Kidney replacement therapy during extracorporeal membrane oxygenation: pathophysiology, technical considerations, and outcomes

Abstract

The use of extracorporeal membrane oxygenation has been increasing over time, in part due to the COVID-19 pandemic. Whilst lifesaving, complications that must be managed are also associated with its use. AKI and fluid overload are complications of concern due to their associations with poor outcomes, and ability to be managed by additional interventions such as the use of kidney replacement therapy. Various modalities, timings, and types of kidney replacement therapy are currently being used and outcomes regarding its concurrent use with extracorporeal membranous oxygenation across centers may be mixed. In this review, we discuss the pathophysiology of AKI, methods, modalities and impact of concurrent extracorporeal membrane oxygenation and kidney replacement therapy.

Introduction

The use of extracorporeal membrane oxygenation (ECMO) has increased substantially over time, particularly following the COVID-19 pandemic [1–3]. As an extracorporeal life support, ECMO drains venous blood from the body, oxygenates and removes carbon dioxide, and returns the blood to either the venous circulation (in venovenous ECMO commonly for pulmonary indications), or arterial circulation (in venoarterial ECMO commonly for cardiac indications) [4–6]. In extension, venoarterial ECMO can be used in cardiac arrest in a mode known as extracorporeal cardiopulmonary resuscitation (ECPR) [7]. While ECMO can potentially reduce mortality in well-selected patients with clear indications, this must be balanced with its potential harms. One of the most common complication while receiving ECMO is acute kidney injury (AKI). A recent meta-analysis found that a significant proportion of patients receiving both VV and VA ECMO also received kidney replacement therapy (KRT) [3,8], and patients receiving concurrent therapies had significantly higher mortality [8–12]. Recognizing the impact of AKI in patients receiving ECMO, the Extracorporeal Life Support Organization released a guideline detailing recommendations with regards to fluid and electrolyte management, and KRT [13]. In this manuscript, we outline the indications of KRT and ECMO in patients with critical illness, technical considerations and potential challenges, and patient outcomes based on an updated review of the literature. We sought to include a holistic approach covering aspects of pathophysiology of AKI in ECMO patients, the options available for treatment including KRT, its consequences and impact on drug dosing for patients, outcomes and overall costs in this narrative review.

To support our literature review, we conducted a search of Medline via PubMed from origin through 31 December 2024, using the search terms ‘extracorporeal membrane oxygenation’ and ‘renal replacement therapy’ or ‘haemodialysis/filtration’. This yielded 466 studies. We then reviewed the abstracts of each reference, and shortlisted relevant full text studies to include in our review.

Pathophysiology of acute kidney injury and fluid overload during extracorporeal membrane oxygenation

The incidence of AKI requiring KRT in patients receiving ECMO remains high, with its incidence for patients receiving VA ECMO at 60.8% and VV ECMO at 45.7% [9]. While understanding the pathophysiology behind ECMO and the occurrence of AKI, let us briefly review the classification systems of AKI that has been used in ECMO patients. As with critically ill patients in ICU, AKI is commonly defined using the RIFLE [risk, injury, failure, loss and end-stage], AKIN [acute kidney injury network] and KDIGO [Kidney disease improving global outcomes] criteria in patients receiving ECMO support, highlighted by a relative increase in the serum creatinine of at least 50% within 7 days, or a reduction in urine output to <0.5 mL/kg/h for at least 6 h (Table 1) [14]. There are multiple reasons for patients receiving ECMO to be at high risk of AKI. The acute insult of critical illness in patients with limited functional reserves can result in prolonged periods of hypoperfusion, hypoxia, and cardio-renal syndrome [15,16]. Interventional factors including ECMO itself can contribute to an exaggerated inflammatory response from blood contact with artificial surfaces, complement activation and cytokine storms [17,18]. Its effects on the microcirculation at end-organs (including the kidneys) may be similar to those observed in sepsis. Ischemia-reperfusion injury after ECMO initiation further exacerbates microvascular dysfunction, with nephrons being susceptible to damage from oxygen free radicals after reperfusion of previously hypoxic cells [19]. Hemolysis from red cell stress induced during ECMO can cause hemoglobinuria directly damaging kidneys [20], and disrupt homeostatic balance of oxygen, nitrogen and reactive oxygen/nitrogen species [21]. This again worsens microvascular dysfunction leading to AKI. Fluid overload from ECMO is another pertinent factor contributing to AKI. During the initiation of ECMO, sustained resuscitation may result in patients receiving large amounts of fluids, especially in its early phase [22,23]. Moreover, such patients are more likely to receive blood products and drug administration which require additional fluids, further adding on to positive fluid balance [13,24]. Numerous studies have shown that a net positive fluid balance during ECMO is associated with mortality [25,26]. While strict fluid balance charting and intermittent diuretics can be given to reduce fluid load, this may not be sufficient, and in refractory overload, KRT may be indicated [13]. Figure 1 summarizes the indications for KRT in patients receiving ECMO, and Table 2 summarizes potential strategies to prevent and treat AKI during ECMO.

Table 1.

AKI criteria.

Classification system	Class	Serum creatinine (SrCr) criteria	Urine output (UO) criteria
RIFLE	Risk	SrCr x 1.5	UO <0.5 ml/kg/hour x 6 h
	Injury	SrCr x 2	UO < 0.5 ml/kg/hour x 12 h
	Failure	SrCr x 3 or ≥ 4 mg/dl with an acute rise > 0.5 mg/dl	UO < 0.3 ml/kd/hour x 24 h or anuria x 12 h
	Loss of kidney function	Complete loss of kidney function > 4 weeks
	End-stage kidney disease	End stage kidney disease > 3 months
AKIN	Stage 1	SrCr x 1.5 or ≥ 0.3 mg/dl	UO < 0.5 ml/kg/hour x 6 h
	Stage 2	SrCr x 2	UO < 0.5 ml/kg/ hour x 12 h
	Stage 3	SrCr x 3 or ≥ 4 mg/dl with an acute rise > 0.5 mg/dl	UO < 0.3 ml/kd/hour x 24 h or anuria x 12 h
KDIGO	Stage 1	SrCr x 1.5–1.9 in 7 days or ≥ 0.3 mg/dl in 48 h	UO <0.5 ml/kg/hour x 6 h
	Stage 2	SrCr x 2–2.9	UO < 0.5 ml/kg/ hour x 12 h
	Stage 3	SrCr x 3 or ≥ 4 mg/dl with an acute rise > 0.5 mg/dl	UO < 0.3 ml/kd/hour x 24 h or anuria x 12 h

Figure 1.

Indications for KRT in ECMO.

KRT: kidney replacement therapy, ECMO: extracorporeal membrane oxygenation

Table 2.

Currently available strategies to prevent and treat AKI in patients receiving ECMO.

Supportive care	Early detection of AKI (AKIN48-hour score) Fluid restriction Diuretics Avoidance of nephrotoxic drugs
KRT	Performed in series with ECMO	Addition of haemofilter Addition of CKRT machine before or after ECMO pump
	Performed in parallel with ECMO	Addition of separate CKRT machine with separate access from ECMO

The prevalence of AKI in patients receiving VA ECMO are higher than in VV ECMO, and this may be related to the fluid dynamics and pathophysiology behind each mode of ECMO. In VV ECMO, blood is returned to the venous system in an anterograde manner, i.e., along the flow of circulation. However, in VA ECMO (specifically peripheral femoro-femoral VA ECMO), the blood is returned to the arterial circulation in a retrograde manner in the common iliac artery. Computational fluid dynamics studies in VA ECMO have shown that the retrograde placement of the return cannula in the femoral artery disrupts laminar flow of blood, and results in vortex formation at the level of the inferior mesenteric and renal arteries [27]. This is associated with differential wall shear stress and secondary flows, which in turn leads to hemolysis, hypoperfusion, and acute kidney injury.

The impact of fluid balance on outcomes of patients receiving ECMO

Strict control of fluid balance is essential in improving patient outcomes. A large retrospective study found that positive fluid balance was associated with mortality for up to a year, but patients who received KRT (whether CKRT or IHD) with positive fluid balance were spared of this risk [28]. Poor fluid balance (particularly on day 3 of ECMO) has been established as a poor prognostic factor in ECMO patients [25,29,30]. As such, by potentially helping in more precise control of fluid balance, KRT may provide survival benefits in patients receiving ECMO with poor fluid balance.

A recent systematic review and meta-analysis found that patients receiving KRT while receiving ECMO had a significantly higher risk of mortality (up to 80% higher mortality rates) [8]. Yet, this may be a reflection of patient selection and disease severity, rather than the potential benefits. As with any intervention in patients with critical illness (particularly as invasive as ECMO), it is logistically and ethically challenging to estimate the counterfactual survival in patients who do have fluid overload or AKI but are randomized to not receive KRT.

In children, fluid overload is more well established as a predictor of mortality. A 10% rise in peak fluid balance led to 9% increase in ECMO mortality and 17% increase in hospital mortality [31]. With fluid balance being vital for survival in patients receiving ECMO, strict monitoring and correction of fluid levels are suggested to be crucial in managing such patients. Symons et al. found that using an integrated pump driven CKRT compared to a free-flow system was associated with significantly shorter ECLS and median KRT duration, suggesting that precise fluid management may aid in patient recovery [32]. CKRT when compared to no CKRT can help reduce fluid overload [33], and utilizing haemofiltration may also help in improving outcomes by reducing duration of ECMO, mechanical ventilation, blood transfusion requirements, and improving caloric intake [34,35].

KRT and neurological outcomes in patients receiving ECMO

There has been keen interest in investigating adverse neurological outcomes in patients receiving ECMO models [36–39]. KRT has been shown in the ELSO registry to be associated with acute brain injury and ischemic stroke in patients receiving ECPR, and acute brain injury and intracranial hemorrhage in patients receiving VA-ECMO [37,39]. Multiple pathways may be implicated in the pathogenesis of neurological injury. First, acute kidney injury is associated with an increase in inflammatory cytokines, catecholamines, and uremic acidosis, predisposing patients to neurological injury [40]. Cerebral blood flow and autoregulation may also be disrupted while on ECMO and KRT. Centrifugal pumps used in the ECMO circuit may contribute to impaired cerebral autoregulation due to a loss of pulsatile arterial blood flow [41]. This may be further exacerbated when patients are placed on KRT, where impaired autoregulatory mechanisms may be unable to withstand intradialytic hypotension [42]. KRT can also result in cerebral edema, termed disequilibrium dialysis syndrome (DDS). Driven by the effects of shift in plasma osmolality, KRT promotes a decrease in urea, increase in bicarbonate and subsequent decrease of pH in cerebrospinal fluid. This leads to cerebral edema with a fall in cerebral blood flow, causing ischemia and a cycle of greater cerebral edema [40].

Timing of KRT in ECMO

The timing of KRT remains controversial, with studies reporting mixed results on the benefits of early initiation. In the pediatric population, rather than correcting fluid overload (which has been found to not improve outcomes), guidelines recommend prevention of fluid overload of more than 10% [13]. In such instances, early initiation of CKRT allows for improved fluid balance management, which in theory results in mortality benefits. Cohort studies have found that neonates and children receiving CKRT later in more severe states of fluid overload had higher mortality rates, and tended to receive ECMO for longer durations [34,43–45]. Yet, others have found that earlier continuous venovenous hemodialysis in patients receiving ECMO for cardiac causes were associated with mortality [46].

Concurrent use of CKRT and ECMO in the adult population has been shown to be independently associated with mortality [8,25]. However, such results may simply be due to these patients being sicker compared to those who require ECMO alone. In a pilot RCT of patients receiving VA ECMO for post cardiotomy cardiogenic shock, Li et al. found that early initiation of KRT allowed for lower cumulative fluid balance and a trend (though not statistically significant in view of a smaller sample size) toward lower mortality and increased ECMO weaning. However, there were no significant differences in terms of adverse events including nosocomial infection or bleeding [47]. Similarly, Paek et al.’s cohort study found that early CKRT in ECMO patients did not improve mortality nor hospital stay [48]. In fact, some have found that initiating KRT prior to ECMO was associated with poorer outcomes [49]. While this may be multifactorial, patients having AKI prior to ECMO initiation would have more severe disease and hence, potentially poorer outcomes. Whilst not specifically on ECMO patients, several RCTs on adults with critical illness have noted no benefit in early initiation of KRT as well, with some even reporting harm such as increased dependence on KRT and catheter related bloodstream infections [50,51]. With few studies yet published on ECMO and KRT, the timing of KRT remains contentious. Seeing the benefits of earlier control of volume balance and its limited impact on mortality, an earlier decision for KRT may be beneficial in patients with severe cardiogenic shock on ECMO. As a guiding principle, KRT should be initiated when fluid overload cannot be managed sufficiently with diuretics, or when there are severe metabolic derangements from AKI [13].

Unadjusted observational studies may be insufficient to estimate the effect of earlier vs. later KRT in patients receiving ECMO. First, patients receiving earlier KRT while on ECMO may represent a subset of the population who are acutely deteriorating and hence, the use of KRT may not be associated with mortality as much as the acute disease severity at the time of initiation. Second, patients who receive later must necessarily survive for a certain time period before they receive KRT. As such, the survival time of these patients is skewed and potentially longer than the actual survival times one would expect in a real-life clinical scenario, also known as ‘immortal time bias’. Further causal estimation methods including propensity score estimation and adjustment, weighting or matching, and target trial emulation with adherence adjusted estimates may be more appropriate in such settings.

Modalities and circuits configuration in relation to ECMO: in parallel or in series?

Various KRT modalities can be used to control fluid balance. This includes intermittent modalities such as IHD and peritoneal dialysis (PD), and continuous modalities such as CKRT. CKRT consists of continuous veno-venous haemofiltration (CVVH), hemodialysis (CVVHD), and haemodiafiltration (CVVHDF). Whilst there is no concrete evidence that suggests any modality conferring greater mortality benefits, CKRT may often be more suitable in ECMO patients due to their haemodynamic instability [52]. Additionally, CKRT provides a tighter control of fluid balance and is able to achieve superior solute clearance. Administering CKRT can be done via adding a haemofilter or CKRT device into the ECMO circuit, or by including a separate venous access for renal support.

In general, there are two ways KRT can be configured in the context of ECMO: in series (where the RRT and ECMO devices share the same circuit), or in parallel (two separate circuits for KRT and ECMO individually, Figure 2). There are benefits and potential harms to both approaches, and these are summarized in Table 3. Figure 2 describes each KRT configuration, and there potential benefits and harms.

Figure 2.

ECMO and CKRT circuit configurations.

KRT: kidney replacement therapy; CKRT: continuous kidney replacement therapy; ECMO: extracorporeal membrane oxygenation

Table 3.

Configurations of KRT and ECMO.

Circuit arrangement		Advantages	Disadvantages
In series	Addition of haemofilter	Less technically challenging than CKRT machine Less expensive Smaller priming volume required	Increased errors in measurement of ultrafiltrate Unable to tolerate high pressures, requiring stopcock or flow restrictor
	Addition of CKRT machine before ECMO pump		Increased risk of air embolism Increased risk of ECMO pump clotting Requires over riding of CKRT machine settings to accommodate low arterial pressures
	Addition of CKRT machine after ECMO pump	Reduced risk of air entrapment Optimal blood flow (if CKRT inlet is distal to oxygenator and outlet is proximal to pump)	Less accurate measurement of ultrafiltrate volume compared to parallel circuit Complex set up
In parallel		Decreased inaccuracies of ultrafiltrate measurement Simpler set up of CKRT circuit	Increased risk of catheter related complications Additional requirement of extracorporeal blood volume

In a series configuration, the KRT circuit is integrated into the ECMO circuit. This can be done via the addition of a haemofilter, or a CKRT device into the ECMO circuit. The use of a haemofilter in series with the ECMO circuit may be beneficial as it requires a smaller priming volume, is technically less challenging, and less expensive. However, measurement of the ultrafiltrate volume may be inaccurate and difficult to control. In addition, as haemofilters are not designed to tolerate the high pressures in the ECMO circuit, a stopcock or flow restrictor may be required to adjust its flow rate. This comes with its own potential for flow turbulence, resulting in hemolysis and thrombus formation, which in turn require more medications or transfusions that worsen fluid balance. A method to circumvent this would be to situate the CKRT device within the ECMO circuit. Yet, there are several potential harms that are associated with this method, which can include accidental air entrapment, clot embolism, pressure changes, frequent alarms, and recirculation depending on the location for the CKRT device. Management of such complications needs to be closely monitored by competently trained nursing staff and ECMO specialists. Research in simplifying the circuit is still ongoing. A recent preclinical trial was successful in transforming the kidney membrane into a lung membrane by adding 3% concentrated H2O2, allowing the combination of kidney and lung function in a single membrane [53]. If successful in future trials, such a system can greatly reduce the complexity of combined ECMO and KRT and reduce costs.

Arranging the circuits in parallel (i.e., in two separate circuits and catheters) eliminates the potential issues of inaccurate ultrafiltrate volume measurement, and complications mentioned previously. Setting up and changing of the CKRT circuit may also be simpler, which can be accomplished by a bedside nurse without the need of a ECMO perfusion specialist [54]. However, disadvantages arise with the additional catheter required, where complications such as infections and bleeding at the new catheter site have to be managed. Moreover, this method requires additional extracorporeal blood volume which may impede on the performance of ECMO [55].

The evidence of circuit configuration for ECMO is only emerging. A recent study found that there were no significant differences in outcomes between those who were initiated on a ‘integrated’ and a ‘parallel’ configuration of ECMO and KRT. However, patients receiving parallel KRT had a significantly longer initiation time and shorter filter life, and the rates of local bleeding were significantly higher as well [56]. More investigation is required in order to find the ‘optimum’ settings of initiating KRT while patients receive ECMO.

Drug dosing on ECMO-CKRT

Appropriate dosing of medications for patients receiving concurrent ECMO and CKRT remains a challenge due to its effect in altering drug pharmacokinetics (pK). It has been suggested that as ECMO increases the volume of distribution, higher initial doses of medication are required [57]. However, this may also lead to impaired drug clearance and prolong their duration of effects. Additionally, ex vivo studies have found that the PVC tubing and membrane oxygenator adsorbs lipophilic drugs, sequestrating it later on and making pK even harder to control [58]. The addition of CKRT further complicates the matter, with drug clearance being affected by drug solubility, molecular weight and protein binding, as well as KRT dialysate and ultrafiltration rates [59]. Some drugs seem to be more affected than others. In a prospective study of patients receiving antibiotics while on ECMO, certain drugs were able to hit their pK objectives, while others performed poorly. Imipenem and aminoglycosides were amongst those that had subtherapeutic plasma concentrations [60]. Another prospective study found that ECMO patients had lower serum concentrations of piperacillin and standard dose meropenem compared to non-ECMO patients, whilst CKRT was associated with higher concentrations of the above drugs compared to their non-CKRT counterparts [61]. Anticoagulation dosing is another challenge when combining ECMO and CKRT. The addition of CKRT during ECMO increases the risk of thrombus formation due to slower blood flow and increased circuit surface area. However, over-coagulation is another major concern with bleeding being a common complication in ECMO [62]. Additional anticoagulation is thus not routinely used in patients receiving both ECMO and KRT when heparin is already used [63]. In situations with low heparin or heparin-free ECMO, the use of regional citrate anticoagulation has been found to be a safe and effective [64]. Literature on the topic remains scarce especially in the adult population, with many drugs having little reported studies on its effects with ECMO [57]. Therapeutic drug monitoring is recommended until more data becomes available on appropriate dosing regiments for these patients. Table 4 summarizes the evidence surrounding some commonly used antibiotics, sedatives, and analgesics in the context of critical care and ECMO.

Table 4.

Literature findings of pharmacokinetics (PK) and pharmacodynamics (PD) of common antibiotics and sedatives.

Drug	Author	Literature findings
Piperacillin-Tazobactam	Bauer 2012 [88]	A study on patients treated with Piperacillin-Tazobactam and concomitant CRRT found that the volume of distribution for piperacillin was 34.5 L (IQR = 30.5L), and for tazobactam it was 38.1 L (IQR = 27.1L). Elimination of Piperacillin was faster with a median half-life of 9.6h (IQR = 4.2h) than Tazobactam which had a median half-life of 11.5h (IQR = 8.4h). Clearance was variable between patients, with the dialysis circuit clearing slightly under one half of piperacillin and slightly over one half of the tazobactam. In terms of PD, 83% of patient achieved the PD goal fT > MIC = 64 μg/ml > 50% when considering the total drug concertation (free and bound), and 77% achieved this goal when considering the unbound form only. All patients achieved the more liberal goal of fT > MIC = 16 μg/ml > 50%.
Meropenem	Peng 2022 [89]	A study on CRRT patients found that adequate PK/PD targets could be achieved with Meropenem regimens of 1 g every 6 h infused over 30 min, 1 g every 8 h infused over 3 h, and 2 to 4 g every 24 h infused over 24 h. Endogenous clearance of meropenem was lower than in non CRRT patients at 3.03 L/h, and the volume of distribution was 34% higher at 28.8 L
Vancomycin	Jung 2021 [90]	A prospective cohort study on adult ECMO patients found that Vancomycin clearance and steady-state volume of distribution were 4.01 L/h (0.0542 L/h/kg) and 29.6 L (0.400 L/kg), respectively. AUC/MIC values of 400 to 600 were hard to attain with any dosing strategies, making it hard to achieve efficacy and safety targets in ECMO patients. Therapeutic drug monitoring is recommended.
Propofol	Cheng 2018 [91]	An article summarizing drug dosing in ECMO patients anticipated Propofol to be significantly sequestered in the ECMO circuit due to it being highly lipophilic and a protein bound drug. Lemaitre et al. confirmed this when it found that 70% of propofol was diminished within the first 30 min of the study. [58] Higher doses of propofol may thus be needed for adequate sedation.
Fentanyl	Ha 2017 [92]	In a study evaluating altered drug PK in patients receiving ECMO, 30–40% fentanyl was found to be sequestered in modified tubing, and that 80–86% of it was sequestered in circuits. On average 96% of fentanyl was lost to circuit in 24 h. Increased doses may thus be required in these patients or alternative drugs should be considered.
Dexmedetomidine	Smuszkiewicz 2017 [93]	A study looking at the PK of dexmedetomidine in ICU patients found that the PK parameters were consistent with existing literature, with 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance.
Midazolam	Patel 2022 [94]	A narrative review on the impact of ECMO on drug pharmacokinetics summarized midazolam to be highly lipophilic thus causing a concern for drug sequestration. Shekar et al. demonstrated this, where patients required increase in midazolam dose of 18 mg/d after ECMO commenced to maintain deep sedation goals. [95]

Outcomes of patients with AKI receiving ECMO

AKI is common amongst adults receiving ECMO, and can affect up to 62.8%, with a high hospital or 90 day mortality rate of 62% [9]. A recent meta-analysis assessing patients receiving VA-ECMO for cardiogenic shock cited renal failure as the most frequent complication, and KRT requirement as its third [62], and another study found that CKRT initiation and duration was independently associated with mortality [65]. Whilst the combination of ECMO and KRT may be reported to be associated with increased mortality, this may not be the case for all patients with AKI. A recent study comparing ECMO patients without AKI, with AKI, and with AKI and CKRT showed that there was no significant difference in ICU mortality between the 3 groups [66]. This was despite the fact that patients with AKI on CKRT had poorer prognostic factors such as a higher SOFA score, lactate levels and more frequent inotropic therapy.

Besides mortality benefits, KRT’s effectiveness in renal recovery are also evident. Renal recovery can be defined as the patient’s ability to be weaned off KRT, or by improvement of the patient’s serum creatinine. Deatrick et al. reports a 93% recovery rate in VV ECMO patients on CKRT who developed AKI during ECMO and survived till hospital discharge [67]. In contrast, Devasagayaraj et al.’s study of patients receiving VV ECMO with and without AKI found that only 71% of the AKI population were able to regain full renal recovery [68]. In the above studies, patients were considered to have renal recovery based on their ability to wean off KRT. A retrospective cohort analysis has also found that the type of ECMO support (VV or VA) does not affect renal recovery rate. The study defined renal recovery based on the patient’s serum creatinine. Studies conducting longitudinal follow up on patients receiving ECMO with AKI found that nearly 50% of patients progressed to acute kidney disease (i.e., persisting up to 90 days), and only 42% of patients with KDIGO 3 AKI had complete renal recovery [69]. Interestingly, longer CKRT duration has been found to be associated with increased morbidity with long term ESKD. A nationwide cohort study examining patients receiving ECMO and KRT revealed that patients who received KRT for more than a week were at higher risk of ESKD compared to those receiving CKRT for 3 days or less. However, patients receiving longer durations of KRT had lower hospital mortality, though this may be confounded by immortal time bias [70]. Overall, improved survival has been noticed in recent years, with a recent meta-analysis highlighting the mortality decreasing from 74.1% to 56.1% when comparing studies from before and after 2016 [8]. This could be attributed to the growing number of publications within the last few years, creating more granularity in the data, and better clinical applications with technological advancements.

The incidence of AKI in the neonatal-pediatric patients on ECMO is likewise high as in adults, with an estimated incidence of 60–74% [71]. Whilst there may be higher mortality associated with concurrent ECMO and CKRT, patients that survive tend to have favorable outcomes in renal recovery. Paden et al. demonstrated this, where 96% of patients receiving concurrent CKRT and ECMO were successfully weaned off KRT at hospital discharge [72]. Additionally, of the 23 patients that were initiated on CKRT due to AKI, 20 managed to gain full renal function by discharge. The remaining patients were found to either have primary renal pathologies, or were later successfully taken off any KRT. Meyer et al. reported similar outcomes, with 93% of survivors on ECMO and CKRT achieving full renal recovery [73].

CKRT and ECMO in toxicology

CKRT and ECMO can be used to manage patients with severe intoxication and poisoning. Indications for KRT require drugs that are dialyzable, comprising a low molecular weight, low degree of protein binding and a low volume of distribution [74]. Commonly it is used for alcohol, salicylate, valproate, metformin and lithium overdose. While CKRT holds the advantage of being safer for haemodynamically unstable patients, its lower clearance rate often makes it inferior to intermittent hemodialysis (IHD), and thus being reserved only for patients who cannot tolerate IHD [75]. The use of ECMO for toxicology patients have just been increasing, and is indicated for patients with refractory cardiogenic shock [76]. This is particularly so for cardiovascular drugs, with benefits in maintaining cardiac output and tissue perfusion while enhancing toxic substance metabolism [77,78]. Case reports have shown its successful use with drugs such as amlodipine, lisinopril, hydrochlorothiazide and metoprolol as well as toxins such as aluminum phosphide [77,79,80]. Current literature on the combined use of ECMO and CKRT for these patients is limited, but may be explored for combined organ support.

Advances in extracorporeal technologies and future directions

Advancements in extracorporeal machines are still progressing, with increasing interest in incorporating extracorporeal carbon dioxide removal devices (ECCO₂R) for hypercapnic respiratory failure along with CKRT devices. ECCO₂R focuses on removing carbon dioxide and does not provide significant oxygenation in contrast to ECMO, often being used together with invasive mechanical ventilatory devices. The Hemolung (ALung Technoloqies, PA, USA) and PrismaLung (Baxter, IL, USA) are such devices that are being used recently and has been shown as effective in improving PaCO₂ levels and hypercapnic acidosis [81,82]. The addition of CKRT for the patient is made easier when combined with ECCO₂R, due to their similar flow rates, making a comprehensive lung and renal support system possible. Studies are emerging on its use, with a recent retrospective review showing its safety and effectiveness with the PrismaLung and Prismaflex (Baxter, IL, USA) on ARDS patients [83]. More trials are required to determine its overall benefit. Devices which incorporate dialysis filters with oxygenators are currently being investigated both in hollow fiber and microfluidic artificial lungs [84]. Ultimately, we believe that the future area of research in extracorporeal technologies lies in integrating the hemofilter into the extracorporeal circuit and membrane oxygenator, which may help to avoid mechanical (for example, air embolism, circuit malfunctions) and hemolytic complications, making for a more efficient use of devices and circuits.

Resource use and economic implications of ECMO and KRT

Combining ECMO and KRT demands substantial resources with the use of specialized equipment, specially trained medical professionals and longer hospital stay. ECMO therapy itself incurs great costs, compared to non ECMO patients [85]. Moreover, ECMO use has seen an increased in utilization from 2019 to 2020 since the SARS-CoV-2 pandemic, which will likely amplify hospital and patients’ financial burden alike [86]. A large prospective study has also found the large costs associated with KRT, where ICU patients can expect to incur $3,629.80 more per day with CKRT treatment compared to patients without CKRT [87]. While there are limited studies which comment on the costs of combined ECMO and KRT therapy, longer ICU and hospital stay that has been found in these patients undoubtedly will contribute to higher resources utilization and subsequent costs [8].

Conclusion

In this review, we outlined the literature surrounding the use of ECMO in patients with critical illness, acute kidney injury and fluid overload, the use of KRT, and its technical considerations and outcomes. It is evident that much of the evidence surrounding this topic is only emerging, and more needs to be done to identify the right population who can stand to benefit from KRT while receiving ECMO. Beyond this, advanced statistical techniques can help inform the causal effect of other aspects including the timing, modality, and dose of KRT. KRT can potentially help save lives in patients who might otherwise die without it, yet it is important to consider its indications, complications, and patient eligibility for initiation in extremely sick patients who would need stabilization on extracorporeal life support systems.

Funding Statement

There was no funding source for this study.

Authors’ contributions

Study conception and design: KR; Search strategy and screening of articles: MPXLL; Drafting of manuscript: MPXLL, RRL; All authors provided critical conceptual input, interpreted the data analysis, critically revised the manuscript for intellectual important content, read, and approved the final draft.

Disclosure statement

RRL receives research support from the Clinician Scientist Development Unit, Yong Loo Lin School of Medicine, National University of Singapore. KR is part of the Extracorporeal Life Support Organization (ELSO) Steering Committee, and chairs its Publication Committee. He has received honoraria from Xenios for educational lectures on ECMO. All other authors declare no competing interests.

Availability of data and materials

All data generated or analyzed during this study are included in the published studies and their supplementary information files.