Long-Term Outcome in a Pediatric Patient with Atypical Hemolytic Uremic Syndrome (aHUS) with Sustained Eculizumab (ECU) Treatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4682-4682 ◽  
Author(s):  
Ralph A. Gruppo ◽  
Bradley P Dixon
Keyword(s):  
Renal Function ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Efficacy And Safety ◽  
Off Label Use ◽  
Off Label ◽  
Serious Infections ◽  
Uremic Syndrome ◽  
Initial Hospitalization

Abstract Abstract 4682 Background. aHUS is a rare and life-threatening genetic disease characterized by systemic thrombotic microangiopathy (TMA) due to chronic, uncontrolled complement activation. Genetic mutation can be identified in only 50–70% of aHUS patients. Systemic TMA manifests as endothelial injury, hemolytic anemia, and platelet consumption, leading to multiorgan damage/failure. Despite chronic plasma exchange/infusion (PE/PI), >50% of aHUS patients die, require dialysis, or have permanent renal damage within 1 yr of diagnosis. Off-label use of eculizumab, a humanized high-affinity monoclonal antibody against complement protein C5, was previously reported to produce clinical remission of TMA in an 18-mo-old boy with a fourth relapse of aHUS (Gruppo et al, NEJM 2009). Results of more recent 26-wk, controlled, prospective, open-label, single-arm trials have demonstrated that eculizumab is effective in aHUS patients resistant to PE/PI or patients undergoing chronic PE/PI in inducing hematologic and TMA remission, restoring renal function, and improving QoL. No difference in response to eculizumab is seen in patients with or without an identified mutation. Long-term efficacy and safety outcomes for sustained eculizumab treatment of aHUS have not yet been reported. Aim. To provide a 3-yr follow-up of our previously-reported pediatric patient regarding the long-term efficacy and safety of eculizumab treatment for aHUS. Methods. Retrospective data collection analysis. Results. A 4-yr-old boy born at 34-wk gestation, initially presented with TMA at 4 d of age: Hg 8.5 g/dL, plt 18×109/L, BUN 34 mg/dL, Cr 1.0 mg/dL, LDH 6077 U/L (normal <920 U/L), and schistocytes on blood smear. Levels of ADAMTS13 activity and complement proteins C3–C9, factor H, factor I, and factor B were normal. Analysis of complement factor H, factor I, factor B, C3, MCP, and THBD genes did not identify any mutations; factor H autoantibody was not detected. PE/PI resulted in clinical improvement after 13 d. Relapses occurred at 3, 9, and 11 mo of age with remission occurring with re-institution of PE/PI. A fourth relapse occurred at 18 mo of age after discontinuation of plasma infusions. Despite daily plasmapheresis, severe TMA persisted with worsening renal function (BUN 62, Cr 3.2) and platelet count <25×109/L, requiring institution of hemodialysis. Following initiation of eculizumab therapy in this 12-kg infant, hematologic and renal improvement began within 48 hr and remission occurred within 10 d, allowing permanent discontinuation of dialysis and PE/PI. Eculizumab 600mg was administered every 2 wk and continued for 4 mo with sustained clinical remission, then reduced to the currently recommended weight-based dose of 300mg every 2 wk, with 36 mo of ongoing therapy; PK/PD blood sampling has confirmed sustained terminal complement blockade at both eculizumab dosages. Renal function has improved over time and been maintained to 36 mo (data cut-off). Despite normal growth, neurocognitive development is delayed likely secondary to germinal matrix hemorrhage during initial hospitalization. Bilateral sensorineural hearing loss possibly secondary to aminoglycoside antibiotic therapy during his initial hospitalization required bilateral cochlear implants. Eculizumab infusions have been well tolerated without adverse events. Despite 2 surgical procedures and minor upper respiratory infections, he has maintained normal hematologic and renal parameters with ongoing long-term eculizumab treatment, with no serious infections. Current Hg 12.2 gm/dL, HCT 34.5%, plt 211×109/L, Retic 0.8%, no schistocytes on blood smear, LDH 695 U/L, haptoglob 22 mg/dL (normal 16–200 mg/dL), BUN 20 mg/dL, Cr 0.4 mg/dL, and cystatin C GFR 108 mL/min. Urinalysis is negative for blood. Modest proteinuria (urine protein/Cr ratio 0.4 mg/dL) and hypertension (related to previous renal injury) is controlled with enalapril. The patient continues to receive penicillin prophylaxis. Conclusion: Long-term treatment with eculizumab has maintained complete continuous suppression of TMA and maintained normal renal function, with no adverse events or serious infections for 36 months of ongoing treatment for aHUS. Disclosures: Gruppo: Alexion Pharmaceuticals: Honoraria. Off Label Use: Eculizumab for treatment of atypical hemolytic uremic syndrome. Dixon:Regeneron Pharmaceuticals: Equity Ownership.

scholarly journals Long-term renal function under plasma exchange in atypical hemolytic uremic syndrome

2011 ◽  
Vol 26 (10) ◽  
pp. 1915-1916 ◽  
Author(s):  
Jean-Claude Davin ◽  
Jaap Groothoff ◽  
Valentina Gracchi ◽  
Antonia Bouts
Keyword(s):  
Renal Function ◽  
Hemolytic Uremic Syndrome ◽  
Plasma Exchange ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Uremic Syndrome

Long-term successful liver–kidney transplantation in a child with atypical hemolytic uremic syndrome caused by homozygous factor H deficiency

2016 ◽  
Vol 31 (12) ◽  
pp. 2375-2378 ◽  
Author(s):  
Emmanuel Gonzales ◽  
Tim Ulinski ◽  
Dalila Habes ◽  
Georges Deschênes ◽  
Véronique Frémeaux-Bacchi ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Factor H Deficiency ◽  
Uremic Syndrome

scholarly journals Clinical-Laboratory- Genetic Profile and Outcomes of Patients with Atypical Hemolytic Uremic Syndrome and Restrictive Use of Eculizumab: A Single Center Experience and a Brief Review

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3159-3159
Author(s):  
Fnu Amisha ◽  
Manojna Konda ◽  
Paras Malik ◽  
Arya Mariam Roy ◽  
Appalanaidu Sasapu
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Genetic Profile ◽  
Complement Factor ◽  
Single Center ◽  
Inclusion Criteria ◽  
Atypical Hus ◽  
Uremic Syndrome

Abstract Background Atypical HUS (aHUS) is a rare thrombotic microangiopathy (TMA) caused by complement dysregulation. Eculizumab is a humanized monoclonal antibody targeting against complement factor C5. Ravulizumab, a longer acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for treatment of aHUS in 2019. Here we describe the clinical presentation, laboratory, genetic profile, treatment along with long-term sequelae of patients diagnosed with aHUS. The outcomes of restrictive use of eculizumab and the use of ravulizumab were also studied. Materials and Methods We conducted a single center retrospective cohort study, searching electronic medical records of patients diagnosed and treated for aHUS at University of Arkansas for Medical Sciences, from January 1, 2013 to January 31, 2021, after IRB approval. Inclusion criteria :1) Presence of microangiopathic hemolytic anemia (MAHA) with thrombocytopenia 2) ADAMTS13 activity &gt; 10 % 3) Age &gt; 18. Exclusion criteria: 1) Age &lt; 18 years 2) TMA associated with hemolytic uremic syndrome, scleroderma renal crises, anti-phospholipid syndrome. Results Seventeen patients meeting the inclusion criteria were enrolled in the study. The mean age at diagnosis was 47.4 ± 17.9 years. Most of the patients were Caucasians (n=10, 58%) and females (n= 14, 82%). All the patients except one had acute kidney injury (AKI) at presentation (n=16, 94.1%), the most frequent extra-renal presentation was CNS involvement -seizures, confusion and altered mental status (n= 7, 41.2 %) followed by Gastrointestinal- non-bloody diarrhea, nausea and vomiting (n=5, 29.4 %) [Figure 1]. Lab investigations are described in [Table 1]. Complement genetic testing was done in 100% of study population. Factor H related genes 1/3 (CFHR1/3) and complement factor H (CFH) were the most commonly found pathogenic mutations [Table 2]. In this study, pregnancy and infection (n= 4, 23.5% each) were identified as the most common triggers [Figure 2]. For two of the patients, it was the first pregnancy and for the other two, it was their second and third pregnancies. They presented at the second, sixth, and sixteenth week postpartum respectively. Eleven (64.70%) patients developed chronic kidney disease (CKD) with six (35.29%) patients progressing to end stage renal disease (ESRD). Two (11.76 %) pregnant patients developed cardiomyopathy, two (11.76%) patients developed pulmonary complications (pneumonia and pulmonary hypertension) and three (17.64%) patients developed epilepsy. All the postpartum females in our study were able to breastfeed while on eculizumab with no long-term complications in the neonates. One patient had two subsequent deliveries with no ante, intra, or post-partum consequences or repeated triggers of aHUS. Fourteen patients (82.3%) received therapeutic plasma exchange, four (23.5%) patients received iv methyl prednisone (1mg/kg) and two (11.7%) patients received IVIg prior to initiating eculizumab. Over time, five (29.41%) patients opted to completely stop drug therapy and four patients (23.52%) chose to shift to ravulizumab because of the ease of treatment duration (every 8 weeks rather than every 2 weeks for eculizumab). All these nine patients remained in remission with stable hematologic and renal parameters on subsequent follow-ups [Table 3]. Three patients (17.6 % mortality) died in our study due to causes unrelated to aHUS. Conclusions: The clinical diagnosis of atypical HUS can be challenging especially with extra-renal manifestations. Females were four times more affected than males. PCMs were present in 11 patients. Early diagnosis and treatment with C5 inhibitors improves morbidity and mortality. The decision to discontinue or switch eculizumab to ravulizumab will likely decrease healthcare costs and improve patient compliance but should be based on disease severity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Tigecycline Use in Neonates: 5-Year Experience of a Tertiary Center

2018 ◽  
Vol 14 (03) ◽  
pp. 103-107 ◽  
Author(s):  
Mehmet Gunel ◽  
Erdal Ozbek ◽  
Mehmet İpek
Keyword(s):  
Pediatric Patients ◽  
Newborn Infants ◽  
Drug Resistant ◽  
Efficacy And Safety ◽  
Off Label Use ◽  
Off Label ◽  
Extensively Drug Resistant ◽  
Serious Infections ◽  
Tertiary Center ◽  
Alternative Drugs

AbstractThe off-label use of tigecycline to treat serious infections has been reported in pediatric patients. We report four newborn infants diagnosed with sepsis caused by extensively drug-resistant Klebsiella pneumoniae and successfully treated with tigecycline. If no alternative drugs are available, tigecycline may be considered as an option for nosocomial infections even in newborn infants. However, further reports are needed to establish its efficacy and safety.

Efficacy of Eculizumab in a Plasmatherapy-Dependent Patient with Atypical Hemolytic Uremic Syndrome with C3 Mutation Following Plasmatherapy Withdrawal

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4579-4579
Author(s):  
Valerie Chatelet ◽  
Veronique Fremeaux-Bacchi ◽  
Maxence Ficheux ◽  
Thierry Lobbedez ◽  
Bruno Hurault-Deligny
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Platelet Count ◽  
Hemolytic Uremic Syndrome ◽  
Complement Activation ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Renal Transplants ◽  
Uremic Syndrome

Abstract Atypical hemolytic uremic syndrome (aHUS) is a rare microangiopathic hemolytic anemia characterized by chronic intravascular hemolysis, consumptive thrombocytopenia, microvascular glomerular thrombosis and acute renal failure. Atypical HUS develops as the result of unregulated complement activation either through genetic abnormalities in one or more complement proteins or more rarely the development of autoantibodies to complement factor H. Complement dysregulation has been shown to cause cause subendothelium exposure and activation of platelets resulting in a chronic proinflammatory and prothrombotic state. The prognosis for aHUS is poor as 25% of patients die during acute phases of the disease and 50% progress to end-stage-renal disease. In addition, the majority of renal transplants result in loss of the graft. Plasmatherapy (PT), either plasmapheresis, plasma infusion, or both, is currently used in an attempt to control complement activation and thereby reduce the thrombotic microangiopathy (TMA) and declining renal function, but this therapy is cumbersome and not effective in all patients. Eculizumab, an antibody targeting complement C5, blocks activation of terminal complement and generation of the proinflammatory and prothrombotic molecules C5a and C5b-9. In previous studies eculizumab significantly blocked complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria, subsequently reducing thrombotic events and improving renal function. In this study, we report the first case of eculizumab treatment in a patient with recurrent aHUS after renal transplantation who refused further PT. The patient is a 42-year-old female diagnosed with a familial form of aHUS with a C3 mutation leading to a binding defect between C3b and the complement control molecules factor H and membrane cofactor protein. The patient showed reduced serum levels of C3c (670 mg/L) suggesting C3 consumption. The patient had received 2 previous renal transplants, the last of which was performed in 2004; aHUS recurred after each transplant and required PT. In March 2007 the patient experienced an acute episode of aHUS and received 2 intensive PT sessions (60 treatments over 9 mos) to resolve the recurrence. In April 2008, the patient presented with septicemia and acute renal failure and was hospitalized for 10 days. In May 2008 her platelet count dropped to 170 ×109/L, haptoglobin became undetectable (&lt; 0.15 g/L), and schistocytes increased to 3.7% suggesting an acute TMA exacerbation, confirmed by renal biopsy. Plasmatherapy was initiated with a course of high dose steroids and IV immunoglobulins. The administration of frequent PT treatments (16 treatments over 5 weeks) resulted in an improvement in the ongoing TMA. However, despite intensive PT, the patient continued to suffer from severe fatigue and daily episodes of diarrhea and chose to discontinue this therapy. As a result, disease deterioration was observed (see 10 Days of No PT in Table). The clinical deterioration established the need for an alternative treatment to reduce TMA and stabilize renal function. PT (3 treatments) was performed as a bridging treatment to eculizumab. Treatment with eculizumab was initiated 4 days following the last PT. The patient received a meningococcal vaccine 4 days prior to treatment with eculizumab and then prophylactic antibiotics (ciprofloxacin) after the vaccination. The patient received 4 doses of eculizumab, 900 mg IV approximately every 7 days, and then 1200 mg 7 days later, and is scheduled to receive chronic dosing at 1200 mg every 14 days. Platelet count, hemolysis and renal function were monitored. After one month of eculizumab treatment, and without concomitant PT, platelet count increased (range from 227 to 284 ×109/L), schistocytes decreased to 0.8% and haptoglobin increased to within normal limits (1.5 g/L; see “Ecu Dose 5”). Levels of C3c fluctuated between 420 and 690 mg/L, creatinine levels were stable and no further episodes of diarrhea were reported. In summary, the data suggest that chronic blockade of complement C5 with eculizumab maintained renal function and reduced platelet consumption and hemolysis without PT in a patient with aHUS previously dependent on frequent PT. Based on these results clinical trials are warranted to confirm the activity of eculizumab for the treatment of patients with recurrent aHUS that are dependent on PT.

Time To Hematologic and Renal Improvements In Atypical Hemolytic Uremic Syndrome Patients With Long Disease Duration and Chronic Kidney Disease (CKD) Treated With Eculizumab

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2186-2186
Author(s):  
Christoph Licht ◽  
Petra Muus ◽  
Christophe Legendre ◽  
Yahsou Delmas ◽  
Maria Herthelius ◽  
...  
Keyword(s):  
Renal Function ◽  
Platelet Count ◽  
Hemolytic Uremic Syndrome ◽  
Disease Duration ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Time Dependent ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Uremic Syndrome

Abstract Introduction Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening, chronic, and progressive disease of thrombotic microangiopathy (TMA). Plasma exchange/plasma infusion (PE/PI) has been shown to lack efficacy in patients (pts) with aHUS. Despite PE/PI, up to 65% of pts sustain permanent renal damage, progress to end-stage renal disease, or die within 1 year (yr) of diagnosis. Among aHUS pts with long disease duration and CKD receiving chronic PE/PI, significant improvements in hematologic parameters and renal function were achieved in a clinical trial of eculizumab (Ecu). The current analysis was undertaken to gain better insight into the timing of hematologic and renal improvements in a 26-week (wk), Phase 2 trial with a long-term extension. Methods aHUS pts ≥12 yrs of age with long disease duration and CKD receiving chronic PE/PI were enrolled. This analysis assessed the percentage of pts achieving each of the following outcomes – all for ≥2 consecutive measurements, ≥4 wks apart – at specific time points: Platelet count normalization (≥150x109/L); LDH ≤ULN; serum creatinine (Cr) decrease ≥25%; eGFR increase ≥15 mL/min/1.73 m2; and CKD improvement ≥1 Stage. Results 20 pts aged ≥12 yrs receiving long-term PE/PI were enrolled and treated with Ecu in a 26-wk, single-arm, Phase 2 trial, and 19 continued in the extension study. The median time (range) from aHUS diagnosis to screening was 48.3 months (0.7–285.8), and the median time from the current manifestation of aHUS to screening was 8.6 months (1.2–45). The median duration of Ecu treatment at the time of the data cut was 114 wks. Mean baseline values were as follows: platelet – 228x109/L; Hb – 10.7 g/L; LDH – 223 U/L; Cr – 287 μmol/L; and eGFR – 30.8 mL/min/1.73 m2. 3 pts had platelet counts <150 x109/L at baseline, and 4 had LDH levels >ULN. The timing and duration of the criteria-defined hematologic and renal improvements during continued treatment with Ecu are shown in Figure 1. At wk 4, the percentage of pts achieving platelet and LDH normalization was 75% and 50%, respectively (the first assessable time point based on the criteria definition). 90% of pts had platelet count normalization by wk 8, which was sustained with ongoing Ecu treatment for the remainder of the study period. 85% of pts had LDH ≤ULN by wk 8, which increased to 95% by wk 12 (Figure 1). With ongoing Ecu treatment, 10% of pts achieved Cr decrease (≥25%) at wk 14, and 55% by wk 80. eGFR increase (≥15 mL/min/1.73 m2) was first seen at wk 18 (by 5% of pts). This proportion increased to a maximum of 40% at wk 104 with ongoing Ecu treatment. CKD improvement (≥1 Stage) was seen at wk 4 by 5% of pts. This proportion increased to 60% at wk 76 with ongoing Ecu treatment (Figure 1). Significant mean changes from baseline in eGFR were observed as early as wk 4, and were followed by time-dependent improvements through the end of the study (Figure 2). All patients were able to discontinue PE/PI. Conclusions The use of Ecu in aHUS pts with long disease duration and CKD on long-term PE/PI led to sustained normalization of hematologic values within the first month of treatment, followed by time-dependent improvements in renal function. These data demonstrate that improvement in renal function may be achieved over time in pts with long-standing aHUS and CKD, and underscore the importance of ongoing and consistent treatment with Ecu. The underlying mechanism of the observed renal function improvement over the study period (e.g., normalization of endothelial cell function) warrants further exploration. Disclosures: No relevant conflicts of interest to declare.

The novel use of convalescent plasma in patients with COVID 19 in Basra governorate, Case series review

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Saad Hammadi ◽  
Ali Hashim ◽  
Abbas Ali ◽  
Rafid Abbood ◽  
Hassanein Ali ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Case Series ◽  
Passive Immunity ◽  
The Novel ◽  
Efficacy And Safety ◽  
Off Label Use ◽  
Plasma Therapy ◽  
Off Label ◽  
Plasma Donation ◽  
Patient Series

Background: The idea of convalescent plasma usage is to give passive immunity to the patients, so their immune system stands a good chance of combating the virus.this study will review 6 cases of eligible covid 19 patients that had been treated with convalescent plasma therapy in Basra covid 19 quarantine Objectives: to demonstrate efficacy and safety of convalescent plasma in the patient series that had been enrolled . Method: this study had pioneered a new method to collect up to 3,000 mL in one session by an off-label use of Spectra Optia Apheresis systems by TerumoBCT /Exchange set to collect convalescent plasma. In this study 250 mL convalescent plasma had been given each of the 6 patients, from one donor. respose in spo2,dyspnoea and tachypnoea was observed ,any reaction to plasma also had been monitored . Result: Our case series have demonstrated both safety and effectiveness of convalescent plasma. This study was successful in reaching our primary and secondary outcomes in all 6 patients (improvement in SpO2 and symptoms). With negligible difference in time of post transfusion response Conclusion: convalescent plasma is apperantly safe and effective, In this study 250 mL convalescent plasma had been given each of the 6 patients, from one donor using Therapeutic Plasma Exchange (TPE) protocol by Spectra Optia Apheresis system/TerumoBCT. Keywords: convalescent plasma, COVID-19, SARS CoV-2, apheresis, plasma exchange, plasma donation

Sign in / Sign up

Export Citation Format

Share Document