Introduction: Anticoagulation is recommended during continuous kidney replacement therapy (CKRT) to prolong the filter lifespan for optimal filter performance. We aimed to evaluate the effect of anticoagulation during CKRT on dialysis dependence and mortality within 90 days of intensive care unit (ICU) admission.
Method: Our retrospective observational study evaluated the first CKRT session in critically ill adults with acute kidney injury (AKI) in Singapore from April to September 2017. The primary outcome was a composite of dialysis dependence or death within 90 days of ICU admission; the main exposure variable was anticoagulation use (regional citrate anticoagulation [RCA] or systemic heparin). Multivariable logistic regression was performed to adjust for possible confounders: age, female sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, liver dysfunction, coagulopathy (international normalised ratio[INR] >1.5) and platelet counts of less than 100,000/uL).
Results: The study cohort included 276 patients from 14 participating adult ICUs, of whom 176 (63.8%) experienced dialysis dependence or death within 90 days of ICU admission (19 dialysis dependence, 157 death). Anticoagulation significantly reduced the odds of the primary outcome (adjusted odds ratio [AOR] 0.47, 95% confidence interval [CI] 0.27–0.83, P=0.009). Logistic regression analysis using anticoagulation as a 3-level indicator variable demonstrated that RCA was associated with mortality reduction (AOR 0.46, 95% CI 0.25–0.83, P=0.011), with heparin having a consistent trend (AOR 0.51, 95% CI 0.23–1.14, P=0.102).
Conclusion: Among critically ill patients with AKI, anticoagulation use during CKRT was associated with reduced dialysis or death at 90 days post-ICU admission, which was statistically significant for regional citrate anticoagulation and trended in the same direction of benefit for systemic heparin anticoagulation. Anticoagulation during CKRT should be considered whenever possible.
What is New
- This is a large cohort study on continuous kidney replacement therapy (CKRT) practices in adult ICU patients.
- Two-thirds of patients with new onset acute kidney injury in ICU progress to develop chronic dialysis or death within 90 days of ICU admission.
- Mortality was highest amongst patients who did not receive anticoagulation with heparin or citrate.
- Anticoagulation during CKRT should be considered whenever possible.
- Future studies can be designed to look at the association of filter lifespan and efficiency with patient-centred outcomes, and the reasons for omitting anticoagulation.
Acute kidney injury (AKI) affects 21.6% of critically ill adult patients,1 with 5–7% requiring kidney replacement therapy (KRT).2 AKI carries significant prognostic and socioeconomic implications—chronic kidney disease (CKD) progression over 1 year has been described in 21%, 30%, and 79% of initial survivors with septic AKI reversal, recovery and non-recovery, respectively.3 AKI also increases the risk of developing end-stage kidney disease4 leading to a significant healthcare and socioeconomic burden.5 With the increasing incidence of AKI6 and resultant end-stage kidney disease (ESKD), there has been increasing interest for effective treatment modalities, specifically therapies that might mitigate the rates of dialysis dependence.
Anticoagulation during continuous kidney replacement therapy (CKRT) prolongs the lifespan of the extra-corporeal circuit and optimal filter performance.7 Regional citrate anticoagulation (RCA) is preferred due filter running times; reduces bleeding complications; allows effective control of acid–base status; and reduces adverse events like heparin-induced thrombocytopenia (HIT).8 The ideal anticoagulation strategy for CKRT remains debated,9-11 with limited data on patient-centred outcomes such as eventual dialysis dependence or ICU mortality.12 Heparin anticoagulation may not be feasible for patients who have ongoing bleeding manifestations or diathesis, or post-surgical patients in the early post-operative period.
Little is known about the contemporary KRT practices in Singapore.13 Leveraging the collaboration with the Society of Intensive Care Medicine Singapore-National Investigators for Clinical Epidemiology and Research (SICM-NICER), we embarked on this study aiming to evaluate current trends, and the association of anticoagulation use on patient-centred outcomes. The primary outcome was dialysis dependence or death within 90 days of ICU admission.
Study design and setting
We conducted a nationwide study in Singapore, a diverse nation of 5.7 million people. With 16 restructured hospitals and a range of specialised ICUs—including medical, surgical and subspecialty units (neurosurgical, cardiology and cardiothoracic)—our study covered the critical care landscape. This retrospective observational study encompassed all critically ill patients in participating adult ICUs across these restructured hospitals.
We included patients who had AKI and received CKRT between 1 April 2017 and 30 September 2017, and patients with ESKD were excluded. ESKD and AKI was defined as per the Kidney Disease Improving Global Outcomes (KDIGO) criteria.14
Data sources and definitions
We extracted details of the patients’ KRT regimen and disease progression from electronic and paper medical records. At each individual site, patient details were collected and de-identified before being compiled by the principal investigator. Our analysis focused on the initial KRT session; specifically, only sessions with complete data were included. We excluded non-continuous modes of KRT such as intermittent haemodialysis, sustained low-efficiency dialysis (SLED) and peritoneal dialysis. All patients who received RCA for CKRT, received calcium-free dialysate and replacement solutions. Details about filter lifespan and performance were not collected. To quantify the degree of heemodynamic support, we utilised an inotrope score.15 Liver dysfunction was defined as presence of liver cirrhosis or bilirubin (>35 μmol/L).16 Coagulopathy was defined as INR>1.5, and thrombocytopenia was defined as platelet counts of <100,000/μL.
Continuous variables are presented as mean (standard deviation [SD]) and median (inter-quartile range [IQR]). Categorical variables are presented as number (%).
The initial KRT episode was analysed with multivariate logistic regression for factors associated with dialysis dependence or death at 90 days post-ICU admission. Logistic regression was done using key prognostic factors (i.e. age, female sex, APACHE II, liver dysfunction, coagulopathy, thrombocytopenia), and other possible confounders from Tables 1 and 2 with univariate P values of <0.05. Odds ratios were derived with 95% confidence intervals.
Table 1. Patient demographics and ICU stay characteristics.
|Patients not on anticoagulation
|Patients on anticoagulation
Age, mean±SD, years
Female, n (%)
BMI mean±SD, kg/m2
Diabetes mellitus, n (%)
Hypertension, n (%)
Ischaemic heart disease, n (%)
Chronic kidney disease, n (%)
COPD, n (%)
Cancer, n (%)
Liver dysfunction,* n (%)
Coagulopathy,** n (%)
Thrombocytopenia,*** n (%)
|Cause of AKI
Sepsis, n (%)
Hypovolemia/ shock, n (%)
Nephrotoxic agents, n (%)
Major surgery, n (%)
Hepatorenal syndrome, n (%)
Cardiogenic shock, n (%)
Post-obstructive, n (%)
Others (e.g. rhabdomyolysis, pancreatitis), n (%)
Emergency department, n (%)
General ward, n (%)
Operating theatre, n (%)
High dependency unit/ intermediate care unit, n (%)
Others (e.g. endoscopy suite), , n (%)
|APACHE II score, mean±SD||27.3±9.5||28.4±9.8||26.4±9.3||0.091|
|Vasopressor use, n (%)||221 (80.1)||109 (83.8)||112 (76.7)||0.181|
|Inotrope score, mean±SD||3.2±2.0||3.4±2.0||3.0±2.0||0.079|
|Respiratory support received before CKRT
HFNC, n (%)
NIV, n (%)
Mechanical ventilation, n (%)
|ICU LOS (days), median (IQR)||7 (3-16)||6.5 (3-16)||7 (3-17)||0.982|
Survived ICU stay, n (%)
Survived at 30 days of ICU admission, n (%)
Survived at 90 days of ICU admission, n (%)
|Mechanical ventilation free days up to 28 days, mean±SD||11.4±12.2||10.4±11.8||12.3±12.4||0.217|
|Fluid balance 24 hours prior to KRT (mL), median (IQR)||1291.2 (580.5-2258.0)||1321.50 (636.9- 2440.3)||1090.0 (434.8-2109.2)||0.479|
|Duration of oliguria before KRT, median (IQR)||10.0 (2.3-20)||12 (6-24)||10 (0-18)||0.381|
|Peak creatinine prior to KRT, μmol/L, median (IQR)||298 (214-489)||286.5 (200-465)||313 (219-514)||0.070|
^Patients may have more than 1 comorbidity
AKI: acute kidney injury; CKRT: continuous kidney replacement therapy; COPD: chronic obstructive pulmonary disease; HFNC: high-flow nasal cannula; ICU: intensive care unit; INR: international normalised ratio; IQR: interquartile range; LOS: length of stay; NIV: non-invasive ventilation, PTT: partial thromboplastin time; SD: standard deviation
*Liver dysfunction (defined as presence of liver cirrhosis or bilirubin >35 μmol/L)
** Platelet <100,000/μL
Table 2. Characteristics of continuous kidney replacement therapy (CKRT) sessions.
|Patients not on anticoagulation
|Patients on anticoagulation
|Type of anticoagulation, n(%)
|Prescription, n (%)
|Indication,^ n (%)
Routine / regular session
Clearance of toxins
|Timing of KRT, n (%)
After office hours
|Duration of first CKRT (hours), median (IQR)||19.5 (8.3-35.0)||19.0 (6.0-34.0)||20.0 (10.0-34.0)||0.840|
|Time to first circuit change (min), median (IQR)||455.0 (8.0-1192.0)||585.0 (120.0-1475.0)||165.0 (0-879.8)||0.096|
|Complications after CKRT,^ n (%)
|Prescribed dose for CKRT (ml/kg/hour), median (IQR)||33.3 (30.0-35.0)||33.0 (30.0-35.0)||35.0 (30.0-35.0)||0.096|
|Number of replacement/dialysate fluid bags
Bag 1, median (IQR)
Bag 2, median (IQR)
^ May have more than 1 per session
KRT: Kidney replacement therapy; SD: standard deviation
Given the non-interventional nature of the study, waiver of informed consent was granted by the National Healthcare Group Domain Specific Review Board (DSRB reference 2017/01010) and mutually recognised by SingHealth Centralised Institutional Review Board (CIRB).
A total of 14 ICUs across 6 hospitals in Singapore contributed data to the study. The study population is described in Fig. 1. A total of 867 patients received KRT during the study period. The characteristics of 276 patients were analysed, and characteristics of their ICU stay, are described in Table 1. The most common cause of AKI was in association with sepsis, and the median ICU length of stay (LOS) was 7 days. In total, 176 patients (63.8%) experienced dialysis dependence or death within 90 days of ICU admission (19 dialysis dependence, 157 death).
Fig. 1. Study population flowchart.
AKI: acute kidney injury; KRT: kidney replacement therapy; CKRT: continuous kidney replacement therapy; ESKD: end stage kidney disease; IHD: Intermittent hemodialysis, SLED: slow low efficiency dialysis, PD: peritoneal dialysis
Continuous veno-venous hemodiafiltration (CVVHDF) was the top choice for initial CKRT mode, accounting for 62% of sessions. Other modes included continuous veno-venous hemodialysis (CVVHD) (19.6%), continuous veno-venous hemofiltration (CVVH) (17.0%), and slow continuous ultrafiltration (SCUF) (1.1%). Table 2 provides further details on the characteristics of the CKRT sessions. The median time to first circuit change was 455.0 minutes (IQR 8.0–1192.0 minutes). Circuit changes were done for various reasons such as interruptions of CKRT for procedures, refractory haemodynamic instability, or circuit clotting or clogging.
Among the 276 patients receiving CKRT, anticoagulation during the first CKRT session during the ICU admission was associated with reduction of dialysis dependence and mortality at 90 days (adjusted OR [AOR] 0.47, 95% CI (0.27–0.83), P=0.009) (Table 3). Repeating the logistic regression analysis using anticoagulation as a 3-level indicator variable, demonstrated that citrate anticoagulation was associated with mortality reduction (AOR 0.46, 95% CI 0.25–0.83, P=0.011) and with heparin having a consistent trend (AOR 0.51, 95% CI 0.23–1.14, P=0.102), compared to no anticoagulation use. In contrast, liver dysfunction, coagulopathy and thrombocytopenia did not have significant independent associations of dialysis dependence or death at 90 days.
Table 3. Multivariable logistic regression of factors associated with dialysis dependence or death at 90 days post intensive care unit admission.
|Dialysis dependence or death at 90 days||Odds ratio||95% CI of odds ratio||P value|
|Oliguria and anuria||2.95||1.59-5.50||0.001|
|Anticoagulation as a 3-level indicator variable|
APACHE II: Acute Physiology and Chronic Health Evaluation II; CI: confidence interval
*Liver dysfunction (defined as presence of liver cirrhosis or bilirubin >35 μmol/L)
** INR >1.5
*** Platelet <100,000/μL
This is the largest-ever observational study of AKI patients undergoing CKRT in Singapore. Among ICU patients who suffered AKI, 63.8% were left with dialysis dependence or died within 90 days. Mortality was highest in patients who did not receive anticoagulation with either heparin or citrate, and citrate anticoagulation was associated with reduced mortality. Heparin anticoagulation showed a consistent trend with the odds ratio in the same direction as citrate anticoagulation, but did not similarly reach significance, likely due to the smaller sample size for heparin (n=46), compared to citrate anticoagulation (n=100).
Sepsis was the leading cause of AKI in our study, in keeping with international data.2 The 90-day mortality rate of 43.1% is consistent with international studies2 as well and underscores the high mortality rate of AKI. The most common mode of CKRT in Singapore was CVVHDF, which is consistently favoured in published literature because of its lower failure rate compared to other modalities of CKRT.17 This is comparable with patients who had AKI who received SLED.18
Comparing between patients who had anticoagulation during KRT against those who did not (Table 1), there were more patients in the group that did not receive anticoagulation with platelet counts <100,000/μL. This could be a biomarker for bleeding risk. However, after adjusting for it during multivariable analysis, anticoagulation use retained a significant association with the primary outcome. There were differences in the prescribers who chose anticoagulation and those who omitted anticoagulation, but this may just reflect anticoagulation preference, rather than expertise with renal care. We therefore did not adjust for it in multivariable analysis.
Patients in the group receiving anticoagulation had higher numbers with hypokalemia and hypophosphataemia. This may be due to regional citrate anticoagulation, but we did not adjust for these as complications did not precede exposure to anticoagulation. The number of replacement or dialysate fluid bags were different between groups. However, we did not adjust for this as this did not precede exposure to anticoagulation.
There were more patients in the anticoagulation group with oligo-anuria than patients who did not receive anticoagulation, though the reason for this is unclear. Nonetheless, we adjusted for this and anticoagulation used remained significantly associated with the primary outcome. Oligo-anuria preceding CKRT was found to be an adverse prognostic factor (Table 3), consistent with a large series that showed it was an independent risk factor for death or end-stage kidney disease in AKD patients.19 These could be due to less morphologic and functional damage in non-oliguric compared with oliguric AKI (found in animal studies20), and the absence of oliguria in AKI reflects less severe disease.21
Anticoagulation in some form is recommended during CKRT to prolong filter lifespan, because problems with filter clotting will lead to interruptions to CKRT and may result in loss of blood which is in the circuit. Ideally, CKRT should be prescribed with anticoagulation. However, in critically ill patients, this is often contraindicated due to bleeding diathesis, recent surgery precluding use of heparin, or liver failure precluding the use of regional citrate anticoagulation, which will lead to metabolic acidosis and reduced ionised calcium. In severely critically ill patients, disease-induced coagulopathy or thrombocytopenia may also render anticoagulation unnecessary.
With regard to medical contraindications, patients in our study did not have statistically significant differences in the presence of liver dysfunction or coagulopathy, but there were more with thrombocytopenia (platelet counts <100,000/μL) in the group that did not receive anticoagulation.
We can postulate the reasons why prescribers omit anticoagulation in the initial KRT session. Patients are acutely ill with organ failure, thus the preference to avoid systemic anticoagulation to not increase bleeding risks and to avoid regional citrate anticoagulation to minimise pH and electrolyte changes (e.g. calcium, magnesium and phosphate). Regional citrate anticoagulation (RCA) also requires familiarity with the protocol and logistically poses more challenges.
Interruptions to CKRT impact on physiological stability, patient treatment, with added costs. The literature consistently shows RCA is beneficial for filter lifespan, with lower adverse events, compared to heparin anticoagulation.10 Despite this, the evidence for anticoagulation strategies and impact on mortality is not strong,22 and still being investigated. For instance, in one previous study, there was no difference in mortality, metabolic alkalosis, circuit loss and the amount of blood transfused between patients with heparin anticoagulation and RCA.23
One of the postulated reasons for the findings is that anticoagulation had a beneficial impact on filter efficacy,24 as delivered dose is reported to be highest in treatments where RCA was employed, with lower odds of death compared to CKRT with heparin anticoagulation.24
However, we are unable to detect this association as this study did not collect data on filter efficacy by calculating effluent urea nitrogen/blood urea nitrogen ratios. We also did not specifically study filter lifespan or distinguish between interruptions to initial CKRT due to filter performance or extrinsic factors (such as need for interventions).
The strength of this study is that data were obtained from mixed, surgical, cardiac and medical units, which increases the generalisability of the data. This is also the first period prevalence study showing anticoagulation practices during CKRT in Singapore.
The limitations of this study are that it was a retrospective study, which was dependent on existing clinical databases, and thus there were missing or incomplete data. Not all units in Singapore participated in the study due to logistical reasons, but all tertiary hospitals are represented in this data. We also did not consider subsequent KRT sessions the patients received, which may have contributed to the prognosis. However, the initial KRT sessions early in AKI and critical illness may pose the highest risk, whereas subsequent sessions may be routine KRT while awaiting kidney recovery and have less prognostic impact. Other conditions that contraindicate anticoagulation may have led to the primary outcome, but we have adjusted for illness severity, liver dysfunction and thrombocytopenia, and they were all not found to be associated with the primary outcome.
Anticoagulation during CKRT should be considered whenever possible. However, there are non-anticoagulant factors such as type and location of vascular access, blood flow rates and haematological conditions that influence filter efficiency and lifespan17; and anticoagulation is just one factor influencing filter performance. Future studies can consider studying specifically filter duration and efficiency and take into consideration all KRT sessions received by the patient. Future studies should also investigate other physician considerations for not using anticoagulation.
Among critically ill patients with AKI, anticoagulation use during CKRT was associated with reduced dialysis or death at 90 days post-ICU admission, which was statistically significant for regional citrate anticoagulation and trended in the same direction of benefit for systemic heparin anticoagulation. Anticoagulation during CKRT should be considered whenever possible.
The authors have no relevant financial or non-financial interests to disclose.
The authors would like to extend their gratitude to Ms Li Li for her assistance in data extraction.
- Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013;8:1482-93. Erratum in: Clin J Am Soc Nephrol 2014;6;9:1148.
- Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-8.
- Chua HR, Wong WK, Ong VH, et al. Extended Mortality and Chronic Kidney Disease After Septic Acute Kidney Injury. J Intensive Care Med 2020;35:527-35.
- Chew ST, Ng RR, Liu W, et al. Acute kidney injury increases the risk of end-stage renal disease after cardiac surgery in an Asian population: a prospective cohort study. BMC Nephrol 2017;18:60.
- Khan BA, Singh T, Ng ALC, et al. Health economics of kidney replacement therapy in Singapore: Taking stock and looking ahead. Ann Acad Med Singap 2022;51:236-40.
- Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015;41:1411-23.
- Bai M, Zhou M, He L, et al. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med 2015;41:2098-110.
- Brandenburger T, Dimski T, Slowinski T, et al. Renal replacement therapy and anticoagulation. Best Pract Res Clin Anaesthesiol 2017;31:387-401.
- Stucker F, Ponte B, Tataw J, et al. Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial. Crit Care 2015;19:91.
- Gattas DJ, Rajbhandari D, Bradford C, et al. A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med 2015;43:1622-9.
- Bagshaw SM, Laupland KB, Boiteau PJ, et al. Is regional citrate superior to systemic heparin anticoagulation for continuous renal replacement therapy? A prospective observational study in an adult regional critical care system. J Crit Care 2005;20:155-61.
- Zarbock A, Küllmar M, Kindgen-Milles D, et al. Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial. JAMA 2020;324:1629-39.
- Srisawat N, Lawsin L, Uchino S, et al. Cost of acute renal replacement therapy in the intensive care unit: results from The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study. Crit Care 2010;14:R46.
- Kellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 2013;17:204.
- Belletti A, Lerose CC, Zangrillo A, et al. Vasoactive-Inotropic Score: Evolution, Clinical Utility, and Pitfalls. J Cardiothorac Vasc Anesth 2021;35:3067-77.
- Slowinski T, Morgera S, Joannidis M, et al. Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study. Crit Care 2015;19:349.
- Brain M, Winson E, Roodenburg O, et al. Non anti-coagulant factors associated with filter life in continuous renal replacement therapy (CRRT): a systematic review and meta-analysis. BMC Nephrol 2017;18:69.
- Phongphitakchai A, Boonsrirat U. Survival and Predictors of Mortality in Acute Kidney Injury Patients Treated with Sustained Low Efficiency Dialysis. Ann Acad Med Singap 2020;49:306-11.
- Xiao YQ, Cheng W, Wu X, et al. Novel risk models to predict acute kidney disease and its outcomes in a Chinese hospitalized population with acute kidney injury. Sci Rep 2020;10:15636.
- Honda N, Hishida A. Pathophysiology of experimental nonoliguric acute renal failure. Kidney Int 1993;43:513-21.
- Avila MO, Zanetta DM, Abdulkader RC, et al. Urine volume in acute kidney injury: how much is enough? Ren Fail 2009;31:884-90.
- Zhang Z, Hongying N. Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy. Intensive Care Med 2012;38:20-8.
- Li R, Gao X, Zhou T, et al. Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: A meta-analysis of randomized controlled trials. Ther Apher Dial 2022.
- Claure-Del Granado R, Macedo E, Soroko S, et al. Anticoagulation, delivered dose and outcomes in CRRT: The program to improve care in acute renal disease (PICARD). Hemodial Int 2014;18:641-9.