Pharmacotherapeutic Evaluation of Covid-19 Patients Suffering from Acute Kidney Injury
Muhammad Osama Yaseen1, Misha Yaseen2, Tahir Mehmood Khan1,3*, Inayat Rehman4, Amal K. Suleiman5, Mirza Rafi Baig6, Ammar A. Jaber6, Ahmed Telb7, Farah Nofal Alnafoosi7
1Institute of Pharmaceutical Sciences, University of veterinary and Animal Sciences, Lahore, Pakistan. 2CMH Kharian Medical College, Kharian, Pakistan. 3School of Pharmacy, Monash University, Bandar Sunway, Selangor, Malaysia. 4Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan. 5College of Pharmacy, Faculty of Medicine, University of Almaarefa, Riyadh 11597 – Kingdom of Saudi Arabia. 6Department of Clinical Pharmacy & Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, United Arab Emirates. 7Clemenceau Medical Center, United Arab Emirates.
Abstract
The risk of developing Acute Kidney Injury (AKI) increases manifold during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, the aim of this study is to conduct a comprehensive pharmacotherapeutic evaluation of AKI in COVID-19 patients. A retrospective cohort study was conducted from July to August 2021 among COVID-19 patients admitted to the Institute of Kidney Diseases, Hayatabad Medical Complex hospital in Peshawar Pakistan. The data were extracted based on demographics, diagnosis, laboratory parameters, vital signs, and the treatment used during hospitalization. The association of independent variables was explored using parametric statistics such as regression analysis, one-way ANOVA, and Kruskal-Wallis. Data of N=595 COVID-19 patients with positive PCR tests as per pre-defined criteria were collected. It was observed that fever (n=575 [96.6%]), shortness of breath (n=570 [95.8%]), dry cough (n=449 [75.5%]) and body aches (n=129 [21.7%]) were some of the most common symptoms among the patients. Most of the patients were on a multi-drug regimen during hospitalization. Overall, it was observed that most of the laboratory variables significantly declined in COVID-19 patients with Stage III AKI. Mortality among the patients with AKI was 42% [0.418 [0.269 – 0.632], p=<0.001] as compared to non-AKI patients. There was a significant reduction in mortality by 96% (1.968 [1.277 – 3.033], p-0.002) with the use of intravenous dexamethasone. The prime goal of a clinician is to avoid the use of nephrotoxic drugs during hospitalization and maintain adequate oxygen saturation in order to avoid the development of AKI in COVID-19 patients.
Keywords: COVID-19, SARS-CoV-2, Kidney disease, AKI, Renal failure
INTRODUCTION
The coronavirus class of pathogens is single-stranded RNA viruses which consist of different varieties that mainly infect humans and non-humans [1]. These viruses belong to family coronaviridae in order nidovirales and subfamily of alpha-coronavirus, beta-coronavirus, gamma coronavirus, and delta-coronavirus [2]. In late 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged on the global stage and caused coronavirus disease (COVID-19) all around the globe without any discrimination [3]. Comparative analysis of clinical features of COVID-19 suggests that the infected patients show pneumonia-like symptoms. However, common symptoms after the onset of SARS-CoV-2 infection include cough, fever, and fatigue, while some other symptoms are diarrhea, dyspnea, hemoptysis, sputum production, and lymphopenia [4, 5]. Although respiratory symptoms are the main clinical manifestations of this disease renal involvement during the disease is also a serious concern as hospitalized COVID-19 patients are at increased risk of developing acute kidney injury (AKI) [6].
The risk of acute kidney injury (AKI) increases manifold during SARS-CoV-2 infection [7]. The exact mechanism of action of COVID-19 associated AKI is still unknown; however, it is believed to be associated with multi-organ shock and failure indicating acute tubular necrosis during AKI [7]. Elevated blood urea nitrogen (BUN), baseline serum creatinine, proteinuria, and hematuria are some of the manifestations of AKI during COVID-19 [8]. The symptoms of AKI sometimes become so severe during COVID-19 that they can’t be controlled through conservative management; hence, there starts to exist an urgent need for renal replacement therapy (RRT) [9]. Continuous renal replacement therapy (CRRT) has been very successful in reducing the level of inflammatory cytokine levels [10].
Various studies have reported the development of acute kidney injury during the hospital stay of COVID-19 patients and the injury was more common among critically ill patients or patients with other comorbid conditions. In a cohort study on 99 critically ill coronavirus patients, AKI was developed in 42.9% of patients and the majority of these patients had KDIGO (Kidney Disease Improving Global Outcomes) stage III AKI [11]. A retrospective study conducted on hospitalized patients in New York city summarized that patients suffering from COVID-19 showed a higher incidence of AKI with increased requirement for mechanical ventilation, intensive care facility, and renal replacement therapy, as compared to patients without COVID-19 [12]. In clinical investigations of COVID-19, AKI is presented as an independent predisposing cause of mortality [13]. Studies have shown that critically ill AKI patients infected with coronavirus are at increased risk of mortality ranging from 8% to 23% [14, 15]. Some studies even showed an in-hospital mortality rate of 62%, 77%, and 80% among COVID-19 patients with Stage I, Stage II, and Stage III AKI, respectively [16].
Globally, there is very limited data on AKI in COVID-19 patients and Pakistan is lagging far behind the rest of the world in reporting these incidents [17]. Thus, an understanding of how the kidney behaves during SARS-CoV-2 infection and how this infection leads to acute kidney injury is urgently needed, especially in the Pakistani population. Investigation of such findings from Pakistan in the form of a retrospective cohort would help us better understand the variable clinical manifestations of AKI in COVID-19 patients which will ultimately help in better handling of coronavirus patients over the course of time. Keeping in view the aforementioned realities, the motivation behind this study is to conduct a comprehensive pharmacotherapeutic evaluation of AKI in COVID-19 patients. This study aims to compare the incidence, risk factors, and outcomes associated with AKI between normal and risk populations.
MATERIALS AND METHODS
Study Design and Population
A retrospective cohort study was conducted from July to August 2021 among COVID-19 patients admitted at the Institute of Kidney Diseases, Hayatabad Medical Complex hospital in Peshawar Pakistan. This medical complex was given the responsibility of treatment of patients suffering from COVID-19. This medical complex was one of the single facilities in Peshawar which hosted the greatest number of COVID-19 patients daily at that time. Ethical approval for this study was taken from the Institutional Review Board of the Hayatabad Medical Complex. A confirmed case of COVID-19 was defined by a positive RT-PCR assay of a specimen collected via nasopharyngeal swab. The inclusion criteria for this study were; 1) all adult patients who tested positive by polymerase chain reaction (PCR) testing of a nasopharyngeal sample for SARS-CoV-2 infection, 2) only first hospitalization record was included for the patients who had multiple qualifying hospital admissions, 3) only quantitative data from Institute of Kidney Disease, Hayatabad Medical Complex hospital were included. Whereas exclusion criteria for this study were 1) data of those patients were excluded if they were transferred to hospitals out of the health system from where it was impossible to obtain data, 2) Data from those patients were excluded from whom the consent was not obtained, and finally, 3) no data outside of Institute of Kidney Disease, Hayatabad Medical Complex hospital was included.
Data Collection
The data were extracted based on demographics, diagnosis, laboratory parameters, vital signs, and the treatment used during the hospitalization. Demographics include the gender and age of the participants. Diagnosis and classification of AKI were based on Kidney Disease Improving Global Outcomes (KDIGO) guidelines [18]. Serum creatinine of more than 0.3 mg/dl or increase to more than 1.5–1.9 times from the baseline serum creatinine level was categorized as Stage I AKI; a serum creatinine of more than 2–2.9 times from the baseline value was categorized as Stage II AKI; whereas, serum creatinine of three times more than the baseline value or a level of more than 4 mg/dl was categorized as Stage III AKI. Laboratory parameters were collected from day one of the hospitalizations till the last day at the hospital. Vital signs were included along with laboratory parameters. A list of various drugs used for the management of COVID-19 and associated symptoms were also included and compared for various outcomes.
Statistical Analysis
The collected data were processed by using Statistical Package for Social Science (SPSS) software program for windows version 21.0 (SPSS Inc., Chicago, IL). The data were analyzed using appropriate descriptive analysis such as mean and standard deviation. Apart from this, the association of independent variables like gender, age, etc., with dependent variables like clinical symptoms, hospitalization, infection severity, co-morbidity, development of AKI, and mortality was explored using parametric statistics such as regression analysis, one-way ANOVA, and Kruskal-Wallis (only if the data were not normally distributed). The statistical significance level was 0.05 with a confidence interval of 95%.
RESULTS AND DISCUSSION
Demographic Details of the Participants
Data of N=595 COVID-19 patients with positive PCR tests as per pre-defined criteria were collected from the nephrology ward of HMC hospital. The mean age of the patients was 53 years ± 13.55; whereas, the majority of the patients were of the age of 60 years or above. The average number of days of hospitalization of the patients was 6 days ± 13.55; whereas, most of the patients (n=423 [71.0%]) were either discharged or declared dead within the first 10 days of hospitalization. About 65.8% of the patients included in this cohort study were male. Most of the patients were suffering from diabetes mellitus (n=282 [47.3%]) and hypertension (n=244 [41.0%]). After assessing laboratory parameters, patients were categorized based on KDIGO criteria into Stage I (n=133 [22.3%]), Stage II (n=22 [3.6%]), and Stage III (n=42 [7.1%]) AKI. Further details of the demographic characteristics of patients suffering from COVID-19 are mentioned in Table 1.
Table 1. Demographic characteristics of COVID-19 patients (n=595) |
|||
Variables |
Groups |
N |
% |
Age (in years) Mean 53 years ± 13.55 |
11-20 21-30 31-40 41-50 51-60 60 and above |
12 42 88 119 157 177 |
2.0 7.0 14.7 20.0 26.3 29.7 |
Gender |
Male Female |
392 203 |
65.8 34.1 |
Number of days Hospitalized
Mean 6 days ± 13.55 Range 03 - 30 days |
Discharged on the same day 1-10 Days 11-15 16-20 21-25 26-30 |
57 423 77 25 3 10 |
9.6 71.0 12.9 4.2 0.5 1.6 |
Comorbidities |
Hypertension Diabetes mellitus Asthma/ COPD Rheumatoid / Osteo arthritis Liver and Biliary complications [ HEP B, C, Gallstones, Biliary constriction Other CVS disorders like PCI, CABG, CAD, etc Tuberculosis Thrombosis/ PE/DVT |
244 282 38 8 31 99 10 3 |
41.0 47.3 6.3 1.3 5.2 16.7 1.7 0.5 |
AKI classification on admission |
No AKI Stage I Stage II Stage III |
398 133 22 42 |
66.8 22.3 3.6 7.1 |
Clinical Symptoms of the Patients
It was observed that fever (n=575 [96.6%]), shortness of breath (n=570 [95.8%]), dry cough (n=449 [75.5%]) and body aches (n=129 [21.7%]) were some of the most common symptoms among the participant as shown in Table 2. In terms of AKI, most of these symptoms were prevalent in patients with Stage I AKI. Whist, the shock was observed to be significantly higher among the patients suffering from AKI-Stage I. Most of the patients on the ventilator (n=12 [33.33%]) were from the AKI Stage III, of whom a majority of these patients have undergone dialysis (p=<0.001). It was observed that the chance of fatal outcomes was higher among the patients suffering from AKI (p=<0.001) as compared to non-AKI patients. Although a majority of the patients (n=305 [51.2%]) were discharged stable from the hospital yet a significant number of patients (n=188 [31.6%]) were expired.
Table 2. Clinical features and overall outcome of COVID-19 patients according to the stages of AKI |
||||||
Variables |
No AKI n=429 |
Stage I n=151 |
Stage II n=30 |
Stage III n=62 |
Total |
P-value |
Symptoms Fever SOB Dry Cough Body Aches Sore Throat Anorexia Shock Loose Motion Hemoptysis Fits Flu |
366 359 283 82 50 22 10 22 1 1 15 |
132 133 98 22 11 7 11 6 0 0 9 |
24 27 22 8 1 0 2 3 0 0 0 |
54 51 46 17 7 4 2 1 0 0 1 |
576 570 449 129 69 33 25 32 1 1 25 |
0.727 0.454 0.478 0.118 0.262 0.587 0.038* 0.319 0.904 0.908 0.251 |
Mechanical Ventilator On ventilator Not on ventilator |
13 377 |
7 126 |
4 17 |
12 39 |
36 559 |
<0.001* |
Overall Outcome Discharged with creatinine above normal Discharged (recovered with hemodialysis done) Discharged stable Discharged and on hemodialysis Expired Still Admitted |
0 0 273 0 84 34 |
26 0 28 0 55 14 |
7 0 3 0 15 1 |
12 1 1 1 34 6 |
45 1 305 1 188 55 |
<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* |
Medication Use in Patients
Most of the patients were on a multi-drug regimen during hospitalization. Steroidal drugs (n=544), multiple antibiotics (n=514), low molecular weight heparin (n=481), proton-pump inhibitors (n=413), paracetamol (n=350), multiple fluids (n=257), insulin (n=215), single antibiotic (n=149), and multivitamins (n=117) were the most common medication used in patients. Overall details of medication use in patients are shown in Figure 1. Azithromycin (n=578), ceftriaxone (n=322), cefoperazone (n=156), and meropenem (n=142) were the most commonly used antibiotics among patients. Other antibiotics used by patients are shown in Figure 2.
|
Figure 1. List of various medications used in COVID-19 patients |
|
Figure 2. List of various antibiotics used in COVID-19 patients |
Laboratory Variables of Patients in Association with AKI
Overall, it was observed that most of the laboratory variables significantly declined in COVID-19 patients with Stage III AKI. The creatinine value was very high both at admission and at the discharge of patients. Serum Electrolytes (SE) were in the normal range for most of the patients; however, the mean sodium concentration level gradually increased with the successive AKI stages. Complete Blood Count (CBC) values also worsened with successive worsening of AKI in patients. Liver Function Test (LFT) revealed that the values of liver markers increased over the course of hospitalization, indicating liver failure in many patients along with AKI. In addition, the oxygen saturation, pulse rate, and blood pressure were observed to be significantly lower in the Stage III groups. Further details of the laboratory parameters of COVID-19 patients with categorization into various stages of AKI are mentioned in Table 3.
Table 3. Laboratory parameters of COVID-19 patients |
|||||
Lab test |
N |
Mean |
Std. Deviation |
P-Value |
|
Creatinine at admission |
No AKI Stage I Stage II Stage III |
231 96 21 44 |
1.19 1.39 2.02 3.19 |
1.765 0.305 0.657 3.012 |
<0.001* |
Creatinine at discharge |
No AKI Stage I Stage II Stage III |
286 74 12 16 |
0.92 1.28 1.73 4.10 |
0.178 0.353 0.723 3.289 |
<0.001* |
Urea |
No AKI Stage I Stage II Stage III |
404 141 30 62 |
42.12 63.32 91.80 125.03 |
32.714 26.292 52.007 94.659 |
<0.001* |
Sodium |
No AKI Stage I Stage II Stage III |
347 141 27 61 |
136.77 136.43 138.37 139.46 |
6.207 8.400 11.287 9.204 |
0.031* |
Potassium |
No AKI Stage I Stage II Stage III |
346 141 27 61 |
4.22 4.50 4.56 4.71 |
0.716 0.809 1.226 0.949 |
<0.001* |
Chloride |
No AKI Stage I Stage II Stage III |
346 141 27 61 |
98.36 98.53 102.24 100.93 |
8.320 7.677 10.241 10.104 |
0.024* |
RBC |
No AKI Stage I Stage II Stage III |
201 79 17 41 |
199.24 231.85 211.94 221.80 |
107.503 175.837 117.363 118.570 |
0.258 |
Hemoglobin |
No AKI Stage I Stage II Stage III |
347 127 30 61 |
13.56 13.18 12.96 12.65 |
7.338 2.018 1.902 2.472 |
0.664 |
WBC |
No AKI Stage I Stage II Stage III |
347 127 30 61 |
12.00 12.86 15.13 27.95 |
5.820 5.453 5.383 1956.464 |
0.017* |
Platelets |
No AKI Stage I Stage II Stage III |
347 127 30 61 |
245.60 239.14 270.00 241.62 |
101.251 111.329 167.124 126.158 |
0.565 |
Neutrophils |
No AKI Stage I Stage II Stage III |
334 137 29 61 |
81.18 79.58 83.95 83.37 |
44.335 13.901 11.029 10.697 |
0.876 |
Lymphocytes |
No AKI Stage I Stage II Stage III |
354 127 29 61 |
13.83 13.95 9.37 8.99 |
11.083 12.801 5.187 9.240 |
0.030* |
PT |
No AKI Stage I Stage II Stage III |
213 92 21 43 |
14.49 15.55 16.70 17.23 |
5.860 7.013 5.420 8.611 |
0.460 |
APTT |
No AKI Stage I Stage II Stage III |
196 82 19 42 |
30.54 30.20 35.89 34.01 |
8.468 6.802 8.743 10.235 |
0.050 |
INR |
No AKI Stage I Stage II Stage III |
213 93 21 43 |
1.29 1.27 1.32 1.42 |
1.205 0.598 0.362 0.748 |
0.864 |
LDH |
No AKI Stage I Stage II Stage III |
245 79 17 32 |
617.61 815.28 879.94 868.84 |
374.315 503.551 582.704 322.295 |
<0.001* |
ALT |
No AKI Stage I Stage II Stage III |
360 137 28 56 |
60.70 65.66 110.25 117.79 |
66.194 69.936 144.444 308.278 |
0.020* |
ALP |
No AKI Stage I Stage II Stage III |
354 136 29 56 |
99.92 107.86 117.24 148.52 |
66.128 54.923 56.319 238.589 |
0.050 |
Total bilirubin |
No AKI Stage I Stage II Stage III |
354 136 29 56 |
0.72 0.78 1.07 1.11 |
1.849 0.907 1.353 2.593 |
0.334 |
CRP |
No AKI Stage I Stage II Stage III |
286 103 19 39 |
21.77 14.47 13.67 84.91 |
81.214 11.883 9.064 398.888 |
0.034* |
Ferritin |
No AKI Stage I Stage II Stage III |
237 79 14 33 |
1388.28 1461.11 1481.79 1660.50 |
1765.571 1626.054 1171.368 848.622 |
0.842 |
D-DIMER |
No AKI Stage I Stage II Stage III |
196 90 19 36 |
10.23 32.41 3.60 13.10 |
64.287 179.079 2.689 20.053 |
0.375 |
Oxygen Saturation |
No AKI Stage I Stage II Stage III |
344 138 30 62 |
83.0443 79.4570 72.6667 79.2581 |
12.88103 13.32053 17.44416 14.02683 |
<0.001* |
Pulse rate in BPM |
No AKI Stage I Stage II Stage III |
359 138 30 59 |
94.6425 94.7667 103.9000 109.1613 |
16.98658 19.81709 23.88962 74.08064 |
0.001* |
Systolic Blood Pressure |
No AKI Stage I Stage II Stage III |
361 142 28 62 |
151.5164 122.0867 117.6667 120.8065 |
578.40775 21.25806 20.95699 29.16142 |
0.882 |
Temperature |
No AKI Stage I Stage II Stage III |
361 142 30 62 |
99.0925 99.2220 99.4000 99.3435 |
4.97653 1.30805 1.22051 1.43705 |
0.944 |
Diastolic Blood Pressure |
No AKI Stage I Stage II Stage III |
361 138 32 60 |
77.5316 77.9333 72.6667 75.6935 |
11.03306 15.41361 17.20732 17.45213 |
0.163 |
One-way ANOVA has applied; * p-value < 0.05 is statistically significant
Association of Mortality with Different Variables
After applying multiple linear regression analysis, it was found that the risk of mortality was 56% when the age of COVID-19 patients was 50 years or above (0.566 [ 0.364 – 0.873], p=0.008). Moreover, mortality among the patients with AKI was 42% [0.418 [0.269 – 0.632], p=<0.001] as compared to non-AKI patients. Additionally, mechanical ventilation significantly increased the chances of the mortality by 9% [0.095 [0.043 – 0.219], p=<0.001]. High oxygen saturation (more than 90%) could significantly [2.446 [1.550 – 3.803], p=<0.001] reduce the chances of mortality. It was further noted that the chances of mortality could also be significantly reduced with low lymphocytes level and better regulation of diastolic blood pressure.
Analysis of the drugs used in hospitalized patients revealed that the mortality was significantly higher with the use of meropenem by 62% (0.625 [ 0.396 – 0.982] p=0.041), intravenous hydrocortisone by 58% (0.582 [ 0.358 – 0.943] p=0.028), hydroxy-chloroquine by 42% (0.423 [ 0.245 – 0.727] p=0.002) and oral steroids by 16% (0.161 [ 0.092 – 0.277] p=<0.001) as compared to any other drug. However, there was a significant reduction in mortality by 96% (1.968 [ 1.277 – 3.033], p-0.002) with the use of intravenous dexamethasone. Further details of the predictors of mortality among COVID-19 patients are highlighted in Table 4.
Table 4. Predictors for mortality among COVID-19 patients |
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Variables |
β(CI) |
Std. Error |
p-value |
Age Gender AKI On Ventilator |
0.566 [ 0.364 – 0.873] 1.227 [0.791 – 1.903] 0.418 [0.269 – 0.632] 0.095 [0.043 – 0.219] |
0.213 0.224 0.204 0.408 |
0.008* 0.361 <0.001* <0.001* |
Oxygen Sat CPR Lymph Systolic BP Diastolic BP LDH |
2.446 [1.550 – 3.803] 0.484 [0.318 – 0.734] 1.863 [1.237 -2.807] 1.195 [0.792- 1.805] 3.350 [1.906- 5.888] 0.983 [0.663 – 1.457] |
0.227 0.213 0.209 0.210 0.288 0.201 |
<0.001* 0.001* 0.003* 0.396 <0.001* 0.930 |
Oral steroids Intravenous hydrocortisone Intravenous dexamethasone Intravenous methylprednisolone LMWH Hydroxy Chloroquine Azithromycin Ceftriaxone Meropenem |
0.161 [ 0.092 – 0.277] 0.582 [ 0.358 – 0.943] 1.968 [ 1.277 – 3.033] 1.118 [ 0.637 – 1.962] 1.340 [ 0.883 – 2.033] 0.423 [ 0.245 – 0.727] 0.780 [0.451 – 1.348] 1.052 [ 0.723 – 1.530] 0.625 [ 0.396 – 0.982] |
.277 .246 .220 .287 .213 .276 .279 .191 .231 |
<0.001* 0.028* 0.002* 0.697 0.170 0.002* 0.373 0.792 0.041* |
Linear regression was applied, *p-value< 0.05 was considered statistically significant, β= standardized beta, CI= Confidence Interval
This study included an adequate sample size and provided a comprehensive baseline clinical characteristic of the patients. It gave in-depth information on patients’ co-morbidities, clinical symptoms associated with COVID-19, treatment received during hospitalization, and laboratory reports based on Serum Electrolyte (SE), Complete Blood Count (CBC), Liver Function Test (LFT), Renal Function Test (RFT), etc. AKI was classified based on KDIGO guidelines using this clinical data. Various associations were explored to understand the different clinical manifestations of the COVID-19. Follow-up was ensured to record the outcomes of this disease in an infected patient.
Fever, shortness of breath, and dry cough were the most prevalent symptoms among coronavirus patients. Categorization of symptoms according to the stages of AKI revealed that these symptoms were more common in patients with no AKI than those of AKI patients, especially those who were at the third stage of AKI. The results of this study are almost similar to another study on a large population in China which reported a high prevalence of fever, cough, and other symptoms in a similar proportion [19]. Most of the patients had hypertension and diabetes mellitus in our study. This is because of the presence of a high burden of Non-communicable diseases (NCDs) along with other infectious diseases in Pakistan [20]. According to the reports, comorbidities are significantly associated with the severity of coronavirus infection and poor outcomes [21]. Though the evidence on the association of diabetes with disease severity and subsequent mortality is very limited; however, one study with a large sample size concluded that diabetes is significantly associated with mortality and severity of COVID-19 [22]. The association between diabetes and COVID-19 was not explored in our study but the presence of a large number of diabetic patients raises concerns. Similarly, there is no clinical evidence regarding the association of hypertension with COVID-19 clinical symptoms, but some studies reported worsening of symptoms in hypertensive patients [23].
Various laboratory parameters were found highly abnormal for patients with type three AKI as compared to the patients with no AKI. The creatinine value was very high both at admission and at the discharge of patients. The mechanism associated with the increase of SARS-CoV-2 associated creatinine is the accumulation of coronavirus in the kidney which cause renal cell damage and subsequent necrosis [14]. Lymphopenia was present in almost all of the patients in this study. Various studies indicated that lymphopenia is the typical characteristic of the SARS-CoV-2 infection [24]. High IL-6 levels, coupled with increased concentration of tumor necrotic factor-alpha (TNF-alpha) in coronavirus patients induce apoptosis of lymphocytes [25]. Our study found highly abnormal liver markers which proves the fact that coronavirus also affects the liver of the host. Various studies pointed out that high-level Alanine transaminase (ALT) and Aspartate transaminase (AST) are due to the indirect effect of COVID-19 which leads to liver dysfunction [24]. A high level of Alkaline phosphatase (ALP) in the patients is reflective of an overridden immune system and serves as an early indication of multiple organ injury that needs to be ascertained [26].
Oxygen saturation of the patients was very low, especially those patients who were at the third stage of AKI. The first sign of this disease is actually the failure of the respiratory system which is often termed “silent hypoxemia” [27]. This impaired respiratory system leads to decreased oxygenation. This often leads to respiratory failure within 8-14 days. A decrease in oxygen saturation and a rise in breathing rates are indicative of impaired pulmonary diffusion. Histopathological examination of such patients often reveals diffused alveolar damage [28]. This study also found a gradual lowering of oxygen saturation in AKI patients. Moreover, after assessing the association between oxygen saturation and mortality it was found that more than 90% oxygen saturation could significantly decrease the chances of mortality in COVID-19 patients. The findings of this study are similar to another study conducted in China among COVID-19 patients. In that study, the patients were given oxygen supplementation at the cut-off value of more than 90%, and it was revealed that high oxygenation significantly reduced the chances of mortality among patients [29].
Mortality in COVID-19 patients was significantly associated with AKI (p<0.05) and the rate of mortality due to AKI complications was found to be 42%. The risk of mortality was found significantly higher (56%) in elderly people of age 50 years or above. It could be associated with the progressive changes in the lungs anatomy of elderly people coupled with muscular atrophy that leads to physiological changes in pulmonary functions such as reduced lungs reserve, reduced airway clearance, and reduced defense barrier related functions [30-32]. C-reactive protein levels were also very high in elderly patients than in younger or middle-aged patients [33]. Computerized tomographic studies showed that the multilobe lesions were significantly higher in elderly COVID-19 patients than in younger patients [34]. Computerized tomography is the most rapid and direct method to quickly identify the damage caused by SARS-CoV-2 to the lungs and understand the severity of the disease. Oral steroids were found to be significantly associated with mortality in COVID-19 patients in this study. The majority of patients were on oral steroids which may have been contributed to high mortality in patients. Moreover, it is a known fact that steroids cause a decline in immune functions that could provide a breeding ground for SARS-CoV-2 replications and subsequent severity of the disease [35]. Contrary to this, it was found that the risk of mortality was reduced by the use of dexamethasone in patients. A clinical trial on COVID-19 patients concluded that the use of dexamethasone combined with standard care methods significantly increased ventilator-free days and reduced mortality in patients [36].
Patients suffering from COVID-19 show various degrees of kidney damage caused by the virus. This can be evaluated based on blood urea nitrogen (BUN), creatinine levels, and other structural changes including edema or inflammation of renal parenchyma, focal fibrosis, epithelial cell necrosis with interstitial hyperemia [37, 38]. Increased release of pro-inflammatory factors in response to the viral attack is associated with the development of COVID-19-related acute kidney injury [39]. Norepinephrine and other drugs including antiviral agents, antibiotics, and NSAIDs also have the potential to cause acute kidney injury, especially in elderly patients or those having comorbid conditions like cancer, cardiovascular disease, or diabetes [37]. Diagnosis of AKI in COVID-19 patients is associated with the diagnosis of viral infection [40]. Generally, COVID-19-associated AKI is treated with CRRT along with other supportive therapies that are used against viral infection. CRRT is also of importance as it may also reduce the overload of inflammatory cytokines and if used in the early stages of AKI, could reduce the mortality rate in critically ill patients [41]. In our study, COVID-19 patients suffering from AKI showed an increased mortality rate than those without AKI and those who get discharged from the hospital, do not have complete renal recovery. It is important to timely diagnose AKI in COVID-19 patients as it may not only increase the mortality rate but can also lead to chronic kidney disease in hospital discharged patients [42].
The specific treatment for AKI is yet to be discovered but the early prognosis and early management of underlying conditions that are associated with AKI could reduce the number of AKI incidences in COVID-19 patients. These management modalities range from avoidance of various nephrotoxic drugs to the management of hypoxemic conditions. Early optimization of hemodynamics and blood volume should be considered in a high-risk group of patients to ensure effective and adequate renal perfusion pressures. However, if the patient doesn’t respond to the conventional management strategies, then the next logical step is the utilization of Continuous Renal Replacement Therapy. This study will help clinicians and other decision-makers in making a sound clinical decisions based on the evidence provided by it. It will help in understanding the conclusive unfolding of this pandemic. This study also opens the room for opportunities for further studies to be conducted on this topic and explore various outcomes. It will serve as a pivot around which other studies could diversify their scope.
CONCLUSION
Renal involvement during the disease is of concern as hospitalized COVID-19 patients are at increased risk of developing acute kidney injury (AKI) which may lead to increased severity of disease and even death. Our study found that the clinical symptoms of the COVID-19 patients worsen with successive stages of AKI. Various factors could either increase or decrease the chances of mortality in AKI patients suffering from COVID-19. There is no specific treatment for AKI; however, the prime goal of a clinician is to avoid the use of nephrotoxic drugs during the course of hospitalization and maintain adequate oxygen saturation in order to avoid the development of AKI or to avoid the worsening of already developed AKI in COVID-19 patients. CRRT could be considered the last option in patients who are unresponsive to conservative management of AKI.
ACKNOWLEDGMENTS: We would like to thank Dr. Maqbool Ali for his valuable input in this article and for reviewing the work.
CONFLICT OF INTEREST: None
FINANCIAL SUPPORT: None
ETHICS STATEMENT: None
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