Citrate dose for continuous hemofiltration: effect on calcium and magnesium balance, parathormone and vitamin D status, a randomized controlled trial

Background Regional citrate anticoagulation may cause a negative calcium balance, systemic hypocalcemia and parathormone (PTH) activation but randomzed studies are not available. Aim was to determine the effect of citrate dose on calcium (Ca) and magnesium (Mg) balance, PTH and Vitamin D. Methods Single center prospective randomized study. Patients, requiring continuous venovenous hemofiltration (CVVH) with citrate, randomized to low dose citrate (2.5 mmol/L) vs. high dose (4.5 mmol/L) for 24 h, targeting post-filter ionized calcium (pfiCa) of 0.325–0.4 mmol/L vs. 0.2–0.275 mmol/L, using the Prismaflex® algorithm with 100% postfilter calcium replacement. Extra physician-ordered Ca and Mg supplementation was performed aiming at systemic iCa > 1.0 mmol/L. Arterial blood, effluent and post-filter aliquots were taken for balance calculations (area under the curve), intact (i), oxidized (ox) and non-oxidized (nox) PTH, 25-hydroxy-Vitamin D (25D) and 1,25-dihydroxy-Vitamin D (1,25D). Results 35 patients were analyzed, 17 to high, 18 to low citrate. Mean 24-h Ca balance was - 9.72 mmol/d (standard error 1.70) in the high vs − 1.18 mmol/d (se 1.70)) (p = 0.002) in the low citrate group and 24-h Mg-balance was − 25.99 (se 2.10) mmol/d vs. -17.63 (se 2.10) mmol/d (p = 0.008) respectively. Physician-ordered Ca supplementation, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH, oxPTH or noxPTH were not different between groups. Over 24 h, median PTH decreased from 222 (25th–75th percentile 140–384) to 162 (111–265) pg/ml (p = 0.002); oxPTH from 192 (124–353) to 154 pg/ml (87–231), p = 0.002. NoxPTH did not change significantly. Mean 25 D (standard deviation), decreased from 36.5 (11.8) to 33.3 (11.2) nmol/l (p = 0.003), 1,25D rose from 40.9 pg/ml (30.7) to 43.2 (30.7) pg/ml (p = 0.046), without differences between groups. Conclusions A higher citrate dose caused a more negative CVVH Ca balance than a lower dose, due to a higher effluent Calcium loss. Physician-ordered Ca supplementation, targeting a systemic iCa > 1.0 mmol/L, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH and oxPTH declined, suggesting decreased oxidative stress, while noxPTH did not change. 25D decreased while 1,25-D rose. Mg balance was negative in both groups, more so in the high citrate group. Trial registration ClinicalTrials.gov: NCT02194569. Registered 18 July 2014.

Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication via intracellular calcium regulation

Background Empagliflozin is a SGLT-2 inhibitor used in the treatment of Type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Aim Our aim in the present study is to observe the effect of the concomitant use of amitriptyline and empagliflozin together, which have an effect on sodium and calcium balance in myocytes, on QTc by using ECG. Materials and methods Twenty-four male Wistar-Albino rats were randomized into four groups. The control group received only serum physiologic (1ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT+EMPA group (n: 6) received amitriptyline and empagliflozin at same dose. Under anesthesia; QT and QTC intervals were measured at baseline, first, and second hours. Results The differences in QT and QTc values between the AMT group and control group were observed from the 1nd hour (Table 1, Figure 1). It was detected that the measurements of the control group were within normal limits. In the control group, QT was 77.33±9.02 ms at the basal, 73.50±2.26 ms at the 1st hour, 78.17±6.18 ms at the 2nd hour. QTc calculation was 165.42±18.34±10.5 ms at the basal, 166.63±17.92 msat the 1st hour, 184.65±12.86 ms at the 2nd hour. ECG findings of the EMPA group were within normal limits and similar to the control group (Table 1). The durations of QT interval and QTc calculations were found to be statistically longer in the AMT group than the control group at the 1st and 2nd hour (p≤0.001). Empagliflozin significantly ameliorated AMT-induced QT and QTc prolongation. The durations of QT interval were significantly lower at first (p<0,001) and 2nd hours (p<0.01) in the AMT+EMPA group compared to the AMT group. Moreover, QTc calculation was significantly lower in the AMT+EMP group than the AMT group at 1st and 2nd hour (P<0.01) (Table 1). Electrocardiographic comparisons of all groups for one second within the second hour can be seen in Figure 2. Conclusion In the present study, we have detected that empagliflozin significantly ameliorates amitriptyline induced QT prolongation. This effect is probably due to the opposite effects of these two agents in the intracellular calcium balance. It's known that; toxic dose of amitriptyline increases the amount of Sarcoplasmic Ca and the calcium permeability of Ryanodine channels, decreases SERCA-mediated Ca-reuptake by decreasing the calcium binding capacity of calsequestrin, and these leads QTc prolongation. It has been shown that empagliflozin increases Ca reuptake by causing a significant increase in SERCA activity, and decreases Ca sparks by causing inhibition of Ryanodine activity. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QTc prolongation in the diabetic patients receiving amitriptyline. FUNDunding Acknowledgement Type of funding sources: None. Table 1. QT, QTc durations and HR for groups Figure 1. ECG traces – a: CON, b: EMPA, c: AMT, d: AMT+EMP

Recurrent Hypocalcemic Tetany as the Initial Presentation in Some Persons with Hyperthyroidism: A Case Series

This is a case series of recurrent hypocalcemic tetany as the initial presentation in some cases of hyperthyroidism. Literature review has revealed more reports of hypercalcemia than hypocalcemia as a feature of hyperthyroidism. The recurrence of hypocalcemic tetany in the 3 cases reported ceased following the treatment of hyperthyroidism. The aim of this case series is to alert clinicians to the fact that hypocalcemic tetany can be the initial clinical presentation of hyperthyroidism. It also highlights the resilience of managing endocrine patients in resource-poor settings with the aid of high clinical acumen and fewer-than-expected laboratory investigations. Further research is needed to investigate our hypothesis that disordered calcium metabolism in thyrotoxicosis may manifest in successive phases of hypercalcemia-normocalcemia-hypocalcemia. The rate at which individual thyrotoxic patient traverses these phases may be directly proportional to the background vitamin D deficiency, negative calcium balance, and bone mineral density.

Bothrops moojeni Venom and Its Components Strongly Affect Osteoclasts’ Maturation and Protein Patterns

Osteoclasts (OCs) are important for bone maintenance, calcium balance, and tissue regeneration regulation and are involved in different inflammatory diseases. Our study aimed to evaluate the effect of Bothrops moojeni’s venom and its low and high molecular mass (HMM and LMM) fractions on human peripheral blood mononuclear cell (PBMC)-derived OCs’ in vitro differentiation. Bothrops moojeni, a Brazilian lanced-head viper, presents a rich but not well-explored, venom composition. This venom is a potent inducer of inflammation, which can be used as a tool to investigate the inflammatory process. Human PBMCs were isolated and induced to OC differentiation following routine protocol. On the fourth day of differentiation, the venom was added at different concentrations (5, 0.5, and 0.05 µg/mL). We observed a significant reduction of TRAP+ (tartrate-resistant acid phosphatase) OCs at the concentration of 5 µg/mL. We evaluated the F-actin-rich OCs structure’s integrity; disruption of its integrity reflects bone adsorption capacity. F-actin rings phalloidin staining demonstrated that venom provoked their disruption in treated OCs. HMM, fraction reduces TRAP+ OCs at a concentration of 5 µg/mL and LMM fraction at 1 µg/mL, respectively. Our results indicate morphological changes that the venom induced cause in OCs. We analyzed the pattern of soluble proteins found in the conditioned cell culture medium OCs treated with venom and its fractions using mass spectrometry (LC-MS/IT-Tof). The proteomic analyses indicate the possible pathways and molecular mechanisms involved in OC reduction after the treatment.

Biological Effects of Global System of Mobile Communication- A Review

In this study, a review of the biological effects of Global System of Mobile Communication handset was carried out using available literature and safety standards for radiofrequency of the National and International Agencies in conjunction with the International Committee for Non-Ionizing Radiation Protection (ICNIRP). The dose received by a biological tissue in time 0.5 minutes of dose as stated by the aforementioned agencies is equal to the microwave of 10mw/cm2 SAR of 2 w/kg. The Specific Absorption Rate (SAR) limit of tissue for occupational workers for a whole body is 0.04 w/kg and for non-occupational workers is 0.08 w/kg. Additionally, GSM users exceeding the above SAR limits are likely to suffer from physiological effects of various forms such as alteration of calcium balance in the nerve tissues and inhibition of cells growth in the human amniotic, disruption of biorhythms due to the influence of electromagnetic field on the epiphysis resulting in dizziness, headaches and brain tumour.

Calcium isotope fractionation by osteoblasts and osteoclasts, across endothelial and epithelial cell barriers and with binding to proteins

Timely and accurate diagnosis of osteoporosis is essential for adequate therapy. Calcium isotope ratio (δ44/42Ca) determination has been suggested as a sensitive, non-invasive and radiation-free biomarker for the diagnosis of osteoporosis, reflecting bone calcium balance. The quantitative diagnostic is based on the calculation of the δ44/42Ca difference between blood, urine and bone. The underlying cellular processes, however, have not been studied systematically. We quantified calcium transport and δ44/42Ca fractionation during in-vitro bone formation and resorption by osteoblasts and osteoclasts and across renal proximal tubular epithelial cells (HK-2), endothelial cells (HUVEC) and enterocytes (Caco-2) in transwell systems, and determined transepithelial electrical resistance characteristics. δ44/42Ca fractionation was furthermore quantified with calcium binding to albumin and collagen. Calcified matrix formed by osteoblasts was isotopically lighter than culture medium by -0.27 ± 0.03‰ within 5 days, while a consistent effect of activated osteoclasts on δ44/42Ca could not be demonstrated. A transient increase in δ44/42Ca in the apical compartment by 0.26‰ occured across HK-2 cells, while δ44/42Ca fractionation was small across the HUVEC barrier, and absent with Caco-2 enterocytes, and with binding of calcium to albumin and collagen. In conclusion, δ44/42Ca fractionation follows similar universal principles as during inorganic mineral precipitation; osteoblast activity results in δ44/42Ca fractionation. δ44/42Ca fractionation also occurs across the proximal tubular cell barrier and needs to be considered for in-vivo bone mineralization modelling. In contrast, the effect of calcium transport across endothelial and enterocyte barriers on blood δ44/42Ca should be low and is absent with physiochemical binding of calcium to proteins.

Efficacy, Safety, and Calcium Balance of an Accelerated Citrate Anticoagulated Membrane-Based Plasma Exchange Algorithm

<b><i>Introduction:</i></b> To assess the safety, efficacy, and calcium flux of an accelerated algorithm for regional citrate anticoagulation in membrane-based plasma exchange. <b><i>Methods:</i></b> This was an observational study in patients receiving citrate anticoagulated, membrane-based plasma exchange at the Canberra Hospital between July 2017 and May 2020. Data were collected prospectively using an electronic medical record and compared to data from our previous published algorithm. <b><i>Results:</i></b> There were 134 plasma exchange sessions performed during the observational period. Circuit clotting occurred in 4 sessions, and 1 session was affected by symptomatic hypocalcaemia. A systemic ionized calcium &#x3c;0.96 mmol/L was seen in 19.4% of sessions, which was a similar frequency to that seen in our previous algorithm. A systemic ionized Ca &#x3c;0.81 mmol/L occurred in 4 sessions (all asymptomatic). This hypocalcaemia occurred towards the end of the sessions, after switching from albumin to fresh frozen plasma replacement fluid. Median treatment time was 135 min, compared to 219 min in our previously published algorithm. Mean net Ca gain/session was 7.7 ± 2.3 mmol. <b><i>Conclusion:</i></b> An accelerated algorithm for regional citrate anticoagulation achieves substantial time saving while maintaining efficacy and safety. The 4 episodes of systemic ionized calcium &#x3c;0.81 mmol/L may have been due to recirculation of infused citrate but, probably more likely, are due to the additional citrate load imposed by use of fresh frozen plasma in these sessions. Future algorithms need to better account for the citrate load present in fresh frozen plasma.