Prof. Vincenzo Cantaluppi
SCDU Nefrologia e Trapianto Renale, Dipartimento di Medicina Traslazionale
Università del Piemonte Orientale (UPO) “A. Avogadro”
Azienda Ospedaliera Universitaria “Maggiore della Carità”
Corso Mazzini 18, IT–28100 Novara (Italy)
E-Mail [email protected]
Perspectives in Acute Kidney Injury
La Manna G, Ronco C (eds): Current Perspectives in Kidney Diseases.
Contrib Nephrol. Basel, Karger, 2017, vol 190, pp 19–30 (DOI: 10.1159/000468833)
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Citrate Anticoagulation during Continuous Renal Replacement Therapy
Davide Ricci · Laura Panicali · Maria Grazia Facchini · Elena Mancini
Nephrology Dialysis Hypertension Department, Teaching Hospital Policlinico S. Orsola-Malpighi, Bologna, Italy
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Abstract
During extracorporeal dialysis, some anticoagulation strategy is necessary to prevent the coagulation of blood. Heparin has historically been used as an anticoagulant because of its efficacy combined with low cost. However, a variable incidence of hemorrhagic complications (5–30%) has been documented in patients undergoing continuous renal replacement therapy (CRRT) with heparin as an anticoagulant. Citrate has anticoagulation properties secondary to its ability to chelate calcium, which is necessary for the coagulation cascade. Citrate may thus be used in a regional anticoagulation (RCA), limited to the extracorporeal circuit of CRRT, to avoid systemic anticoagulation. Recent meta-analysis confirmed the advantage of RCA over heparin in terms of incidence of bleeding during CRRT. Moreover, an increase in filter lifespan is documented, with a secondary advantage in reaching the prescribed dialysis dose. In our experience, we could confirm this positive effect. In fact, with a progressive increase in the proportion of CRRT with citrate as RCA, we obtained a reduction in the number of filters used for every 72 h of treatment (from 2.4 in 2011 to 1.3 in 2015), and most importantly, a reduction in the difference between the prescribed and delivered dialysis doses (from 22 to 7%). Citrate has an intense effect on the acid-base balance as well, if fully metabolized through the Krebs cycle, due to the production of bicarbonate. Even more severely ill patients, such as those with liver dysfunction, may be treated with RCA without severe complications, because modern machines for CRRT are equipped with simple systems that are able to manage the citrate infusion and control the calcium levels, with minimal risks of metabolic derangements.
© 2017 S. Karger AG, Basel
Introduction
Continuous renal replacement therapy (CRRT) is widely used for treating acute kidney injury (AKI). Although there are several experiences on CRRT without anticoagulation [1], some anticoagulation strategy is generally thought to be required to avoid circuit blood clotting. During CRRT, blood is conducted through an extracorporeal circuit, activating coagulation by a complex interaction between patient and circuit. Critically ill patients may also develop a procoagulant state frequently due to sepsis; activation of the coagulation system is triggered by proinflammatory cytokines that enhance the expression of tissue factor on activated mononuclear and endothelial cells and simultaneously downregulate natural anticoagulants, thus initiating thrombin generation, subsequent activation of platelets, and inhibition of fibrinolysis. The beginning of clotting in the extracorporeal circuit has traditionally been attributed to contact activation of the intrinsic coagulation system. However, the bioincompatibility reaction is more complex and is incompletely understood. The activation of tissue factor, leucocytes, and platelets plays an additional role [2].
In spite of the high bleeding risk related to AKI itself [3], systemic anticoagulation with unfractioned heparin has historically been used to maintain the patency of the extracorporeal circuit for CRRT. However, a high incidence of hemorrhagic complications has been documented with wide variability (5–30%) related to differences in patient populations and anticoagulation protocols [4]. Furthermore, a kind of “inverse correlation” between the hemorrhagic risk for the patient and the coagulation risk for the circuit was established in 1996 by Wetering. The higher the attention given to avoid the risk of bleeding (by reducing heparin), the higher is the incidence of thrombotic events to the extracorporeal circuit, and vice versa [5].
To avoid this drawback, both prostaglandin E1 and prostaglandin I2 have been tested in CRRT, but their high cost and hypotension due to vasodilatation are distinct limits to their routine use [2]. Regional citrate anticoagulation (RCA) offers an attractive alternative, and the 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guidelines for AKI recommend the use of RCA as the preferred anticoagulation modality for CRRT in patients without contraindications for citrate, even in the absence of increased bleeding risk or impaired coagulation [6].
Citrate: Mechanism of the Anticoagulant Action
Sodium citrate, infused before the filter, chelates calcium, essential to the coagulation process. The ensuing regional hypocalcemia in the filter inhibits thrombin generation. Citrate is partially removed by filtration or dialysis [7], and the remaining amount, infused into the patient, is rapidly metabolized in the citric acid (Krebs) cycle, especially in the liver, muscle, and renal cortex. The calcium previously chelated is released into the patient’s blood as a result of citrate metabolism, whereas the calcium lost with the effluent needs to be replaced by calcium solution administered to the patient. Systemic coagulation is thus unaffected (Fig. 1).
Fig. 1. Schematic representation of the regional citrate anticoagulation implemented in an extracorporeal circuit of CRRT. The citrate solution is infused before the dialyzer, at a flow rate proportional to blood flow, citrate dose, and solution citrate concentration. Citrate chelates calcium: the resulting effect is the extreme reduction of ionized calcium (iCa) in blood (ideal target 0.3–0.4 mmol/L). Calcium must be administered to the patient to restore the physiological level (1.1–1.25 mmol/L). A specific infusion line is needed either downstream of the dialyzer or directly to the patient. The calcium-citrate complexes are partially lost in the effluent, depending on the dialysis dose. The metabolic load of citrate to the patient will be the difference between citrate infused into the circuit and citrate lost with the effluent (correlation between the effluent volume and the amount of citrate lost).
For anticoagulation, the citrate dose is adjusted to blood flow so as to achieve an ionized calcium (iCa) concentration <0.3–0.5 mmol/L in the filter [4]; the lower the calcium concentration, the higher the degree of anticoagulation [