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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 42  |  Issue : 3  |  Page : 127-133

Correlation of inflammatory markers with renal dysfunction and their outcome in symptomatic adult COVID-19 patients


1 Department of Anaesthesiology and Critical Care, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Radiology, Base Hospital, New Delhi, India
3 Department of Internal Medicine, Shree Hospital, New Delhi, India
4 Department of Ophthalmology, Command Hospital (SC), Pune, Maharashtra, India

Date of Submission10-May-2021
Date of Decision07-Jul-2021
Date of Acceptance22-Jul-2021
Date of Web Publication06-Sep-2021

Correspondence Address:
Prof. Shalendra Singh
Department of Anaesthesiology and Critical Care, Armed Forces Medical College, Pune - 410 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_155_21

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  Abstract 


Background: Acute kidney injury (AKI) is one of the most common complications associated with mortality. Aim: This study aims to find the correlation between renal dysfunction and inflammatory markers and their outcome in COVID-19 patients. Methods: The study was carried out in 100 patients whose inflammatory markers were available on the day of admission among the 814 patients with COVID-19. Results: Fifty-six percent of patients had moderate, and 36% of patients had severe disease outcomes including mortality in nine patients. Out of all the factors studied, advanced age, presence of chronic liver disease, increased levels of blood urea, serum creatinine and lactate dehydrogenase (LDH), decreased creatinine clearance were found to be significantly associated with risk of mortality (P < 0.05). Out of all the factors studied, advanced age increased interleukin (IL)-6 values, increased serum ferritin values, and known cases of hypertension (HTN) were found to be significantly associated with the occurrence of AKI (P < 0.05). The death rate among those with AKI was more than double, i.e., 13.3% compared to only 5.5% without AKI. It was found that only IL-6 was significantly more in those who died having AKI compared to those who recovered with AKI (P < 0.05) but other inflammatory markers were not significantly associated with this (P > 0.05). Conclusion: Significant risk factors of AKI were advanced age, increased IL-6 values, increased serum ferritin values, and known cases of HTN. Significant risk factors for mortality were advanced age, presence of chronic liver disease, increased levels of blood urea, serum creatinine and LDH, decreased creatinine clearance.

Keywords: Acute kidney injury, COVID-19, inflammatory markers, interleukin-6, serum ferritin, hypertension, chronic liver disease, creatinine clearance


How to cite this article:
Wadke R, Singh S, Gupta A, Samel SS, Taank P. Correlation of inflammatory markers with renal dysfunction and their outcome in symptomatic adult COVID-19 patients. J Med Sci 2022;42:127-33

How to cite this URL:
Wadke R, Singh S, Gupta A, Samel SS, Taank P. Correlation of inflammatory markers with renal dysfunction and their outcome in symptomatic adult COVID-19 patients. J Med Sci [serial online] 2022 [cited 2022 Jun 29];42:127-33. Available from: https://www.jmedscindmc.com/text.asp?2022/42/3/127/325596




  Introduction Top


Even after more than 1 year, COVID-19 is posing a challenge to researchers and clinicians due to its variability in the clinical presentation and the uncertainty about the complications; it can cause ranging from confusion to severe organ damage. Hence, attempts are going on to define the predictors of organ damage as well as mortality among patients with COVID-19 so that early diagnosis can be done for those at high risk and special care, and management is given to save the lives free from complications. In this regard, more emphasis is given on laboratory biomarkers as they are easy to obtain, inexpensive, and give fast results.[1],[2]

Among all complications of COVID-19, acute kidney injury (AKI) is the most common complication associated with COVID-19 cases.[3],[4] On average the incidence of AKI has been reported as 11% with a range of 8%–17% but more in the patients admitted to intensive care units (ICUs) where it was found to be 23% with a range of 14%–35%.[5] Different methods of estimation and reporting affect the variation in the reported incidence of AKI in COVID-19 cases across different studies.[6] AKI due to COVID-19 can be due to different mechanisms involved like direct kidney infection; complement activation leading to secondary inflammation of the kidneys; or microthrombosis leading to AKI.[7] High levels of interleukin (IL)-6 are seen in patients with the severe systemic inflammatory response in severe disease cases which leads to inflammation of the renal parenchyma.[8] Complement activation is uncertain which causes dysfunction of the endothelial cells as well as intravascular coagulation and ultimately leads to AKI. Hence, IL-6 and complement both should be targeted while treating COVID-19 cases with AKI.

Hence, it is important to study the correlation between the inflammatory markers and renal dysfunction as well as predictors of outcomes such as death and AKI. With this background, the present study was carried out to study the correlation between renal dysfunction and inflammatory markers and their outcome in symptomatic adult COVID-19 patients.


  Materials and Methods Top


Study design

This is a retrospective record-based study that was conducted at a newly raised COVID-19 dedicated hospital under PM cares fund in New Delhi, namely, Sardar Vallabh Bhai Patel COVID Hospital.[9] The study period was from July 13, 2020, to October 01, 2020 (IEC S. No IEC/2020/324).

Participants

All hospitalized COVID-19 cases with confirmed infection who were admitted for treatment of COVID-19 infection diagnosed by a rapid antigen test or reverse transcription-polymerase chain reaction on the nasal/throat swab sample were included. All cases were treated with standard protocol. Adult cases (more than 18 years of age) of both sexes who were admitted in the ICU of the hospital and for whom inflammatory markers were sent were included in the study. Institutional ethical committee approval was taken. Data were retrieved from retrospectively maintained medical records including demographic data, investigation, and clinical information. Consent waiver was granted given the retrospective nature of analysis and emergent nature of the pandemic. Confidentiality was maintained by the de-identification of data. All the data were analyzed at the cut-off date of October 14, 2020. All patients were given treatment as per the standard protocol. Investigations such as serum urea, serum creatinine, C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, serum ferritin, and IL-6 were carried out on day 0 (day of admission). For few cases, as indicated, these parameters were investigated to monitor the progress of the disease and the effect of treatment. Because these data (renal function test and inflammatory markers) was not available for all cases for all days, it was not included in the final analysis.

Definitions and measures

The clinical classification for COVID-19 severity was defined according to the WHO criteria. Mild cases are defined as “symptomatic patients meeting the case definition for COVID-19 without evidence of viral pneumonia or hypoxia.” Moderate cases are defined as, “Adolescent or adult with clinical signs of pneumonia (fever, cough,dyspnea, fast breathing) but no signs of severe pneumonia, including SpO2 >90% on room air”. Severe cases are defined as, “ Adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) plus one of the following: respiratory rate >30 breaths/min; severe respiratory distress; or SpO2 <90% on room air.”[10]

Statistical analysis

The data were entered in the Microsoft Excel worksheet. Student's t-test was used for continuous data and Yate's corrected Chi-square was used for categorical data. Pearson Chi-square was used to study the correlation. P < 0.05 was considered statistically significant.


  Results Top


Hundred patients out of the 814 patients admitted in ICU for whom inflammatory markers investigation was done on the day of admission were taken for study. The majority of patients are male (71%) and in the age group of 60–69 years (26%) [Table 1].
Table 1: Demographic profile and characteristics of patients

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The incidence of AKI in the present study was 45%. Based on the WHO guidelines, 8% of patients had mild, 56% of patients had moderate, and 36% of patients had severe disease outcomes including mortality in nine patients. The most common symptom was fever in 85% of the cases and the least common was wheeze in 4% of the cases [Table 1]. Data revealed that 25% of the cases had a history of contact with the positive case [Table 1]. Out of all the factors studied, advanced age, presence of chronic liver disease, increased levels of blood urea, serum creatinine and LDH, decreased creatinine clearance were found to be significantly associated with risk of mortality (P < 0.05) [Table 2]. Out of all the factors studied, advanced age increased IL-6 values, increased serum ferritin values, and known cases of hypertension (HTN) were found to be significantly associated with the occurrence of AKI (P < 0.05) [Table 3].
Table 2: Risk factors of mortality in COVID patients

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Table 3: Risk factors of acute kidney injury and effects of acute kidney disease on mortality in COVID patients

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It was found that blood urea and serum creatinine were significantly correlated with IL-6, LDH, and serum ferritin whereas creatinine clearance was significantly correlated only with IL-6 [Table 4]. CRP and D-dimer were not found to be correlated with any of the renal dysfunction parameters. The death rate among those with AKI was more than double, i.e., 13.3% compared to only 5.5% without AKI but this difference was not found to be statistically significant (P < 0.05) [Table 2]. It was found that only IL-6 was significantly more in those who died having AKI compared to those who recovered with AKI (P < 0.05) but other inflammatory markers were not significantly associated with this (P > 0.05) [Table 5].
Table 4: Correlation between renal dysfunction parameters and inflammatory markers

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Table 5: Association between those who died with the presence of acute kidney disease and inflammatory markers

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  Discussion Top


Evidence shows that the disease progresses fast as a result of the inflammatory response which is due to the rapid replication of the virus. This leads to the destruction of cells which attracts cytokine storms leading to an increase in the inflammatory markers such as serum ferritin, CRP, and IL-6.[11] Uribarri et al. studied 758 patients with a mean age of 66 ± 18 years and the majority were males which is similar to the present study findings.[12] They noted that advanced age, presence of HTN, and increased LDH were predictors of mortality and we also observed similar findings except HTN.[12] Zahid et al. also found that the median age was higher, i.e., 66 years, and the majority were males. The incidence of AKI was 27.3% while it was 45% in the present study [Table 6].[13] They noted that the risk factors of AKI were being male, presence of HTN, use of nonsteroid anti-inflammatory drugs, increased levels of ferritin, and troponin 1 whereas we also found that increased serum ferritin, presence of HTN, as prominent risk factors for AKI. They found that AKI was a significant predictor of mortality but we did not find so. They also noted that increased blood urea is one of the determinants for mortality which is similar to the present study. Sang et al. observed among 210 patients studied the male preponderance and advanced median age which is similar to the present study.[14] In their study, 43.8% developed AKI which is also similar to the present study. The risk factors which they found were age, elevated creatinine among others as risk factors for the development of AKI and we also observed the same. The mortality rate in their study was 44.3% which is very high compared to the present study, and this difference may be because all patients were ICU patients of severe category whereas we had a mix of cases. They found that age was one of the independent risk factors among others and we also found that advanced age was an important risk factor for death.
Table 6: Comparison of present study findings with other studies in relation to acute kidney disease

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Xia et al. found that the incidence of AKI was 50.6% over a median period of 21 days. We found an incidence of 45% [Table 6].[15] They noted that age and increased IL-6 levels were significant risk factors for AKI and we also found these two factors among others. They noted that risk factors for death were being male, increased D-dimer, IL-6 was important, but in the present study, we did not find a significant increase of D-dimer, IL-6 in the mortality group.

Suleyman et al. observed that females were more (55.9%) in their study while we found that males were more in the present study.[16] Cough was the most common presenting symptom in 74.9% of the cases followed by fever in 68% of the cases while in the present study, fever was the most common presenting symptom in 85% of the cases followed by cough in 73% of the cases. They found that the risk factors for admission to ICU were being male, severe obesity, and Chronic kidney disease (CKD) while this aspect was not studied by us.

Kolhe et al. retrospectively studied 4759 COVID-19 cases with AKI as a primary outcome and death as a secondary outcome and compared them with 3374 negative cases.[17] The incidence of AKI was 26.2% in COVID-19 cases compared to only 12.4% in negative cases. Risk factors of AKI were older age, use of mechanical ventilation, presence of congestive cardiac failure, presence of chronic liver disease, and chronic kidney disease. The death rate was significantly more in patients having AKI compared to those without AKI but we did not find this association. Ferrando et al. included 663 patients in their study and found that the mortality was 31% in ICU cases.[18] Hypoxemia, organ failure, high rate of complications, acute respiratory distress syndrome, AKI, shock, arrhythmias were more in those who died. Prominent risk factors were advanced age in their study which is similar to the present study. Upadhyaya et al. found that the presence of obesity, age more than 65 years, and being from urban areas were significant risk factors for mortality while we did not study obesity and residence but advanced age was found to be a significant risk factor in the present study.[19]

Our study revealed that blood urea and serum creatinine were significantly correlated with IL-6, LDH, and serum ferritin whereas creatinine clearance was significantly correlated only with IL-6. This laboratory finding can be due acute phase reaction in COVID-positive patient associated with AKI simultaneously or it can AKI Stages 1 and 2 not needing dialysis.

There are some limitations to our study. The exact interaction between COVID-19 and AKI that leads to the worsening of COVID-19 needs to be studied further at the molecular level. It has been suggested that the link between diabetes mellitus (DM) and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is angiotensin-converting enzyme-2 (ACE-2) that is believed to be one of the co-receptors that are used by the SARS-CoV-2 to infect cells.[20] Higher levels of ACE-2 have been reported in patients with DM and/or HTN as compared to healthy individuals who may aid in the natural pathogenesis of the diseases. However, this is a limitation of our study as we do not control for medications taken in our analysis due to insufficient information regarding the same. Further, several other parameters that have been previously shown to be associated with COVID-19 outcome such as obesity are not taken. Further, we do not have information about new-onset hyperglycemia and were not able to comment on its association with the COVID-19 outcome.


  Conclusion Top


Significant risk factors of AKI were advanced age, increased IL-6 values, increased serum ferritin values, increased blood urea, increased creatinine and low creatinine clearance, and known cases of HTN. Significant risk factors for mortality were advanced age, presence of chronic liver disease, increased levels of blood urea, serum creatinine and LDH, decreased creatinine clearance.

Acknowledgment

We would like to acknowledge the nursing staff and medical professionals, especially the residents of the Department of Anaesthesiology and Critical Care, AFMC, Pune, who have tirelessly worked to alleviate the suffering caused by this pandemic and facilitated the collection of good quality data for this publication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Weidmann MD, Ofori K, Rai AJ. Laboratory biomarkers in the management of patients with COVID-19. Am J Clin Pathol 2021;155:333-42.  Back to cited text no. 1
    
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Cattelan AM, Di Meco E, Trevenzoli M, Frater A, Ferrari A, Villano M, et al. Clinical characteristics and laboratory biomarkers changes in COVID-19 patients requiring or not intensive or sub-intensive care: A comparative study. BMC Infect Dis 2020;20:934.  Back to cited text no. 2
    
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Nadim MK, Forni LG, Mehta RL, Connor MJ Jr., Liu KD, Ostermann M, et al. COVID-19-associated acute kidney injury: Consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. Nat Rev Nephrol 2020;16:747-64.  Back to cited text no. 3
    
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Chan L, Chaudhary K, Saha A, Chauhan K, Vaid A, Baweja M, et al. Acute kidney injury in hospitalized patients with COVID-19. medRxiv. Preprint. 2020 May 8.  Back to cited text no. 4
    
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Gabarre P, Dumas G, Dupont T, Darmon M, Azoulay E, Zafrani L. Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med 2020;46:1339-48.  Back to cited text no. 5
    
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Wiersema R, Jukarainen S, Eck RJ, Kaufmann T, Koeze J, Keus F, et al. Different applications of the KDIGO criteria for AKI lead to different incidences in critically ill patients: A post hoc analysis from the prospective observational SICS-II study. Crit Care 2020;24:164.  Back to cited text no. 6
    
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Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43.  Back to cited text no. 8
    
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Uribarri A, Núñez-Gil IJ, Aparisi A, Becerra-Muñoz VM, Feltes G, Trabattoni D, et al. HOPE COVID-19 investigators. Impact of renal function on admission in COVID-19 patients: An analysis of the international HOPE COVID-19 (Health Outcome Predictive Evaluation for COVID 19) Registry. J Nephrol 2020;33:737-45.  Back to cited text no. 12
    
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Sang L, Chen S, Zheng X, Guan W, Zhang Z, Liang W, et al. The incidence, risk factors and prognosis of acute kidney injury in severe and critically ill patients with COVID-19 in mainland China: A retrospective study. BMC Pulm Med 2020;20:290.  Back to cited text no. 14
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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