Veterans Affairs

Ticagrelor therapeutic for autosomal dominant polycystic kidney disease

New treatment for kidney diseases associated with elevated arginine vasopressin (AVP)

Medical & Biotechnology

The Department of Veterans Affairs has funded the research and development of a novel drug therapy that can improve the treatment of a common kidney disease. The patent-pending technology is now available to businesses for product development.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney, with a prevalence at birth ranging from 1 per 500 to 1000 people worldwide. It is caused by mutations in the PKD1 (85%) or PKD2 (15%) genes, which encode for polycystin-1 or polycystin-2 proteins, respectively. The hallmark of ADPKD is the formation of cysts in both kidneys, which gradually grow in size. Over time, new cysts form resulting in a decline of kidney function. By the age of 55 years, about 50% of the ADPKD patients develop end-stage renal disease (ESRD), which requires dialysis therapy or renal transplantation. There is no specific therapy for ADPKD. Its management is limited to control of high blood pressure, and symptomatic treatment of complications.

Kidneys affected by cysts. (Centers for Disease Control and Prevention image)

Researchers at the VA have now developed a treatment for ADPKD focused on decreasing arginine vasopressin (AVP) production in hypothalamus thereby inhibiting cyst growth in a kidney. The researchers use ticagrelor – a platelet aggregation inhibitor to lower the circulating level of AVP thus reducing signaling by AVP-dependent V1 and V2 receptors in a cell (renal collecting duct cell). This leads to decreased cellular calcium and secondary messenger cAMP level.

As compared to the currently available alternative for the reduction in the activity of AVP and production of cAMP in the kidney – vasopressin V2 receptor antagonism by tolvaptan – ticagrelor treatment has specific and clear advantages. First, administration of tolvaptan blocks the vasopressin V2 receptor and thus causes severe polyuria (loss of water in the urine), nocturia (frequent urination in the night), thirst and dry mouth in a vast majority of the patients. Other common side effects of tolvaptan are constipation, loss of appetite, dry skin, nausea, vomiting, and potential for acute liver failure. Furthermore, tolvaptan is metabolized by the CYP3A4 system, which may result in increased interactions with other medications. Although tolvaptan exhibits dose-related pharmacokinetics, it is unpredictable in ADPKD patients (or animals) who have varying degrees of renal dysfunction, thus necessitating therapeutic drug monitoring.

Use of ticagrelor may also be effective at treating dilutional hyponatremia a disorder characterized by an excess of body water relative to the body content of sodium. Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients (25-30%), associated with increased morbidity and mortality. Hyponatremia also represents a huge economic burden on the health care system, typically costing $10,000 more per hospitalized patient, over other hospitalized patients that do not have hyponatremia. It is often seen in patients with congestive heart failure, cirrhosis of the liver and in SIADH (syndrome of inappropriate antidiuretic hormone secretion). In these conditions, the plasma levels of AVP are inappropriately high.

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