Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic hereditary kidney disorder, with a prevalence of 1 in 1,000 to 1 in 400. It is characterized by the widespread formation and progressive enlargement of cysts in both kidneys, ultimately leading to kidney failure. ADPKD is a systemic disorder, often accompanied by various extrarenal manifestations, including liver cysts, intracranial aneurysms, and cardiac valve abnormalities.
Etiology and Pathogenesis
Molecular Genetic Mechanisms
ADPKD is primarily caused by mutations in the PKD1 gene on chromosome 16p13.3 (85% of cases) or the PKD2 gene on chromosome 4q22-23. PKD1 and PKD2 encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Mutations in these genes result in renal tubular dilatation and the formation of cysts.
The Ciliary Hypothesis and "Two-Hit" Hypothesis
PC1 and PC2 are expressed in the primary cilia of renal tubular epithelial cells. Structural and functional abnormalities in these proteins lead to abnormal proliferation of tubular epithelial cells, accumulation of fluid within cystic cavities, reconstruction of extracellular matrix, and ultimately tubular dilatation and cyst formation. Somatic mutations in the normal allele of PKD1 or PKD2, triggered by acquired factors such as infection or toxicity, drive the development and progression of cysts, a process referred to as the "two-hit" hypothesis.
Clinical Manifestations
The clinical presentation of ADPKD varies widely, with disease onset often occurring in adulthood and involvement of multiple organs.
Renal Manifestations
Renal Cysts
Extensive cyst formation in both kidneys is the hallmark of ADPKD. Cysts increase in size and number as the disease progresses. Some patients may develop abdominal masses that are firm, nodular, and move with respiration.
Kidney Stones
Kidney stones are observed in approximately 20% of patients, most commonly consisting of uric acid and/or calcium oxalate.
Infections
Infections are the leading cause of fever in ADPKD patients. Common presentations include cystitis, pyelonephritis, cyst infections, and perinephric abscesses.
Cyst Hemorrhage and Gross Hematuria
These complications are attributed to cyst wall vascular rupture, stones, infections, or malignancies. About 40% of patients experience recurrent gross hematuria during the course of the disease, primarily caused by vascular rupture in the cyst walls.
Pain
Flank or abdominal pain occurs in approximately 60% of patients and is among the earliest symptoms. Acute pain may result from cyst rupture, hemorrhage, urinary obstruction, or infection, whereas chronic pain often arises from the stretching of renal capsules, pedicles, or surrounding tissues by enlarged kidneys or cysts.
Hypertension
Hypertension is among the earliest and most common manifestations, occurring in approximately 30% of affected children and 60% of patients who develop renal failure. The prevalence rises to 80% in end-stage renal disease patients.
Anemia
Compared with other causes of kidney failure, anemia in ADPKD tends to appear later and is generally mild in severity.
Proteinuria
Persistent proteinuria is common, typically with urinary protein levels less than 1 g/24 h. Proteinuria serves as an important risk factor for the progression of renal dysfunction.
Chronic Renal Failure
Approximately 50% of individuals aged 60 and older with ADPKD progress to end-stage renal disease.
Extrarenal Manifestations
Cystic Changes
Cystic lesions may involve the liver, pancreas, spleen, ovaries, arachnoid, and pineal gland. Liver cysts are the most common, though they rarely impair liver function.
Non-Cystic Abnormalities
These include cardiac valve abnormalities, colonic diverticula, intracranial aneurysms, and abdominal wall hernias. Intracranial aneurysms are the leading cause of early mortality. A small proportion of patients may present with vascular spasm-related headaches. About 30% of patients develop mitral valve prolapse.
Diagnosis
The diagnosis of ADPKD is primarily based on family history, clinical manifestations, imaging studies, and genetic testing.
Clinical Diagnostic Criteria
The diagnostic criteria for ADPKD include primary and secondary criteria, as shown in Table 1. A definitive diagnosis is established when both the primary and at least one secondary criterion are met.
Table 1 Clinical diagnostic criteria for ADPKD
Diagnostic Methods
Family History
Patients often have a clear familial inheritance pattern consistent with autosomal dominance, with a transmission risk of approximately 50% in offspring, affecting both males and females equally.
Imaging Studies
Ultrasound, CT, and MRI can all be utilized for diagnosis.
Ultrasound is considered the first-line diagnostic tool due to its cost-effectiveness and safety. Diagnostic criteria are outlined in Table 2. Color Doppler ultrasound shows multiple cysts of varying sizes within the kidneys, with spotty patterns of blood flow between cyst walls.
Table 2 Ultrasound diagnostic and exclusion criteria for ADPKD
CT demonstrates enlarged kidneys with numerous cysts of varying sizes. CT findings typically show a cyst density in the range of 8–20 Hu.
MRI provides high diagnostic accuracy, with evaluation criteria outlined in Table 3. MRI can calculate the cyst-to-normal kidney tissue cross-sectional area ratio, offering an objective measure of ADPKD progression.
Table 3 MRI diagnostic and exclusion criteria for ADPKD
Genetic Testing
Genetic testing may be considered under the following circumstances:
- Sporadic cases with no clear family history.
- Imaging studies that are atypical or difficult to distinguish from other cystic kidney diseases.
- Reproductive counseling.
- Early diagnosis in children with suspected ADPKD.
- Living kidney donors with a positive family history.
Differential Diagnosis
ADPKD needs to be differentiated from other cystic kidney diseases.
Autosomal Recessive Polycystic Kidney Disease (ARPKD)
ARPKD primarily affects newborns, with a prevalence of approximately 1 in 26,500, and it is associated with mutations in the PKHD1 gene. Most patients present at birth with kidney failure or progress to end-stage renal disease (ESRD), often accompanied by congenital hepatic fibrosis and Caroli disease (congenital cystic dilatation of intrahepatic bile ducts).
Multicystic Renal Dysplasia
This is the most common cystic kidney disorder in infants. Survivors typically have unilateral disease, with the affected kidney showing extensive cyst formation and no urinary function. The contralateral kidney is usually unaffected but may exhibit compensatory hypertrophy or hydronephrosis due to ureteral obstruction.
Simple Renal Cyst (SRC)
SRC commonly develops after the age of 40, with the prevalence increasing with age. Unlike ADPKD, there is typically no family history, kidney size remains normal, and cysts are single-chambered, located in the renal cortex. There is no clustering of smaller cysts or extrarenal manifestations such as liver cysts, and the condition follows a benign course.
Acquired Renal Cystic Disease (ARCD)
ARCD is most commonly observed in patients undergoing dialysis for more than 10 years. There is generally no family history, and the disease is often asymptomatic. Vigilance is needed for potential malignant transformation of cysts.
Medullary Sponge Kidney (MSK)
MSK is characterized by cyst formation due to dilatation of the medullary collecting ducts, usually associated with calcium deposition and kidney stones. Typical findings on urography include radial brush-like streaks or small cystic lesions in the renal calyces.
Treatment
The management of ADPKD involves general management, control of complications, and pharmacological therapy, with the primary goal being the delay of disease progression.
General Management
Adequate water intake is recommended, and strenuous contact sports should be avoided. For hypertension, a low-sodium diet is advised, while electrolyte disturbances and acid-base balance should be closely regulated in kidney failure.
Management of Complications
Hypertension
Blood pressure control is essential to slow disease progression. ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are commonly used.
Urinary Tract Infections
Lipophilic antibiotics that are effective against the causative agent and capable of penetrating cyst walls are preferred, with bacterial cultures from blood or urine and drug sensitivity tests guiding the choice of antibiotics.
Hemorrhage
Hematuria caused by cyst rupture and bleeding is often self-limiting and improves with bed rest. For refractory cases, selective renal artery embolization can be performed.
Pain
Acute pain management depends on the underlying cause, whereas chronic pain is typically monitored with rest. The World Health Organization's (WHO) analgesic ladder may be used when pain is severe or persistent. Cyst aspiration or decortication can be considered in cases where pain remains intractable.
End-Stage Renal Disease (ESRD)
Renal replacement therapies, such as kidney transplantation, hemodialysis, or peritoneal dialysis, are required in patients who develop ESRD.
Polycystic Liver Disease
Most cases do not require treatment. However, management options based on disease severity include cyst aspiration and sclerotherapy, cyst decortication, partial hepatectomy, or liver transplantation.
Intracranial Aneurysms
Asymptomatic aneurysms with a diameter of less than 7 mm typically do not require immediate intervention. Aneurysms larger than 10 mm, those that are rapidly growing, or associated with symptoms may warrant interventional or surgical treatment.
Pharmacological Therapy
Tolvaptan, a selective vasopressin V2 receptor (VPV2R) antagonist, has shown efficacy in inhibiting cyst growth in ADPKD. It is clinically used to treat adult patients with rapidly progressing disease.