**3. The benefits of regional citrate anticoagulation**

Regional citrate anticoagulation does not increase the patient's bleeding risk and is, therefore, not only an ideal mode of anticoagulation in any patient with high bleeding risk or active bleeding but also for the average hemodialysis patient. Furthermore, citrate anticoagulation avoids all the other potential side effects of heparin use noted above, which also makes it a choice mode of anticoagulation in patients with HIT type II. Aside from these

Fig. 2. Pre-dialyzer ionized calcium (iCa) concentration plotted against plasma citrate

During regional citrate anticoagulation, citrate enters the body in the form of both free citrate and calcium-citrate complexes. When this citrate is metabolized, each molecule yields three molecules of bicarbonate, which will have an impact on the acid-base status. Also, calcium is released from calcium-citrate complexes as they are metabolized, which impacts serum calcium concentration. The use of trisodium citrate or Acid Citrate Dextrose (ACD) solution further entails an additional sodium load to the patient that should be taken into account. In clinical practice, the dialysis prescriptions for regional citrate anticoagulation typically incorporate reduced sodium (by about 2 mmol/L) and bicarbonate (by about 5 mmol/L) concentrations. Magnesium concentration in the dialysate may be increased since citrate also complexes magnesium, leading to increased magnesium losses across the

Over the years, different algorithms for the administration of regional citrate anticoagulation have been suggested and studied, both for intermittent as well as continuous hemodialysis. These algorithms usually define blood and dialysate flow rates, the starting rates for citrate infusion and calcium substitution, rules on how these rates should be adjusted in case of iCa deviations from the specified circuit or systemic target ranges, time points for monitoring iCa, and downward adjustments for sodium and bicarbonate in the dialysate. Since citrate and calcium kinetics during dialysis depend on many factors, including the type of dialyzer used and the blood and dialysate flow rates, such algorithms generally are only applicable to the particular dialysis setting for which they have been validated. The purpose of all these algorithms is always to make the administration of regional citrate anticoagulation as safe and simple as possible, i.e. to minimize the risk for calcium or acid-base derangements, circuit clotting or other complications while requiring as little monitoring or intervention by the staff as possible.

Regional citrate anticoagulation does not increase the patient's bleeding risk and is, therefore, not only an ideal mode of anticoagulation in any patient with high bleeding risk or active bleeding but also for the average hemodialysis patient. Furthermore, citrate anticoagulation avoids all the other potential side effects of heparin use noted above, which also makes it a choice mode of anticoagulation in patients with HIT type II. Aside from these

**3. The benefits of regional citrate anticoagulation** 

concentration.

dialyzer.

obvious advantages, however, there are several additional benefits to using regional citrate anticoagulation. One of these appears to be improved biocompatibility of the dialysis procedure: comparing heparin anticoagulation with citrate anticoagulation, Böhler et al. found that citrate anticoagulation reduced complement activation, neutropenia and lactoferrin release with the use of cuprophane dialyzers, and significantly inhibited neutrophil degranulation with the use of polymethyl methacrylate membranes [12]. Likewise, Gritters and colleagues compared anticoagulation using unfractionated heparin, low molecular weight heparin and citrate in a randomized crossover trial and found that citrate anticoagulation suppressed the dialysis-associated degranulation of polymorphonuclear cells and platelets. Furthermore, pro-atherogenic oxidized low-density lipoprotein levels were reduced by a median of 26% after only one week on citrate anticoagulation [13]. In view of the heightened inflammatory state of chronic hemodialysis patients, the reduction of oxidative stress, complement and cell activation associated with citrate dialysis may be a relevant benefit with regard to reducing the high cardiovascular morbidity in these patients. Hofbauer et al. compared anticoagulation with unfractionated heparin, low molecular weight heparin and citrate during dialysis with a single-use polysulfone dialyzer and used scanning electron microscopy to quantify the degree of membrane-associated clotting [14]. The highest degree of cell adhesion and thrombus formation was observed with unfractionated heparin, and it was only slightly reduced with the use of low molecular weight heparin. With regional citrate anticoagulation, on the other hand, thrombus formation was found to be negligible, indicating a far superior anticoagulation using citrate compared to both unfractionated and fractionated heparin. Gabutti et al. employed a randomized controlled cross-over design to compare standard heparin dialysis with regional citrate anticoagulation, dosed to achieve a similar degree of coagulation activation, and study the effects on complement activation and interleukin-1 beta release. In this setting, complement activation was slightly but significantly higher in the citrate dialysis group, but at the same time, interleukin-1 beta release was markedly reduced. Citrate can, and often is, dosed higher in regional citrate anticoagulation than was done in this study, and it stands to reason that with such higher citrate concentrations, complement activation would have been lower than with standard heparin dialysis, associated perhaps with a further decrease in interleukin-1 beta secretion. In line with Hofbauer's results mentioned above, regional citrate anticoagulation appears to allow for markedly prolonged filter patency times in continuous dialysis [15-18]. Lastly, a recent study by Oudemans-van Straaten and colleagues found higher patient and kidney survival in critically ill patients on citrate versus low-molecular weight heparin [19]. On top of these benefits, citrate is a relatively inexpensive compound compared to heparin.

### **4. The downsides of regional citrate anticoagulation**

The single biggest concern with regional citrate anticoagulation is the development of potentially life-threatening systemic calcium derangements. Acute changes in systemic iCa can develop quickly when calcium elimination across the dialyzer (in the form of free calcium and calcium-citrate complexes), calcium release from the metabolism of calciumcitrate complexes, and calcium substitution (from the calcium infusion and/or the dialysate, if a calcium-containing dialysate is used) are mismatched. From this concern springs the need to monitor, at least initially, systemic iCa levels fairly closely during regional citrate anticoagulation. This, along with the more complex setup, presents a significant strain on

Citrate Anticoagulation in Hemodialysis 223

for a particular patient) with any degree of reliability, then these factors must be taken into account. Needless to say, the interactions between all these factors cannot possibly be assessed (let alone integrated over an entire treatment and beyond) based on intuition or clinical experience. Computer-aided calcium and citrate kinetic modeling is the only way to simulate in detail the processes during regional citrate anticoagulation. We have recently published a comprehensive, yet versatile, mathematical model for citrate dialysis [25]. A refinement of this model (comprised of our original model combined with a statistical correction component), recently presented as a talk at the XLVII ERA-EDTA conference in Munich, Germany, showed excellent prediction quality [26]. When applied to 120 patients on pure dialysate-side citrate dialysis (dialysate containing 2.4 mEq/L citrate and 2.25 mEq/L calcium), the model overestimated end-dialysis ionized calcium levels by only 0.026 mmol/L on average. While current clinical citrate dialysis algorithms are only applicable to a rather narrow setting for which they have been developed, computer-aided calcium and citrate kinetic modeling affords much greater flexibility and could possibly even be adapted

As was mentioned above, the calcium substitution in regional citrate anticoagulation is currently dosed empirically and adjusted so as to keep systemic iCa within the physiologic range. However, it must be born in mind that this approach pays no heed to the question of calcium mass balance. This is, of course, not done deliberately but simply from necessity, because clinicians have no way of assessing intradialytic calcium mass balance reliably, let alone under such complex conditions as occur in regional citrate anticoagulation. The difference between calcium substitution and calcium loss across the dialyzer membrane determines the intradialytic calcium mass balance, and from this perspective, the calcium substitution should be chosen so as to effect the desired mass balance. The challenges with determining what calcium mass balance is required for a given patient is a related but separate issue and shall not be discussed here. With higher citrate infusion rates, and accompanying citrate accumulation and calcium "trapped" systemically in the form of calcium-citrate complexes, calcium mass balances can easily become positive. In practice, this point is often dismissed and calcium substitution rates justified with reference to the need to maintain serum ionized calcium within the normal range. What becomes clear, however, when simulating citrate dialysis is that many roads lead to Rome, and, within limits, different calcium mass balances can be achieved without compromising the extracorporeal anticoagulation by modifying parameters such as dialysate calcium and citrate concentrations and blood and dialysate flow rates. Dialysis dose issues certainly have to be considered, and the combination of calcium and citrate kinetic modeling with urea kinetic modeling would be a particularly powerful tool. Conversely, the same calcium mass balance can be achieved in different ways, potentially allowing for individualization of the citrate dialysis prescription according to particular patient characteristics, such as impaired liver function or reduced calcium buffering capacity. In view of the ever-increasing awareness of the potential importance of calcium mass balance for long-term outcomes in hemodialysis patients, calcium and citrate kinetic modeling offers a unique opportunity for actively incorporating this parameter into the dialysis prescription. This may turn out to be crucial for translating the compelling short-term benefits associated with regional citrate anticoagulation into long-term improvements in cardiovascular outcomes and ultimately survival. Currently, this mode of anticoagulation is thoroughly ignoring this aspect and is lagging behind the trend towards neutral calcium mass balance seen in standard heparin hemodialysis. Similar to calcium mass balance considerations, dialysis-related sodium

on-the-fly to different conditions.

staff resources and, consequently, can make citrate dialysis more costly than standard heparin dialysis. The prolonged filter patency times seen with citrate anticoagulation, however, may also introduce cost savings compared to heparin dialysis in continuous dialysis therapies [20]. The administration of buffer base in the form of citrate can further lead to metabolic alkalosis [20-22]. Hypernatremia can occur secondary to the additional sodium load administered with the citrate infusion (e.g., in the form of trisodium citrate, which carries 3 moles of sodium for each mole of citrate) [5, 21]. With high citrate infusion rates and/or in patients with impaired liver function (liver failure, cirrhosis), systemic citrate accumulation may occur. Measurements of plasma citrate concentrations are not usually readily available in clinical laboratories, but citrate accumulation may be detected by looking for its effects on calcium levels: citrate accumulation traps calcium in the form of calcium-citrate complexes. The growing plasma pool of calcium-citrate complexes and the insufficient release of calcium from this pool via citrate metabolism lead to a drop in systemic iCa which is spotted in systemic iCa measurements and countered by an increase in the calcium substitution rate in order to restore systemic iCa to physiologic levels. Under such conditions, the amounts of free calcium, calcium-protein complexes and the increased amount of calcium-citrate complexes add up to an increased total calcium concentration. Therefore, citrate accumulation may be detected by an increased total calcium concentration or an increased ratio of total to ionized serum calcium concentration [23]. An increased anion gap may also point towards citrate accumulation [24].
