Pilgrims of Hope Group

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder, characterized by the progressive development and enlargement of fluid-filled cysts within the renal parenchyma, ultimately leading to the destruction of normal kidney tissue, a decline in glomerular filtration rate, and end-stage renal disease (ESRD).

The disease is primarily caused by mutations in the PKD1 or PKD2 genes, which encode polycystin-1 and polycystin-2, respectively, leading to abnormalities in tubular epithelial cell function, including uncontrolled proliferation, abnormal fluid secretion, and a vicious cycle of cyst expansion under the influence of growth-promoting hormones.

Historically, treatment for ADPKD focused predominantly on supportive care, including rigorous blood pressure control (often with ACE inhibitors or ARBs) and managing complications such as pain, cyst infection, and hematuria. However, the therapeutic landscape was transformed by the introduction of agents that target the molecular drivers of cystogenesis. A key pathological pathway involves the activation of the adenylyl cyclase pathway by arginine vasopressin (AVP), which binds to the V2 receptor on the renal collecting duct cells, stimulating cyclic AMP (cAMP) production. Elevated cAMP is a major driver of cell proliferation and fluid secretion in ADPKD cysts. Tolvaptan, a selective vasopressin V2 receptor antagonist, works by blocking this AVP-mediated signaling cascade, thereby reducing intracellular cAMP levels. Clinical trials have demonstrated that this intervention can significantly slow the rate of increase in total kidney volume (TKV) and the decline in estimated glomerular filtration rate (eGFR) in patients with rapidly progressing disease. However, the use of this specific agent requires careful patient selection and continuous monitoring for potential side effects, particularly hepatotoxicity and the management of increased water excretion (polyuria), which underscores the complex risk-benefit profile of this first disease-modifying therapy.