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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 42  |  Issue : 4  |  Page : 153-159

Coronavirus Disease-2019 and the kidneys: A tragedy of reciprocal damage and management challenges


1 Department of Chest Diseases, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt; Department of Respiratory Therapy, College of Medical Rehabilitation Sciences, Taibah University, Medina, Saudi Arabia
2 Department of Internal Medicine, Nephrology Unit, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
3 Department of Chest Diseases, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
4 Department of Chemistry, Biochemistry Unit, Faculty of Science, Damanhour University, Damanhour, Egypt
5 Department of Chemistry/Biochemistry, Faculty of Science, Cairo University, Cairo, Egypt
6 Department of Family and Community Medicine, College of Medicine, Taibah University, Medina, Saudi Arabia
7 Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences; Department of Medical Technology, Molecular Diagnostic Lab, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia

Date of Submission05-May-2021
Date of Decision17-Aug-2021
Date of Acceptance23-Aug-2021
Date of Web Publication30-Oct-2021

Correspondence Address:
Prof. Eman Sobh
Department of Chest Diseases, Faculty of Medicine for Girls, Al-Azhar University, Cairo

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_150_21

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  Abstract 


Coronavirus disease 2019 (COVID-19) has been reported to affect nearly all body systems. Kidney affection has been observed in several studies. The effect of COVID-19 on renal function is beyond that occurring in pneumonia or severe respiratory distress cases. Renal affection is attributed to several factors, including the mechanism of viral injury. Patients with preexisting kidney injury are at increased risk of infection. Early detection and management are crucial to avoid morbidity and mortality, prevent the spread and contamination of hemodialysis Units. Early detection and treatment of kidney involvement in COVID-19 are vital to avoid increased morbidity and mortality. Proper selection of drugs and fluid management is vital in cases with kidney involvement. This review aims to discuss the clinical and pathophysiological affection of the kidney in COVID-19.

Keywords: Acute kidney injury, chronic kidney disease, coronavirus, COVID-19, kidney injury, severe acute respiratory syndrome-coronavirus-2


How to cite this article:
Sobh E, Al-Adl AS, Awadallah MF, Abdelsalam KG, Awad SS, Surrati AM, Alhadrami HA. Coronavirus Disease-2019 and the kidneys: A tragedy of reciprocal damage and management challenges. J Med Sci 2022;42:153-9

How to cite this URL:
Sobh E, Al-Adl AS, Awadallah MF, Abdelsalam KG, Awad SS, Surrati AM, Alhadrami HA. Coronavirus Disease-2019 and the kidneys: A tragedy of reciprocal damage and management challenges. J Med Sci [serial online] 2022 [cited 2022 Aug 18];42:153-9. Available from: https://www.jmedscindmc.com/text.asp?2022/42/4/153/353043




  Introduction Top


Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of the current pandemic COVID-19 as announced by the World Health Organization (WHO) 1 year ago.[1],[2] SARS-CoV-2 is a novel single-strand RNA coronavirus.[3] Although SARS-CoV-2 is a respiratory pathogen invading the respiratory tract mainly and causing several respiratory symptoms; several reports have been published describing hundreds of extrapulmonary manifestations affecting nearly everybody organ, including the cardiovascular, gastrointestinal, genitourinary, and central nervous systems.[4] It is very important to understand the mechanisms, the clinical presentation, and the consequences of affection of these organs. Kidney involvement in COVID-19 is still not fully understood. In this review, we aim to investigate factors associated with kidney injury in COVID-19 and through light on the current situation, diagnosis, and management.


  Epidemiology and Evidence of Kidney Injury in COVID-19 Top


Several studies reported that kidney injury is prevalent in COVID-19 patients, especially those admitted to intensive care unit (ICU).[5] The prevalence of acute kidney injury (AKI) in COVID-19 is widely different across reports. It ranges from 0.5% to 29%.[6],[7] The incidence rate is variable and is as high as 50% in ICU patients.[8],[9],[10] Reports from countries outside China had higher rates of kidney injury in COVID-19.[5]

Controversary, Wang et al.[11] evaluated reports of 116 hospitalized patients with COVID-19 confirmed cases from China. Using the standardized definitions of AKI[12] and chronic kidney disease (CKD),[13] they reported that 111 patients without CKD did not develop abnormal kidney function during the observation period. Twelve patients had a mild increase in blood urea nitrogen or serum creatinine after SARS-CoV-2 infection which did not meet the criteria for AKI (<26 μmol/L within 48 h and trace albuminuria). These abnormalities returned to normal during follow-up without treatment directed to the kidney. Furthermore, patients with CKD had a stable condition of kidney function without deterioration. They concluded that COVID-19 was not a cause of AKI or exacerbation of CKD despite the presence of SARS-CoV-2 RNA in the urine of some patients.[11]

The high incidence of AKI in some reports of COVID-19 may be attributed to delayed hospitalizations and exhaustion of health care resources. The discrepancy in the frequency of kidney injury in COVID-19 in several studies may be attributed to the variability in the definition of AKI used in each study, different study types, sample size, frequency of serum creatinine testing, and clinical condition. Critically ill patients were more likely to develop AKI than stable cases.

Some studies reported evidence from renal biopsy and autopsy as evidence for the affection of both tubular and parenchymal components of the kidney.[14] Light microscopy examination of the renal autopsy showed prominent proximal acute tubular injury, diffuse erythrocyte aggregation, and obstruction of peritubular and glomerular capillaries with no obvious thrombi or fragmentation. Few cases showed pyelonephritis, hemosiderin granules deposition, or nonspecific inflammation with lymphocyte infiltrations. No evidence of vasculitis, hemorrhage, or interstitial inflammation was detected.[14] Electron microscopy showed coronavirus like particles in the renal tubular epithelium and podocytes.[14] Kissling et al. reported a 63-year-old male with collapsing glomerulopathy; renal biopsy showed acute tubular necrosis and severe focal segmental glomerulosclerosis, reverse transcriptase-polymerase chain reaction was negative from both renal biopsy extract and blood. Electron microscopy revealed coronavirus like particles.[15]

However, most of the case studies in Su et al.'s study were diabetic, hypertensive, or had cancers which all are risk factors of kidney injury. The patient in Kissling et al. report was also hypertensive.[14],[15] Besides, the detection of intracellular corona virus-like particles has been opposed to being naturally occurring intracellular organelles participating in cell metabolism,[16] and it was detected in electron microscopic examination of renal biopsies from pre-COVID rea patients. It may be explained by the coating of endocytic vesicles by proteins which cause the electron-dense area around these vesicles mimicking the appearance of coronavirus particles.[17] Isolation of SARS-CoV-2 virus has been reported in urine[18] and in kidney tissue.[19] Nucleoprotein antigens of SARS-CoV-2 were detected by indirect fluorescence method in a nuclear or cytoplasmic pattern in kidney tubules autopsies.[14]


  The Spectrum of Kidney Involvement in COVID-19 Top


COVID-19 may be complicated by newonset AKI, worsening of preexisting chronic renal impairment. CKD and renal transplant patients may also suffer from increased risk for infection with SARS-CoV-2, and increased complications besides hemodialysis sessions may be postponed because of fear of getting infected. The management of kidney disease within the COVID-19 needs special considerations.

COVID-19 and acute kidney injury

Current situation

AKI was reported in several viral infections, including SARS-CoV[20] and H1N1 infections.[21] AKI is frequently reported in COVID-19 patients.[22] A dose-response relationship was present between stages of AKI and death. The risk of mortality was increased nearly four times in those with stage three AKI.[23] In mild-to-moderate cases, AKI is infrequent. Clinical presentation is usually subclinical. Proteinuria, hematuria, and elevated levels of serum creatinine and/or blood urea nitrogen were found on hospital admission. Evidence of kidney injury was linked to more severe disease and increased mortality.[23] While in critically ill patients, AKI was more frequent and was associated with nonsurvival.[7] The presence of AKI is a bad prognostic factor.[23],[24]

Mechanism of acute kidney injury in COVID-19:

The etiology is not well established and still questioned. Several mechanisms are proposed. Direct injury to the kidney cells as the virus enters the cell through angiotensin-converting enzyme receptors-2 which are abundantly expressed in the kidneys.[25] This binding is activated by S-protein called TMPRSS2, which is called priming which is present in proximal tubules.[25] Immune-related mechanisms including cytokine storm, immune complexes deposition, and dysregulation of the immune response to viral infection due to the imbalance between immune clearance and immune tolerance responses resulting in immune overreaction and damage to organs. Other mechanisms include endothelial cell injury, dysregulation in glucose, and lipid metabolism.[26] Preexisting kidney injury can be exacerbated by viral infections, severe inflammation, and/or sepsis.[25] The increased risk of infections in patients with CKD may be attributed to the effect of uremia on the immune system. Decreased renal function leads to increased uremic toxins and systemic inflammation resulting in oxidative stress and release of inflammatory cytokines.[27],[28] This effect is associated with impaired innate[29] and adaptive immunity[30] with impaired/altered immune cell function including monocytes,[31] neutrophils,[32] and lymphocytes.[33],[34] Dialysis is also associated with immune system dysregulation.[35]

Several factors contribute to aggravated kidney injury in patients with preexisting kidney disease, including comorbidities as diabetes mellitus, anemia and cardiovascular disease, Vitamin D deficiency, sodium retention, oxidative stress, and complement activation.[36] Hypoxemia also exaggerates renal injury.[26]

Besides, drugs that are used in the treatment of COVID-19 may have adverse effects on renal function, isolation, and poor fluid management may increase dehydrating condition and lead to tubular necrosis. It is well established that acute lower respiratory tract infections such as pneumonia and severe respiratory impairment as ARDS may lead to AKI due to inflammatory cytokines, decreased renal blood flow, and dysfunction of the renal vascular bed.[37] The indirect effect of COVID-19 on renal function may be attributed to delayed diagnosis and management due to fear of infection or lockdown in some areas.

On the other hand, patients with AKI are at increased risk of respiratory complications with increased morbidity and mortality. They are at risk to develop respiratory failure requiring mechanical ventilation (MV), prolonged duration of, and/or weaning from MV, cardiogenic pulmonary edema, and noncardiogenic pulmonary edema.[38]

Consequences of both COVID-19 and AKI have a high risk of morbidity and mortality.

Diagnosis of AKI

AKI is defined as an abrupt decrease in kidney function, including both structural damage and loss of function.[39] According to KDIGO clinical practice guideline for AKI,[12] AKI is defined as any of the following: Increase in serum creatinine (SCr) by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 h; or increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume <0.5 ml/kg/h for 6 h.[12]

Urine analysis in COVID-19

Proteinuria and hematuria were found in mild to moderate diseases.[7] Hematuria is nonspecific and can be attributed to several factors, including AKI, coagulopathy, and inflammatory process.[7],[40] Elevated serum creatinine and/or blood urea nitrogen.[23] A recent study[41] highlighted the importance of performing urine analysis in COVID-19 and may provide important information for risk prediction and clinical management. They examined data of urine samples collected at emergency department admission in 226 patients who have been diagnosed with COVID-19 and found that urine samples white blood cells and red blood cells in 81.4% and 70.4% of samples, respectively. Bacteria were found in 19.9% of cases, while nearly half of the cases (49.1%) had casts including hyaline-granular, hyaline, granular, epithelial, and leukocytes, casting (31.9%, 26.1%, 6.6%, 1.8%, and 0.4%, respectively). In-hospital deaths significantly had more prevalent tubular cells and granular casts compared to those with favorable outcomes.[41]

Management of acute kidney injury in COVID-19

The management of AKI during COVID-19 is the same as non-COVID-19 cases in addition to special precautions regarding fluid therapy and doses of some drugs and ventilator strategies that have minimal adverse effects on the kidneys.[5] Infection control measures should be taken into considerations to avoid contamination of hemodialysis units or cross-transmission among health care personnel and other patients.[42] COVID-19 patients with AKI or at risk of AKI should be closely observed for hemodynamic status, especially blood pressure and cardiac output. Nephrotoxic drugs should be avoided. In those with ARDS or respiratory failure, proper choice of MV settings to avoid worsening of renal injury or hemodynamic status. Conservative fluid therapy, optimal RRT, and control of acid-base status are advised for those on invasive MV.[43] The optimal time to start hemodialysis in AKI is not clear and conservative therapy should be tried to avoid hemodialysis.[44] Continuous renal replacement therapy (CRRT) has been proven to be effective for the removal of inflammatory cytokines in several viral infections, including SARS, MERS, as well as in sepsis.[45] RRT decision depends on volume status, kidney function, potassium level, and acid-base status. Early RRT in COVID-19 can prevent worsening of AKI and provide organs perfusion, especially for those with hemodynamic instability. Anticoagulation therapy is required to avoid thrombotic events.[44]

COVID-19 and chronic kidney disease

CKD is defined as abnormalities in structure or function of the kidney detected as decreased glomerular filtration rate (GFR) <60 ml/min/1.73 m2 and/ or presence of one or more markers of kidney damage as albuminuria, urine sediment abnormalities, electrolytes, and other abnormalities due to tubular disorders, structural abnormalities detected by histology, imaging, or history of kidney transplantation. The duration of these abnormalities should be present for more than 3 months.[13]

Infectious complications are serious in patients with end-stage renal disease. It contributes to 10% of deaths of dialysis patients.[46] CKD was associated with an increased risk of pneumonia.[47] Pneumonia in dialysis patients was associated with cardiovascular disease and death.[48] CKD was associated with an increased risk of severe SARS-CoV-2 infection.[49] Patients with CKD and COVID-19 were more likely to be hospitalized and admitted to the critical care unit.[50] T-cell immunity is diminished in transplant recipients so they are at increased risk of bacterial and viral infections.[51] Previous influenza pandemic (H1N1) was associated with increased hospitalization and mortality in patients with end-stage renal disease.[52] Annual mortality secondary to sepsis is increased in dialysis patients and further increased in kidney transplant recipients.[53]

COVID-19 and hemodialysis

COVID-19 has a rapid rate of transmission which is variable in the general population. Meanwhile, the prognosis is still unclear in those on hemodialysis.[42] Patients with CKD receiving hemodialysis therapy are more vulnerable to infections because of advanced age, comorbidities, and impaired immune system.[54] Moreover, hemodialysis patients have a higher risk of exposure than the general population, attributed to their need to attend the dialysis center by public transport several times a week, the long exposure time at dialysis units, and waiting areas thus favoring cross-contamination.[42] Respiratory infections, especially pneumonia are one of the most common causes of increased morbidity and mortality in hemodialysis patients.[48] A large percentage of patients may be asymptomatic and share vehicles during their way to the hemodialysis center.[55] Owing to the rapid rate of transmission of SARS-CoV-2 and the increased number of cases reported among hemodialysis patients, prevention and isolation measures should be strictly applied to minimize the risk of spread across hemodialysis patients and healthcare professionals.[42]

Several scientific societies and international organizations developed guidelines for prevention and containment of COVID-19 in hemodialysis centers which are updated frequently. Hemodialysis centers need also to adopt their own protocols for the implementation of these guidelines.[56] Hemodialysis patients should be provided by information leaflets about the current epidemic and triage to screen for suspicious symptoms related to COVID-19, physical separation, and evaluation before entry into the dialysis room.[55] A real-time polymerase chain reaction (RT-PCR) of the nasopharyngeal swab and chest radiography are performed.[55] Those patients should receive their dialysis session in a separate room till the results of RT-PCR are obtained.[42] Patients with positive results for SARS-CoV-2 should receive their hemodialysis sessions in the COVID-19 zone.[55] All patients and healthcare professionals should follow infection control measures, including personal protective equipment and using special elevators and track for movement of RT-PCR-positive cases in the center. Critically ill patients with COVID-19 who require renal transplant are kept on CRRT till the resolution of infection.[42]

COVID-19 and kidney transplantation

Kidney transplant recipients are at increased susceptibility to many viral infections leading to justifiable anxiety about the effects of COVID-19. Clinical presentation and imaging of COVID-19 in kidney transplant patients were like that of nontransplant patients.[36] The most common manifestations reported in a systematic review included fever (52% to 95%), cough (49% to 78%), and dyspnea (28% to 70%).[57] Gastrointestinal symptoms were high as 53% in one study.[58] AKI at presentation or graft dysfunction at presentation.[59],[60],[61] asymptomatic infection was not reported in the studies included in the systematic review.[57]

Nair et al. studied 10 kidney transplant recipients who tested positive for SARS-CoV-2, 9 of them were admitted to the hospital. Comorbidities were prevalent in these cases. 20% of them had leukopenia. 90% were receiving immunosuppression, and 70% were receiving prednisolone. 50% developed AKI and 30% died.[51] Causes of death in ESRD and kidney transplant patients are attributed to cytokine storm and immunosuppression,[62] comorbid conditions, advanced age, and increased risk of exposure during dialysis.[53]

Early data reported indicate that hospitalized kidney transplant recipients infected with COVID-19 have high mortality. Comprehensive reporting regarding screening, comorbidities, investigations, management, and outcomes of this category of patients is important to improve the current knowledge.[57]


  EFFECT OF COVID-19 MEDICATIONS ON THE KIDNEYS Top


Kidney injury can affect the metabolism of some drugs used in the treatment of COVID-19. Some drugs are excreted through the kidneys as hydroxychloroquine (HCQ),[63] and remdesivir.[64] Some vitamin supplementations that are given empirically are metabolized in the kidneys as cholecalciferol (Vitamin D).[65]

Chloroquine and HCQ may have immunomodulatory effect and decrease inflammatory cytokines; however, studies showed no beneficial value in COVID-19 patients, in addition, it may be associated with increased mortality.[66] Renal insufficiency is a reported side effect of HCQ.[67] Obeidat et al. presented a case of male patient infected with SARS-CoV-2 who received HCQ for 5 days and stopped due to cardiac and renal toxicity. Postmortem examination of the kidneys revealed acute tubular injury and glomerulosclerosis, microangiopathy and intracapillary thrombosis, and tubular vacuolization. The case is highly suspected to be due to HCQ drug-induced phospholipidosis (DIPL).[68] Another case of DIPL was reported in systemic lupus erythematosus patient receiving HCQ.[69] HCQ was linked to sudden cardiac arrest in hemodialysis patients.[70]

Remdesivir side effects on the kidneys include acute renal failure, elevated serum creatinine, decreased estimated GFR, and decreased creatinine clearance.[64] There are limited data available about the use and safety of remdesivir in those with severe renal impairment.[71] Lopinavir/Ritonavir reported side effects to include increased serum concentration of some drugs, hematuria, and renal failure. All are uncommon and can occur in nearly 2% of cases.[72]

Off-label Vitamin D supplements are used in COVID-19 patients. Overdoses can lead to increased cholecalciferol levels in the blood with some side effects due to hypercalcemia and may cause renal failure. Patients with CKD may need supplementation with Vitamin D due to altered metabolism, so caution should be taken as the correction is only needed.[65]


  Prevention of Kidney Injury in COVID-19 Top


Early suspicion and diagnosis of COVID-19 patients and management are important to avoid AKI. Caution during the treatment of CKD patients should be taken during the choice of drugs, fluid replacement, and infection control measures. In COVID-19 patients, it is recommended to use isotonic crystalloid solutions for correction of hypovolemia, avoid or stop nephrotoxic drugs if not essential, besides conservative fluid management strategy in those with respiratory failure.[73] Daily monitoring of serum creatinine and urine output for patients with ARDS or respiratory failure.[43]


  Concluding Remarks Top


Kidney injury is common in COVID-19. It may be due to direct or indirect viral injury. Early detection and management are important to prevent morbidity and mortality. Conservative fluid strategy and optimal MV settings in COVID-19 patients with respiratory failure are essential to avoid worsening of kidney functions. Early renal replacement therapy is advised in AKI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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