Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Inheritance of polycystic kidney disease (PKD) is

Autosomal dominant polycystic kidney disease (ADPKD) has an incidence of 1/1000 and accounts for about 5% of patients with end-stage kidney disease (ESKD) requiring renal replacement therapy Overview of Renal Replacement Therapy Renal replacement therapy (RRT) replaces nonendocrine kidney function in patients with renal failure and is occasionally used for some forms of poisoning. Techniques include continuous hemofiltration... read more . Clinical manifestations are rare before adulthood, but penetrance is essentially complete; all patients ≥ 80 years have some signs.

In contrast, autosomal recessive polycystic kidney disease Autosomal recessive polycystic kidney disease The urinary tract is a common location for congenital anomalies of varying significance. Many anomalies are asymptomatic and diagnosed via prenatal ultrasonography or part of a routine evaluation... read more is rare; incidence is 1/10,000. It frequently causes renal failure during childhood.

In 86 to 96% of cases, ADPKD is caused by mutations in the PKD1 gene on chromosome 16, which codes for the protein polycystin 1; most other cases are caused by mutations in the PKD2 gene on chromosome 4, which codes for polycystin 2. A few familial cases are unrelated to either locus.

Polycystin 1 may regulate tubular epithelial cell adhesion and differentiation; polycystin 2 may function as an ion channel, with mutations causing fluid secretion into cysts. Mutations in these proteins may alter the function of renal cilia, which enable tubular cells to sense flow rates. A leading hypothesis proposes that tubular cell proliferation and differentiation are linked to flow rate and that ciliary dysfunction may thus lead to cystic transformation.

Vasopressin promotes cell growth and fluid secretion via the cyclic AMP pathway, which leads to increase in the size and number of cysts in polycystic kidney disease.

Early in the disorder, tubules dilate and slowly fill with glomerular filtrate. Eventually, the tubules separate from the functioning nephron and fill with secreted rather than filtered fluid, forming cysts. Hemorrhage into cysts may occur, causing hematuria. Patients are also at higher risk of acute pyelonephritis Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys ( pyelonephritis), and lower tract infections, which involve the bladder ( cystitis), urethra... read more , cyst infections, and urinary calculi Acute pyelonephritis Bacterial urinary tract infections (UTIs) can involve the urethra, prostate, bladder, or kidneys. Symptoms may be absent or include urinary frequency, urgency, dysuria, lower abdominal pain... read more (in 20%). Vascular sclerosis and interstitial fibrosis eventually develop via unknown mechanisms and typically affect < 10% of tubules; nonetheless, renal failure Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more develops in about 35 to 45% of patients by age 60.

Extrarenal manifestations are common:

Autosomal dominant polycystic kidney disease usually causes no symptoms initially; one half of patients remain asymptomatic, never develop renal insufficiency or failure, and are never diagnosed. Most patients who develop symptoms do so by the end of their 20s.

Symptoms include low-grade flank, abdominal, and lower back pain due to cystic enlargement and symptoms of infection. Acute pain, when it occurs, is usually due to hemorrhage into cysts or passage of a calculus Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more . Fever is common with acute pyelonephritis Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys ( pyelonephritis), and lower tract infections, which involve the bladder ( cystitis), urethra... read more , and rupture of cysts into the retroperitoneal space may cause a fever that can last for weeks. Hepatic cysts Hepatic Cysts Isolated hepatic cysts are commonly detected incidentally on abdominal ultrasonography or CT ( 1). These cysts are usually asymptomatic and have no clinical significance. The rare congenital... read more may cause right upper quadrant pain if they enlarge or become infected.

Valvular disorders rarely cause symptoms but occasionally cause heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more and require valvular replacement Surgery and percutaneous procedures Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more .

Symptoms and signs of unruptured cerebral aneurysm Brain Aneurysms Brain aneurysms are focal dilations in the cerebral arteries. In the United States, brain aneurysms occur in 3 to 5% of people. Brain aneurysms can occur at any age but are most common among... read more can be absent or may include headache, nausea and vomiting, and cranial nerve deficits; these manifestations warrant immediate intervention.

Signs are nonspecific and include hematuria Isolated Hematuria Hematuria is red blood cells (RBCs) in urine, specifically > 3 RBCs per high-power field on urine sediment examination. Urine may be red, bloody, or cola-colored (gross hematuria with oxidation... read more and hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more (each in about 40 to 50%) and, in 20% of patients, proteinuria in the subnephrotic range (< 3.5 g/24 hours in adults). Anemia is less common than in other types of chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , presumably because erythropoietin production is preserved. In advanced disease, the kidneys may become grossly enlarged and palpable, causing fullness in the upper abdomen and flank.

The diagnosis of polycystic kidney disease is suspected in patients with the following:

Patients should be counseled before undergoing diagnostic testing, particularly if they are asymptomatic. For example, many authorities recommend against testing asymptomatic young patients because no disease-modifying treatment is effective at this age and diagnosis has potential negative effects on mood and on the ability to obtain life insurance on favorable terms.

Diagnosis is usually by imaging, showing extensive and bilateral cystic changes throughout the kidneys, which are typically enlarged and have a moth-eaten appearance due to cysts that displace functional tissue. These changes develop with age and are less often present or obvious in younger patients.

Ultrasonography is usually done first. For patients with family history of ADPKD, ultrasound criteria (based on age and number of renal cysts) are used to diagnose or exclude ADPKD. Imaging criteria are not established in patients with negative or unknown history. CT or MRI are often done after establishing the diagnosis of ADPKD. CT and MRI are more sensitive than ultrasound in detecting cysts and can be useful in equivocal cases and for measuring cyst and kidney volume, which can have prognostic implications.

Urinalysis Urinalysis In patients with renal disorders, symptoms and signs may be nonspecific, absent until the disorder is severe, or both. Findings can be local (eg, reflecting kidney inflammation or mass), result... read more , renal function tests, and complete blood count (CBC) are done, but results are not specific.

Urinalysis detects mild proteinuria and microscopic or macroscopic hematuria. Gross hematuria may be due to a dislodged calculus Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more or to hemorrhage from a ruptured cyst. Pyuria is common even without bacterial infection; thus diagnosis of infection should be based on culture results and clinical findings (eg, dysuria, fever, flank pain) as well as urinalysis. Initially, blood urea nitrogen (BUN) and creatinine are normal or only mildly elevated, but they slowly increase, especially when hypertension is present. Rarely, CBC detects polycythemia.

Patients with symptoms of cerebral aneurysm require high-resolution CT or magnetic resonance angiography. However, most experts do not recommend routine screening for cerebral aneurysm in asymptomatic patients. A reasonable approach is to screen patients with autosomal dominant polycystic kidney disease (ADPKD) who have a family history of hemorrhagic stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more or cerebral aneurysm Subarachnoid Hemorrhage (SAH) Subarachnoid hemorrhage is sudden bleeding into the subarachnoid space. The most common cause of spontaneous bleeding is a ruptured aneurysm. Symptoms include sudden, severe headache, usually... read more .

Genetic testing for polycystic kidney disease (PKD) mutations is currently reserved for any of the following:

Genetic counseling is recommended for 1st-degree relatives of patients with ADPKD.

Strict control of hypertension Treatment Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more is essential. Typically an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker is used. In addition to controlling blood pressure, these medications help block angiotensin and aldosterone, growth factors that contribute to renal scarring and loss of renal function. Urinary tract infections Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys ( pyelonephritis), and lower tract infections, which involve the bladder ( cystitis), urethra... read more (UTIs) should be treated promptly. Percutaneous aspiration of cysts may help relieve severe pain due to hemorrhage or compression but has no effect on long-term outcome. Nephrectomy is an option to relieve severe symptoms due to massive kidney enlargement (eg, pain, hematuria) or recurrent UTIs.

Hemodialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more , peritoneal dialysis Peritoneal Dialysis Peritoneal dialysis uses the peritoneum as a natural permeable membrane through which water and solutes can equilibrate. Compared to hemodialysis, peritoneal dialysis is Less physiologically... read more , or kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more is required in patients who develop chronic renal failure. ADPKD does not recur in grafts.

Supportive measures include increased fluid intake (particularly water) to suppress vasopressin release, even if only partially, in patients who are able to safely excrete the load.

Tolvaptan, a vasopressin receptor 2 antagonist, is a medication that may benefit patients with ADPKD (1, 2 Treatment references Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more ). Tolvaptan appears to slow increase in renal volume and decline in renal function, but it can cause adverse effects via free water diuresis (eg, thirst, polydipsia, polyuria) that can make adherence difficult. Tolvaptan has been reported to cause severe liver failure and is hence contraindicated in patients with significant liver impairment or injury. Tolvaptan may be especially beneficial for patients at higher risk for rapid progression of kidney disease. Expert consultation is recommended before starting tolvaptan due to its potential adverse effects. Tolvaptan has not been studied in children and is not recommended in those < 18 years of age.

In children with ADPKD, early use of pravastatin may slow the progression of structural kidney disease (3 Treatment references Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more ).

Renal failure develops in 35 to 45% of patients with autosomal dominant polycystic kidney disease (ADPKD) by age 60. By age 75, 50 to 75% of patients require renal replacement therapy Overview of Renal Replacement Therapy Renal replacement therapy (RRT) replaces nonendocrine kidney function in patients with renal failure and is occasionally used for some forms of poisoning. Techniques include continuous hemofiltration... read more (dialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more or transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more ). On average, glomerular filtration rate (GFR) declines by about 5 mL/minute/year after the fourth decade of life. Predictors of more rapid progression to renal failure include the following:

Cyst and kidney volume measurements predict risk of progression to chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more and end-stage kidney disease, often before changes in routine laboratory studies. For example, cyst size and kidney size predict 8-year risk of chronic kidney disease more accurately than age, degree of proteinuria, or serum blood urea nitrogen (BUN) or creatinine. Kidney size is the most important predictor for progression, particularly total kidney volume >1500 mL (1 Prognosis references Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more ).

Phosphaturic hormone fibroblast growth factor (FGF) 23 elevation was associated with increased kidney size and annualized rate of estimated glomerular filtration rate (eGFR) decline but interestingly did not enhance risk prediction for disease progression (2 Prognosis references Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more ).

ADPKD does not increase risk of renal cancer, but if patients with ADPKD develop renal cancer, it is more likely to be bilateral. Renal cancer rarely causes death. Patients usually die of heart disease (sometimes valvular), disseminated infection, or ruptured cerebral aneurysm.