Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ ...damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, β2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F1+2 and d-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973.
•This exploratory study describes the effect of eculizumab on multiple physiologic pathways affected by complement dysregulation in aHUS.•The results highlight the importance of sustained terminal complement blockade, even in patients with improved clinical laboratory values.
Background
Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through ...minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment.
Methods
Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4–8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period.
Results
No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m
2
at baseline, 93.5 mL/min/1.73m
2
at 26 weeks, and 104 mL/min/1.73m
2
at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study.
Conclusions
Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4–8 weeks.
Trial registration
Trial identifiers:
Trial ID: ALXN1210-aHUS-312
Clinical
trials.gov
: NCT03131219
EudraCT number: 2016-002499-29
Graphical abstract
Background Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe ...end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. Study Design Open-label single-arm phase 2 trial. Setting & Participants Patients 18 years or older with aHUS (platelet count <150 × 103 /μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal ULN, and serum creatinine ≥ ULN) were included in this multicenter multinational study. Intervention Intravenous eculizumab (900 mg/wk for 4 weeks, 1,200 mg at week 5 and then every 2 weeks) for 26 weeks. Outcomes & Measurements Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 103 /μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. Results 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline ( P < 0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. Limitations Single-arm open-label design. Conclusions Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.
Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize ...end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 95% confidence interval 0.41–0.73, whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%–38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.
Purpose
The aim of this multicenter trial was to generate a
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IFP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan.
Methods
This study included 510 sets of ...SPECT data from 256 healthy controls (116 men and 140 women; age range, 30–83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom.
Results
The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30–39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70–79 age group.
Conclusions
This study provided a large-scale quantitative database of
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IFP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.
Although the development of effective therapeutic drugs and radical treatment options for dementia and Alzheimer's disease (AD) remains urgent, progress in recent clinical trials of AD drugs has been ...less than adequate. In order to advance the progress of clinical trials, it is necessary to establish more efficient methods of recruitment. In Japan, there are registration systems stratified by mild cognitive impairment and preclinical and clinical stages of early and advanced stage dementia, but there is no registration system for healthy individuals yet. Therefore, in the present study, we developed a large-scale, internet-based health registry to investigate factors associated with cognitive function among registered participants. A total of 1038 participants completed the initial questionnaire and word list memory test. Among these participants, 353 individuals completed a second questionnaire and memory test. Stepwise multiple regression analysis was performed using IBM SPSS version 23.0 for Windows at a statistical significance level of p<0.05. We found that mood, motivation, and a decreased ability to perform activities of daily living were significantly associated with cognitive function. The results of the present study suggest that maintaining social involvement is important to prevent decreases in physical activity, daily function, mood, and motivation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE:Hippocampal subfield volumetry should be more useful than whole hippocampal (WH) volumetry for diagnosing Alzheimer disease (AD). This study sought to confirm this.
METHODS:We investigated ...cognitively normal (CN) participants and patients with mild cognitive impairment (MCI) or AD using high-resolution T2-weighted and 3-dimensional T1-weighted magnetic resonance imaging. Using medial temporal subregion volumetry, we investigated discriminative power for MCI and AD versus CN.
PATIENTS:We recruited 30 CN participants, 30 amnestic MCI patients, and 49 AD patients between April 2015 and October 2016.
RESULTS:For AD, discriminative power of the combined volumes of the subiculum, entorhinal cortex, and cornu ammonis 1 was highest area under the curve (AUC)=0.915; 85.7% sensitivity, 86.7% specificity, 86.1% accuracy, and was significantly higher than that of the WH volume (AUC=0.887; 90.0% sensitivity, 75.5% specificity, 84.5% accuracy) (P=0.019). For MCI, discriminative power of the subiculum volume was highest (AUC=0.747; 80.0% sensitivity, 73.3% specificity, 76.7% accuracy), but was only slightly higher than that of the WH volume (AUC=0.730; 56.7% sensitivity, 90.0% specificity, 73.3% accuracy).
CONCLUSIONS:Using the combined volumes of the subiculum, entorhinal cortex, and cornu ammonis 1 may enable greater diagnostic accuracy compared with the WH volume or any single subfield in AD patients.
Objective
Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of ...interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of (
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)I N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ((
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)I FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults.
Methods
We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject’s striatum and then converted the
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I FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60 years).
Results
When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding.
Conclusion
Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.
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