Extracorporeal membrane oxygenation and acute kidney injury: a single-center retrospective cohort

To assess the relationship between acute kidney injury (AKI) with outcomes among patients requiring extracorporeal membrane oxygenation (ECMO). This is a single-center, retrospective cohort study of adult patients admitted to intensive care units (ICU) at a tertiary referral hospital requiring ECMO from July 1, 2015, to August 30, 2019. We assessed the temporal relationship of AKI and renal replacement therapy with ECMO type (VV vs. VA). The primary outcome was in-hospital mortality rates. We used Kruskal–Wallis or chi-square tests for pairwise comparisons, cause-specific Cox proportional hazards models were utilized for the association between AKI prevalence and in-hospital mortality, and a time-dependent Cox model was used to describe the association between AKI incidence and mortality. After the screening, 190 patients met eligibility criteria [133 (70%) AKI, 81 (43%) required RRT]. The median age was 61 years, and 61% were males. Among AKI patients, 48 (36%) and 85 (64%) patients developed AKI before and after ECMO, respectively. The SOFA Day 1, baseline creatinine, respiratory rate (RR), use of vasopressin, vancomycin, proton pump inhibitor, antibiotics, duration of mechanical ventilation and ECMO, and ICU length of stay were higher in AKI patients compared with those without AKI (P < 0.01). While ICU and in-hospital mortality rates were 46% and 50%, respectively, there were no differences based on the AKI status. The type and characteristics of ECMO support were not associated with AKI risk. Among AKI patients, 77 (58%) were oliguric, and 46 (60%) of them received diuretics. Urine output in the diuretic group was only higher on the first day than in those who did not receive diuretics (P = 0.03). Among ECMO patients, AKI was not associated with increased mortality but was associated with prolonged duration of mechanical ventilation and ICU length of stay.

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary support technology derived from intraoperative cardiopulmonary bypass machines.ECMO utilization rate continues to rise among patients with cardiovascular and/or respiratory failure 1-3 .Although ECMO is a life-saving therapy, it is associated with many complications, including acute kidney injury (AKI).The incidence of AKI among patients who require ECMO is reported to be about 50% 4 .
It has been reported that ECMO patients who develop AKI have unfavorable outcomes, particularly among more severe AKI requiring kidney replacement therapy (AKI-D).The hospital mortality rate in ECMO patients with AKI-D is 3.7 folds higher than those without AKI-D 5 .AKI is associated with a higher risk of mortality in ECMO patients, leading to higher morbidity and increased hospital costs 4,6 .OPEN 1 Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. 2 Division of Life Sciences and Medicine, Department of Critical Care Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, Anhui, China. 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA. 4 Division of Critical Care, Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA. 5 Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA. 6Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China. 7Anesthesiology Clinical Research Unit, Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA. 8 ICU, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China. 9ICU, DongE Hospital Affiliated to Shandong First Medical University, Shandong, China.* email: kashani.kianoush@mayo.edu The association between AKI and ECMO outcomes has been vigorously investigated in recent years.The potential risk factors are the use of nephrotoxic drugs, hypoperfusion, bleeding, plasma-free hemoglobin levels, and duration of ECMO support 4,7,8 .However, the differences in patient outcomes based on the temporal relationship between AKI diagnosis and ECMO is not explored.In addition, there is a paucity of data related to the long-term outcomes of AKI among ECMO patients, chances of liberation from continuous renal replacement therapy (CRRT), and the impact of the type of ECMO support.Therefore, we aimed to explore these characteristics in this historical cohort of ECMO patients.

Methods
Subjects.All adult patients ≥ 18 years old who received ECMO support [venovenous (VV) or venoarterial (VA)] at Mayo Clinic, Rochester, Minnesota, from July 1, 2015, to August 30, 2019, were included.We excluded patients who did not provide Minnesota research authorization or were admitted to ICU while on ECMO from outside institutions.As our goal was to assess the relationship between AKI and ECMO, those with chronic, end-stage or acute kidney disease were excluded, including individuals who had end-stage kidney disease and received any dialysis modality within 14 days of admission.Only the first cannulation was considered for the type of support in patients with multiple cannulations.Patient data were abstracted from the electronic health records and the Mayo Clinic ICU database 9 .The Institutional Review Board (IRB) at Mayo Clinic, Rochester, Minnesota, has reviewed and approved this single-center retrospective cohort study.Obtaining informed consent was waived by Institutional Review Board (IRB) at Mayo Clinic, Rochester, Minnesota, due to retrospective nature of the study.All experiments were performed following relevant guidelines and regulations indicated by IRB.
We divided the cohort into three groups, (1) individuals with AKI before ECMO initiation, (2) patients who developed AKI after ECMO initiation, and (3) ECMO patients without AKI.Clinical outcomes were assessed, including mortality, chronic kidney disease, need for long-term dialysis, and kidney recovery.Patients without AKI were divided into two groups according to the type of ECMO support (VA vs. VV) to evaluate for additional mechanistic explanations.Those with AKI who required CRRT while on ECMO were divided into two groups: (1) CRRT machine connected to the ECMO circuit; (2) CRRT done conventionally with a separate dialysis catheter.

Measurement.
Definitions.AKI and its stages were adjudicated according to the KDIGO guidelines 10,11 .
Patients with an increase in SCr by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 h or an increase in SCr to ≥ 1.5 times baseline within seven days or urine output < 0.5 ml/kg/h for 6 h were included in the AKI cohort.Following AKI detection, we staged AKI using serum creatinine and urine output criteria from the KDIGO guidelines 10,11 .Supplemental Table 1 shows the AKI staging criteria.The baseline creatinine was calculated as the median of all the creatinine values within 180 days before the index ICU admission.In the absence of baseline serum creatinine levels, the back-calculation of serum creatinine using Modification of Diet in Renal Disease formula for GFR of 75 ml/min/1.73m 212 .
Time zero was the ECMO initiation time.Patients were followed until death or hospital discharge.
ECMO management.Mayo Clinic ECMO center follows the Extracorporeal Life Support Organization (ELSO; https:// www.elso.org/ Resou rces/ Guide lines.aspx) guidelines for ECMO indications, equipment setup, and ECMO management parameters.Mayo Clinic primarily uses Cardiohelp ECMO consoles (Getinge AB) with HLS Set Advanced 7.0 disposable oxygenators.Alternatively, a CentriMag (Abbott) pump paired with a Quadrox-i oxygenator (Getinge AB) was also used.Our ECMO team closely monitors the ECMO circuit for evidence of thrombosis (visual inspection, post-oxygenator blood gas analysis, and to detect thrombolysis) and hemolysis (daily plasma free-hemoglobin levels and daily thromboelastogram complete blood counts).
Variables and outcomes.Patient demographics, clinical characteristics, hemodynamics, and laboratory data were abstracted from the electronic medical records.In addition, the type and parameters of ECMO support, mechanical ventilation, RRT, vasoactive drugs, and transfusion therapy were also collected.All enrolled patients were followed until discharge from the hospital, and the hospital survivors were followed for one year after discharge from the hospital.The primary outcome was in-hospital mortality.Secondary outcomes included the safety and effect of diuretic use among those with AKI.

Statistical analysis.
Continuous data are presented as median (IQR), and categorical data are presented as frequency (percent).Pairwise comparisons were made for all variables to examine their association with AKI using Kruskal-Wallis or chi-square tests.The association between AKI prevalence (at ECMO initiation) and inhospital mortality was assessed using cause-specific Cox proportional hazards models representing hazard ratios with 95% confidence intervals and p-values.The ICU mortality rates were presented using cumulative incidence curves with discharge as a competing risk.A time-dependent Cox model was used to describe the association between AKI incidence and mortality among those without prevalent AKI after adjusting for CCI, the severity of illness scores (APACHE and SOFA on day one of ECMO), lactate, baseline serum creatinine level, age, sex, and type of ECMO support (VV vs. VA).In the time-to-event analysis for AKI development after ECMO, time zero was defined as the time of ECMO initiation, with death as an event and hospital discharge as a censoring factor.Results were reported as hazard ratios with 95% confidence intervals and p-values.
Additionally, the cohort was divided into (1) AKI before ECMO initiation, (2) AKI developed during ECMO, and (3) without AKI.We conducted a cause-specific hazard model among patients in groups 2 and 3 by censoring patients at the ECMO completion or in-hospital death with AKI development as a dependent variable.Hazard ratios, 95% confidence interval, p-value, and Kaplan Meier curves were generated to assess the impact of the type of ECMO support (i.e., VV vs. VA) on the development of AKI.ECMO support type was defined as the initial setting, and crossover between VV and VA was not considered.Additionally, we evaluated the associations between the initial ECMO flow rate and pump speed on AKI development.
Among those who did not have chronic kidney disease before admission and were discharged alive, the frequency of de Novo CKD at 90 days and 1 year and the need for long-term dialysis were assessed.Among those with AKI requiring CRRT, the frequency of the CRRT liberation rate was calculated.In addition, the death rate after ECMO completion was described.Finally, we conducted a cause-specific hazards model among AKI patients who required CRRT to assess the death rate.CRRT initiation time was time zero for this analysis, and patients were censored at the time of ECMO liberation.A Kruskal-Wallis test was used for the patients in group 1 to compare urine output based on the diuretic challenge on days 1, 2, and 3.
Ethical standard.Institutional Review Board (IRB) at Mayo Clinic, Rochester, Minnesota, has reviewed and approved this single-center retrospective cohort study.Due to the retrospective nature of the study, obtaining informed consent was waived by Institutional Review Board (IRB) at Mayo Clinic, Rochester, Minnesota.All experiments were performed following the 1964 Helsinki declaration and its later amendments for comparable ethical standards along with relevant national guidelines and regulations indicated by IRB.
The incidence of de Novo CKD among those survivors and ECMO-liberated patients was relatively modest (~ 10% at 90 days and 1-year follow-up).Among those who developed AKI requiring CRRT, 25 (64%) were liberated from CRRT due to improvement in kidney function, 12 (31%) withdrew CRRT due to a change in goals of care, and 2 (5%) stopped CRRT for other reasons (Table 3).The association with in-hospital mortality with groups was not significant (prevalent AKI as the reference; incident AKI HR 1.05 [95%CI 0.34-3.20]and no AKI HR 0.65 [95%CI 0.20-2.15];Supplemental Table 2).There were no statistical differences in clinical outcomes of those who developed AKI before or after ECMO initiation (Table 4).
The urine output on day one was higher in patients who received diuretics than those who did not (P = 0.03; Table 6).However, urine output was not statistically different based on diuretic utilization after the first day of ECMO (P > 0.05).In addition, the mortality did not change based on diuretic administration (HR 0.90, 95%CI 0.42-1.92,P = 0.8).Table 5.The risk of AKI based on ECMO type.

Discussion
This comprehensive assessment of a large cohort of ECMO patients and AKI in a tertiary hospital demonstrates a very high incidence of AKI (70%) and AKI requiring dialysis (43%) among ECMO patients.Moreover, we found no significant correlations between AKI and in-hospital mortality after adjustments for CCI, the severity of illness, lactate, baseline serum creatinine level, age, sex, and type of ECMO support.Of our secondary outcomes, the duration of mechanical ventilation and ICU length of stay were significantly higher among patients with AKI than those without AKI.We found a clinically relevant but statistically insignificant higher risk of AKI among those on VV-ECMO compared to VA-ECMO (HR 0.52, P = 0.06).The statistical insignificance could be due to type II error secondary to a smaller sample size.The trend mentioned above may further indicate the need to investigate this particular AKI risk factor.The ECMO settings, including flow rate and pump speed, were not associated with AKI risk.However, this analysis is limited because only the initial settings were considered.Diuretics were safe and were associated with improvement in urine output only on the first day.Higher RR, usage of vasopressin, vancomycin, PPI, quinolones, radiocontrast, and phenylephrine administration were more common among AKI patients.The temporal relationship between AKI and ECMO did not impact CRRT liberation rate, CKD at 90 days, and one year.
Comparison with previous studies.With the progressive ECMO utilization in the past decade, the AKI incidence has been increasingly reported as 30-70% 5,[13][14][15][16][17] .This is substantially higher than other etiologies of AKI in intensive care units [18][19][20] .The pathophysiology of AKI among ECMO patients is quite complex and mostly remains unclear.The potential AKI risk factors are low cardiac output syndrome, exposure to nephrotoxic agents (i.e., vasoactive drugs, antibiotics, radiocontrast), new-onset sepsis, fluid overload, ischemia-reperfusion injury, proinflammatory mediators release, oxidative stress, hemolysis, hemorrhage, and/or thrombosis [21][22][23][24][25] .A recent meta-analysis demonstrated that AKI incidence among VA-ECMO patients (60.8%) was higher than that of VV-ECMO (45.7%) 5 .Our study found that the risks were similar, but the small sample size of VV-ECMO patients could have influenced the result.One of the main differences between the two modalities is that VA-ECMO provides smaller pulse pressure while VV-ECMO maintains pulsatile cardiac output 26 .Pulsatile flow may protect microcirculation and kidney perfusion 27,28 .Lee et al. observed a lower AKI rate with higher ECMO pump speed 29 .In contrast, increased ECMO flow rate and pump speed on day one were not associated with AKI risk.One limitation of our analysis is that only the settings on day one were considered.Therefore, prospective studies are required to more thoroughly assess the effects of ECMO pump speed on AKI risk in ECMO patients.
In-hospital mortality in AKI patients is nearly twice that of those without AKI 30 .In contrast, in our study, in-hospital mortality was similar amongst the groups.Furthermore, after adjustment for confounders, we found no differences in mortality among those with prevalent AKI, incidental AKI, and no AKI.Our findings differ from a recent study that showed AKI as an independent risk factor for mortality in patients requiring ECMO 31 .The reason for this difference could be variabilities in sample size.Thus, a more extensive multicenter study may be needed for further clarification.
An earlier study reported that diuretics in critically ill patients with acute kidney injury were associated with an increased risk of death.Another investigation focused on administering diuretics in oliguric AKI patients on ECMO 32 indicated that more than half of ECMO patients with AKI were oliguric, and up to 60% received a diuretic challenge.We compared the urine output during the first 3 days between those with and without diuretic administration.We noted that urine output responded to diuretics only on day 1 and did not impact mortality rates.This demonstration may indicate that diuretic administration is likely safe and effective if used earlier during ECMO support.
RRT requirement is common among ECMO patients with severe AKI [33][34][35] .Recent studies compare the advantages and disadvantages of RRT initiation and the direct connection of RRT to a central venous catheter vs. connection to the ECMO circuit 16,[36][37][38][39][40][41] .In a recent systematic review, Ostermann et al. 42 concluded that the mortality risk is not dependent on the methods of combining ECMO and RRT.In our study, 35% of RRTs were done via a central venous catheter and 65% via the ECMO circuit.The type of RRT connection was not associated with mortality.While connecting CRRT to the ECMO circuit can avoid additional catheter-associated complications, it could be associated with adverse events, such as ECMO circuit clotting, pressure alarms, and the inability to control the net ultrafiltration rates 43,44 .
Recently, a large-scale survey was conducted in China about drug-induced hospital-acquired AKI.Antiinfectives, diuretics, and proton pump inhibitors were the top 3 drug classes associated with AKI risk 45 .Despite the potential nephrotoxicity of vancomycin, given its efficacy against gram-positive cocci, especially MRSA, its use among ECMO patients may be inevitable.There are also investigations highlighting PPI usage was associated with adverse kidney outcomes and significantly increased the risks of AKI [46][47][48][49] .Our study indicated that incidental AKI was significantly more common when PPIs were administered (P < 0.01).Therefore, reducing PPI use or shortening its utilization could decrease AKI risk.We found vasopressin utilization was more common among incidental AKI patients (P < 0.01), possibly due to the higher severity of illness, indicating a higher risk of AKI and more hemodynamic instability.In clinical trials [50][51][52][53][54] , vasopressin reduced AKI development and progression and lowered mortality in patients with septic shock or after major procedures.Vasopressin, vancomycin, and PPIs may be independent predictors of AKI among ECMO patients.Among drugs used in this cohort, NSAIDs were used among 58% of patients.Based on our protocols, while NSAIDs are recommended over opioids for low-risk patients, when AKI risk increases, they are discontinued.In our cohort, almost all NSAIDs used during the index admission were before the need for ECMO or increased AKI risk.
This study possesses several strengths.First, we comprehensively evaluated AKI risk factors and impacts among ECMO patients in a large cohort.Second, we compared prevalent and incidental AKI (AKI before and after ECMO initiation) with each other and with those without AKI.Furthermore, we assessed the association of ECMO strategies with AKI and clinical outcomes.Finally, we included 1-year follow-up to assess the long-term major outcomes of ECMO and AKI.However, our study possesses several limitations.First, this study was a single-center retrospective study subject to all associated biases common to historical cohort studies.Due to the study design, we cannot assert a causal relationship in our findings, and the results only indicate correlations for hypothesis generation.Second, all included patients were adults, and findings cannot be extended to the pediatric population.Third, the sample size, particularly VV-ECMO, was low.In addition, information regarding the ECMO indication was missing from our database.Finally, as we excluded patients with CKD, future studies may need to explore the role of chronic kidney disease in the relationship between ECMO and AKI.

Conclusion
AKI among ECMO patients is very common.As ECMO patients' mortality is often related to cardiorespiratory failure or other ECMO-related complications, we did not find any association between AKI and mortality in this cohort.Hospital length of stay and duration of mechanical ventilation were longer in those with AKI than in those without AKI.All of these findings need further prospective investigations.

Figure 2 .
Figure 2. In-hospital mortality based on groups.

Figure 3 .
Figure 3.The association between AKI and ECMO based on the type of ECMO support (VV vs. VA).

Table 1 .
Baseline characteristics and outcomes based on the timing of AKI.CCI Charlson Comorbidity Index, APACHE Acute Physiology, and Chronic Health Evaluation, SOFA Sequential Organ Failure Assessment, ECMO extracorporeal membrane oxygenation, HR heart rate, RR respiratory rate, MAP mean arterial pressure, SPO 2 oxygen saturation by pulse oximetry, IVIG intravenous immunoglobulin, NSAIDs non-steroidal antiinflammatory drugs, PPI proton pump inhibitor, DIC diffuse intravascular coagulation, ICU intensive care unit, MV mechanical ventilation.

Table 2 .
The association between groups and in-hospital mortality.This table includes two separate models.The first model compares in-hospital mortality among patients with AKI before ECMO (group 1) to the other groups.The second shows the risk of in-hospital mortality after developing AKI in the subset of patients that did not have AKI before ECMO.

Table 3 .
Frequency of de Novo CKD in survivors and ECMO-liberated.

Table 4 .
Outcomes based on the temporal relationship between AKI and ECMO.

Table 6 .
The association between initiation of diuretics and urine output in oliguric AKI patients.