COVID-19-associated acute kidney injury

COVID-19 infection can affect many organs and lead to organ failure. Kidneys are vital organs that can be affected by coronavirus. Acute kidney injury (AKI), a sudden deficit in kidney function, is a complication of COVID-19 and associated with a higher risk of mortality. AKI is frequently seen in critically ill patients with pre-existing conditions. Identifying high-risk patients for AKI and regular monitoring of kidney function tests in these patients play a major role in preventing AKI.

• Coronavirus disease 2019 (COVID-19) was first detected in December 2019 in Wuhan, Hubei, China.^[1]
• Early reports from China revealed no association between COVID-19 and Acute kidney injury. These reports showed AKI was not seen among COVID-19 hospitalized patients and only a mild rise in BUN or creatinine (10.8%) and mild proteinuria (7.2%) developed. ^[2]
• However, recent study found 75.4% of hospitalized patients with COVID-19 pneumonia developed kidney complications such as hematuria, proteinuria, and AKI. ^[3]

• COVID-19-associated AKI may be classified into 3 subtypes:^[4]
  • Prerenal AKI
  • Rhabdomyolysis-induced AKI
  • Intrinsic AKI (the most common subtype of AKI.)

• Angiotensin-converting enzyme 2 (ACE2), is a primary receptor for SARS-CoV-2 entry into cells, mostly presents in renal tubular epithelial cells as well as lungs and heart.^[5]
• Kidney injury following COVID-19 infection is less frequent than severe lung injury, however ACE2:ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system)^[5]
• After SARS-CoV-2 enters through the nasal cavity, it may travel to the kidneys and enter the bloodstream leading to severe inflammatory response activation and cytokine storm.
  • Cytokine induced AKI may occur due to intrarenal inflammation, hyperpermeability of vessels, hypovolemia and cardiomyopathy, leading to cardiorenal syndrome type 1 that is characterized by third space volume overload such as pleural effusion, edema and intravascular volume loss (hypovolemia) and hypotension.^[6]
    • cardiomyopathy and COVID-19-associated myocarditis can lead to hypotension and reduction in renal perfusion.
  • The major cytokine is IL-6, which induces inflammation and lung endothelial cell injury, leading to ARDS and hypoxia that subsequently cause renal tubular cell injury and AKI. ^[7][6]

• Other Cytokine releasing factors in critically ill patients with COVID-19 include:^[6]
  • Extracorporeal membrane oxygenation (ECMO)
  • Mechanical ventilation
  • Continuous renal replacement therapy

• To conclude, COVID-19-associated AKI can occur as a result of:^[5]
  • Sepsis and cytokine storm
  • Hypovolemia and Hypotension
  • Hypoxemia
  • Blood clots formation due to hypercoagulable state, leading to impaired blood flow in the renal arterioles.

• COVID-19 associated AKI may be caused by SARS-CoV-2, which has a Kidney tropism.
• Recent study found SARS-CoV-2 antigens in renal tubules which suggests the direct damage of SARS-CoV-2 on the kidneys.^[8]
  • Angiotensin-converting enzyme 2 (ACE2), which is a primary receptor for SARS-CoV-2 entry into cells, mostly presents in Kidneys as well as lungs and heart.^[5]
    • High expression of ACE2 was found in the renal proximal tubular cells and rarely in podocytes. ^{[9] [10]}

• COVID-19-associated AKI must be differentiated from other diseases that cause AKI, such as congestive heart failure, hemorrhage, dehydration, liver failure, urinary tract obstruction, Interstitial nephritis, glomerulonephritis and nephrotoxic medications.

To review the differential diagnosis of AKI, click here.

• The prevalence of AKI among patients with COVID-19 hospitalized in ICU is approximately 0.6-29% in China ^[11] and 22.2% in the USA.^[12]
• Approximately 43% of critically ill patients with COVID-19 developed AKI during the admission period. ^[4]
• In a cohort study on 99 patients with severe COVID-19, AKI was reported in 42 patients (42.9%) and among them 32 (74.4%) patients had severe AKI (stage III based on KDIGO definition). ^[13]
• The actual incidence of AKI in critcally ill patients with COVID-19 is uncertain but estimated between 27-85%. “Acute Kidney Injury in COVID-19 Patients | COVID-19”.
• Differences of AKI prevalence among studies could be related to several factors, including:^[13]
  • Patient characteristics
    • Comorbidities
    • smoking history
    • Medications history
    • Race
  • Severity of COVID-19
  • Differences of COVID-19 management among countries

• AKI commonly affects elderly. The incidence of AKI increases with age; the mean age at diagnosis is 57.1 years. ^[4]

• Men are more commonly affected and have higher risk of COVID-19 complications. ^[14]
• 57.1% of AKI cases following COVID-19 were male.^[4]

• There is no racial predilection to COVID-19 associated AKI.

• The most potent risk factors in the development of COVID-19 associated AKI include:^{[15] [16]}
  • Elderly
    • Age>60 years
  • Comorbidities
    • Hypertension
    • Coronary artery disease
    • Chronic kidney disease
    • Liver disease
    • Diabetes
    • History of AKI

• Serial monitoring of kidney function tests should be considered in high risk patients.^[16]

• AKI is more likely to develop in the late stages of COVID-19 in critically ill patients.^[17]
• Severe COVID-19 pneumonia and severe acute respiratory distress syndrome are associated with developing AKI.^[3]

• Approximately half of the new AKI cases following COVID-19 is mild with good short-term prognosis.

• If no improvement occurs during follow-up, it is contributed to higher mortality.^[3]

• The diagnosis of AKI is based on the KDIGO criteria, which includes:^[18]
  • Elevated serum Creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
  • Elevated serum Creatinine to ≥1.5 times baseline within the previous 7 days; or
  • Urine volume < 0.5 ml/kg/h for >6 hours

• COVID-19-associated AKI commonly occurs between 5 to 9 days after hospitalization. ^[13]
• Patients in the early stages of kidney failure may be asymptomatic.
• If left untreated, patients may progress to develop Azotemia and Uremia, which occur due to the buildup of waste materials in the blood.
• Symptoms of kidney injury include ^[19]:
  • Nausea and Vomiting
  • Weakness
  • Fatigue
  • Weight loss
  • Loss of appetite

• Physical examination of patients with AKI is usually remarkable for^[19]:
  • Signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucosa
  • Fluid retention, leading to edema and swelling of periorbital and extremities
  • Confusion due to severe dehydration and electrolyte imbalances
  • Decrease in urine output:Oliguria or Anuria
  • cardiac arrhythmia due to electrolyte imbalances such as high level of Potassium

• Laboratory findings consistent with the diagnosis of COVID-19-associated AKI include^[20]:
  • Elevated serum creatinine
  • Elevated BUN level
    • Plasma BUN–creatinine ratio> 20 in prerenal AKI
    • Plasma BUN–creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
  • Fractional excretion of sodium (FENa)
    • (FENa)< 1% in prerenal AKI
    • (FENa)> 2% in intrinsic AKI or acute tubular necrosis
  • Urinary sediment
    • Hyaline casts in prerenal AKI
    • Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
  • Several biomarkers have been found to diagnose and predict AKI that include: ^[21][22][23]
    • neutrophil gelatinase-associated lipocalin (NGAL)
    • kidney injury molecule 1 (KIM-1)
    • liver-type fatty acid-binding protein
    • interleukin 18 (lL-18)
    • insulin-like growth factor-binding protein 7
    • tissue inhibitor of metalloproteinase 2 (TIMP-2)
    • calprotectin
    • urine angiotensinogen (AGT)
    • urine microRNA

• There are no specific ECG findings associated with AKI. However, electrolyte disturbances such as hyperkalemia might lead to various ECG abnormalities.

• There are no x-ray specific findings associated with AKI. However, X-ray may be used in the diagnosis of AKI associated volume overload.
• To view the x-ray finidings on COVID-19, click here.
  

• Ultrasound may be helpful in the diagnosis of AKI. Findings on ultrasound suggestive of AKI include hydrenephrosis and reduced renal blood flow.^[24]

• There are no CT scan findings associated with AKI.
• To view the CT scan findings on COVID-19, click here.

• There are no MRI findings associated with AKI.
• To view the MRI findings on COVID-19, click here.
  

• 99m Technetium (Tc) scan may be helpful in the diagnosis of AKI, which shows reduced renal blood flow and tubular function.^[24]
• To view other imaging findings on COVID-19, click here.
  

• There are no other diagnostic studies associated with AKI.
• To view other diagnostic studies for COVID-19, click here.
  

• Management of AKI following COVID-19 includes antiviral therapies, identifying electrolyte disorders, and intravenous fluid resuscitation.^[17]
  • Early diagnosis and treatment of AKI in patients with COVID-19 can avoid the progression of AKI into ESRD and reduce mortality.^[17]

• Treatment of AKI following COVID-19 includes:^{[17] [16]}
  • Correction of hypovolemia and hypotension by the administration of adequate intravenous fluid
    • Isotonic crystalloid is recommended among all patients who develop AKI. ^[18]
  • Correction of electrolyte disorders
  • antiviral therapy:
    • Recently, Remdesivir has been found effective against COVID-19. ^[25]
  • Anticoagulants in hypercoagulable conditions
  • Loop diuretics
    • In volume overload conditions
    • Diuretics should not be used regularly as they predispose patients to volume depletion.

• renal replacement therapy is recommended among patients with AKI who develop ^[26]
  • volume overload
  • severe metabolic acidosis
  • refractory hyperkalemia
  • uremic complications
    • Pericarditis
    • uremic encephalopathy
  • If AKI is unresponsive to supportive therapy
  • in hemodynamically unstable patients
    • The dialysis of choice in hemodynamically unstable patients with COVID-19 is continuous venovenous hemodialysis.
• renal replacement therapy is associated with hypercoagulation.^[16]
• To view COVID-19-associated hemodialysis, click here.
  
• Sequential extracorporeal therapy
  • It removes cytokines, which reduces systemic inflammation and subsequent organ failure.^[17]

Surgical intervention is not recommended for the management of COVID-19 associated AKI.

• Effective measures for the primary prevention of AKI include:^[27]
  • Volume resuscitation
    • Patients with COVID-19 should be evaluated for intravascular volume status based on physical examination and fluid balance.^[16]
    • Isotonic saline is recommended as a prevention strategy for patients who are at increased risk for AKI by expanding intravascular volume. ^[18]
  • Monitoring renal function tests
    • Serial monitoring of BUN, serum creatinine, and electrolytes such as sodium, potassium and bicarbonate should be considered frequently every 48 hours or more in high risk patients.^[16]
  • Avoidance of drugs and nephrotoxins in high risk patients^[28]

• Effective measures for the secondary prevention of AKI is using biomarkers for early diagnosis and treatment of AKI in early stages before it causes significant complications.^[29][21]

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