Anticoagulation in Chronic Kidney Disease

Introduction:

Chronic kidney disease (CKD) patients are at an increased risk of thromboembolic events due to the hypercoagulable state of the blood as a result of altered homeostatic mechanisms. More than 15 % of patients with CKD are at an increased risk of atrial fibrillation as a result of increased platelet activity and pro-inflammatory events. Oral anticoagulants play a major role in preventing such complications and increasing the survival rates of patients with chronic kidney disease. Each anticoagulant shares unique pharmacological properties; hence it is important for the nephrologist to have a wide knowledge of these drugs to select the appropriate anticoagulant for the respective patients.

What Is Chronic Kidney Disease?

The gradual loss of kidney function characterizes chronic kidney disease. This results in the build-up of waste products and excess fluid in the body. In the early stages, it would not produce any symptoms. The symptoms appear as the disease advances, producing harmful effects on the body.

What Are the Causes of Chronic Kidney Disease?

The causes of chronic kidney disease include:

• Diabetes mellitus.

• Hypertension.

• Vesicoureteral reflux (irregular urine flow from the bladder back up the ureters that link the bladder to the kidneys).

• Interstitial nephritis (inflammation of the spaces between tubules of the kidney).

• Glomerulonephritis (refers to damaged glomeruli or small filters present inside the kidneys).

• Kidney stones.

• Polycystic kidney disease (a hereditary condition where groups of cysts form inside the kidneys, making the kidneys grow larger and lose their functioning).

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• Inherited kidney diseases (also known as autosomal dominant polycystic kidney disease).

• Prostate hypertrophy (age-related prostate gland enlargement that may make it difficult to urinate).

• Pyelonephritis (inflammation of the kidneys occurring due to bacterial infection).

What Are the Stages of Chronic Kidney Disease Based on the Estimated Glomerular Filtration Rate?

Chronic kidney disease can be categorized into five stages based on the eGFR (estimated glomerular filtration rate), and they are as follows:

• Stage 1 (Normal or High): When the eGFR value is greater than or equal to 90.

• Stage 2 (Mild Reduction): When the eGFR value is between 60 to 89.

• Stage 3a (Mild to Moderate Reduction): When the eGFR value is between 45 to 59.

• Stage 3b (Moderate to Severe Reduction): When the eGFR value is between 30 to 44.

• Stage 4 (Severe Reduction): When the eGFR value is between 15 to 29.

• Stage 5 (Most Severe Reduction): When the eGFR value is less than 15.

What Are the Symptoms of Chronic Kidney Disease?

The symptoms include:

• Nausea.

• Vomiting.

• Fatigue and weakness.

• Loss of appetite.

• Muscle cramps.

• Urinating more or less.

• Decreased mental sharpness.

• Swelling of feet and ankles.

• Pruritus (itching).

• High blood pressure (hypertension).

• Shortness of breath.

• Chest pain.

What Are Anticoagulants?

Anticoagulants are medicines that help to prevent blood from clotting. They are usually indicated in patients with high chances of clot formation, such as cardiac patients and patients with a history of stroke.

Why Is Anticoagulation Important in Patients with Chronic Kidney Disease?

In patients with chronic kidney disease, there is altered homeostasis of the body, causing uremia (increased uric acid in the blood), anemia (decreased red blood cell count), abnormal mineral metabolism, systemic inflammation, activation of the renin-angiotensin-aldosterone system, and platelet hyperactivity. All the above-discussed factors have an impact on the cardiovascular system, increasing the hypercoagulability of the blood resulting in clot formation and increasing the chances of thrombosis (blood clots blocking arteries and veins) and embolism (sudden blockage of arteries due to a foreign body or clots).

What Is the Pathogenesis of Hypercoagulation in Patients With Chronic Kidney Disease?

The pathogenesis in the blood hypercoagulability of patients with chronic kidney disease includes three components called Virchow's triad. The factors include:

• Stasis and turbulent flow of the blood.

• Endothelial injury to the walls of the blood vessels.

• Increased platelet activity (hypercoagulability).

All three factors would contribute to the initiation of inflammation and increase the coagulation activity of the platelets. Another important factor that would increase the risk of coagulation in chronic kidney disease patients is uremia. Increased uric acid levels in the blood would increase the levels of clotting factors such as fibrinogen, thrombomodulin, von Willebrand factor, etc., resulting in atherosclerosis and arterial stiffness, thereby contributing to cardiovascular complications.

What Is the Frequency of Complications Due to Hypercoagulability in Patients With Chronic Kidney Disease?

Studies report that the risk in predialysis patients with chronic kidney disease ranges from four percent to 21 %. In patients with pre-existing ST-elevation myocardial infarction, the risk increases to 30 %. The risk of thromboembolism is estimated to be 29 % in patients with mild CKD and may increase up to 134 % in patients under dialysis for CKD treatment. As compared to the general population, patients with CKD are at a 2.5 to 5.5 times higher risk for thromboembolic events.

What Are the Anticoagulants Used in Patients With Chronic Kidney Disease?

The commonly used oral anticoagulants in chronic kidney disease patients include Warfarin, Dabigatran, Rivaroxaban, Apixaban, etc. These drugs require dose adjustment in patients with CKD based on their pharmacological properties.

• Warfarin: Warfarin is a vitamin-K-dependent factor inhibitor. It is metabolized by the CYP2C9 enzyme that breaks down the Warfarin complex. No renal dose adjustment is required in the case of Warfarin in patients with CKD, as kidneys are not involved in the metabolism of Warfarin. It is nondialyzable, and its binding to the effector is not reversible.

• Dabigatran: Dabigatran is a direct thrombin inhibitor, which is metabolized by the esterase enzyme. Renal dose adjustment is needed in the case of Dabigatran, as 80 % of the drug is excreted by the kidneys. It is dialyzable, and its binding to the effector is reversible.

• Rivaroxaban: Rivaroxaban is a free and clot-bound factor Xa inhibitor. Renal dose adjustment is essential in Rivaroxaban as 66 % of the drug is excreted by the kidneys, and the rest, 36 %, remains unchanged with minimal excretion in feces. It is nondialyzable, and its binding to the effector is reversible.

• Apixaban: Apixaban is a free and clot-bound factor Xa inhibitor. It is metabolized in the liver by an enzyme called CYP3A4. 25 % of the drug is excreted by the kidneys, and the rest is in feces. No renal dose adjustment is required in the case of Apixaban. A small amount of it is dialyzable, and its binding to the effector is reversible.

What Is the Necessary Dose Adjustment Required in Patients With Chronic Kidney Disease?

• Warfarin: It usually does not require any dose adjustment as it is not metabolized by the kidneys. But it is essential to alter the dose based on the estimated glomerular filtration rate values.

• Dabigatran: When the eGFR values are above 50, then 150 mg of Dabigatran can be given twice daily. When the eGFR values are below 30, and above 15, then 75 mg of Dabigatran can be given twice daily. In the case of patients with end-stage renal disease and eGFR less than 15, it is not recommended to prescribe Dabigatran.

• Rivaroxaban: When the eGFR values are above 50, then 20 mg of Rivaroxaban can be given once daily. When the eGFR values are below 30, and above 15, then 15 mg of Rivaroxaban can be given once daily. In the case of patients with end-stage renal disease and eGFR less than 15, it is not recommended.

• Apixaban: When the eGFR values are above 50, then 5 mg of Apixaban can be given twice daily. When the eGFR values are below 30, and above 15, then 2.5 mg of Apixaban can be given twice daily. In the case of patients with end-stage renal disease, adding an eGFR of less than 15 is not recommended.

Conclusion:

Anticoagulation is one of the vital steps in treating patients with chronic kidney disease, as patients with CKD are at a 2.5 to 5.5 times higher risk of developing thromboembolic and cardiovascular complications. It is important to put them under anticoagulants to decrease platelet hyperactivity and reduce the hypercoagulability of the blood. Prophylactic anticoagulants would help them survive better and reduce unnecessary complications.