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Hyperlactatemia Predicts Citrate Intolerance With Regional Citrate Anticoagulation During Continuous Renal Replacement Therapy.
Tan, JN, Haroon, SWP, Mukhopadhyay, A, Lau, T, Murali, TM, Phua, J, Tan, ZY, Lee, N, Chua, HR
Journal of intensive care medicine. 2019;(5):418-425
Abstract
PURPOSE We aim to determine whether hyperlactatemia, which suggests multi-organ dysfunction and impaired organic substrate metabolism, may predict intolerance to regional citrate anticoagulation (RCA) during continuous venovenous hemofiltration (CVVH). METHODS We performed a single-center, retrospective observational study in critically ill patients with acute kidney injury or end-stage renal disease and evaluated the association of peak serum lactate levels with citrate intolerance (CI) during the initial 72 hours of RCA-CVVH, defined by serum total-to-ionized calcium >2.5 plus systemic hypocalcemia. RESULTS Eighty-eight patients were studied (aged 59 ± 14 years, 66% males, Acute Physiology and Chronic Health Evaluation II: 31 ± 8). Citrate was dosed at median 2.1 mmol/L of blood flow, with citrate load of 30 mmol/h, and CVVH effluent of 43 mL/kg/h. Twenty patients developed CI. Comparing patients with CI versus none, peak lactate levels were 8 (5-11) versus 3 (2-6) mmol/L, calcium replacement was 13 (10-17) versus 11 (8-12) mmol/h, and standard base excess was -4 (-12 to 1) versus 2(-4 to 7) mmol/L, respectively ( P < .05). Citrate intolerance developed in 38%, 44%, and 55%, in patients with peak lactate >4, >6, >7 mmol/L, respectively, versus 7% in those with peak lactate ≤4 mmol/L ( P ≤ .001), despite comparable citrate load and effluent rates across all categories. On multivariate analysis, hyperlactatemia and hyperbilirubinemia predicted CI ( P ≤ .01), which was associated with increasing calcium infusion requirement. Higher peak lactate from >4 to >7 mmol/L predicted CI with graded increase in odds ratio and specificity from 59% to 87%, but the corresponding negative predictive value from 93% to 87%. Area under nonparametric receiver operating characteristic curve for peak lactate and CI was 0.78. CONCLUSION Hyperlactatemia predicts CI during RCA-CVVH with reasonable discriminatory performance in critically ill patients. Serum lactate surveillance may help preempt issues with citrate toxicity.
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Flexitrate regional citrate anticoagulation in continuous venovenous hemodiafiltration: a retrospective analysis.
Lenga, I, Hopman, WM, O'Connell, AJ, Hume, F, Wei, CCY
BMC nephrology. 2019;(1):452
Abstract
BACKGROUND Flexitrate, an innovative regional citrate anticoagulation (RCA) protocol, was compared to traditional RCA (tRCA) and Heparin anticoagulation protocols in intensive care patients treated with continuous renal replacement therapy (CRRT). METHODS A single-center, retrospective, cohort study, was done in a 26-bed intensive care unit in a large community hospital. Eighty dialysis sessions (Flexitrate = 2852 h, tRCA = 3580 h and Heparin = 2026 h), performed in 53 patients, were evaluated for filter life, RCA control, and metabolic control. RESULTS In the Flexitrate cohort, 3.8% of filters clotted, compared to 16.9% with tRCA and 28.3% with Heparin (p < 0.001 for Flexitrate compared to either tRCA or Heparin). Filter survival was significantly improved with Flexitrate compared to tRCA (HR 0.24, p = 0.018) or Heparin (HR 0.14, p = 0.004). Anticoagulation control was superior with Flexitrate with Patient Ionized Calcium out of target a median of 16% of the time, compared to 27% for tRCA (p < 0.001). Filter Ionized Calcium was out of target a median of 6.8% of the time, compared to 23% for tRCA (p = 0.03). Flexitrate produced significantly less alkalosis, hypernatremia, and hypocalcemia than tRCA, and overall metabolic control was comparable to Heparin anticoagulation. The only adverse metabolic outcome with Flexitrate was increased hypomagnesemia. CONCLUSIONS The Flexitrate protocol extended filter life, delivered more consistent anticoagulation, and provided superior metabolic control compared to a tRCA protocol. Filter life was superior to Heparin anticoagulation, with similar metabolic control. A randomized control trial comparing these protocols is recommended.
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Aspergillus niger citrate exporter revealed by comparison of two alternative citrate producing conditions.
Odoni, DI, Vazquez-Vilar, M, van Gaal, MP, Schonewille, T, Martins Dos Santos, VAP, Tamayo-Ramos, JA, Suarez-Diez, M, Schaap, PJ
FEMS microbiology letters. 2019;(7)
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Abstract
Currently, there is no consensus regarding the mechanism underlying Aspergillus niger citrate biosynthesis and secretion. We hypothesise that depending on the experimental setup, extracellular citrate accumulation can have fundamentally different underlying transcriptomic landscapes. We show that varying the amount and type of supplement of an arginine auxotrophic A. niger strain results in transcriptional down-regulation of citrate metabolising enzymes in the condition in which more citrate is accumulated extracellularly. This contrasts with the transcriptional adaptations when increased citrate production is triggered by iron limitation. By combining gene expression data obtained from these two very distinct experimental setups with hidden Markov models and transporter homology approaches, we were able to compile a shortlist of the most likely citrate transporter candidates. Two candidates (An17g01710 and An09g06720m.01) were heterologously expressed in the yeast Saccharomyces cerevisiae, and one of the resultant mutants showed the ability to secrete citrate. Our findings provide steps in untangling the complex interplay of different mechanisms underlying A. niger citrate accumulation, and we demonstrate how a comparative transcriptomics approach complemented with further bioinformatics analyses can be used to pinpoint a fungal citrate exporter.
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Role of Citrate in Pathophysiology and Medical Management of Bone Diseases.
Granchi, D, Baldini, N, Ulivieri, FM, Caudarella, R
Nutrients. 2019;(11)
Abstract
Citrate is an intermediate in the "Tricarboxylic Acid Cycle" and is used by all aerobic organisms to produce usable chemical energy. It is a derivative of citric acid, a weak organic acid which can be introduced with diet since it naturally exists in a variety of fruits and vegetables, and can be consumed as a dietary supplement. The close association between this compound and bone was pointed out for the first time by Dickens in 1941, who showed that approximately 90% of the citrate bulk of the human body resides in mineralised tissues. Since then, the number of published articles has increased exponentially, and considerable progress in understanding how citrate is involved in bone metabolism has been made. This review summarises current knowledge regarding the role of citrate in the pathophysiology and medical management of bone disorders.
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Functionalization Of T Lymphocytes With Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles For Magnetically Controlled Immune Therapy.
Mühlberger, M, Janko, C, Unterweger, H, Friedrich, RP, Friedrich, B, Band, J, Cebulla, N, Alexiou, C, Dudziak, D, Lee, G, et al
International journal of nanomedicine. 2019;:8421-8432
Abstract
PURPOSE Immune activation with T cell tumor infiltration is beneficial for the prognosis of patients suffering from solid cancer. Depending on their immune status, solid tumors can be immunologically classified into three groups: "hot" tumors are infiltrated with T lymphocytes, "cold" tumors are not infiltrated and "immune excluded" tumors are only infiltrated in the peripheral tumor tissue. Checkpoint inhibitors provide new therapeutic options for "hot" tumors by triggering the immune response of T cells. In order to enable this for cold tumors as well, T cells must be enriched in the tumor. Therefore, we use the principle of magnetic targeting to guide T cells loaded with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONCitrate) to the tumor by an externally applied magnetic field. METHODS SPIONCitrate were produced by alkaline coprecipitation of iron(II) and iron(III) chloride and in situ coating with sodium citrate. The concentration-dependent cytocompatibility of the particles was determined by flow cytometry and blood stability assays. Atomic emission spectroscopy was used for the quantification of the particle uptake into T lymphocytes. The attractability of the loaded cells was observed by live-cell imaging in the presence of an externally applied magnetic field. RESULTS SPIONCitrate displayed good cytocompatibility to T cells and did not show any sign of aggregation in blood. Finally, SPIONCitrate-loaded T cells were strongly attracted by a small external magnet. CONCLUSION T cells can be "magnetized" by incorporation of SPIONCitrate for magnetic targeting. The production of the particle-cell hybrid system is straightforward, as the loading process only requires basic laboratory devices and the loading efficiency is sufficient for cells being magnetically controllable. For these reasons, SPIONCitrate are potential suitable candidates for magnetic T cell targeting.
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Opportunistic complexes of E. coli L-asparaginases with citrate anions.
Lubkowski, J, Chan, W, Wlodawer, A
Scientific reports. 2019;(1):11070
Abstract
Active sites of enzymes are highly optimized for interactions with specific substrates, thus binding of opportunistic ligands is usually observed only in the absence of native substrates or products. However, during growth of crystals required for structure determination enzymes are often exposed to conditions significantly divergent from the native ones, leading to binding of unexpected ligands to active sites even in the presence of substrates. Failing to recognize this possibility may lead to incorrect interpretation of experimental results and to faulty conclusions. Here, we present several examples of binding of a citrate anion to the active sites of E. coli L-asparaginases I and II, even in the presence of the native substrate, L-Asn. A part of this report focuses on a comprehensive re-interpretation of structural results published previously for complexes of type I L-asparaginase (EcAI) from E. coli. In two re-refined structures a citrate anion forms an acyl-enzyme reaction intermediate with the catalytic threonine. These results emphasize the importance of careful and critical analysis during interpretation of crystallographic data.
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Citric-acid dialysate improves the calcification propensity of hemodialysis patients: A multicenter prospective randomized cross-over trial.
Ter Meulen, KJ, Dekker, MJE, Pasch, A, Broers, NJH, van der Sande, FM, van der Net, JB, Konings, CJAM, Gsponer, IM, Bachtler, MDN, Gauly, A, et al
PloS one. 2019;(12):e0225824
Abstract
INTRODUCTION The concentration of dialysate calcium (dCa) has been suggested to affect vascular calcification, but evidence is scarce. Calcification propensity reflects the intrinsic capacity of serum to prevent calcium and phosphate to precipitate. The use of citric-acid dialysate may have a beneficial effect on the calcification propensity due to the chelating effect on calcium and magnesium. The aim of this study was to compare the intradialytic and short-term effects of haemodialysis with either standard acetic-acid dialysate with dCa1.50 (A1.5) or dCa1.25 (A1.25), as well as citric-acid dialysate with dCa1.50 (C1.5) in bicarbonate dialysis on the calcification propensity of serum. METHODS Chronic stable hemodialysis patients were included. This multicenter randomized cross-over study consisted out of a baseline week (A1.5), followed by the randomized sequence of A1.25 or C1.5 for one week after which the alternate treatment was provided after a washout week with A1.5. Calcification propensity of serum was assessed by time-resolved nephelometry where the T50 reflects the transition time between formation of primary and secondary calciprotein particles. RESULTS Eighteen patients (median age 70 years) completed the study. Intradialytic change in T50 was increased with C1.5 (121 [90-152]min) compared to A1.25 (83 [43-108]min, p<0.001) and A1.5 (66 [18-102]min, p<0.001). During the treatment week, predialysis T50 increased significantly from the first to the third session with C1.5 (271 [234-291] to 280 [262-339]min, p = 0.002) and with A1.25 (274 [213-308] to 307 [256-337]min, p<0.001), but not with A1.5 (284 [235-346] to 300 [247-335]min, p = 0.33). CONCLUSION Calcification propensity, as measured by the change in T50, improved significantly during treatment in C1.5 compared to A1.25 and A1.5. Long-term studies are needed to investigate the effects of different dialysate compositions concentrations on vascular calcification and bone mineral disorders.
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Citric Acid Production from Acorn Starch by Tannin Tolerance Mutant Aspergillus niger AA120.
Zhang, N, Jiang, JC, Yang, J, Wei, M, Zhao, J, Xu, H, Xie, JC, Tong, YJ, Yu, L
Applied biochemistry and biotechnology. 2019;(1):1-11
Abstract
In this study, acorn starch was investigated as a new material for fermenting production of citric acid by using a tannin tolerance mutant strain Aspergillus niger AA120. The mutant A. niger AA120 was obtained by initially atmospheric pressure plasma at room temperature (ARTP) mutagenesis and then tannin gradient domestication. ARTP experiments showed that a "double-saddle" shape of survival rate curve was achieved, and a positive mutation rate of 63.6% was reached by setting the implantation time of mutagenesis to 100 s. In contrast to the original stain at the presence of 20.0 g/L tannin in the medium, the selected mutant A. niger AA120 exhibits an increase of biomass by 43.76% to 32.9 g/L, and citric acid production capacity by 20.34% to 130.8 g/L, with 8% (w/w) of inoculation quantity, an initial pH of 6.2 and shaking speed of 250 r/min. In this work, we present a referable method for the mutagenesis screening of the A. niger, and the application of acorn starch as a new raw material for the development of the citric acid industry.
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Dissimilatory iron and sulfate reduction by native microbial communities using lactate and citrate as carbon sources and electron donors.
Xia, D, Yi, X, Lu, Y, Huang, W, Xie, Y, Ye, H, Dang, Z, Tao, X, Li, L, Lu, G
Ecotoxicology and environmental safety. 2019;:524-531
Abstract
The bacterial (dissimilatory) iron and sulfate reduction (BIR and BSR) are intimately linked to the biogeochemical cycling of C, Fe, and S in acid mine drainage (AMD) environments. This study examined the response of native microbial communities to the reduction of iron and sulfate in bench experimental systems. Results showed that the reduction of ferric iron and sulfate took place when the electron acceptors coexist. Existence of Fe(III) can postpone the reduction of sulfate, but can enhance the reduction rate. Cultures grown in the presence of 10 mM iron can reach the final level of sulfate bio-reduction rate (~100%) after 35 days incubation. 16 S rDNA -based microbial community analysis revealed that the three genera Anaeromusa, Acinetobacter and Bacteroides were dominated in the ferric-reducing conditions. SRB (Desulfobulbus, Desulfosporosinus and Desulfovibrio) were dominated in the sulfate reduction process. Results in this study highlighted the highly coupled nature of C, Fe, and S biogeochemical cycles in AMD and provided insights into the potential of environmental remediation by native microbial.
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Regional citrate anticoagulation for continuous renal replacement therapy.
Kindgen-Milles, D, Brandenburger, T, Dimski, T
Current opinion in critical care. 2018;(6):450-454
Abstract
PURPOSE OF REVIEW The delivery of an effective dialysis dose in continuous renal replacement therapy (CRRT) depends on adequate anticoagulation of the extracorporeal circuit. In most patients, either systemic heparin anticoagulation (SHA) or regional citrate anticoagulation (RCA) is used. This review will outline the basics and rationale of RCA and summarize data on safety and efficacy of both techniques. RECENT FINDINGS The basic principle of RCA is to reduce the level of ionized calcium in the extracorporeal circuit via infusion of citrate. This way, effective anticoagulation restricted to the extracorporeal circuit is achieved. SHA and RCA were compared in a variety of studies. RCA significantly prolonged filter lifetime, reduced bleeding complications and provided excellent control of uremia and acid-base status. RCA was also safe in the majority of patients with impaired liver function, whereas caution must be exerted in those with severe multiorgan failure and persistent hyperlactatemia. SUMMARY RCA per se is safe and effective for anticoagulation of CRRT. Compared to SHA, efficacy of anticoagulation is improved and adverse effects are reduced. RCA can be recommended as the anticoagulation mode of choice for CRRT in most ICU patients.