Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal ...levels of hematologic measures but does not treat the underlying systemic disease.
We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).
A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.
Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 adults and NCT00844844 adolescents; C08-003 ClinicalTrials.gov numbers, NCT00838513 adults and NCT00844428 adolescents).
Au fil du temps, les définitions du rejet aigu en transplantation rénale ont évolué grâce aux classifications successives de Banff, à l’introduction du C4d et à la recherche des anticorps anti-HLA. ...On oppose désormais schématiquement le rejet aigu cellulaire au rejet aigu humoral à la fois dans sa définition, sa physiopathogénie et donc dans son approche thérapeutique. La classification de Banff reste un outil indispensable pour progresser dans la précision de ces définitions. L’apport des nouvelles technologies (microarrays) devrait entraîner la définition de nouvelles catégories de rejet aigu et donc une nouvelle complexification.
Along the time, the definition of acute rejection has been modified according to the successive Banff classifications, the use of C4d and the identification of anti- HLA antibodies. Both cellular and humoral acute rejection are nowadays considered to be different with regard to definition, pathogenesis and hence treatment. The Banffclassification remains a very useful tool to improve the precision of these definitions. The new technologies such as microarrays should help to identify new aspects of acute rejection.
The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d‐negative antibody‐mediated rejection (ABMR) ...from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor‐specific antibody tests (anti‐HLA and non‐HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i‐IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell–mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus‐based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next‐generation clinical trials.
In this article, the Banff consortium presents the most updated version of the kidney, pancreas, and VCA transplant rejection classification and prospects for implementing intragraft molecular assessment. See the companion report on page 42.
The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers ...discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics‐technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.
The 10th Banff Conference on Allograft Pathology held in Banff, Canada August 9–14, 2009 specifically focused on antibody mediated graft injury, and resulted in implementation of six Banff working groups to evaluate clinical relevance and reproducibility of potential changes to the Banff classification.
The Afar region is a tectonically distinct area useful for studying continental break-up and rifting. Various conflicting models have been suggested to explain the lateral variations of the ...anisotropy in this region. To address this issue, we investigated the tectonics of the Afar region using receiver function and shear-wave splitting measurements based on broadband seismic data from 227 stations in the region. Further, the receiver function results were inverted to obtain the crustal thickness and
V
p
/
V
s
ratio of the region. Our results reveal a thick African crust (thicker than 40 km) with typical
V
p
/
V
s
values for the continental crust, elongated down to 21 km along the rift system with very high
V
p
/
V
s
values near the fractured zones, suggesting crustal thinning near the fractured zones. Our shear-wave splitting measurements indicate a general fast axis orientation of N030E. However, substantial disparities in the fast anisotropy direction exist in the triple junction region, with some stations displaying a direction of N120E, which is perpendicular to the fast directions measured at the surrounding stations. In addition, many stations located close to the rifts and within the Arabian Plate provide mostly null measurements, indicating the presence of fluids or isotropic media. This study uses several methodologies to unravel the structure and evolution of the Afar region, providing valuable insight into the Afar, a tectonically distinct region, which will be useful for elucidating the mechanisms and characteristics of a continental break-up and the rifting process.
Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C0). The aim of ...this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C0. Secondary end points included the number of dose modifications and the delay in achieving the targeted C0. In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C0 at day 3 after initiation of tacrolimus (43.2% vs. 29.1% P = 0.03); they required fewer dose modifications, and the targeted C0 was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C0. Whether this improvement will affect clinical outcomes requires further evaluation.
Clinical Pharmacology & Therapeutics (2010) 87 6, 721–726. doi: 10.1038/clpt.2010.17
The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended‐release tacrolimus (TacER) in kidney transplant recipients (KTRs) ...between 4 and 12 mo after transplantation. Stable steroid‐free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacER dose (TacER C0 7–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent‐to‐treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score i >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score t >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti‐HLA donor‐specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 μg/L during the first year after transplantation in low‐immunological‐risk, steroid‐free KTRs receiving a moderate dose of mycophenolic acid.
This randomized clinical trial compares two different doses of extended‐released tacrolimus 4 months after kidney transplantation in stable steroid‐free recipients and shows that reduction of the tacrolimus dose increases the risk of acute rejection and the appearance of de novo donor‐specific antibodies.
Seismic structure related to the magmatic system beneath the potentially hazardous Changbaishan volcano recently becomes hotly debated. In addition, mantle flow dynamics throughout the back‐arc ...regions in NE Asia remain poorly constrained due to the lack of seismic data in the Korean Peninsula and surrounding ocean regions. In this study we construct a high‐resolution azimuthally anisotropic Rayleigh‐wave phase velocity model in NE Asia, by integrating seismic data from China, North Korea, South Korea, and Japan. The resulting isotropic velocity maps suggest possible existence of a crustal magma chamber beneath the Changbaishan volcano and that the widespread intraplate volcanism in NE Asia likely arises from the upwelling asthenosphere. The obtained anisotropic maps reveal trench‐normal return flow patterns in the back‐arc regions of NE Asia with local variations between East China and northeast China as controlled by the subduction geometry of the Pacific slab.
Plain Language Summary
The transition from a more subduction‐driven geodynamic setting to a continental one in NE Asia makes it an ideal laboratory for investigating the formation and evolution of continental intraplate volcanism associated with mantle dynamics. However, due to the lack of seismic data in the Korean Peninsula and surrounding ocean regions, seismic structures beneath these intraplate volcanoes and mantle flow dynamics operating in this region are still not well resolved. We build a high‐resolution seismic velocity model of NE Asia in this study by utilizing seismic data collected from China, North Korea, South Korea, and Japan. We find significant low‐velocity anomalies in the middle‐lower crust beneath the Changbaishan volcano, which indicates there might be a deep crustal magma chamber beneath this giant volcano. In the upper mantle region, the intraplate volcanoes are underlain by markable low seismic velocities, suggesting that the intraplate volcanism is likely to originate from the upwelling asthenosphere. Our seismic imaging results in East and NE China confirm previous studying results that claim the subduction geometry of the Pacific slab results in different mantle flow patterns in East and NE China. The subducting Pacific slab is also responsible for the trench‐normal fast direction observed within the back‐arc regions. Our presented model provides seismic constraints and deepens our understanding on the intraplate volcanism and associated mantle dynamics in NE Asia.
Key Points
A middle‐lower crustal magma chamber is imaged beneath the Changbaishan volcano
Intraplate volcanism in NE Asia is likely fed by upwelling asthenosphere
Trench‐normal return flow patterns with local variations between East and northeast China are revealed in the back‐arc regions of NE Asia
PDF
