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1.
Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients.
Zamai, L
Cells. 2021;(3)
Abstract
The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to "clinical" manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.
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2.
An Observational Cohort Study of the 2-Month Use of Regional Citrate Anticoagulation in Maintenance Hemodialysis Patients with Cerebral Hemorrhage.
Bi, X, Zhang, Q, Zhuang, F, Lu, W, Wang, Y, Ding, F
Medical science monitor : international medical journal of experimental and clinical research. 2021;:e930513
Abstract
BACKGROUND Regional citrate anticoagulation (RCA) is a recommended anticoagulation alternative for patients at high risk of bleeding while undergoing intermittent hemodialysis. Previous reports implied the risk of citrate application on bone metabolism. It is unclear whether long-term use of RCA is safe for maintenance hemodialysis patients in terms of bone metabolism. MATERIAL AND METHODS Seven patients with cerebral hemorrhage were included in the study. Blood samples were collected at baseline and 4 and 8 weeks after treatment. Spent dialysate samples were collected during each mid-week dialysis session, using the partial dialysate collection method. All patients were treated with RCA for 4 to 8 weeks, according to their clinical condition. We assessed bone metabolism-associated parameters, bone turnover markers, and magnesium loss at each dialysis session. RESULTS Serum magnesium levels were 1.24±0.13 mmol/L at baseline and significantly decreased to 1.16±0.14 mmol/L after 4 weeks of RCA treatment (P=0.025). Most patients had negative magnesium balance during citrate hemodialysis. Serum total calcium levels did not change significantly after treatment. One bone marker, N-terminal propeptide of type I procollagen (PINP), significantly decreased from 146.07±130.12 mmol/L to 92.42±79.01 mmol/L after citrate treatment (P=0.018). No significant changes were detected in other bone turnover markers. CONCLUSIONS Relatively long-term RCA treatment may decrease serum magnesium levels due to negative magnesium balance. Bone formation marker PINP seemed to decrease after treatment, while other bone turnover markers did not change significantly. Further investigation is needed to verify the effect of RCA on bone remodeling.
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3.
Regional citrate anti-coagulation dose titration: impact on dose of continuous renal replacement therapy.
Ng, CJH, Poh, CB, Koduri, S, Roy, DM, Siau, C, Lim, NL, Chionh, CY
Clinical and experimental nephrology. 2021;(9):963-969
Abstract
BACKGROUND Regional citrate anti-coagulation (RCA) is the recommended anti-coagulation for continuous renal replacement therapy (CRRT). Citrated replacement fluids provide convenience but may compromise effluent delivery when adjusted to maintain circuit ionised calcium levels (circuit-iCa). This study aims to evaluate the effect of RCA titration on the delivered CRRT effluent dose. METHODS This prospective observational study evaluated patients on RCA-CRRT in continuous veno-venous hemodiafiltration mode. Citrated replacement fluid was titrated to target circuit-iCa 0.26-0.40 mmol/L. Patients were then stratified into 'reduced-dose' who required citrate down-titration and 'stable-dose' who did not. RESULTS Data from 200 RCA-CRRT sessions were collected. The reduced-dose RCA group (n = 114) had higher median initial citrate dose (3.00 vs 2.50; P < 0.001) but lower time-averaged dose (2.49 vs 2.60; P < 0.001). In addition, median prescribed effluent dose was 33.3 mL/kg/h (28.6-39.2) but median delivered effluent dose was significantly lower at 29.9 mL/kg/h (25.4-36.9; P < 0.001). Mortality was higher in the reduced-dose RCA group (39.5% vs 25.6%; P = 0.022) and in patients with delivered-to-prescribed effluent dose ratio of < 0.9 vs ≥ 0.9 (51.3% vs 29.2%; P = 0.014). CONCLUSION RCA titration can significantly impact delivered CRRT effluent dose. Measures should be taken to address the CRRT dose deficit and prevent poor outcomes due to inadequate dialysis.
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4.
Citrate dose for continuous hemofiltration: effect on calcium and magnesium balance, parathormone and vitamin D status, a randomized controlled trial.
Boer, W, Fivez, T, Vander Laenen, M, Bruckers, L, Grön, HJ, Schetz, M, Oudemans-van Straaten, H
BMC nephrology. 2021;(1):409
Abstract
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.
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5.
BRAzil magnesium (BRAMAG) trial: a double-masked randomized clinical trial of oral magnesium supplementation in pregnancy.
de Araújo, CAL, Ray, JG, Figueiroa, JN, Alves, JG
BMC pregnancy and childbirth. 2020;(1):234
Abstract
BACKGROUND There is conflicting evidence about the role of oral magnesium supplementation in the prevention of preterm birth and related adverse outcomes. The objective of this study was to compare magnesium citrate with placebo in the prevention of adverse perinatal and maternal outcomes among women at higher risk. METHODS This multicenter, double-masked, placebo-controlled randomized superiority clinical trial compared oral magnesium citrate 300 mg to matched placebo, from 12 to 20 weeks' gestation until delivery. This trial was completed in three centers in northeastern Brazil. Eligible women were those with a singleton pregnancy and ≥ 1 risk factor, such as prior preterm birth or preeclampsia, or current chronic hypertension or pre-pregnancy diabetes mellitus, age > 35 years or elevated body mass index. The primary perinatal composite outcome comprised preterm birth < 37 weeks' gestation, stillbirth > 20 weeks, neonatal death or NICU admission < 28 days after birth, or small for gestational age birthweight < 3rd percentile. The co-primary maternal composite outcome comprised preeclampsia or eclampsia < 37 weeks, severe gestational hypertension < 37 weeks, placental abruption, or maternal stroke or death during pregnancy or ≤ 7 days after delivery. RESULTS Analyses comprised 407 women who received magnesium citrate and 422 who received placebo. The perinatal composite outcome occurred among 75 (18.4%) in the magnesium arm and 76 (18.0%) in the placebo group - an adjusted odds ratio (aOR) of 1.10 (95% CI 0.72-1.68). The maternal composite outcome occurred among 49 (12.0%) women in the magnesium arm and 41 women (9.7%) in the placebo group - an aOR of 1.29 (95% CI 0.83-2.00). CONCLUSIONS Oral magnesium citrate supplementation did not appear to reduce adverse perinatal or maternal outcomes in high-risk singleton pregnancies. TRIAL REGISTRATION ClinicalTrials.gov NCT02032186, registered January 9, 2014.
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6.
Impact of the dialysate acid component on haemodialysis mortality rates.
Couchoud, C, Hannedouche, T, Bauwens, M, Ecochard, R, Lassalle, M, Frimat, L, Choukroun, G, Lobbedez, T
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(7):1244-1249
Abstract
BACKGROUND No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.
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7.
Comparison of Two Dietary Supplements for Treatment of Uric Acid Renal Lithiasis: Citrate vs. Citrate + Theobromine.
Hernandez, Y, Costa-Bauza, A, Calvó, P, Benejam, J, Sanchis, P, Grases, F
Nutrients. 2020;(7)
Abstract
BACKGROUND Uric acid (UA) renal lithiasis has a high rate of recurrence and a prevalence ranging from 10% and 15%, depending on the population. The most important etiological factor is persistence of urinary pH below 5.5 and one of the most common treatments is alkalization with citrate. Recent studies demonstrated that theobromine, which is abundant in chocolate and cocoa, is a potent inhibitor of UA crystallization. AIM: The aim was to compare the efficacy of citrate versus citrate + theobromine as treatment for UA lithiasis. METHODS This randomized cross-over trial investigated the efficacy of two treatments in 47 patients with UA renal lithiasis. Urine volume, pH, UA excretion, theobromine excretion, and risk of UA crystallization (RUAC) at baseline and at the end of each intervention period were measured. RESULTS Each treatment significantly reduced the risk of UA crystallization compared to basal values. The RUAC after citrate + theobromine was lower than the RUAC after citrate, although this difference was not statistically significant. CONCLUSION The combined consumption of citrate and theobromine may be a promising strategy for the prevention of UA kidney stones.
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8.
Energy expenditure and caloric targets during continuous renal replacement therapy under regional citrate anticoagulation. A viewpoint.
Jonckheer, J, Spapen, H, Malbrain, MLNG, Oschima, T, De Waele, E
Clinical nutrition (Edinburgh, Scotland). 2020;(2):353-357
Abstract
BACKGROUND Indirect calorimetry (IC) is the gold standard for measuring energy expenditure in critically ill patients However, continuous renal replacement therapy (CRRT) is a formal contraindication for IC use. AIMS To discuss specific issues that hamper or preclude an IC-based assessment of energy expenditure and correct caloric prescription in CRRT-treated patients. METHODS Narrative review of current literature. RESULTS Several relevant pitfalls for validation of IC during CRRT were identified. First, IC measures CO2 production (VCO2) and O2 consumption to calculate resting energy expenditure (REE) with the Weir equation. VCO2 measurements are influenced by CRRT because CO2 is exchanged during the blood purification process. CO2 exchange also depends on type of pre- and/or postdilution fluid(s). CO2 dissolves in different forms with dynamic but unpredictable impact on VCO2. Second, the effect of immunologic activation and heat loss on REE caused by extracorporeal circulation during CRRT is poorly documented. Third, caloric prescription should be adapted to CRRT-induced in- and efflux of different nutrients. Finally, citrate, which is the preferred anticoagulant for CRRT, is a caloric source that may influence IC measurements and REE. CONCLUSION Better understanding of CRRT-related processes is needed to assess REE and provide individualized nutritional therapy in this condition.
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9.
Metabolic diagnoses of recurrent stone formers: temporal, geographic and gender differences.
Huynh, LM, Dianatnejad, S, Tofani, S, Carrillo Ceja, R, Liang, K, Tapiero, S, Jiang, P, Youssef, RF
Scandinavian journal of urology. 2020;(6):456-462
Abstract
BACKGROUND Metabolic factors underlying the recent increase in stone prevalence over the past decades are not well understood. Herein, we evaluate temporal, geographic and gender-specific trends in metabolic risk factors in recurrent kidney stone formers. PATIENTS AND METHODS A systematic literature review of metabolic risk factors for stone formation was conducted, inclusive of the last four decades. Studies with inadequate 24 h urine metabolic data, pediatric or those with less than 50 patients were excluded. The primary outcome was prevalence of each metabolic risk factor, compared between studies published prior to the year 2000 vs those following. Geographic and gender differences were secondary outcomes. RESULTS Twenty-eight articles met inclusion criteria, of which 10 (n = 1578) were published prior to the year 2000 and 18 (n = 8747) were published thereafter. Comparing these groups, an increase in hyperoxaluria (29% vs 33%; p = 0.002), hypercalciuria (35 vs 36%; p = 0.446), hyperuricosuria (17% vs 22%; p < 0.0001), low urine volume (28 vs 38%; p < 0.0001) and hypocitraturia (23% vs 44%; p < 0.0001) was observed. The prevalence of hyperoxaluria, hypercalciuria, hyperuricosuria and hypocitraturia were significantly higher in males. There were also significant geographical differences, with higher prevalence of hyperoxaluria and hypocitraturia in non-Western countries and higher prevalence of hypercalciuria in Western countries. Prevalence of hyperoxaluria is increasing in the US. CONCLUSION Prevalence of metabolic risk factors for nephrolithiasis significantly increased in recent years. These findings are hypothesis-generating and may provide valuable insight into the epidemiology, prevention and management of recurrent stone disease. Dietary modifications and innovative medical therapies are needed to decrease metabolic risk factors underlying nephrolithiasis.
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10.
Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy - A Safe and Effective Low-Dose Protocol.
Poh, CB, Tan, PC, Kam, JW, Siau, C, Lim, NL, Yeon, W, Cui, HH, Ding, HT, Song, XY, Yan, P, et al
Nephrology (Carlton, Vic.). 2020;(4):305-313
Abstract
AIMS: Regional citrate anticoagulation (RCA) is the preferred mode of anticoagulation for continuous renal replacement therapy (CRRT). Conventional RCA-CRRT citrate dose ranges from 3 to 5 mmol/L of blood. This study explored the effectiveness of an RCA protocol with lower citrate dose and its impact on citrate-related complications. METHODS This prospective observational study compared two RCA-CRRT protocols in the intensive care unit. RCA Protocol 1 used an initial citrate dose of 3.0 mmol/L while Protocol 2 started with 2.5 mmol/L. The citrate dose was titrated by sliding scale to target circuit-iCa 0.26-0.40 mmol/L. Calcium was re-infused post-dialyzer and titrated by protocol to target systemic-iCa 1.01-1.20 mmol/L. RESULTS Two hundred RCA-CRRT sessions were performed (81 Protocol 1; 119 Protocol 2). The median age was 65.4 years and median APACHE-II score was 23. Citrate dose for Protocol 1 was significantly higher than Protocol 2 in the first 12 h. The circuit clotting rate was similar in both arms (Protocol 1: 9.9%; Protocol 2: 9.2%; P = 0.881). With Protocol 2, circuit-iCa levels were 2.42 times more likely to be on target (P = 0.003) while the odds of hypocalcaemia was 4.67 times higher with Protocol 1 (P < 0.001). There was a wider anion gap was noted with Protocol 1, which suggests a propensity for citrate accumulation with higher citrate exposure. CONCLUSION The RCA protocol with a lower initial citrate dose of 2.5 mmol/L blood had less citrate-related complications with no loss of efficacy. A more precise RCA prescription at the start of treatment avoids unnecessary citrate exposure and improves safety.