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Background Regional citrate anticoagulation (RCA) is a widely used strategy for continuous renal replacement therapy (CRRT). Most of the current guidelines recommend liver failure as one of the contraindications for citrate anticoagulation. However, some studies suggested that the use of citrate for CRRT in liver failure patients did not increase the risk of citrate-related complications. The purpose of this systematic review is to summarize the current evidences on the safety and efficacy of RCA for CRRT in liver failure patients. Methods We performed a comprehensive search on PubMed, Embase, and the Cochrane Library databases from the inception to March 1, 2018. Studies enrolled adult (age > 18 years) patients with various levels of liver dysfunction underwent RCA-CRRT were included in this systematic review. Results After the study screening, 10 observational studies with 1241 liver dysfunction patients were included in this systematic review. The pooled rate of citrate accumulation and bleeding was 12% [3%, 22%] and 5% [2%, 8%], respectively. Compared with the baseline data, the serum pH, bicarbonate, and base excess (BE), the rate of metabolic alkalosis, the serum ionized calcium (ionCa) and total calcium (totCa) level, and the ratio of total calcium/ionized calcium (totCa/ionCa) significantly increased at the end of observation. However, no significant increase was observed in serum citrate (MD − 65.82 [− 194.19, 62.55]), lactate (MD 0.49 [− 0.27, 1.26]) and total bilirubin concentration (MD 0.79 [− 0.70, 2.29]) at the end of CRRT. Compared with non-liver failure patients, the live failure patients showed no significant difference in the pH (MD − 0.04 [− 0.13, 0.05]), serum lactate level (MD 0.69 [− 0.26, 1.64]), and totCa/ionCa ratio (MD 0.03 [− 0.12, 0.18]) during CRRT. The median of mean filter lifespan was 55.9 h, with a range from 22.7 to 72 h. Conclusions Regional citrate anticoagulation seems to be a safe anticoagulation method in liver failure patients underwent CRRT and could yield a favorable filter lifespan. Closely monitoring the acid base status and electrolyte balance may be more necessary during RCA-CRRT in patients with liver failure.

Regionally anticoagulated continuous renal replacement therapy with citrate is the first choice for critically ill patients with acute kidney injury. If citrate that reaches the patient exceeds the metabolic capacity, metabolic alkalosis will follow. Bicarbonate from the treatment fluids will also reach the patient and add to the bicarbonate load. Net buffer load is a parameter calculated by the dialysis machine software from the treatment fluid contents, the fluid flows and the filter properties. Each time the treatment settings are altered the net buffer load will be re-calculated. This parameter is integrated as a static safety parameter in the Prismax version 3 software, and will guide the operator on a possible development of metabolic alkalosis with the current settings. Algorithms for estimating the net buffer load were developed. Hourly clinical data from electronic medical records from 60 patients' continuous renal replacement treatments at the Adult Intensive Care Unit, Skåne University Hospital, Lund, Sweden was used to simulate net buffer load. The relation between net buffer load and acid base status at steady state was evaluated. Net buffer load was also calculated from three previous studies for comparison to our present cohort. The mean net buffer load was +0.09 ±0.04 mmol/h/kg in the present cohort, and comparable to historic cohorts from literature. We could not establish a correlation to steady state arterial bicarbonate. The pre blood pump citrate containing replacement fluid flow rate was affecting net buffer load most of all parts of the dialysis circuit, with a r2 Pearson correlation coefficient of 0.65 (p<0.001). The net buffer load parameter can alert the operator on the expected impact of the dialysis circuit on patient's acid base status. It was possible to calculate realistic net buffer load values during 60 CRRT treatments.

A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope 27Al, both in animals and man. These limitations are absent in studies with 26Al as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans—especially in toxicological relevant tissues like bone and brain—is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of 26Al tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated 26Al dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous 26Al data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans.

ABSTRACT Despite the high prevalence of age‐dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. We investigated the efficacy of long‐term oral K3Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age‐associated disc calcification. K3Citrate reduced the incidence of disc calcification without affecting the vertebral bone structure, knee calcification, plasma chemistry, or locomotion in LG/J mice. Notably, a positive effect on grip strength was evident in treated mice. FTIR spectroscopy of the persisting calcified nodules indicated K3Citrate did not alter the mineral composition. Mechanistically, activation of an endochondral differentiation in the cartilaginous endplates and nucleus pulposus (NP) compartment contributed to LG/J disc calcification. Importantly, K3Citrate reduced calcification incidence by Ca2+ chelation throughout the disc while exhibiting a differential effect on NP and endplate cell differentiation. In the NP compartment, K3Citrate reduced the NP cell acquisition of a hypertrophic chondrocytic fate, but the pathologic endochondral program was unimpacted in the endplates. Overall, this study for the first time shows the therapeutic potential of oral K3Citrate as a systemic intervention strategy to ameliorate disc calcification. An endochondral differentiation process in the CEPs drives pathologic disc calcification in aging LG/J mice, and NP cell hypertrophic transdifferentiation secondarily contributes. Supplementing drinking water with 80 mM K3Citrate during aging markedly reduced disc calcification, attenuated NP cell transdifferentiation, and mildly improved NP and AF fibrotic outcomes. CEP endochondral processes persisted, suggesting an extracellular process, such as calcium chelation, prevents disc calcification.

Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Regional citrate anticoagulation (RCA) is critical for extracorporeal anticoagulation in continuous renal replacement therapy done at the bedside. To make patients’ data more secure and to help with computer-based monitoring of dosages, we suggest a system that uses machine learning. This system will give early alerts about citric acid overdose and advise changes to how much citrate and calcium gluconate are infused into the patient’s body. Citric acid overdose causes significant clinical risks, emphasizing the need for better adaptable anticoagulation procedures that can respond quickly. The study puts forward a new structure that uses edge computing and federated learning to make better citrate anticoagulation procedures. We proposed the resource-aware Federated Learning with Dynamic Client Selection (RAFL-Fed) algorithm in our method. In this setup, every client takes part by training a local model locally and then sending its outcome to a main server. The algorithm chooses clients for each training session depending on their computing resources, which keeps things efficient and scalable. The server collects the client inputs using weighted averages to update the global model. This step is performed repeatedly across many communication cycles, letting the system adjust to changing data trends from different locations. We put RAFL-Fed to the test on the MIMIC-IV dataset, and it outperformed other methods, getting a high accuracy of 0.9615 (IID) and 0.9571 (Non-IID), also with the lowest loss values being 0.2625 and 0.2469 in that order. It also noted the best MAE at 0.1731 (Non-IID) and a bit higher at 0.2081 (IID). Along with the high sensitivity at 0.9968, specificity stood strong as well, measuring 0.9449, plus latency was only 0.123s, which shows how effective it is for early detection of citric acid overdose as well as adjusting in real-time in the regional citrate anticoagulation process. The proposed method shows a promising solution for the real-time monitoring and adjustment of citrate anticoagulation regimens, greatly enhancing patient data security and treatment effectiveness in clinical settings. This method signifies a significant advancement in handling anticoagulation therapy.

For hemodialysis patients at high risk of bleeding, a regional anticoagulant can be used, such as citrate or nafamostat mesylate (NM). The objective of this study was to evaluate NM as an alternative to citrate for anticoagulation in hemodialysis patients at high risk of bleeding. This retrospective single-center study included consecutive patients in our dialysis center treated with either citrate or NM anticoagulation for hemodialysis from January 2022 to December 2023.The primary outcome was major clotting, defined as premature dialysis due to extracorporeal circuit clotting. The secondary outcome was the incidence of a major bleeding episode during or after hemodialysis. In total, 651hemodialysis sessions were performed in 196 patients and were compared (289 citrate and 362 NM anticoagulation). A lower number of premature dialysis due to clotting occurred in the NM sessions compared to citrate sessions (0.84% vs.5.19%,  = 0.001). NM was associated with a lower risk of major clotting compared with citrate during treatment (OR:0.063; CI: 0.008-0.475;  = 0.007). Regarding second outcome, no more major bleeding events related to NM occurred compared to citrate. Among hemodialysis patients with high risk of bleeding, anticoagulation with NM, compared with citrate anticoagulation, provided relatively better efficacy, with no bleeding increment. NM is a valid alternative to citrate for hemodialysis patients at high risk of bleeding.

Correspondence to Dr Meghan Roberts, Paediatric Critical Care Unit, Queen's Medical Centre Nottingham Children's Hospital, Nottingham, UK; meghan.roberts@nhs.net We present our analysis of citrate versus heparin anticoagulation for children in two UK paediatric intensive care units undergoing continuous renal replacement therapy (CRRT). Ethics approval This project was defined as a service evaluation by the Health Research Authority definitions, and was exempt from Research Ethics Committee approval (23449C). Circuit life span in critically ill children on continuous renal replacement treatment: a prospective observational evaluation study.

ABSTRACT Divalent cations such as calcium and ferrous sulfate interfere with the absorption of levothyroxine due to complexing. To our knowledge, the effects of magnesium on levothyroxine absorption have never been studied. The open‐label cross‐over pharmacokinetic study was conducted in 15 healthy, euthyroid adults. 1 mg of levothyroxine was administered in tablet form alone or co‐administered with either magnesium aspartate or magnesium citrate. Participants received all three treatments, separated by a washout period, but were randomly allocated 1:1:1 to one of three treatment sequences. We measured thyroxine (T4) over a 6‐h period after ingestion. The primary endpoint was the area under the curve (AUC) of thyroxine; secondary endpoints were Cmax and Tmax. Coadministration of magnesium aspartate significantly reduced thyroxine AUC by 12% (geometric mean ratio, GMR = 0.88, 95% CI 0.81–0.95, p = 0.002) and coadministration of magnesium citrate reduced thyroxine AUC non‐significantly by 7% compared with levothyroxine alone (GMR = 0.93, 95% CI 0.86–1.01, p = 0.076). Cmax was significantly reduced by 7% and Tmax was significantly increased by 17% when magnesium aspartate was co‐administered. The changes in Cmax and Tmax were smaller when magnesium citrate was co‐administered. In conclusion, magnesium reduces the absorption of levothyroxine. However, we found smaller effects compared to those already described for other divalent cations, possibly due to the liquid formulation. Hypothyroid patients should nonetheless take levothyroxine separated from magnesium‐containing formulations, especially if TSH levels are desired to be within a narrow range. If taken together, magnesium citrate may be a better option than magnesium aspartate.