineous parents presented to her local hospital at the age of 4 months and was diagnosed with aHUS.	NA	7 days	300 mg of eculizumab 7 days after admission, followed 7 days later by a further dose and then doses at 3-week intervals.	She was discharged on hospital day 14, immediately after the second eculizumab infusion. The plasma LDH level remained persistently elevated, despite ongoing eculizumab therapy. The alternative, classical, and mannose-binding lectin complement pathways were all suppressed to <20% of normal activity (as assessed by CH50 and AP50 hemolytic assays), confirming drug action. The high levels of sC5b-9 were interpreted as indicating ongoing dysregulated complement activation. The dose was increased to 300 mg Q2W when the patient weighed only 9 kg, instead of adhering to the 10 kg limit recommended by the manufacturer. Six weeks after increasing the dose frequency, the sC5b- 9 concentration remained elevated at 167 ng/mL 2 weeks after the preceding dose. A trough plasma eculizumab concentration was then measured and found to be satisfactory at 347.2 μg/mL, with levels of >99 μg/mL considered to be therapeutic. The simultaneous plasma LDH was 734 IU/L.
Xie et al (2012)^Citation97	Heterozygous nonsense mutation in CFH reduced CFH plasma levels	Female patient aged 31 years with aHUS and acute kidney injury low C3 level and progression to ESRD despite plasma therapy and corticosteroids.	Pre-transplant: C5 functional activity and sMAC were suppressed after eculizumab infusion. Intraoperatively, she received a unit of platelets and a unit of packed RBCs because Hb fell from 8.4 g/dL to 6.2 g/dL. Post-transplant, her Hb fell from 8.3 g/dL to 5.9 g/dL and LDH was consistent with low-grade hemolysis. Haptoglobin remained normal, LDH remained mildly elevated for several days. sMAC remained low after surgery and functional C5 and CH50 levels were undetectable. Urine output increased and creatinine decreased preoperatively to 0.8 mg/dL by POD day 4.	Pretransplant	First dose of eculizumab (900 mg) intravenously after apheresis 1 week before transplantation; a second dose of 1,200 mg eculizumab was given after apheresis the day before transplantation. She completed induction phase with two weekly doses, then switched to maintenance phase every 2 weeks.	CMV infection that responded to valgancyclovir. One year after kidney transplantation, no anemia or hemolysis and serum creatinine was 0.88 mg/dL. On maintenance dose with undetectable CH50.
Ohanian et al (2011)^Citation40	Unknown	A previously described woman aged 50 years with aHUS had a remarkable recovery with eculizumab, which safely reversed profound neurologic damage and eliminated the need for dialysis.	NA	6 days	Initially eculizumab 900 mg Q4W. On week 5, she commenced maintenance therapy starting at 1,200 mg Q2W. Due to nausea and vomiting, the maintenance dose was reduced to 600 mg weekly (beginning with dose 7). After receiving 600 mg weekly for 9 doses, eculizumab was then reduced to 600 mg Q2W.	Six months after the initial diagnosis, the patient continued to have improved renal function on maintenance doses of eculizumab as low as 600 mg Q2W.

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; AMR, antibody-mediated rejection; CBC, complete blood count; CFB, complement factor B; CFH, complement factor H; CFHR, complement factor H-related; CMV, cytomegalovirus; DD, deceased donor; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Hb, hemoglobin; HD, hemodialysis; IV, intravenous; LDH, lactate dehydrogenase; LNRD, living nonrelated donor; LRD, living related donor; MCP, membrane cofactor protein; NA, not applicable; PE, plasma exchange; PI, plasma infusion; POD, postoperative day; QW, once per week; Q2W, once every 2 weeks; Q4W, once every 4 weeks; RBC, red blood cell; SCr, serum creatinine; sMAC, soluble membrane attack complex; TMA, thrombotic microangiopathy.

LegendreCMLichtCMuusPTerminal complement inhibitor eculizumab in atypical hemolytic-uremic syndromeN Engl J Med2013368232169218123738544

 PubMed Web of Science ®Google Scholar

LichtCGreenbaumLAMuusPEfficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studiesKidney Int20158751061107325651368

 PubMed Web of Science ®Google Scholar

SevincMBasturkTSahutogluTPlasma resistant atypical hemolytic uremic syndrome associated with a CFH mutation treated with eculizumab: a case reportJ Med Case Rep2015919225925370

 PubMedGoogle Scholar

ThajudeenBSussmanABracamonteEA case of atypical hemolytic uremic syndrome successfully treated with eculizumabCase Rep Nephrol Urol20133213914624570684

 PubMedGoogle Scholar

Sengul SamanciNAyerMErgenAOzturkSAn effective treatment of atypical hemolytic uremic syndrome with plasma exchange and eculizumab: a case reportTransfus Apher Sci201552331431625634788

 PubMed Web of Science ®Google Scholar

RafiqATariqHAbbasNShenoyRAtypical hemolytic-uremic syndrome: a case report and literature reviewAm J Case Rep20151610911425708146

 PubMedGoogle Scholar

NguyenMHMathewJJDenunzioTMCarmichaelMGDiagnosis of atypical hemolytic uremic syndrome and response to eculizumab therapyHawaii J Med Public Health2014739 suppl 1222425285252

 PubMedGoogle Scholar

RigothierCDelmasYRoumeninaLTDistal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAlambda antibodyAm J Kidney Dis201566233133626015278

 PubMed Web of Science ®Google Scholar

OhanianMCableCHalkaKEculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndromeClin Pharmacol2011351222287852

 PubMedGoogle Scholar

SalemGFlynnJMCatalandSRProfound neurological injury in a patient with atypical hemolytic uremic syndromeAnn Hematol201392455755823139014

 PubMed Web of Science ®Google Scholar

PoveyHVundruRJungleeNJibaniMRenal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysisClin Nephrol201482532633123557793

 PubMed Web of Science ®Google Scholar

DavidRHochberg-KleinSAmerRResolution of ocular involvement with systemic eculizumab therapy in atypical hemolytic-uremic syndromeEye (Lond)201327899799823722719

 PubMed Web of Science ®Google Scholar

ArdissinoGWally OssolaMBafferoGMRigottiACugnoMEculizumab for atypical hemolytic uremic syndrome in pregnancyObstet Gynecol20131222 pt 248748923884270

 PubMed Web of Science ®Google Scholar

MussoniMPVenezianoFABoettiLInnovative therapeutic approach: sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolytic-uremic syndromeTransfus Apher Sci201451213413625294113

 PubMed Web of Science ®Google Scholar

ZschiedrichSPragerEPKuehnEWSuccessful treatment of the postpartum atypical hemolytic uremic syndrome with eculizumabAnn Intern Med201315917623817717

 PubMed Web of Science ®Google Scholar

TsaiHMKuoEEculizumab therapy leads to rapid resolution of thrombocytopenia in atypical hemolytic uremic syndromeAdv Hematol2014201417 Article ID 295323

 Google Scholar

FakhouriFDelmasYProvotFInsights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 casesAm J Kidney Dis2014631404824021908

 PubMed Web of Science ®Google Scholar

ArdissinoGTelFTestaSSkin Involvement in atypical hemolytic uremic syndromeAm J Kidney Dis201463465265524290245

 PubMed Web of Science ®Google Scholar

Diamante ChiodiniBDavinJCCorazzaFEculizumab in anti-factor h antibodies associated with atypical hemolytic uremic syndromePediatrics20141336e1764e176824843055

 PubMed Web of Science ®Google Scholar

CoppoRPeruzziLAmoreADramatic effects of eculizumab in a child with diffuse proliferative lupus nephritis resistant to conventional therapyPediatr Nephrol201530116717225173358

 PubMed Web of Science ®Google Scholar

VaisbichMHHenriquesLSWatanabeAEculizumab for the treatment of atypical hemolytic uremic syndrome: case report and revision of the literatureJ Bras Nefrol201335323724124100744

 PubMedGoogle Scholar

HisanoMAshidaANakanoEAutoimmune-type atypical hemolytic uremic syndrome treated with eculizumab as first-line therapyPediatr Int201557231331725868950

 PubMed Web of Science ®Google Scholar

NooneDAl-MatrafiJTinckamKAntibody mediated rejection associated with complement factor h-related protein 3/1 deficiency successfully treated with eculizumabAm J Transplant20121292546255322681773

 PubMed Web of Science ®Google Scholar

CullinanNGormanKMRiordanMWaldronMGoodshipTHJAwanACase report: benefits and challenges of long-term eculizumab in atypical hemolytic uremic syndromePediatrics20151356e1506e150925941307

 PubMed Web of Science ®Google Scholar

MacheCJAcham-RoschitzBFremeaux-BacchiVComplement inhibitor eculizumab in atypical hemolytic uremic syndromeClin J Am Soc Nephrol2009481312131619556379

 PubMed Web of Science ®Google Scholar

BelingheriMPossentiITelFCryptic activity of atypical hemolytic uremic syndrome and eculizumab treatmentPediatrics20141336e1769e177124843058

 PubMed Web of Science ®Google Scholar

ChristmannMHansenMBergmannCSchwabeDBrandJSchneiderWEculizumab as first-line therapy for atypical hemolytic uremic syndromePediatrics20141336e1759e176324843059

 PubMed Web of Science ®Google Scholar

DorresteijnEMvan de KarNCCransbergKEculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet countPediatr Nephrol20122771193119522399074

 PubMed Web of Science ®Google Scholar

BekassyZDKristofferssonACCronqvistMEculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesionsNephrol Dial Transplant201328112899290724009284

 PubMed Web of Science ®Google Scholar

HuHNagraAHaqMRGilbertRDEculizumab in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvementPediatr Nephrol20142961103110624317637

 PubMed Web of Science ®Google Scholar

TschumiSGuggerMBucherBSRiedlMSimonettiGDEculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findingsPediatr Nephrol201126112085208821877169

 PubMed Web of Science ®Google Scholar

MichauxKBacchettaJJavouheyECochatPFremaux-BacchiVSellier-LeclercALEculizumab in neonatal hemolytic uremic syndrome with homozygous factor H deficiencyPediatr Nephrol201429122415241925149852

 PubMed Web of Science ®Google Scholar

OhtaTUrayamaKTadaYEculizumab in the treatment of atypical hemolytic uremic syndrome in an infant leads to cessation of peritoneal dialysis and improvement of severe hypertensionPediatr Nephrol201530460360825318620

 PubMed Web of Science ®Google Scholar

AricetaGArrizabalagaBAguirreMMorteruelELopez-TrascasaMEculizumab in the treatment of atypical hemolytic uremic syndrome in infantsAm J Kidney Dis201259570771022196848

 PubMed Web of Science ®Google Scholar

Al-AkashSIAlmondPSSavellVHJrGharaybehSIHogueCEculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutationPediatr Nephrol201126461361921125405

 PubMed Web of Science ®Google Scholar

Roman-OrtizEMendizabalOSPintoSLopez-TrascasaMSanchez-CorralPRodriguez deCSEculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid genePediatr Nephrol201429114915323982707

 PubMed Web of Science ®Google Scholar

CayciFSCakarNHancerVSUncuNAcarBGurGEculizumab therapy in a child with hemolytic uremic syndrome and CFI mutationPediatr Nephrol201227122327233122903728

 PubMed Web of Science ®Google Scholar

LapeyraqueALFremeaux-BacchiVRobitaillePEfficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndromePediatr Nephrol201126462162421161283

 PubMed Web of Science ®Google Scholar

VilaltaRLaraEMadridALong-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndromePediatr Nephrol201227122323232622890512

 PubMed Web of Science ®Google Scholar

AzukaitisKLoiratCMalinaMAdomaitieneIJankauskieneAMacrovascular involvement in a child with atypical hemolytic uremic syndromePediatr Nephrol20142971273127724352218

 PubMed Web of Science ®Google Scholar

SharmaSPradhanMMeyersKELe PalmaKLaskinBLNeonatal atypical hemolytic uremic syndrome from a factor H mutation treated with eculizumabClin Nephrol201584918118525816809

 PubMed Web of Science ®Google Scholar

BesbasNGulhanBKarpmanDNeonatal onset atypical hemolytic uremic syndrome successfully treated with eculizumabPediatr Nephrol201328115515822956028

 PubMed Web of Science ®Google Scholar

GiordanoMCastellanoGMessinaGPreservation of renal function in atypical hemolytic uremic syndrome by eculizumab: a case reportPediatrics20121305e1385e138823027168

 PubMed Web of Science ®Google Scholar

SchalkGKirschfinkMWehlingCA complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumabPediatr Nephrol20153061039104225752761

 PubMed Web of Science ®Google Scholar

GullerogluKFidanKHancerVSBayrakciUBaskinESoylemezogluONeurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumabPediatr Nephrol201328582783023389237

 PubMed Web of Science ®Google Scholar

MalinaMGulatiABaggaAMajidMASimkovaESchaeferFPeripheral gangrene in children with atypical hemolytic uremic syndromePediatrics20131311e331e33523230076

 PubMed Web of Science ®Google Scholar

BaskinEGullerogluKKantarABayrakciUOzkayaOSuccess of eculizumab in the treatment of atypical hemolytic uremic syndromePediatr Nephrol201530578378925384530

 PubMed Web of Science ®Google Scholar

GruppoRARotherRPEculizumab for congenital atypical hemolytic-uremic syndromeN Engl J Med2009360554454619179329

 PubMed Web of Science ®Google Scholar

ZimmerhacklLBHoferJCortinaGProphylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndromeN Engl J Med2010362181746174820445192

 PubMed Web of Science ®Google Scholar

ZuberJLe QuintrecMKridSEculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantationAm J Transplant201212123337335422958221

 PubMed Web of Science ®Google Scholar

NorisMRemuzziGManaging and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantationCurr Opin Nephrol Hypertens201322670471224076560

 PubMed Web of Science ®Google Scholar

WeitzMAmonOBasslerDKoenigsrainerANadalinSProphylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndromePediatr Nephrol20112681325132921556717

 PubMed Web of Science ®Google Scholar

NesterCStewartZMyersDPre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndromeClin J Am Soc Nephrol2011661488149421617085

 PubMed Web of Science ®Google Scholar

KridSRoumeninaLTBeuryDRenal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid proteinAm J Transplant20121271938194422494769

 PubMed Web of Science ®Google Scholar

XieLNesterCMReedAIZhangYSmithRJThomasCPTailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: a case reportTransplant Proc201244103037304023195022

 PubMed Web of Science ®Google Scholar

ParikovaAFronekJPViklickyOLiving-donor kidney transplantation for atypical haemolytic uremic syndrome with pre-emptive eculizumab useTranspl Int201528336636925256057

 PubMed Web of Science ®Google Scholar

RanchDCrowtherBArarMAssanasenCProphylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutationPediatr Transplant2014186E185E18924931815

 PubMed Web of Science ®Google Scholar

AlasfarSAlachkarNAtypical hemolytic uremic syndrome post-kidney transplantation: two case reports and review of the literatureFront Med (Lausanne)201415225593925

 PubMedGoogle Scholar

TranHChaudhuriAConcepcionWGrimmPCUse of eculizumab and plasma exchange in successful combined liver-kidney transplantation in a case of atypical HUS associated with complement factor H mutationPediatr Nephrol201429347748024221349

 PubMed Web of Science ®Google Scholar

MatarDNaqviFRacusenLCCarter-MonroeNMontgomeryRAAlachkarNAtypical hemolytic uremic syndrome recurrence after kidney transplantationTransplantation201498111205121224933457

 PubMed Web of Science ®Google Scholar

AkchurinODograSKaskelFJanDGreensteinSDel RioMPreemptive use of eculizumab for living-donor kidney transplantation in a child with atypical hemolytic uremic syndromeEinstein J Biol Med2015302225

 Google Scholar

MallettAHughesPSzerJAtypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohortIntern Med J201545101054106526247170

 PubMed Web of Science ®Google Scholar

PelicanoMBde CordobaSRDiekmannFAnti-C5 as prophylactic therapy in atypical hemolytic uremic syndrome in living-related kidney transplantationTransplantation2013964e26e2923958887

 PubMed Web of Science ®Google Scholar

NurnbergerJPhilippTWitzkeOEculizumab for atypical hemolytic-uremic syndromeN Engl J Med2009360554254419179328

 PubMed Web of Science ®Google Scholar

LarreaCFCofanFOppenheimerFCampistolJMEscolarGLozanoMEfficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantationTransplantation201089790390420386298

 PubMed Web of Science ®Google Scholar

LoiratCFakhouriFAricetaGAn international consensus approach to the management of atypical hemolytic uremic syndrome in childrenPediatr Nephrol2016311153925859752

 PubMed Web of Science ®Google Scholar

AlachkarNBagnascoSMMontgomeryRAEculizumab for the treatment of two recurrences of atypical hemolytic uremic syndrome in a kidney allograftTranspl Int2012258e93e9522591029

 PubMed Web of Science ®Google Scholar

ChandranSBaxter-LoweLOlsonJLTomlanovichSJWebberAEculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation – a case reportTransplant Proc20114352097210121693335

 PubMed Web of Science ®Google Scholar

WilsonCTorpeyNJaquesBSuccessful simultaneous liver-kidney transplant in an adult with atypical hemolytic uremic syndrome associated with a mutation in complement factor HAm J Kidney Dis201158110911221601332

 PubMed Web of Science ®Google Scholar

KransdorfEPKittlesonMMKobashigawaJAAtypical hemolytic-uremic syndrome immediately after heart transplantationJ Heart Lung Transplant201433666466524630405

 PubMed Web of Science ®Google Scholar

PuJJSidoASuccessful discontinuation of eculizumab therapy in a patient with aHUSAnn Hematol20149381423142524346709

 PubMed Web of Science ®Google Scholar

KourouklarisAIoannouKAthanasiouIPanagidouADemetriouKZavrosMPostpartum thrombotic microangiopathy revealed as atypical hemolytic uremic syndrome successfully treated with eculizumab: a case reportJ Med Case Rep2014830725219386

 PubMedGoogle Scholar

De Sousa AmorimEBlascoMQuintanaLSoleMde CordobaSRCampistolJMEculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing managementJ Nephrol201528564164525712233

 PubMed Web of Science ®Google Scholar

CanigralCMoscardoFCastroCEculizumab for the treatment of pregnancy-related atypical hemolytic uremic syndromeAnn Hematol20149381421142224306089

 PubMed Web of Science ®Google Scholar

GilbertRDFowlerDJAngusEHardySAStanleyLGoodshipTHEculizumab therapy for atypical haemolytic uraemic syndrome due to a gain-of-function mutation of complement factor BPediatr Nephrol20132881315131823624872

 PubMed Web of Science ®Google Scholar