Differences between COVID-19-induced acute kidney injury and chronic kidney disease patients

Abstract Introduction: This article describes the main differences between COVID-19-induced acute kidney injury (AKI-COVID19) in patients with previous normal renal function (AKI-NRF) and those with chronic kidney disease (AKI-CKD) treated in a high complexity clinic in Barranquilla (Colombia). Material and Methods: The patients included in this study (n: 572) were those with a positive diagnosis of COVID-19 confirmed by detection of a positive PCR for SARS-CoV-2. Of these patients, 188 developed AKI during their hospital stay. Patients’ epidemiological data, serum parameters, and clinical frailty status were recorded. Statistical analysis and comparison among AKI-NRF, AKI-CKD, and non-AKI patients were performed. Results: The incidence of COVID-19-induced AKI was 33%, with the majority classified as AKIN 1, 16% requiring renal replacement therapy, and AKI-COVID19 mortality of 68%. A significantly higher prevalence of hypertension, cardiac disease, and serum reactive C-protein and lower albumin values in AKI-CKD patients was recorded. Mortality rate, invasive ventilation requirement, and D-dimer levels were significantly higher in AKI-NRF patients: Conclusion: Different clinical patterns between AKI-NRF and AKI-CKD were documented.


IntroductIon
In late 2019, a new type of acute respiratory insufficiency was described in Wuhan, China. It was later found to be caused by a new variety of coronavirus (SARS-CoV-2), and the disease which it caused was named COVID-19 1,2 . Even though COVID-19 affects mostly the patient's respiratory system, this condition can also alter other organs such as kidneys, intestines, bone marrow, heart, and nervous system 3 .
Likewise, AKI-COVID19 has been reported to occur mainly in critically ill patients, in whom it is an additional factor for poor prognosis, increasing mortality by up to 92% [6][7][8] . Among the risk factors favoring its appearance are the presence of oncologic disease, sepsis, heart failure, and DIC 8 . However, as far as we know, the literature has not yet described whether there are differences between AKI-COVID19 in patients without previous kidney disease and those with CKD. Thus, it was decided to perform a prospective study with the objective of exploring whether there was a significant difference in inflammatory response and mortality between de novo AKI COVID-19 patients and AKI COVID-19 patients, who previously suffered from CKD, who were assisted during the first pandemic wave (2020) in the Clínica de la Costa, Barranquilla (Colombia).

MaterIal and Methods
This was a prospective observational study with patients treated at the emergency room in the Clínica de la Costa, Barranquilla (Colombia) from April 01 to July 11, 2020 due to suspicion of COVID-19. Patients with confirmed COVID-19 diagnosis by positive polymerase chain reaction (PCR) test were included in the study. Additionally, data from admitted COVID-19 patients who developed AKI during their admission was collected in an electronic record specifically designed for this purpose. The AKI patient group was divided into two subgroups: those who had previous normal renal function (AKI-NRF) and those who had previous chronic kidney disease (AKI-CKD). CKD diagnosis was obtained from the patient's electronic clinical record, confirmed by at least one of the following chronic kidney alterations: reduced glomerular filtration rate (≤ 90 mL/min/1.73 m 2 ) with abnormal urinalyses (dysmorphic hematuria, and/or proteinuria), and/or abnormal renal ultrasound (multiple cysts, kidney size reduction, parenchymal hyperechogenicity, renal cortex-medulla border loss) 12 .
Finally, clinical and biochemical parameters were compared among AKI-NRF, AKI-CKD, and NON-AKI patients, represented by those individuals who did not suffer from AKI.
Sample handling and processing for SARS-CoV-2 diagnosis were conducted in accordance with the reverse transcription real-time PCR (RT-PCR) guidelines (Diagnostic detection of 2019-nCoV by realtime RT-PCR Charité Virology, Berlin, Germany) 10 .
People with previous normal kidney function were defined as those with normal glomerular filtration rate (> 90 mL/min/1.73 m 2 ), normal urinalysis, normal renal ultrasound and no personal history of renal disease at admission. AKI in people with previous normal function was defined as an increase in creatininemia of >0.3 mg/ dL compared with their basal serum creatinine value at admission. In addition, each documented episode of AKI was classified according to the AKIN criteria ( Table 1) 11 . AKI in individuals previously diagnosed with CKD was defined as an increase in creatininemia of ≥ 1.5 times respect compared with their basal serum creatinine value at admission 11 .
NON-AKI individuals were defined as admitted patients with no AKI, AKI-NRF, or AKI-CKD during their admission.
The following parameters were obtained daily from each patient during his/her hospitalization: serum creatinine, urea, electrolytes, blood count, bilirubin, transaminases, lactate dehydrogenase (LDH), troponin, C-reaction protein (CRP), ferritin, D-dimer, and coagulation parameters: partial thromboplastin time (PTT), prothrombin time (PT), and international normalized ratio (INR). In addition, presence of proteinuria, hematuria, and/or leukocyturia, as well as the degree of pre-existing frailty status by the Clinical Frailty Scale (CFS) were also documented ( Table 2) 12 .

1-Very fit
Robust, active, energetic, and motivated persons. These persons commonly exercise regularly. They are among the most fit for their age.

2-Well
Persons who have no active diseases and no symptoms, but who are less fit than those in the previous category. They often exercise or are very active from time to time.

3-Managing well
Persons whose medical problems are well controlled but are not regularly active beyond routine walking.

4-Vulnerable
While not dependent on others for daily help, their symptoms often limit activities. A common complaint is being "slowed up" and/or being tired during the day.

5-Mildly frail
These persons often have more evident slowing and need help with more complex activities (managing their finances, medicines, transportation, and heavy housework).

6-Moderately frail
These persons need help with all outdoor activities. Indoors, they need help with cleaning and often have problems climbing stairs. They also need help bathing and may need minimal assistance to get dressed.

7-Severely frail
Completely dependent for personal care either due to physical or cognitive reasons. Even so, they seem stable and not at high risk of dying.

8-Very severely frail
Completely dependent, and close to the end of their life (within 6 months).

9-Terminally ill
Approaching the end of life. This category applies to anyone with a life expectancy <6 months, who is not evidently fragile.
The quantitative variables were summarized as mean and standard deviation (SD) or median and interquartile range. Qualitative variables were summarized as absolute and percent relative frequencies.
Comparisons of quantitative variables between groups defined by the presence of kidney injury were carried out using the ANOVA test for comparison of means in independent samples or the Mood test for comparison of medians. Comparison of qualitative variables was carried out using the Chi-Square association test or Fisher's exact test. The magnitude of associations and correlations were determined using Pearson's linear correlation coefficient, Kendall's tau coefficient, or odds ratios, depending on the type of variables analyzed. Associated probability values less than 0.05 were considered statistically significant.
The statistical software used for this analysis was R Foundation for Statistical Computing, version 4.0.1; Vienna, Austria.
This study was approved by the Ethical Committee of Clinica de la Costa, Barranquilla (Colombia), and informed consent was obtained from all patients.
The prevalence of hypertension and cardiac disease was significantly higher in the AKI-CKD group compared with the AKI-NRF group, and even higher compared to the NON-AKI group (Table 3). However, there was a higher mortality rate in the AKI-NRF group (69%) compared with the AKI-CKD group (56%), but it did not reach statistical significance (p: 0.09). The mortality rate in the AKI group compared with the NON-AKI group (16%) was significantly higher (p: <0.0001).
Regarding artificial organ support requirement, invasive ventilation support was slightly more required in the AKI-NRF group compared with the AKI-CKD group (p: 0.05), but much more required compared with the NON-AKI group (p: <0.001). Conversely, non-invasive ventilation support was significantly more required in the NON-AKI group compared with the AKI-CKD and AKI-NRF groups (p: <0.001) ( Table 4).
There was no significant difference among the studied groups in laboratory parameters except for serum creatinine and urea levels at AKI diagnosis time, which showed the highest level in the AKI-CKD group, followed by the AKI-NRF group, and the lowest values were for the NON-AKI group (p: <0.001) ( Table 5).
Serum glucose and most inflammatory parameters (leucocytes, LDH, and ferritin) were significantly higher in AKI patients compared with NON-AKI patients. Serum CRP levels were slightly higher and albumin was lower in the AKI-NRF group than in the AKI-CKD group. Serum D-dimer was slightly higher in the AKI-NRF group than in the AKI-CKD group. The NON-AKI group showed significantly lower serum CRP and D-dimer, as well as higher serum albumin value compared with the AKI group (Table 5).

dIscussIon
In our study, AKI-COVID19 incidence was 33%, being 26% in previously normal kidney function individuals and 7% in CKD patients. As expected, most CKD patients who were affected by COVID-19 (91%) developed AKI, probably due to their increased susceptibility to kidney damage. AKI-COVID19  incidence in other reports ranges between 5 and 76%. This notorious difference could be due to diverse epidemiological characteristics (age, comorbidities, etc.) and disease severity (ambulatory, critical care, etc.) among the populations studied [13][14][15][16] . As reported in previous literature, AKI-COVID19 appeared within the first week of hospitalization in our study. 15 Likewise, its predominance in males and in older, frail, diabetic, obese, COPD individuals was also documented in other reports. 14. It has been suggested that these chronic inflammatory conditions contribute to the deleterious effect of the immune system overreaction (cytokine storm), which characterizes COVID-19 disease 9, [16][17][18][19][20][21][22] .
Increased serum interleukin-6, ferritin, transferrin, D-dimer, fibrinogen, and CRP are among the most documented characteristic of systemic inflammatory syndrome associated with SARS-CoV-2 acute infection. Ferritin is an intracellular iron storage protein that appears in blood during systemic stress and stimulates the innate immunity cells that trigger the cytokine storm. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] It is worth mentioning that hypertension and cardiac disease were significantly more common in the AKI-CKD group than in the AKI-NRF group. This phenomenon could be explained by the increased prevalence of hypertension and cardiopathy in CKD patients. In this sense, both conditions can induce kidney alteration (e.g., nephroangiosclerosis and cadiorenal syndrome, respectively) or be the consequence of excessive sodium retention and volume overload due to chronic nephropathy. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Furthermore, there was a trend toward higher mortality, higher need for invasive mechanical ventilation, higher serum inflammatory markers (CRP, ferritin, LDH, leukocytes) and serum D-dimer levels (a marker of thrombin generation and fibrinolysis related to endothelial damage) in the AKI-NRF group compared to the AKI-CKD group. At the same time, AKI-CKD patients had significantly higher renal replacement requirement than AKI-NRF (42 vs. 22%, respectively). This phenomenon could be explained by the following hypothesis: both AKI subgroups had similar advanced age, frailty and comorbidities, which explain their worse evolution compared with the younger, robust, and less comorbid individuals in the NON-AKI group. However, the relatively better evolution of the AKI-CKD patients compared with the AKI-NRF patients could be explained by their chronic immunosuppression status associated with chronic nephropathy, which could avoid hyperinflammatory reaction (cytokine storm); the cornerstone of COVID-19-induced damage. 38,39 Concerning the documented AKI subtype (AKIN) at the moment of renal injury diagnosis, the most prevalent class was AKIN 1 and the least frequent was AKIN 2, which is in line with some previous reports. However, other studies reported that AKIN 3 was the most common class, followed by AKIN 1. 14,15 This discrepancy could be attributed to different times of AKI stage at which the condition was diagnosed in each study, i.e., the earlier the diagnosis was made, the lower the reported AKIN score.
• Intra-renal obstruction: myoglobin (rhabdomyolysis). With regards to symptoms at admission, dyspnea and fatigue were more frequent among AKI patients, for both AKI-NRF (82%) and AKI-CKD (77%) compared with NON-AKI patients (47%). This could be explained by the appearance of worst lung COVID-induced compromise and/or lung congestion in AKI patients. The latter condition could be explained by inadequate volume retention secondary to reduced glomerular filtration rate.
Serum glucose and inflammatory (high serum leukocytes and ferritin levels) or cell destruction (high serum LDH level) parameters were significantly higher in AKI patients compared with NON-AKI patients ( Table 5). These findings are reasonable because, first diabetes mellitus was more prevalent in AKI patients and, second, the inflammatory status, represented by the presence of higher leucocyte, ferritin, and LDH levels, was probably worse in patients who developed AKI than in NON-AKI patients.
As expected, the NON-AKI group, which was the least sick, had the highest serum albumin levels and the lowest levels of serum inflammatory parameters, invasive MV requirement, and mortality.
COVID-19-associated mortality in AKI-NRF, AKI-CKD, and NON-AKI patients was 68.46, 55.81, and 15.49%, respectively. COVID-19 mortality in previous reports ranged from 16.1 to 62%. [13][14][15]24 In our study, the variables that showed a significant direct correlation with mortality secondary to COVID-19 were: age, frailty, and presence of AKI. Moreover, length of hospitalization was significantly longer in AKI patients than in NON-AKI patients (p: <0.0001). This findings could be explained by the fact that these patients require more time to cope with SARS-CoV-2 infection because of several reasons, such as insufficient immune response (ageing, frailty) and excessive inflammation (AKI).
Finally, the comparisons between AKI-NRF and AKI-CKD with a trend toward significance (borderline p-value) could be due to the relatively small number of CKD patients in this study (n: 43). Future studies could clarify the real significance of these findings.

conclusIon
This study reported a trend toward a higher inflammatory response and significantly higher mortality rate in de novo AKI in COVID-19 patients than in AKI COVID-19 patients who previously suffered from CKD.

acknowledgMents
The authors are grateful for the valuable collaboration of Zulay Mondol (MD), Carlos Caceres (MD), and William Riascos (MD).