What is acute kidney injury (AKI)?

Acute Kidney Injury (AKI), formerly known as acute renal failure, is a sudden and rapid decline in kidney function that occurs over a short period of time, usually within hours to days. AKI is characterized by a sudden decrease in urine output (oliguria) and/or an increase in serum creatinine levels, which reflects impaired kidney function and reduced filtration of waste products and toxins from the blood.

There are three main types of AKI:

  • Prerenal AKI: Prerenal AKI occurs due to factors that reduce blood flow to the kidneys, such as dehydration, severe blood loss (hemorrhage), heart failure, or conditions that cause severe vasoconstriction of the renal arteries. Reduced blood flow to the kidneys leads to decreased glomerular filtration rate (GFR) and impaired kidney function.
  • Intrinsic AKI: Intrinsic AKI occurs due to direct damage to the kidney tissue itself, often caused by ischemia (lack of blood flow) or toxic injury. Ischemic AKI can result from conditions such as severe hypotension, sepsis, or surgical complications, whereas toxic AKI can result from exposure to nephrotoxic substances, such as certain medications, contrast agents used in imaging studies, or heavy metals.
  • Postrenal AKI: Postrenal AKI occurs due to obstruction of the urinary tract that prevents urine from draining properly from the kidneys. This obstruction can be caused by conditions such as kidney stones, urinary tract infections, tumors, or enlarged prostate gland (in males). Urinary obstruction leads to back pressure on the kidneys, causing kidney damage and impaired function.

The clinical presentation of AKI can vary widely depending on the underlying cause, severity of kidney injury, and individual patient factors. Common signs and symptoms of AKI may include decreased urine output, fluid retention (edema), electrolyte imbalances, metabolic acidosis, nausea, vomiting, fatigue, and confusion. In severe cases, AKI can lead to life-threatening complications, such as hyperkalemia (high blood potassium levels), pulmonary edema (fluid accumulation in the lungs), and uremia (buildup of waste products in the blood).

What is the relationship between AKI and oxidative stress?

Oxidative stress plays a central role in the pathophysiology and progression of kidney damage in AKI. Here’s how AKI and oxidative stress are interrelated:

  • Ischemia-Reperfusion Injury: Ischemia-reperfusion injury, which occurs when blood flow to the kidneys is temporarily interrupted and then restored, is a common cause of AKI. During ischemia, the lack of oxygen and nutrients leads to cellular dysfunction and ATP depletion, triggering the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) upon reperfusion. The sudden influx of oxygen during reperfusion exacerbates oxidative stress, causing oxidative damage to cellular components and mitochondrial dysfunction. ROS and RNS promote inflammation, endothelial dysfunction, and apoptosis (cell death), contributing to kidney injury in AKI.
  • Inflammatory Response: AKI is associated with an inflammatory response characterized by the activation of immune cells and release of pro-inflammatory cytokines and chemokines. Inflammatory cells, such as neutrophils, macrophages, and lymphocytes, produce ROS and RNS as part of the immune response. These reactive species amplify the inflammatory cascade, promote tissue damage, and exacerbate kidney injury in AKI. Oxidative stress-induced inflammation further perpetuates kidney injury and impairs renal function.
  • Mitochondrial Dysfunction: Mitochondrial dysfunction is a key feature of AKI and is closely linked to oxidative stress. ROS generated during ischemia-reperfusion injury and inflammatory activation can damage mitochondrial DNA, proteins, and membranes, impairing mitochondrial function and bioenergetics. Mitochondrial dysfunction leads to increased ROS production, reduced ATP synthesis, and activation of cell death pathways, exacerbating kidney injury in AKI. Targeting mitochondrial ROS production and preserving mitochondrial function may represent potential therapeutic strategies for AKI.
  • Endothelial Dysfunction: AKI is associated with endothelial dysfunction, characterized by impaired nitric oxide (NO) bioavailability, increased vascular permeability, and vasoconstriction. ROS play a critical role in endothelial dysfunction by scavenging NO, promoting oxidative modifications of proteins and lipids, and disrupting endothelial signaling pathways. Endothelial dysfunction contributes to microvascular injury, renal hypoperfusion, and impaired renal blood flow regulation, exacerbating kidney injury in AKI.
  • Antioxidant Defense Mechanisms: The kidneys have intrinsic antioxidant defense mechanisms to neutralize ROS and protect against oxidative damage. However, during AKI, there is often an imbalance between ROS production and antioxidant capacity, leading to oxidative stress. Depletion of antioxidants, such as superoxide dismutase (SOD), catalase, and glutathione, or impaired antioxidant enzyme activity can further exacerbate oxidative stress and kidney injury in AKI. Strategies aimed at enhancing antioxidant defenses or administering exogenous antioxidants may help mitigate oxidative stress and attenuate kidney injury in AKI.