Introduction:
The kidney is a part of the urinary system with a higher blood supply than other organs. Kidneys help maintain equilibrium in the internal environment because of increased blood vessels. Individuals with CKD have the highest incidence of Alzheimer's disease. The cognitive function improves with kidney transplantation. The concept that CKD enhances cognitive decline and AD leads to a new field of analysis regarding the cause and helps in the treatment and prevention of AD.
What Is Alzheimer’s Disease?
Alzheimer’s disease, a brain disorder, is a type of dementia that affects memory, thinking, and the capability to do everyday tasks. It alters the brain and causes the deposition of certain proteins. This leads to brain cell shrinkage and death. The signs of Alzheimer’s disease include alteration in thinking, memory, reasoning, and behavior. It begins with forgetting the conversations and then progresses to more serious problems like the inability to perform daily routines.
Currently, there is no treatment to cure Alzheimer’s disease. Medications are prescribed to improve the symptoms and behavior. Some drugs may help slow or prevent the progression of the condition.
What Is CKD?
Chronic kidney disease or chronic renal disease is the progressive loss of kidney function. Kidneys help in removing waste products and excess fluid from the body. When the kidney function is impaired, it will not filter the blood effectively, accumulating waste and other products in the blood. There is no cure for CKD. The steps will be taken to slow down the progression of the disease and treat the symptoms. CKD is classified into five stages. Stage 1 and 2 cause minor kidney damage, stage 3 and 4 cause moderate to severe kidney damage, and stage 5 causes renal failure or end-stage renal disease. The end-stage renal disease requires dialysis.
What Are the Mechanisms Involved in AD and Cognitive Decline in CKD?
-
Uremic Toxins: The excessive build-up of urinary toxins impacts various organs in the body through blood flow. The impaired kidney function leads to increased PTH (parathyroid hormone) in the blood. The PTH can cross the blood-brain barrier. A study revealed that increased PTH leads to a decline in cognitive functioning of the brain and also due to the presence of PTH2 receptors in the central nervous system. Certain studies revealed the close link between PTH and cognitive function; thus, performing parathyroidectomy in individuals with secondary hyperparathyroidism may improve cognitive function. An increase in PTH due to renal disease may show an association between cognitive decline and PTH in CKD patients. The urinary toxin aluminum crosses the blood-brain barrier and affects brain structure. Aluminum has a vital role in metabolic processes in the CNS. A high serum aluminum level is a significant risk element for cognitive decline. In individuals with impaired renal function, aluminum deposition serves as a factor for cognitive decline in CKD.
-
Common Risk Elements: Many common features exist between the causes of AD and CKD, which include high blood pressure, aging, vascular degeneration, diabetes, and hyperlipidemia. Along with these, amyloid precursor protein (APP) is produced in excess in individuals with kidney disease. Another protein, sorLA (sorting protein-related receptor), controls APP processing and is found in kidney cells and neurons. Any changes in the gene lead to AD.
-
Hypertension: Hypertension increases the likelihood of diabetes. The process behind this is unknown. Hypertension may give rise to hypoxia (low oxygen levels), ischemia (reduced blood flow and oxygen), vascular injury, vascular stiffness (reduced artery flexibility), and vascular calcifications (deposition of calcium on artery walls). These may be linked to the process behind the occurrence of AD. Vascular stiffness promotes the development of CKD and thus increases cognitive decline.
-
Erythropoietin: The kidneys produce a protein called erythropoietin, which helps in the proliferation and generation of erythroid stem cells. It helps to maintain the hemoglobin concentration in the blood. Tubulo-interstitial fibrosis leads to decreased production of EPO, which is seen in CKD. The decreased EPO production increases the risk of AD. EPO plays a crucial role in brain health. EPO or EPOR signaling is essential for the development of the brain. It protects the neurons from apoptosis (cell death), inflammation, oxidative stress, and glutamate excitotoxicity (a process that causes neuronal damage). These factors reveal the importance of EPO's neuroprotective nature in Alzheimer’s disease.
What Are the Markers Related to AD?
-
Amyloid β Protein: The classic characteristics of AD are senile plaques, neuron or synapse loss, and neurofibrillary tangles. Aβ protein (a major component of senile plaques) is directly secreted into the cerebrospinal fluid by the neurons. Aβ protein levels are also high in CKD patients due to the reduced elimination of this protein from the blood. This shows the link between cognitive decline and AD in CKD patients.
-
Tau Protein: Neurofibrillary tangles are another important feature of AD. Tau or phosphorylated tau protein is the main constituent of these tangles. An increase in this protein in CSF is associated with AD. Additionally, the elevation of aluminum in CKD may cause a change in tau protein, which causes AD.
-
Serum Homocysteine: Serum homocysteine is an independent risk variable for AD. In CKD, the removal of serum homocysteine is reduced, and increases the level of it in the blood. This sulfur-containing amino acid is considerably higher in Alzheimer's disease patients. This shows the link between cognitive decline and AD.
What Are the Potential Biomarkers Related to CKD?
-
Proteinuria and Glomerular Filtration Rate (GFR): The urine protein level increases due to some abnormalities in the kidney. This occurs most commonly in CKD, which is caused by defects in the glomerular filtration barriers. GFR measures glomerular filtration function. In CKD, the GFR is lower, excretion of creatinine is lower, and serum concentration of creatinine is higher. Proteinuria and eGFR (estimated glomerular filtration rate) are associated with cognitive decline.
-
Hemoglobin Levels: Erythropoietin is responsible for maintaining the levels of red blood cells. In CKD, the EPO level is reduced, causing anemia. It has been proved that EPO has neuroprotective effects. Thus, a decrease in EPO causes damage to brain cells, resulting in cognitive decline.
-
Urotoxins: Uremic toxins include phosphorus, PTH, and aluminum. In CKD, the concentration of PTH increases, leading to cognitive decline.
Conclusion:
In recent years, the prevalence of cognitive decline or Alzheimer’s disease has been higher in CKD patients. The increased concentration of uremic toxins, high blood pressure, decreased concentration of EPO, vascular injury, or stiffness shows the association of CKD with Alzheimer’s disease. Understanding these mechanisms helps in the diagnosis and treatment of AD in CKD patients.
