Case fatality rate among COVID-19 patients treated with acute kidney replacement therapy

Abstract Introduction: Acute kidney injury (AKI) is a frequent complication of severe COVID-19 and is associated with high case fatality rate (CFR). However, there is scarcity of data referring to the CFR of AKI patients that underwent kidney replacement therapy (KRT) in Brazil. The main objective of this study was to describe the CFR of critically ill COVID-19 patients treated with acute kidney replacement therapy (AKRT). Methods: Retrospective descriptive cohort study. We included all patients treated with AKRT at an intensive care unit in a single tertiary hospital over a 15-month period. We excluded patients under the age of 18 years, patients with chronic kidney disease on maintenance dialysis, and cases in which AKI preceded COVID-19 infection. Results: A total of 100 out of 1479 (6.7%) hospitalized COVID-19 patients were enrolled in this study. The median age was 74.5 years (IQR 64 – 82) and 59% were male. Hypertension (76%) and diabetes mellitus (56%) were common. At the first KRT prescription, 85% of the patients were on invasive mechanical ventilation and 71% were using vasoactive drugs. Continuous veno-venous hemodiafiltration (CVVHDF) was the preferred KRT modality (82%). CFR was 93% and 81 out of 93 deaths (87%) occurred within the first 10 days of KRT onset. Conclusion: AKRT in hospitalized COVID-19 patients resulted in a CFR of 93%. Patients treated with AKRT were typically older, critically ill, and most died within 10 days of diagnosis. Better strategies to address this issue are urgently needed.

Introduction: Acute kidney injury (AKI) is a frequent complication of severe COVID-19 and is associated with high case fatality rate (CFR).However, there is scarcity of data referring to the CFR of AKI patients that underwent kidney replacement therapy (KRT) in Brazil.The main objective of this study was to describe the CFR of critically ill COVID-19 patients treated with acute kidney replacement therapy (AKRT).Methods: Retrospective descriptive cohort study.We included all patients treated with AKRT at an intensive care unit in a single tertiary hospital over a 15-month period.We excluded patients under the age of 18 years, patients with chronic kidney disease on maintenance dialysis, and cases in which AKI preceded COVID-19 infection.Results: A total of 100 out of 1479 (6.7%) hospitalized COVID-19 patients were enrolled in this study.The median age was 74.5 years (IQR 64 -82) and 59% were male.Hypertension (76%) and diabetes mellitus (56%) were common.At the first KRT prescription, 85% of the patients were on invasive mechanical ventilation and 71% were using vasoactive drugs.Continuous venovenous hemodiafiltration (CVVHDF) was the preferred KRT modality (82%).CFR was 93% and 81 out of 93 deaths (87%) occurred within the first 10 days of KRT onset.Conclusion: AKRT in hospitalized COVID-19 patients resulted in a CFR of 93%.Patients treated with AKRT were typically older, critically ill, and most died within 10 days of diagnosis.Better strategies to address this issue are urgently needed.

IntRoductIon
COVID-19 is a coronavirus disease caused by the SARS-CoV-2 virus, whose dissemination began in the Chinese province of Wuhan in late 2019 1 .The renal system is seriously impacted by this illness, especially in symptomatic cases, as reflected by the fact that 25% of these patients present with abnormal serum creatinine at hospital admission 2 .
The incidence of AKI in COVID-19 varies significantly across studies, ranging from 4 to 75% 24- 30 .However, the largest study we found estimated that approximately one-third of hospitalized patients develop this condition 24 .Of these, around 14% require kidney replacement therapy (KRT).Therefore, the incidence of patients treated with acute kidney replacement therapy (AKRT) is around 5% of all hospitalized COVID-19 patients 24 .In patients admitted only to an intensive care unit (ICU), AKRT is used in 20% of the patients 25 .Risk factors for use of AKRT included male sex, hypertension, diabetes mellitus, chronic kidney disease (CKD), elevated body mass index, high levels of D-dimer and greater severity of hypoxia at admission 25 .
In general, around two in every three patients with COVID-19 that are treated with AKRT expire 25,31 .Additionally, AKRT is considered a risk factor for death in ICU patients 30 .Case fatality rate (CFR) falls to approximately 35% when AKI is managed conservatively, considering both KRT and non-KRT cases 24 .Predictors of 28-day mortality in AKRT include advanced age and severe oliguria 25 .We were able to find two Brazilian studies addressing AKI mortality in COVID-19.The study by Zamoner et al. 30 , set in the state of São Paulo (southeastern region of Brazil), found a CFR of 88% in AKRT patients.The research conducted by Samaan et al. 28 , also in São Paulo (southeastern region of Brazil), evaluated AKRT mortality in COVID-19 and reported that 72.5% of the patients expired.Therefore, there is a significant gap in the Brazilian literature regarding mortality in COVID-19-associated AKRT, especially in patients from the northeastern region of Brazil.
The main objective of this study was to determine the CFR of AKRT in COVID-19 patients admitted to an ICU.Our secondary goals were to explore independent predictors of mortality, identify the median survival time of AKRT patients, and calculate the incidence of AKRT in a hospital setting.

Design anD sample
This was an analytical retrospective cohort study.We included all patients with COVID-19 and AKRT admitted to the intensive care unit of a single tertiary hospital in the city of Salvador, Bahia, Brazil, between the 1 st of April 2020 and the 20 th of July 2021, including immunosuppressed and transplanted patients.Pregnant women were not included in this study.A COVID-19 diagnosis required a positive reverse transcription polymerase chain reaction.We excluded patients under the age of 18 years, patients with stage 5 CKD on maintenance dialysis, and cases in which AKI preceded COVID-19 infection.

Data ColleCtion
Initially, the Information and Technology (IT) Department of the hospital released an Excel sheet with all patients diagnosed with COVID-19 that were admitted to the institution between the 1 st of April, 2020, and the 20 th of July, 2021; the sheet also contained information on whether or not the patient was prescribed AKRT during the hospitalization.Thereafter, we performed a thorough review of electronic medical records of the patients who were prescribed AKRT and applied exclusion criteria.For eligible patients, data were extracted from electronic medical records during August and September 2021.

statistiCal analysis
Independent categorical variables were described in absolute and relative frequencies, while numeric ones were classified as normal or skewed according to the Kolmogorov-Smirnoff test.Normally distributed numeric variables were described using mean and standard deviation (SD), while skewed numeric variables were summarized using median and interquartile range (IQR).The Kaplan-Meier estimator was used to report the survival function of the sample.
For the analysis of prognostic markers, patients were divided into two groups according to their life status at discharge (alive or expired).Univariate analysis for the association between death and independent variables involved the use of Fisher's exact test, Student's t-test, and Mann-Whitney U-test.Multivariate analysis was not possible due to a large discrepancy between the size of the expired alive groups.Variables with 5% or more of missing data were excluded from the analysis of risk factors for death.All statistical tests were performed on the Statistical Package for the Social Sciences (SPSS), version 14.0.

Results
A total of 1,479 patients were admitted to the institution between the 1 st of April, 2020, and the 20 th of July, 2021, due to COVID-19.Among these, 126 had at least one AKRT prescription.After applying exclusion criteria, 26 individuals were excluded, leaving 100 (6.7%) AKRT patients for analysis (Figure 1).
Most patients were male (59%) and had a median age of 74.5 years (IQR 64 -82).Among the comorbidities surveyed, systemic arterial hypertension (76%) and diabetes mellitus (44%) were the most common (Table 1).About 85% of the patients were under invasive mechanical ventilation (IMV) at the time of first AKRT prescription, and remained on this treatment for a median of 11 days (IQR 8 -15).Moreover, 71% of patients were under the use of at least one vasoactive drug such as norepinephrine or dobutamine.The most used KRT modality was continuous veno-venous hemodiafiltration (CVVHDF), followed by sustained low-efficiency dialysis (SLED), and conventional hemodialysis.Only 6% of all patients discontinued KRT before either death or hospital discharge (Table 2).
Laboratory studies before the first KRT session are shown in Table 3. Complete blood count alterations included decreased values of hemoglobin (mean of 10.2 mg/dL, SD ± 2.2), hematocrit (mean of 30.2%,SD ± 6.7) and leukocytosis (median of 18,660/mm 3    The CFR was 93%.When we analyzed the survival function of our sample, we found that nearly all deaths occur in the first twenty days of AKRT onset.The first ten days of AKRT onset were decisive for either expiration or discharge for 85% of our patients.This results in a short median time of AKI duration (4 days, IQR 2 -8).The cumulative survival is shown in Figure 2.
Univariate analysis showed an association between death and the following variables: time spent in the ICU (p = 0.005), AKI duration (p = 0.000), use of conventional hemodialysis (p = 0.028), use of SLED (p = 0.002), KRT discharge (p = 0.000), ionized calcium (p = 0.042), C-reactive protein (p = 0.05), and troponin I (p = 0.043).As previously established, these variables were included in a multivariate logistic regression model for analysis of independent association with death (p < 0.05, but no independent association was found.The full univariate analysis is shown in Table 4.

dIscussIon
In this sample of elderly, critically ill patients with COVID-19 who were treated with AKRT, in-hospital CFR was 93%, and most patients died within 10 days of diagnosis.This finding highlights how AKRT is a marker of severe illness and that healthcare professionals must be aware of the grave prognosis it implies.
The mortality in our study was higher than that of similar studies 25,28,30,31 .Gupta et al. 25 conducted a multicenter cohort study of 3099 patients with critical COVID-19 that required ICU care within 67 hospitals across the United States of America, which found a CFR of 63% among AKRT patients.Zamoner et al. 30 conducted a single-center, prospective, observational study in a public and tertiary university hospital in the city of São Paulo, consisting of 101 patients hospitalized with COVID-19.They found a CFR of 88% in AKRT patients.Samaan et al. 28 conducted a multicenter, retrospective, observational study in 13 ICUs in the metropolitan region of the municipality of São Paulo, Brazil, consisting of 375 patients with AKRT associated with COVID-19.Their CFR was 72.5%, which can also be considered high, but lower than ours.The reasons for the difference between the studies are discussed in the following paragraphs.
The patients in our sample were predominantly elderly men with high prevalence rates of relevant comorbidities for COVID-19, especially systemic arterial hypertension (76%) and diabetes mellitus (44%).This shows that AKRT is used in COVID-19 patients with an already compromised health condition, including systemic diseases that may directly affect kidney function.Other studies had similar frequency of the aforementioned comorbidities, but their samples consisted of individuals with a median age younger than ours.Gupta et al. 25 , for instance, studied patients with a median age of 62 years (IQR 51 -71); Zamoner et al. 30 analyzed AKI patients with an average age of 61 ± 14.5 years.Samaan et al. 28 analyzed individuals with a median age of 64 years (IQR 55 -74), whereas in our study the median age was 74.5 years (IQR 64 -82).Prevalence rates for hypertension and diabetes in study were similar to those in the studies conducted by Zamoner et al. 30 , Gupta et al. 25 , and Samaan et al. 28 , except for diabetes mellitus frequency in Zamoner et al. 30 , which was only 7% of AKI patients.
We did not notice any considerable differences between our patients and those in the studies conducted by Zamoner et al. 30 and Samaan et al. 28 regarding severity of illness assessed by the use of mechanical ventilation and vasopressors, but Gupta et al. 25 had a sample that can be considered less critical  than ours.Zamoner et al. 30 reported that 76% of the AKI patients required IMV, similar to the percentage of individuals who were treated with vasoactive drugs.Samaan et al. 28 found an 88.5% rate of IMV and an 85% of vasoactive drug use.The American research had a similar rate of IMV (79%), but a considerably lower rate of vasoactive drug use (51%).
We have also found high mean or median levels of serum urea, creatinine, phosphorus, lactate, D-dimer, and C-reactive protein (CRP).The American study also showed higher levels of D-dimer and C-reactive protein, but lower values of serum creatinine.The latter also implies that our patients had worse renal function in comparison to this other research, as our patients were both older and had higher levels of serum creatinine.
As previously discussed, we found an overall hospital incidence of AKRT in COVID-19 patients of 6.7%.Considering the pandemic status of SARS-CoV-2 infection and the sheer number of COVID-19 cases, this may translate into a significant burden on nephrology services.These statistics might prove helpful for hospital administrators in planning and calculating the need for dialysis-related supplies.The only other study we were able to find that calculated the incidence of AKRT in all hospitalized patients found a frequency of 5.2%, a result we considered similar to ours 24 .In ICUs, the incidence varies from 15 to 20% of admitted patients, who frequently have predisposing conditions that lead to AKRT, like multiple organ dysfunction, shock, and cytokine release syndrome 25,28 .A systematic review with meta-analysis found an overall incidence of 9%, considering both the overall hospital admissions and ICU admissions 29 .
As far as we know, our study is the first to include a survival analysis of AKRT patients associated with COVID-19 in a hospital setting.We used the Kaplan-Meier estimator for graphical representation of survival over AKI duration in days.The median survival time of our patients was considerably short, which shows the critical state of our sample and the severity of AKI within the COVID-19 disease spectrum, specifically when treated with KRT.This reinforces the need for prevention of kidney dysfunction in moderate to severe cases of COVID-19 since it is a severe and life-threatening condition.Samaan et al. 28 also found an AKI duration of 3 days for the patients who did not survive, which is identical to the findings of our study (3 days).Our group of non-expired individuals, however, revealed a median AKI duration of 23 days, while the group of surviving patients in the other study had a median AKI duration of 15 days.This difference can also be explained by the critical state of our sample.
As previously stated, the majority of patients expired.In univariate analysis, we found an association between survival and shorter ICU stay (p = 0.005), shorter AKI duration (p < 0.001), use of conventional hemodialysis (p = 0.028) and/or SLED (p = 0.002), KRT discharge (p < 0.001), levels of ionized calcium (p = 0.042), and lower levels of CRP (p = 0.005) and troponin I (p = 0.043).These results are biologically plausible and reasonable, as less time spent in ICU correlates with both lower frequency of hospital-related health problems and a lower severity of disease.Additionally, longer duration of AKI and absence of KRT discharge indicate severe kidney dysfunction and an overall more critical state of the disease.The use of intermittent hemodialysis (both conventional and SLED) also relates to survival because these patients tend to be more hemodynamically stable compared with those under CVVHDF.Finally, higher levels of CRP and troponin I suggest a more intense pro-inflammatory state and cardiac dysfunction, respectively.
We did not find any factors independently associated with death among COVID-19-associated AKRT.This could be explained by an insufficient sample size and considerable quantitative differences  25,31 .Our research had several limitations.First, it was a retrospective review from a single center.Second, although we screened almost 1500 patients with COVID-19, our data is limited to the 100 patients who required AKRT; this relatively small sample size decreased the precision of our findings and hampered our evaluation of prognostic factors.Third, some of the variables studied were not uniformly registered in patients' charts.Variables that were missing 5% or more of the information were excluded from the analysis.These variables were proteinuria, hematuria, and urinary casts (29% of missing data), 12-hour urine output (24%), and liver enzymes (14%).We also did not formally evaluate patients' immune status and personal history of immunosuppression or transplantation but our sample had 44% of patients with diabetes, 12% with malignancy, and 4% with rheumatic diseases that probably had some degree of immunosuppression (due to underlying disease and/or its treatment), which could have contributed to the high mortality observed in this study.We also did not provide severity scores such as APACHE-II and SOFA; instead, we used need for vasoactive drugs and IMV as markers of disease severity.Finally, we did not have data on the indications for AKRT.
Nevertheless, this study provides important descriptive information regarding the incidence and CFR of AKRT in COVID-19 patients, a subject which has not been thoroughly researched.Moreover, as far as we know, this is the first study to evaluate this clinical condition in the state of Bahia, Brazil.Other similar studies have been conducted in Brazilian territory, but in a different population, specifically from the state of São Paulo.The publication of similar studies from different parts of our country would result in a better understanding of the actual incidence and mortality of AKRT in COVID-19 throughout Brazil.

conclusIon
AKRT was used in 6.7% of patients hospitalized with COVID-19, 93% of which expired.AKRT patients were typically older, critically ill, and most died within 10 days of diagnosis.This finding shows that AKI, especially when KRT is needed, is a serious complication of SARS-CoV-2 infection and should not be overlooked by health services and that better strategies to address this issue are urgently needed.
This study was in accordance with the Declaration of Helsinki and with the resolution 466 of the National Ethics Committee for Research of Brazil (CONEP) and was approved by the Institutional Review Board of the Bahiana School of Medicine and Public Health on the 19 th of May 2021.

Figure 1 .
Figure 1.Application of the inclusion and exclusion criteria.KRT: Kidney replacement therapy.CKD: chronic kidney disease.AKRT: acute kidney replacement therapy.RT-PCR: reverse transcription polymerase chain reaction.