Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder, affecting hundreds of thousands of people globally. It is a progressive condition characterized by the growth of numerous fluid-filled sacs, known as cysts, which develop primarily in the kidneys. Over time, these cysts multiply and enlarge the kidneys, leading to a decline in their ability to filter waste from the blood. This gradual loss of function ultimately results in kidney failure for many individuals.
Defining ADPKD and How Cysts Form
ADPKD is passed down through families in an autosomal dominant pattern. This means a child needs to inherit only one copy of the mutated gene from an affected parent to develop the condition, resulting in a 50% chance of inheritance. The vast majority of cases are caused by mutations in the PKD1 or PKD2 genes, which provide instructions for making polycystin-1 and polycystin-2 proteins. PKD1 mutations are the most common (78% to 85% of cases) and are associated with a more rapidly progressive form of the disease.
The polycystin proteins are located in the primary cilia, tiny, hair-like structures on the surface of renal tubular cells that act as mechanosensors. When these proteins are mutated, the cell’s signaling pathways are disrupted, driving cyst growth through two processes. First, the epithelial cells lining the renal tubules proliferate at an abnormal rate. Second, the cells secrete fluid into the newly formed sac, causing it to expand.
Cyst formation is often explained by the “two-hit” model. This model posits that after inheriting one mutated gene copy (the first hit), a second, spontaneous mutation occurs in the remaining healthy copy within a specific kidney cell. This second hit causes the cell to lose normal polycystin function, leading to unchecked growth and fluid secretion. Thousands of cysts develop, detaching from the nephron and growing autonomously. This expansion compresses surrounding functional kidney tissue, impairing function, and is driven by increased levels of cyclic adenosine monophosphate (cAMP), which stimulates cell growth and fluid movement.
Recognizing the Signs and Symptoms
Symptoms of ADPKD are a direct consequence of growing cysts and compromised kidney function, though they usually appear between ages 30 and 40. One common manifestation is pain, typically felt in the back, flank, or abdomen. This pain can be intermittent or persistent, often resulting from the enlarged kidneys’ size or complications like cyst rupture and bleeding.
High blood pressure (hypertension) is another frequent and early sign, occurring in over 60% of patients before significant kidney function decline. This early hypertension is caused by growing cysts activating the body’s blood pressure regulatory system, increasing cardiovascular risk. Patients may also experience hematuria (blood in the urine), which is often due to a cyst bleeding into the urinary system.
Recurrent urinary tract infections (UTIs) and kidney stones are common problems linked to ADPKD. The structural changes caused by cysts slow urine flow and create pockets where bacteria thrive, increasing infection risk. ADPKD is also a multisystem disorder causing extra-renal complications, most notably liver cysts and, less frequently, aneurysms in the brain’s blood vessels. Liver cysts are common and may cause abdominal pain or fullness if large, though they rarely lead to liver failure.
Diagnosis and Comprehensive Treatment Approaches
Confirming an ADPKD diagnosis typically involves family medical history, physical examination, and imaging studies. Imaging, such as ultrasound, Computed Tomography (CT), or Magnetic Resonance Imaging (MRI), is the primary method used to visualize the kidneys and count cysts. Diagnosis is based on age-specific criteria requiring a certain number of cysts in both kidneys. MRI is particularly useful for accurately measuring Total Kidney Volume (TKV), a key indicator of disease progression.
Genetic testing to identify a mutation in the PKD1 or PKD2 genes may be used when imaging results are inconclusive or to confirm the diagnosis in younger individuals. Determining the specific gene mutation helps estimate the likely rate of disease progression. This information is important for guiding treatment decisions and patient counseling.
Treatment for ADPKD is divided into supportive care for symptoms and disease-modifying therapy to slow progression.
Supportive Care
Supportive care focuses heavily on controlling hypertension, as high blood pressure accelerates kidney damage. Medications that block the renin-angiotensin-aldosterone system (e.g., ACE inhibitors or ARBs) are commonly prescribed to manage blood pressure and protect kidney function. Pain management involves careful use of analgesics, often avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) which can harm the kidneys. Infections are treated aggressively with antibiotics.
Disease-Modifying Therapy
The primary disease-modifying therapy is the medication tolvaptan, approved to slow the decline in kidney function in adults with rapidly progressing ADPKD. Tolvaptan works as a vasopressin V2 receptor antagonist, blocking the action of the vasopressin hormone in the kidney tubules. By blocking this receptor, tolvaptan lowers cyclic AMP levels within the tubular cells. This action reduces the abnormal proliferation and fluid secretion that fuel cyst growth.
Clinical trials show that tolvaptan significantly slows the rate of increase in Total Kidney Volume and reduces the annual decline in the estimated Glomerular Filtration Rate (eGFR), a measure of kidney function. This treatment is typically initiated in patients aged 18 to 55 who show evidence of rapid disease progression. When kidney function declines to End-Stage Renal Disease (ESRD), management shifts to advanced treatment. Options include long-term dialysis, which artificially filters the blood, or a kidney transplant, which offers the best chance for a near-normal quality of life.