Archive \ Volume.13 2022 Issue 2

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

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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