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1.
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.
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Impact of Potassium Citrate vs Citric Acid on Urinary Stone Risk in Calcium Phosphate Stone Formers.
Doizi, S, Poindexter, JR, Pearle, MS, Blanco, F, Moe, OW, Sakhaee, K, Maalouf, NM
The Journal of urology. 2018;(6):1278-1284
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Abstract
PURPOSE To our knowledge no medication has been shown to be effective for preventing recurrent calcium phosphate urinary stones. Potassium citrate may protect against calcium phosphate stones by enhancing urine citrate excretion and lowering urine calcium but it raises urine pH, which increases calcium phosphate saturation and may negate the beneficial effects. Citric acid can potentially raise urine citrate but not pH and, thus, it may be a useful countermeasure against calcium phosphate stones. We assessed whether these 2 agents could significantly alter urine composition and reduce calcium phosphate saturation. MATERIALS AND METHODS In a crossover metabolic study 13 recurrent calcium phosphate stone formers without hypercalciuria were evaluated at the end of 3, 1-week study phases during which they consumed a fixed metabolic diet and received assigned study medications, including citric acid 30 mEq twice daily, potassium citrate 20 mEq twice daily or matching placebo. We collected 24-hour urine specimens to perform urine chemistry studies and calculate calcium phosphate saturation indexes. RESULTS Urine parameters did not significantly differ between the citric acid and placebo phases. Potassium citrate significantly increased urine pH, potassium and citrate compared to citric acid and placebo (p <0.01) with a trend toward lower urine calcium (p = 0.062). Brushite saturation was increased by potassium citrate when calculated by the relative supersaturation ratio but not by the saturation index. CONCLUSIONS Citric acid at a dose of 60 mEq per day did not significantly alter urine composition in calcium phosphate stone formers. The long-term impact of potassium citrate on calcium phosphate stone recurrence needs to be studied further.
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Purification and functional characterization of the vacuolar malate transporter tDT from Arabidopsis.
Frei, B, Eisenach, C, Martinoia, E, Hussein, S, Chen, XZ, Arrivault, S, Neuhaus, HE
The Journal of biological chemistry. 2018;(11):4180-4190
Abstract
The exact transport characteristics of the vacuolar dicarboxylate transporter tDT from Arabidopsis are elusive. To overcome this limitation, we combined a range of experimental approaches comprising generation/analysis of tDT overexpressors, 13CO2 feeding and quantification of 13C enrichment, functional characterization of tDT in proteoliposomes, and electrophysiological studies on vacuoles. tdt knockout plants showed decreased malate and increased citrate concentrations in leaves during the diurnal light-dark rhythm and after onset of drought, when compared with wildtypes. Interestingly, under the latter two conditions, tDT overexpressors exhibited malate and citrate levels opposite to tdt knockout plants. Highly purified tDT protein transports malate and citrate in a 1:1 antiport mode. The apparent affinity for malate decreased with decreasing pH, whereas citrate affinity increased. This observation indicates that tDT exhibits a preference for dianion substrates, which is supported by electrophysiological analysis on intact vacuoles. tDT also accepts fumarate and succinate as substrates, but not α-ketoglutarate, gluconate, sulfate, or phosphate. Taking tDT as an example, we demonstrated that it is possible to reconstitute a vacuolar metabolite transporter functionally in proteoliposomes. The displayed, so far unknown counterexchange properties of tDT now explain the frequently observed reciprocal concentration changes of malate and citrate in leaves from various plant species. tDT from Arabidopsis is the first member of the well-known and widely present SLC13 group of carrier proteins, exhibiting an antiport mode of transport.
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Phosphorus concentration coordinates a respiratory bypass, synthesis and exudation of citrate, and the expression of high-affinity phosphorus transporters in Solanum lycopersicum.
Del-Saz, NF, Romero-Munar, A, Cawthray, GR, Palma, F, Aroca, R, Baraza, E, Florez-Sarasa, I, Lambers, H, Ribas-Carbó, M
Plant, cell & environment. 2018;(4):865-875
Abstract
Plants exhibit respiratory bypasses (e.g., the alternative oxidase [AOX]) and increase the synthesis of carboxylates in their organs (leaves and roots) in response to phosphorus (P) deficiency, which increases P uptake capacity. They also show differential expression of high-affinity inorganic phosphorus (Pi) transporters, thus avoiding P toxicity at a high P availability. The association between AOX and carboxylate synthesis was tested in Solanum lycopersicum plants grown at different soil P availability, by using plants grown under P-sufficient and P-limiting conditions and by applying a short-term (24 hr) P-sufficient pulse to plants grown under P limitation. Tests were also performed with plants colonized with arbuscular mycorrhizal fungi, which increased plant P concentration under reduced P availability. The in vivo activities of AOX and cytochrome oxidase were measured together with the concentration of carboxylates and the P concentration in plant organs. Gene transcription of Pi transporters (LePT1 and LePT2) was also studied. A coordinated response between plant P concentration with these traits was observed, indicating that a sufficient P availability in soil led to a suppression of both AOX activity and synthesis of citrate and a downregulation of the transcription of genes encoding high-affinity Pi transporters, presumably to avoid P toxicity.
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Association of Urinary Citrate With Acid-Base Status, Bone Resorption, and Calcium Excretion in Older Men and Women.
Shea, MK, Dawson-Hughes, B
The Journal of clinical endocrinology and metabolism. 2018;(2):452-459
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CONTEXT Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical measure, changes in response to acid-base status but its association with bone turnover is uncertain. OBJECTIVE We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion. DESIGN, INTERVENTION, AND PARTICIPANTS A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days. OUTCOME MEASURES Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention. RESULTS Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003). CONCLUSION Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults.
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Simple citrate anticoagulation protocol for low flux haemodialysis.
Lim, EK, Seow, YT, Chen, SE, Yang, G, Liaw, ME, Isaac, S
BMC nephrology. 2018;(1):16
Abstract
BACKGROUND For patients unable to receive heparin anticoagulation during haemodialysis, saline flushes to reduce circuit clotting are often the norm. Regional citrate anticoagulation (RCA) although effective is not used by many centres including in Singapore. We wanted to demonstrate the superiority and safety of a simple regional citrate anticoagulation regime, compared to saline flushes, for heparin-free low flux haemodialysis. METHODS This is a prospective, open label, cross over study on 25 sequential haemodialysis sessions for inpatients receiving heparin-free haemodialysis. Patients were allocated either to regional citrate anticoagulation or standard heparin free haemodialysis and subsequently cross over to the alternate method. RCA was carried out using a protocol derived from previous studies. Assessment of anticoagulation was performed using visual inspection of clot formation in dialysis circuits and post-filter ionized calcium (iCa2+) using point-of-care Ionized calcium device at stipulated intervals. Intravenous Calcium gluconate replacement was given to patients receiving citrate adjusting the rate according to pre-filter iCa2+. Laboratory analyses of electrolytes were also assessed at the start and end of the RCA sessions. RESULTS There were no clots in the RCA arm, with 79% (n = 19) in the saline flush arm having some clot, including 1 clotted circuit. Post-filter iCa2+ at various time points were within acceptable range. Electrolyte readings in the RCA group were all within normal limits except for 4 cases of total Calcium:iCa2+ ratio > 2.5. CONCLUSION RCA is confirmed to be superior to saline flushes for circuit patency. We have a simple and safe protocol that can be followed for low flux haemodialysis. The study was approved by Singapore National Health Group domain-specific ethnical committee. NHG DSRB reference number 2014/01037. TRIAL REGISTRATION Trial registration number: ISRCTN69952745 (registration date 8/11/17).
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Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation.
Mahmood, D, Stegmayr, BG
Blood purification. 2018;(3):257-263
Abstract
Anticoagulation with citrate-containing haemodialysate (cHD) is an alternative to tinzaparin haemodialysate (tHD). The study investigated whether cHD would differ when changed from tHD. The same 18 patients were their own controls followed up with cHD for 5 months. LDL-cholesterol decreased at the end of a cHD session (p = 0.01). Neutrophils (p = 0.013) and monocytes (p = 0.007) dropped more during a cHD session. During the follow-up period of cHD, approximately 50% needed additional tinzaparin. Before the cHD session could start, there was a lower total cholesterol at 2 weeks (p = 0.014) and LDL-cholesterol at 1 month (p = 0.011) versus an increase of LDL at 5 months (p = 0.02). Only patients without additional tinzaparin had a reduction of -C-reactive protein (CRP) at 2 months of cHD (p < 0.05) but not later. Solely cHD seems possible only in half of the patients. A greater reduction in granulocytes and monocytes during cHD indicates a more extensive blood membrane interaction, while CRP may be lower.
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A prospective observational study of the change in systemic ionised calcium following 4% citrate locking of venous haemodialysis catheters in intensive care patients.
Shewdin, S, Bong, YC, Okano, S, Chatfield, MD, Walsham, J
Anaesthesia and intensive care. 2018;(4):381-385
Abstract
Traditionally heparin has been the anticoagulant of choice for venous dialysis catheter locking. There is systemic leakage of heparin catheter locking solutions at the time of injection. Alternative agents, such as citrate, are increasingly being used. We are not aware of any data in the critical care literature on the effect of citrate locking of venous dialysis catheters on systemic ionised calcium (iCa2+). To assess the effect of 4% citrate locking of venous dialysis catheters on systemic iCa2+ in intensive care patients we performed a prospective observational study of 50 paired samples in 26 intensive care patients receiving 4% citrate dialysis catheter locking in an adult tertiary intensive care unit between May 2016 and December 2016. Arterial blood gas (ABG) analysis was performed prior to venous dialysis catheter locking and a baseline iCa2+ result obtained. The catheter was locked with 4% citrate solution. A further ABG was sampled between 30 and 120 seconds later and the iCa2+ results were compared. Patients were observed for clinical signs of hypocalcaemia. On average, there was little difference between the pre- and post-catheter locking iCa2+ (median pre-locking iCa2+ 1.19 mmol/l, mean change of +0.004 mmol/l, 95% confidence interval [CI] -0.004 to 0.013, P=0.34). There was no evidence this difference differed by length of catheter P=0.26) or site of catheter P=0.85) insertion, but there was some evidence that this differed by receipt of citrate dialysis circuit anticoagulation P=0.013). Patients who received citrate dialysis circuit anticoagulation had an increase in catheter locking iCa2+ by 0.017 mmol/l (95% CI 0.00 to 0.028). Locking of venous dialysis catheters with 4% citrate solution has no clinically significant effect on systemic iCa2+ in intensive care patients with indwelling venous dialysis catheters.
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Strong ion difference and CVVH: Different response during nadroparin versus citrate anticoagulation.
Buter, H, Koopmans, M, van der Voort, PHJ
Journal of critical care. 2018;:88-92
Abstract
PURPOSE To determine the effect on strong ion difference of citrate as an anticoagulant during continuous veno-venous hemofiltration (CVVH). MATERIALS AND METHODS ICU patients with renal failure and CVVH were included. Patients were treated with either nadroparin (N) or sodium citrate (C) as an anticoagulant. Strong ion difference (SID) apparent (SIDa) and SID effective (SIDe) and strong ion gap (SIG) were calculated at t = 0 and t = 24 h. Citrate concentration was measured in the citrate treated patients. RESULTS Ten patients with N and nine with C were included. In both groups the SIDa did not change significantly. SIG decreased significantly with N (11.4 ± 4.2 to 4.0 ± 3.1 meq/l; p = 0.005) but not with C (9.3 ± 1.9 to 8.1 ± 2.4 meq/l; p = 0.097). The decrease was significantly greater for N compared to C; p = 0.014. This is reflected by the SIDe which increased significantly (p = 0.022) more from 24.7 ± 4.5 to 32.9 ± 3.9 (p = 0.005) for N and from 26.3 ± 5.8 to 29.6 ± 1.6 for C (p = 0.058). CONCLUSION Citrate anticoagulation results in a persistently high SIG during CVVH compared to nadroparin. This is associated with the presence of unmeasured anions such as citrate in the systemic circulation.
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Use of regional citrate anticoagulation for continuous venovenous hemodialysis in critically ill cancer patients with acute kidney injury.
Costa E Silva, VT, Caires, RA, Bezerra, JS, Costalonga, EC, Oliveira, APL, Oliveira Coelho, F, Fukushima, JT, Soares, CM, Oikawa, L, Hajjar, LA, et al
Journal of critical care. 2018;:302-309
Abstract
PURPOSE This study aimed to evaluate the safety and efficacy of a regional citrate anticoagulation (RCA) protocol for continuous venovenous hemodialysis (CVVHD) in cancer patients with acute kidney injury (AKI) in the intensive care unit (ICU) setting. MATERIAL AND METHODS One hundred twenty two consecutive ICU cancer patients with AKI treated with citrate-based CVVHD were prospectively evaluated in this prospective observational study. RESULTS A total of 7198 h of CVVHD therapy (250 filters) were performed. Patients were 61.3 ± 15.7 years old, 78% had solid cancer and the main AKI cause was sepsis (50%). The in-hospital mortality was 78.7%. Systemic ionized calcium (SCai) was 4.35 (4.10-4.60) mg/dL, severe hypocalcemia (SCai <3.6 mg/dL) was observed in 4.3% of procedures and post-filter ionized calcium was 1.60 (1.40-1.80) mg/dL. Median filter patency was 24.8 (11-43) hours. Factors related to filter clotting were: no tumor evidence (OR 0.44, CI 0.18-0.99); genitourinary tumor (OR 1.83, CI 1.18-2.81); platelets number (each 10,000/mm3) (OR 1.02, CI 1.00-1.04); International Normatized Ratio (INR) (OR 0.59, CI 0.41-0.85) and citrate dose (each 10 mL/h) (OR 0.88, CI 0.82-0.95). CONCLUSION Filter patency was relatively short and clotting was associated with active cancer disease, genitourinary tumor, lower citrate dose and lower INR.