Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease : a prospective cohort study

Background : Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function. Patients and methods : In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates. Results : During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1. Conclusion : sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease

Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Aims/hypothesis: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. Methods: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case–control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30–75 ml min−1 [1.73 m]−2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. Results: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. Conclusions/interpretation: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30–75 ml min−1 [1.73 m]−2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers

Characterization of nuclear effects in muon-neutrino scattering on hydrocarbon with a measurement of final-state kinematics and correlations in charged-current pionless interactions at T2K

This paper reports measurements of final-state proton multiplicity, muon and proton kinematics, and their correlations in charged-current pionless neutrino interactions, measured by the T2K ND280 near detector in its plastic scintillator (C8H8) target. The data were taken between years 2010 and 2013, corresponding to approximately 6 × 1020 protons on target. Thanks to their exploration of the proton kinematics and of imbalances between the proton and muon kinematics, the results offer a novel probe of the nuclear-medium effects most pertinent to the (sub-)GeV neutrino-nucleus interactions that are used in accelerator-based long-baseline neutrino oscillation measurements. These results are compared to many neutrino-nucleus interaction models which all fail to describe at least part of the observed phase space. In case of events without a proton above a detection threshold in the final state, a fully consistent implementation of the local Fermi gas model with multinucleon interactions gives the best description of the data. In the case of at least one proton in the final state, the spectral function model agrees well with the data, most notably when measuring the kinematic imbalance between the muon and the proton in the plane transverse to the incoming neutrino. Within the models considered, only the existence of multinucleon interactions are able to describe the extracted cross section within regions of high transverse kinematic imbalance. The effect of final-state interactions is also discussed

Search for light sterile neutrinos with the T2K far detector Super-Kamiokande at a baseline of 295 km

We perform a search for light sterile neutrinos using the data from the T2K far detector at a baseline of 295 km, with an exposure of 14.7ð7.6Þ × 1020 protons on target in neutrino (antineutrino) mode. A selection of neutral-current interaction samples is also used to enhance the sensitivity to sterile mixing. No evidence of sterile neutrino mixing in the 3 þ 1 model was found from a simultaneous fit to the charged-current muon, electron and neutral-current neutrino samples. We set the most stringent limit on the sterile oscillation amplitude sin2 θ24 for the sterile neutrino mass splitting Δm241 < 3 × 10−3 eV2=c4

Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2 x 10(21) Protons on Target

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of $14.7(7.6)\times 10^{20}$ protons on target in neutrino (antineutrino) mode, 89 $\nu_e$ candidates and 7 anti-$\nu_e$ candidates were observed while 67.5 and 9.0 are expected for $\delta_{CP}=0$ and normal mass ordering. The obtained $2\sigma$ confidence interval for the $CP$ violating phase, $\delta_{CP}$, does not include the $CP$-conserving cases ($\delta_{CP}=0,\pi$). The best-fit values of other parameters are $\sin^2\theta_{23} = 0.526^{+0.032}_{-0.036}$ and $\Delta m^2_{32}=2.463^{+0.071}_{-0.070}\times10^{-3} \mathrm{eV}^2/c^4$.Comment: 9 pages, 6 figure

Measurement of the muon neutrino charged-current cross sections on water, hydrocarbon and iron, and their ratios, with the T2K on-axis detectors

We report a measurement of the flux-integrated νμ charged-current cross sections on water, hydrocarbon, and iron in the T2K on-axis neutrino beam with a mean neutrino energy of 1.5 GeV. The measured cross sections on water, hydrocarbon, and iron are σH2OCC=(0.840±0.010(stat.)+0.10−0.08(syst.))×10−38cm2/nucleon, σCHCC=(0.817±0.007(stat.)+0.11−0.08(syst.))×10−38cm2/nucleon, and σFeCC=(0.859±0.003(stat.)+0.12−0.10(syst.))×10−38cm2/nucleon, respectively, for a restricted phase space of induced muons: θμ0.4 GeV/c in the laboratory frame. The measured cross section ratios are σH2OCC/σCHCC=1.028±0.016(stat.)±0.053(syst.)⁠, σFeCC/σH2OCC=1.023±0.012(stat.)±0.058(syst.)⁠, and σFeCC/σCHCC=1.049±0.010(stat.)±0.043(syst.)⁠. These results, with an unprecedented precision for the measurements of neutrino cross sections on water in the studied energy region, show good agreement with the current neutrino interaction models used in the T2K oscillation analyses

Search for heavy neutrinos with the T2K near detector ND280

International audienceThis paper reports on the search for heavy neutrinos with masses in the range 140<MN<493  MeV/c2 using the off-axis near detector ND280 of the T2K experiment. These particles can be produced from kaon decays in the standard neutrino beam and then subsequently decay in ND280. The decay modes under consideration are N→ℓα±π∓ and N→ℓα+ℓβ-ν(−)(α,β=e,μ). A search for such events has been made using the Time Projection Chambers of ND280, where the background has been reduced to less than two events in the current dataset in all channels. No excess has been observed in the signal region. A combined Bayesian statistical approach has been applied to extract upper limits on the mixing elements of heavy neutrinos to electron-, muon- and tau- flavored currents (Ue2, Uμ2, Uτ2) as a function of the heavy neutrino mass, e.g., Ue2<10-9 at 90% C.L. for a mass of 390  MeV/c2. These constraints are competitive with previous experiments

Circulating Osteoprotegerin in Chronic Kidney Disease and All-Cause Mortality

Joanna Kamińska,1,* Marek Stopiński,1,* Krzysztof Mucha,2,3 Michał Pac,2 Marek Gołębiowski,4 Monika A Niewczas,5,6 Leszek Pączek,2,3 Bartosz Foroncewicz2 1Department of Internal Diseases and Dialysis Unit, West Hospital of Saint John Paul II, Grodzisk Mazowiecki, Poland; 2Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; 3Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; 4Department of Clinical Radiology, Medical University of Warsaw, Warsaw, Poland; 5Research Division, Joslin Diabetes Center, Boston, MA, USA; 6Department of Medicine, Harvard Medical School, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Bartosz ForoncewiczDepartment of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, Warsaw, 02-006, PolandTel +48-22-502 1641Fax +48-22-502 2127Email [email protected]: Chronic kidney disease (CKD) is associated with cardiovascular disease (CKD), mineral and bone disorder (CKD-MBD) and high mortality. Bone-related factors such as osteopontin (OPN), osteocalcin (OC), osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF23) were linked to cardiovascular complications of CKD and are expected to have predictive value in CKD patients.Purpose: The aim of this study was to assess the relationship of OPN, OC, OPG and FGF23 to clinical characteristics and to evaluate their ability to predict mortality in patients with different CKD stages.Methods: The following study groups were enrolled: subjects with end-stage renal disease (38 ESRD), CKD stages 3 and 4 (19 CKD3-4) and non-CKD controls (19), respectively. Blood was withdrawn once to perform the measurements and cardiac computed tomography was used to evaluate coronary calcium score (CS). Patients were followed for 5 years for the ascertainment of their all-cause mortality.Results: Serum OPN, OC and OPG concentrations increased significantly along with the progression of renal disease. We found a significant positive correlation among these proteins. Additionally, OPN and OPG were significantly and positively correlated to CS. Serum OPG revealed the strongest correlation to the calcium turnover markers of GFR decline and was significantly associated with an increased risk of death in subjects with CKD3-4 or ESRD (HR 5.8, CI 95%).Conclusion: Single measurement of osteoprotegerin is associated with 5-year all-cause mortality in patients with CKD3-4 or ESRD. We suggest assessing its concentration, preferably in combination with calcium score, to stratify mortality risks in CKD patients.Keywords: calcium score, chronic kidney disease, osteocalcin, osteopontin, osteoprotegeri