Clinical characteristics and factors associated with acute kidney injury among patients hospitalized with coronavirus disease: an observational retrospective study

ABSTRACT BACKGROUND: Coronavirus disease 19 (COVID-19) is a multisystemic disease with high incidence of acute kidney injury (AKI). OBJECTIVE: To describe the clinical characteristics and factors associated with AKI among patients hospitalized with COVID-19. DESIGN AND SETTING: Retrospective cohort conducted at Hospital Civil de Culiacan, Mexico. METHODS: We included 307 patients hospitalized due to COVID-19. AKI was defined and staged based on serum creatinine levels in accordance with the criteria of the Acute Kidney Injury Network (AKIN). Multivariate logistic regression analysis was used to determine factors associated with AKI. RESULTS: The patients’ age was 56 ± 15 years (64.5% male). The incidence of AKI was 33.6% (n = 103). Overall, 53.4% of patients had community-acquired AKI, and 46.6% had hospital-acquired AKI. Additionally, 15.5% of them presented AKIN stage 1; 34% had AKIN stage 2; and 50.5% had AKIN stage 3. Hemodialysis was required for 10.7% of the patients. The factors associated with AKI were chronic kidney disease (odds ratio, OR: 10.8; P = 0.04), use of norepinephrine (OR: 7.3; P = 0.002), diabetes mellitus (OR: 2.9; P = 0.03), C-reactive protein level (OR: 1.005; P = 0.01) and COVID-19 severity index based on chest tomography (OR: 1.09; statistical trend, P = 0.07). Hospital stay (11 ± 7 days; P < 0.001) and mortality (83.5 versus 31.4%; P < 0.05) were greater among patients with AKI. CONCLUSION: AKI was a frequent and serious complication in our cohort of patients hospitalized with COVID-19, which was associated with high mortality and long hospital stay.

(ferritin, D-dimer and C-reactive protein [CRP]) and severity (partial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2] and Sequential Organ Failure Assessment [SOFA] score). 3,7,9 OBJECTIVE Because of the limited information published on this topic in Mexico, the main objective of our study was to describe the clinical presentation, associated factors and prognosis of AKI among patients hospitalized for COVID-19 in this country.

Study design and population
This was a single-center, retrospective and observational cohort study.
The study protocol was reviewed and approved (registration number: We included 307 patients hospitalized due to severe COVID-19 in the internal medicine service between March 18, 2020, and September 11, 2020. Patients older than 18 years of age, of both sexes, and patients with a diagnosis of severe COVID-19 were included. Pregnant women, patients with end-stage CKD, patients on chronic dialysis (hemodialysis or peritoneal dialysis) prior to admission, patients hospitalized for less than 24 hours, cases of mild/moderate COVID-19 and those with incomplete collection of data on the variables studied were excluded (Figure 1).

Data collection and definitions
Clinical variables (age, sex, comorbidities, oxygen saturation and type of respiratory support), radiological variables (severity index based on chest computed tomography [CT]) and laboratory variables (glucose, urea, creatinine, hematic biometry, sodium, potassium, arterial blood gas, CRP, ferritin serum, D-dimer and procalcitonin) were collected at admission and during hospitalization every 24 to 48 hours. The definitive diagnosis of COVID-19 was integrated based on the polymerase chain reaction test results, chest CT findings and serum levels of CRP, ferritin, D-dimer and procalcitonin. AKI was diagnosed and staged at admission (community-acquired AKI [C-AKI]) or during hospitalization (hospital-acquired AKI [H-AKI]) based on the serum creatinine level, in accordance with the criteria of the Acute Kidney Injury Network (AKIN). 10 The type of AKI (C-AKI/H-AKI), dialysis requirement and evolution (transitory AKI, persistent AKI or acute kidney disease [AKD]) of each episode of AKI were studied in accordance with the criteria of the Acute Disease Quality Initiative. 11 Transitory AKI was defined as a complete reversal of AKI in accordance with Kidney Disease Improving Global Outcomes  (KDIGO) criteria within 48 hours of AKI onset. Persistent AKI was defined as continuance of AKI, using serum creatinine criteria, beyond 48 hours after AKI onset. AKD was defined as a condition in which AKI stage 1 or greater was present for ≥ 7 days after an AKI-initiating event. Kidney recovery was defined as a return to baseline creatinine. CKD was defined in accordance with the KDIGO CKD guidelines, based on previously documented findings or during the evaluation for COVID-19. Oliguria was defined as urinary output < 400 ml/day at AKI diagnosis. The impact of AKI on prognosis was studied by comparing mortality and hospital stay (in days) between patients with and without AKI.

Statistical analysis
Descriptive statistics with means/standard deviations or median/ interquartile range were used to describe continuous variables according to distribution data; and frequencies and proportions were used to describe categorical variables. Comparisons between pairs of groups were performed using Student's t test or the Mann-Whitney U test for continuous variables according to distribution data; and the χ 2 test was used for categorical variables.
Comparisons between more than two groups were performed using the Kruskal-Wallis test.
The clinical impact of AKI was evaluated based on in-hospital mortality and the length of hospital stay. Factors associated with the development of AKI were analyzed using multivariate logistic regression analysis. All clinically relevant variables with P-values < 0.05 in bivariate analysis were included for entry into multivariate modeling. Differences were considered statistically significant at P < 0.05.
Data analysis was performed using the IBM SPSS Statistics software for Macintosh, version 22.0 (IBM Corp., Armonk, New York, United States). No formal sample size calculation was carried out, because of the observational and convenience-sampling nature of the study.

General characteristics of the population studied
During the study period, 777 patients were treated for COVID-19 in our hospital, of whom 443 were treated on an outpatient basis and 334 required hospitalization in the internal medicine service. Among the latter patients, who were assessed for eligibility, three patients were excluded because they were younger than 18 years of age and another 24 adult patients were excluded (five who were hospitalized for less than 24 hours and 19 whose data were incomplete). Therefore, 307 patients were included in the final analysis of our study (Figure 1).
The remaining characteristics are shown in Table 1.
At the time of hospital discharge or death, only 35.9% (n = 37) of the patients with AKI had achieved recovery of kidney function. On the other hand, 25.2% (n = 26) of the patients had transitory AKI, 36.9% (n = 38) had persistent AKI and 37.9% (n = 39) had AKD.
In comparing the characteristics according to the type of AKI (transitory AKI, persistent AKI and AKD), we observed that the frequency of oliguria was higher among patients with AKD than among those with either transitory AKI or persistent AKI (65.6% versus 29.6% versus 13.3%, respectively; P < 0.001). The frequency of AKIN 3 episodes was also higher among patients with AKD than among those with either persistent AKI or transitory AKI (72.1% versus 33.3% versus 14.8%, respectively; P < 0.001). In contrast, the frequency of AKIN 1 episodes was higher in patients with transitory AKI than among those with either persistent AKI or AKD (44.4% versus 20% versus 3.3%, respectively; P < 0.001).
Recovery of kidney function was more frequent among patients with transitory AKI than among those with either persistent AKI or AKD (85.2% versus 60% versus 4.9%, respectively; P < 0.001).
There were no statistically significant differences in the frequency of hemodialysis between patients with transitory AKI, persistent AKI or AKD (7.4% versus 0% versus 14.8%, respectively; P = 0.253).
On the other hand, the frequencies of use of invasive mechanical ventilation (65% versus 20.1%; P < 0.05) and use of norepinephrine (56.3% versus 10.8%; P < 0.05) were also higher among patients with AKI than among those without.   Table 3. Comparison of clinical and laboratory characteristics at admission between patients with and without acute kidney injury (AKI) IQR = interquartile range; SD = standard deviation; CT = chest tomography; PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen.  We did not observe any statistically significant differences in relation to age, comorbidities, disease severity markers, severity of AKI episodes, dialysis requirement or recovery of kidney function, between the C-AKI and H-AKI groups ( Table 4).

Factors associated with development of AKI among patients hospitalized due to COVID
In our study, the factors independently associated with AKI were as follows: previous diagnosis of CKD (odds ratio, OR: 10.8;  Table 5).

Clinical impact of AKI on the prognosis of patients hospitalized due to COVID-19
Overall mortality was 48.9% (n = 150), and this was higher among patients with AKI than in those without AKI (83.5% versus 31.4%; P = 0.001). No statistically significant difference in mortality was observed between patients with C-AKI and those with H-AKI (80% and 87.5%, respectively; P = 0.42). On the other hand, the median length of hospitalization in our population was 8 days (range: 3-15 days), which was longer among patients with AKI than among those without AKI (11 versus 7 days; P < 0.001), but not between patients with H-AKI and those with C-AKI) (8 versus 8 days; P = 0.918).
In comparing mortality according to the type of AKI (transitory AKI, persistent AKI and AKD), we observed that, among these three types, mortality was only higher among patients with AKD (74.1% versus 66.7% versus 91.8%, respectively; P < 0.015).
No statistically significant difference in the length of hospitalization was observed between patients with transitory AKI, persistent AKI and AKD (15 versus 10 versus 10 days, respectively; P = 0.285). Table 4. Comparison of clinical and laboratory characteristics at admission between patients with community-acquired acute kidney injury (C-AKI) and those with hospital-acquired acute kidney injury (H-AKI) IQR = interquartile range; SD = standard deviation; NIV = noninvasive ventilation; IV = invasive ventilation; AKIN = acute kidney injury network. PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen. * Serum creatinine at the time of AKI diagnosis.

Variables C-AKI (n = 55) H-AKI (n = 48) P n/median %/IQR n/median %/IQR General characteristics:
Age ( 9 Another important finding from our study was that AKIN stage 3 of AKI occurred most frequently, followed by stage 2 and stage 1, which indicates that AKI was a frequent and serious com- In our population, the overall frequency of dialysis required was 10.7%, with no statistically significant difference between the C-AKI and H-AKI groups. The frequency reported by other researchers has varied widely worldwide, from 0.4% to 22.3%. 3,8,15 This variability in dialysis requirement worldwide could partly be explained by differences in the severity of AKI episodes and the clinical context studied, as well as in the availability and prioritization of dialysis treatment assignments during the pandemic, due to oversaturation of medical services and the poor progno- The overall fatality rate in our population was 48.9%, and it was higher among patients with AKI than among those without AKI. In addition, the median hospital stay was longer among patients with AKI than among those without AKI. It has been consistently demonstrated that AKI has a negative impact on the prognosis of patients hospitalized due to COVID-19 and is associated with a long hospital stay, high mechanical ventilation requirements and fatality. In a meta-analysis on 40 studies with 24,527 patients, Shao et al. reported that the overall fatality rate was 20.3%, and that it was higher among patients with AKI than among those without AKI (63.1% versus 12.9%; P < 0.01), with an OR for mortality of 14.6 (95% CI: 9.94-21.5; P < 0.00001). 8 On the other hand, similar to the findings of Martínez-Rueda et al., 9 we did not observe any statistically significant difference in mortality between patients with C-AKI and those with H-AKI. However, our fatality rate was above the overall fatality rate (48.9% versus 27%), C-AKI fatality rate (80% versus 53%) and H-AKI fatality rate (87.5% versus. 50%) reported by Martínez-Rueda et al. 9 The great variability in the prognosis of these patients observed worldwide might be partially explained by differences in the severity of the patients' conditions, the clinical contexts studied, the hospital resources and infrastructure and the availability of trained and specialized personnel for caring for these patients, among different hospitals during the pandemic. The present study had some limitations. Firstly, it was a retrospective study conducted in a single center. Therefore, it was not possible to include the criterion of urinary volume for diagnosing AKI, which could have underestimated the frequency of AKI in our population. Moreover, the precise cause of each AKI episode could not be determined. Secondly, we did not include variables relating to treatment in our analysis because of the great variability and modifications of the drugs used during the pandemic. Lastly, it was not possible to construct a specific logistic regression model of factors associated with C-AKI and H-AKI because of the small number of cases. Nevertheless, despite these deficiencies, we believe that the results from our study are valid and useful for improving the characterization of AKI episodes among patients hospitalized due to COVID-19.

CONCLUSION
AKI was a frequent and serious complication in our cohort of patients hospitalized due to COVID-19, which was associated with high mortality and long hospital stay. This highlights the importance of close nephrological surveillance for early detection of patients at high risk of developing AKI.