Associations Between Deceased-Donor Urine MCP-1 and Kidney Transplant Outcomes

Existing methods to predict recipient allograft function during deceased-donor kidney procurement are imprecise. Understanding the potential renal reparative role for monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in macrophage recruitment after injury, might help to predict allograft outcomes. Methods: We conducted a substudy of the multicenter prospective Deceased Donor Study cohort that evaluated deceased kidney donors from 5 organ procurement organizations from May 2010 to December 2013. We measured urine MCP-1 (uMCP-1) concentrations from donor samples collected at nephrectomy to determine associations with donor acute kidney injury (AKI), recipient delayed graft function (DGF), 6-month estimated glomerular filtration rate (eGFR), and graft failure. We also assessed perfusate MCP-1 concentrations from pumped kidneys for associations with DGF and 6-month eGFR. Results: AKI occurred in 111 donors (9%). The median (interquartile range) uMCP-1 concentration was higher in donors with AKI compared with donors without AKI (1.35 [0.41–3.93] ng/ml vs. 0.32 [0.11–0.80] ng/ml, P < 0.001). DGF occurred in 756 recipients (31%), but uMCP-1 was not independently associated with DGF. Higher donor uMCP-1 concentrations were independently associated with a higher 6-month eGFR in those without DGF (0.77 [0.10–1.45] ml/min per 1.73 m2 per doubling of uMCP1). However, there were no independent associations between uMCP-1 and graft failure over a median follow-up of ∼2 years. Lastly, perfusate MCP-1 concentrations significantly increased during pump perfusion but were not associated with DGF or 6-month eGFR. Discussion: Donor uMCP-1 concentrations were modestly associated with higher recipient 6-month eGFR in those without DGF. However, the results suggest that donor uMCP-1 has minimal clinical utility given no associations with graft failure

Supplementary Material for: Obesity, Renin-Angiotensin System Blockade and Risk of Adverse Renal Outcomes: A Population-Based Cohort Study

<b><i>Background:</i></b> Obesity substantially increases the risk of the development of chronic kidney disease. Adipose tissue expresses all of the components of the renin-angiotensin system (RAS), contributing to the high prevalence of hypertension in obese patients and driving renal hyperfiltration and subsequent glomerular injury. <b><i>Methods:</i></b> We performed a retrospective cohort study using a United Kingdom primary care database, evaluating the effect of time-updated exposure to RAS blockade versus all other antihypertensive medications in obese, hypertensive, non-diabetic patients. We used Cox proportional hazards modeling with and without marginal structural modeling to assess the hazards of developing a primary outcome of 50% reduction in estimated glomerular filtration rate (eGFR) (across 2 consecutive values), end stage renal disease or death. <b><i>Results:</i></b> A total of 219,701 patients met inclusion criteria, with a median 7.2 years of follow-up. Median baseline eGFR was 72.6 ml/min/1.73 m². Compared to other antihypertensive medications, patients treated with RAS blockade had a modestly elevated hazard of adverse renal outcomes using traditional Cox regression (hazard ratio (HR) 1.04, 95% CI 1.01-1.07) and no significantly increased hazard by marginal structural modeling (HR 1.02, 95% CI 0.97-1.08). Patients treated with RAS blockade had a significantly reduced hazard of incident diabetes, but no significant difference in mortality. <b><i>Conclusion:</i></b> This study, conducted in a large real-world cohort, provides evidence that RAS blockade may not provide benefit with regard to longitudinal renal outcomes in obese, hypertensive patients. Further research is needed to elucidate the hemodynamic and renoprotective role of antihypertensive medications in obese patients

Supplementary Material for: Physical Performance and Frailty in Chronic Kidney Disease

<b><i>Background:</i></b> Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established. <b><i>Methods:</i></b> We measured the Short Physical Performance Battery (SPPB; a summary test of gait speed, chair raises and balance; range 0-12) and the five elements of frailty among 1,111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status. <b><i>Results:</i></b> Median (interquartile range, IQR) age was 65 (57-71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36-62) ml/min/1.73 m², and median SPPB score was 9 (7-10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73 m², the SPPB was 0.51 points lower for eGFR 30-59; 0.61 points lower for eGFR 15-29, and 1.75 points lower for eGFR <15 (p < 0.01 for all comparisons). eGFR 30-59 (odds ratio, OR 1.45; p = 0.024), eGFR 15-29 (OR 2.02; p = 0.002) and eGFR <15 (OR 4.83; p < 0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73 m². <b><i>Conclusions:</i></b> CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions

On the Road to FAIR: 1st Operation of AGATA in PreSPEC at GSI

The Facility for Antiproton and Ion Research (FAIR), under construction at Darmstadt will provide intense relativistic beams of exotic nuclei at its Superconducting-FRagment Separator. High-resolution in-beam γ-ray spectroscopy will be performed in the HISPEC experiment, using the European Advanced GAmma-ray Tracking Array (AGATA). The PreSPEC-AGATA campaign is the predecessor of HISPEC and runs from 2012 to 2014 at GSI Helmholtzzentrum für Schwerionenforschung GmbH. Up to19 AGATA modules were used at GSI's F Ragment Separator in 2012. We report on the status of the experiment including preliminary results from performance commissioning

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice.

Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. While sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior we identified blood-derived high-mobility group box 1 protein (HMGB1) - a prototypical mediator of sterile inflammation - to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation. Transfer of platelets into Hmgb1(-/-) chimeras showed that this cell type is the major source of HMGB1, exposing reduced HMGB1 on their surface upon activation thereby enhancing the recruitment of monocytes. Activated leukocytes in turn support oxidation of HMGB1 unleashing its prothrombotic activity and promoting platelet aggregation. This potentiates the amount of HMGB1 and further nurtures the accumulation and activation of monocytes through RAGE and TLR2, leading to local delivery of monocyte-derived tissue factor and cytokines. Moreover, disulfide HMGB1 facilitates formation of prothrombotic neutrophil extracellular traps (NETs) mediated by RAGE, exposing additional HMGB1 on their extracellular DNA strands. Eventually, a vicious circle of coagulation and inflammation is set in motion leading to obstructive DVT formation. Therefore, platelet derived disulfide HMGB1 is a central mediator of the sterile inflammatory process in venous thrombosis and could be an attractive target for an anti-inflammatory approach for DVT prophylaxis

On the Road to FAIR: 1

The Facility for Antiproton and Ion Research (FAIR), under construction at Darmstadt will provide intense relativistic beams of exotic nuclei at its Superconducting-FRagment Separator. High-resolution in-beam γ-ray spectroscopy will be performed in the HISPEC experiment, using the European Advanced GAmma-ray Tracking Array (AGATA). The PreSPEC-AGATA campaign is the predecessor of HISPEC and runs from 2012 to 2014 at GSI Helmholtzzentrum für Schwerionenforschung GmbH. Up to19 AGATA modules were used at GSI's F Ragment Separator in 2012. We report on the status of the experiment including preliminary results from performance commissioning

Failure of tannic acid to inhibit digestion or reduce digestibility of plant protein in gut fluids of insect herbivores

The rate of hydrolysis of the abundant foliar protein, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBPC), in enzymatically active gut fluid of Manduca sexta larvae is very rapid and is unaffected by the presence of tannic acid, even when tannic acid is present in the incubation mixture in amounts in excess of the amount of RuBPC. When this protein is dissolved in the denatured gut fluids of M. sexta larvae or Schistocerca gregaria nymphs, large amounts of tannic acid must be added to bring about the precipitation of significant quantities of protein. The ability of insect gut fluid to prevent the formation of insoluble tannin-protein complexes is due to the presence of surfactants. On the basis of our results and a review of the findings of other investigators, we argue that there is no evidence that tannins reduce the nutritional value of an insect's food by inhibiting digestive enzymes or by reducing the digestibility of ingested proteins and, further, that the failure of tannins to interfere with digestion is readily explained on the basis of well-documented characteristics of the digestive systems of herbivorous insects. In challenging the currently popular notion that tannins are digestibility-reducing substances, we do not challenge the general utility of either the apparency theory or resource availability theory of plant defense. In debating the merits of these two analyses of plant-herbivore interactions, however, the demise of tannins as all-purpose, dose-dependent, digestibility-reducing defensive substances must be taken into account.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44874/1/10886_2005_Article_BF01880103.pd

Does Chaplygin gas have salvation?

Campos JP, Fabris JC, Perez R, Piattella OF, Velten H. Does Chaplygin gas have salvation? European Physical Journal C. 2013;73(4): 2357.We investigate the unification scenario provided by the generalized Chaplygin gas model (a perfect fluid characterized by an equation of state p = -A/rho(alpha)). Our concerns lie with a possible tension existing between background kinematic tests and those related to the evolution of small perturbations. We analyze data from the observation of the differential age of the universe, type Ia supernovae, baryon acoustic oscillations, and the position of the first peak of the angular spectrum of the cosmic background radiation. We show that these tests favor negative values of the parameter alpha: we find alpha = -0.089(-0.128)(+0.161) at the 2 sigma level and that alpha < 0 with 85 % confidence. These would correspond to negative values of the square speed of sound which are unacceptable from the point of view of structure formation. We discuss a possible solution to this problem, when the generalized Chaplygin gas is framed in the modified theory of gravity proposed by Rastall. We show that a fluid description within this theory does not serve the purpose, but it is necessary to frame the generalized Chaplygin gas in a scalar field theory. Finally, we address the standard general relativistic unification picture provided by the generalized Chaplygin gas in the case alpha = 0: this is usually considered to be undistinguishable from the standard Lambda CDM model, but we show that the evolution of small perturbations, governed by the Meszaros equation, is indeed different and the formation of sub-horizon GCG matter halos may be importantly affected in comparison with the Lambda CDM scenario