What Are the Functions of the Kidney?
The kidney helps regulate electrolytes, acid-base balance, sodium and water homeostasis, metabolizing hormones, and excreting toxins. When acute kidney injury (AKI) occurs, it disrupts cerebral homeostasis at the cellular level and alters neurotransmitter concentration, acid-base balance, circulating cytokines, and drug metabolism.
What Is Acute Kidney Injury?
Acute kidney injury is one of the leading health concerns worldwide that develops within a few hours or days. The condition causes sudden loss of kidney function and retains nitrogenous waste products such as urea and creatinine. The disease causes mortality and systemic inflammation that can affect various organs. Acute kidney injury occurs in hospitalized patients and the elderly.
The central nervous system is vulnerable during acute kidney disease. Individuals suffering from acute kidney injury may develop confusion during disease onset or subsequent course of the disease. These changes could lead to direct and indirect insults to the brain.
The most frequent symptom of acute kidney injury is swelling in the legs, especially ankles. Other symptoms include eye puffiness, fatigue, shortness of breath, confusion, nausea, and chest pain. In severe cases, reduced urination, seizures, and coma can develop.
What Is the Cause of Developing Acute Kidney Injury?
Most patients develop acute kidney injury due to small vessel disease that could also be associated with hypertension, diabetes, and cardiac failure.
Older patients developing acute kidney injury may already have small vessel ischemic brain disease, including white matter changes, lacunar infarcts, and disturbed cerebral autoregulation that could cause additional cerebral injury.
What Are the Risk Factors for the Neurological Manifestation of Acute Kidney Injury?
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Uraemic toxin accumulation.
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Electrolyte imbalance.
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Drug toxicity.
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Thiamine deficiency.
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Renal replacement therapy, including dialysis disequilibrium.
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Encephalopathy (disease affecting the brain) can develop due to sepsis.
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Osmolality disturbance.
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Inflammation.
What Causes Neurological Complications to Develop in Acute Kidney Injury?
A decline in renal clearance of nitrogenous waste, along with continuous production, results in the accumulation of urea, creatinine, guanidine, and homocysteine. The accumulated toxins affect cell and organ functioning. It leads to endothelial vascular damage, neurotoxicity, and cognitive dysfunction.
A high serum sodium concentration and plasma osmolality in the brain result in reactive oxygen species formation. It causes endothelial injury and disruption of the blood-brain barrier and brain transporters. The immune response following AKI results in cytokine-induced disturbance to blood-brain barrier permeability that triggers inflammatory cascades, which further cause brain damage.
The kidneys have an essential role in maintaining cerebral homeostasis, which includes drug and toxin excretion and altering neurotransmitter and cytokine concentration. Uremic encephalopathy can occur due to acute kidney injury.
As acute kidney injury induces inflammation, it causes platelet activation, and raised thrombin activation increases the risk for cerebral ischemia, typical of malaria or leptospirosis-induced acute kidney injury. AKI also alters drug pharmacokinetics, which raises the risk of drug-induced encephalopathy. Neurologic complications following acute kidney injury are a significant cause of mortality.
Cerebral hemorrhage and thrombosis risk increase in individuals with acute kidney injury due to endothelial damage, abnormal platelet function, and coagulation cascade dysregulation. Individuals who develop acute kidney injury secondary to Good Pasture syndrome are at risk for steroid-induced psychosis. There is also a risk for over-immunosuppression in renal transplant patients, leading to encephalopathy.
What Are the Brain Complications Caused by Acute Kidney Injury?
Some of the brain manifestations are:
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Encephalopathy and altered higher mental functions.
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Delirium (confusion and reduced awareness).
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Headache.
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Visual abnormalities.
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Tremor.
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Asterixis (loss of motor control in specific body parts) through multifocal myoclonus.
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Chorea (abnormal involuntary movement).
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Dementia (loss of memory).
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Seizures.
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Coma.
What Are the Brain Consequences of Acute Kidney Injury?
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Disruption of Blood-Brain Barrier Integrity
The blood-brain barrier and blood-cerebrospinal fluid barrier are necessary to maintain cerebral homeostasis. It helps regulate the transport of proteins, amino acids, and essential nutrients in and out of the brain. The integrity of these barriers is managed by tight junctions between endothelial cells and choroid plexus and is supported by astrocytes (star-shaped glial cells). The proteins, amino acids, and inflammatory cells reach the brain tissue if the barrier is disrupted.
Although the association between blood-brain barrier integrity and AKI is not understood, the systemic inflammatory response induced by AKI could be a factor for brain injury. Inflammation can increase endothelial permeability, increase proinflammatory cytokine production, and reduce cytokine clearance.
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Changes in Cerebral Neurotransmitters
Complex brain functions are controlled by numerous interneuronal synapses that use a combination of excitatory and inhibitory neurotransmitters. Any derangement in the metabolism of this neurotransmitter could lead to cerebral function disruption that ranges from a coma to a hyperexcitation state. Any damage to neurotransmitters caused by acute kidney injury can cause the accumulation or depletion of amino acids and neurotransmitters within the brain.
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Changes in Endocrine Function
Peptide hormones in the blood get filtered by the glomerulus and reabsorbed in proximal tubules. The reabsorbed peptide hormones are degraded and recycled into amino acids. In individuals that develop acute kidney injury, free T3 (triiodothyronine) levels decline, but catecholamines, vasopressin, natriuretic peptides, and renin-angiotensin-aldosterone axis increase. An overactive sympathetic nervous system in the kidneys can increase the risk of hypertension and the development of posterior reversible encephalopathy syndrome caused by ischemic injury and edema in the cerebellum and medulla.
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Impact of Inflammatory Changes Induced by Acute Kidney Injury on the Brain
Increased passage of cytokine and inflammatory mediators into the brain can alter brain function and reduce locomotor activity. Inflammatory cells predominantly seen in the brain's cerebral cortex differ from the inflammatory response induced by AKI in other organs.
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Acid-Base Disturbances
The kidney regulates the body's acid-base balance to promote optimal cellular metabolism and function. Acute kidney injury can increase metabolic acidosis in the body, which harms cerebral neuronal metabolism and impairs cerebral function.
An increasingly acidic environment causes protons to activate acid-sensing ion channels, resulting in an influx of sodium and calcium into the cell, which leads to cell depolarization, injury, and death. The pH (potential of Hydrogen) declines intracellularly and within the cerebrospinal fluid, which could cause calcium influx, furthering cell injury.
Conclusion
Patients with acute kidney injury are at risk of developing cerebral dysfunction. Among older individuals, alterations in mental status are common. As acute kidney injury is an inflammatory systemic disease, it promotes brain injury by increasing the circulation of inflammatory mediators and cytokines. These inflammatory mediators can disrupt the blood-brain barrier, affect neuronal homeostasis, and increase endothelial permeability, inducing brain injury. Although there is a clear link between brain injury and acute kidney disease, further studies are needed.
