Polycystic Kidney Disease for ABIM

Polycystic Kidney Disease for the American Board of Internal Medicine

Polycystic kidney disease (PKD) is an inherited disorder characterized by the growth of numerous cysts in the kidneys, leading to progressive kidney enlargement and dysfunction. There are two major forms: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD is more common and affects adults, while ARPKD typically presents in infancy.

Autosomal Dominant Polycystic Kidney Disease (ADPKD):
ADPKD is caused by mutations in the PKD1 gene (85% of cases) or the PKD2 gene (15% of cases). PKD1 mutations are associated with more severe disease and earlier onset of end-stage renal disease (ESRD). Both genes encode proteins (polycystin-1 and polycystin-2) involved in tubular cell function and integrity.
Autosomal Recessive Polycystic Kidney Disease (ARPKD):
ARPKD results from mutations in the PKHD1 gene, which encodes fibrocystin. It primarily affects infants and children, often leading to severe kidney and liver involvement. ARPKD is less common than ADPKD.

Cyst Formation:
In both forms of PKD, cysts arise from renal tubular cells due to abnormal cell proliferation and fluid secretion. These cysts gradually enlarge, compressing and distorting the normal kidney parenchyma, leading to decreased renal function over time.

Progression to ESRD:
As cysts grow, they cause interstitial fibrosis and loss of functional nephrons, which results in progressive renal insufficiency. ADPKD patients typically reach ESRD between the ages of 50 and 70.
Extrarenal Manifestations:
PKD is a systemic disorder, and cysts may develop in other organs, including the liver, pancreas, and spleen. Additionally, vascular abnormalities, such as intracranial aneurysms, can occur in ADPKD.

Autosomal Dominant Polycystic Kidney Disease (ADPKD):
Renal Manifestations:
Hypertension: One of the earliest and most common findings in ADPKD, often appearing before significant renal impairment. Hypertension is due to cyst-induced renal ischemia, which activates the renin-angiotensin-aldosterone system (RAAS).
Flank Pain: Caused by cyst expansion, hemorrhage into cysts, or infection.
Hematuria: Microscopic or gross hematuria may occur, particularly with cyst rupture or infection.
Urinary Tract Infections (UTIs): Cyst infections, often presenting with fever, flank pain, and bacteriuria, are common in ADPKD.
Nephrolithiasis: Kidney stones occur in about 20% of ADPKD patients, usually composed of uric acid or calcium oxalate.
Progressive Renal Failure: The gradual enlargement of cysts leads to progressive decline in kidney function, culminating in ESRD.
Extrarenal Manifestations:
Hepatic Cysts: Occur in up to 80% of ADPKD patients, typically asymptomatic but may cause hepatomegaly or pain if large.
Intracranial Aneurysms: Found in approximately 10% of ADPKD patients, with an increased risk of rupture in those with a family history of aneurysms.
Mitral Valve Prolapse (MVP): Occurs in about 25% of patients and is often asymptomatic, but it can lead to mitral regurgitation.
Colonic Diverticula: Increased prevalence in ADPKD patients, though the clinical significance is unclear.

Autosomal Recessive Polycystic Kidney Disease (ARPKD):
Renal Manifestations:
Typically presents in infancy or childhood with enlarged, echogenic kidneys. Renal dysfunction is often severe at birth, leading to early-onset kidney failure.
Hepatic Involvement:
Congenital hepatic fibrosis is a hallmark of ARPKD, leading to portal hypertension and hepatosplenomegaly. Liver disease may predominate as renal function declines.
Respiratory Distress:
Infants may present with respiratory distress due to pulmonary hypoplasia secondary to oligohydramnios in utero (Potter sequence).

Family History and Clinical Presentation:
In ADPKD, a positive family history (usually autosomal dominant inheritance) and typical clinical findings (e.g., hypertension, flank pain) often suggest the diagnosis.
Imaging:
Ultrasound: The preferred initial test, showing multiple bilateral renal cysts. Diagnostic criteria for ADPKD include detecting at least two cysts in one kidney or one cyst in each kidney in patients younger than 30 years, with more cysts required for older age groups.
CT/MRI: More sensitive for detecting smaller cysts or complicated cases (e.g., infected or hemorrhagic cysts).
Genetic Testing:
May be performed when the diagnosis is uncertain or for family planning purposes. Mutations in PKD1 or PKD2 confirm ADPKD, while PKHD1 mutations confirm ARPKD.

Blood Pressure Control:
ACE Inhibitors or ARBs are first-line agents for controlling hypertension and slowing disease progression by reducing intraglomerular pressure.
Pain Management:
Flank pain due to cysts can be managed with analgesics, cyst aspiration, or surgical cyst decompression in refractory cases.
Treatment of Infections:
Cyst infections are treated with antibiotics that penetrate cysts, such as fluoroquinolones or trimethoprim-sulfamethoxazole. Infected cysts may also require drainage.
Management of Kidney Stones:
Hydration and alkalinization of urine are recommended to prevent stone formation. Surgical or extracorporeal shockwave lithotripsy (ESWL) may be needed for larger stones.
Renal Replacement Therapy:
ESRD is managed with dialysis or kidney transplantation. ADPKD patients are suitable candidates for transplantation, with outcomes similar to those of non-ADPKD patients.
Screening for Intracranial Aneurysms:
Screening with magnetic resonance angiography (MRA) is recommended in ADPKD patients with a family history of aneurysms or prior aneurysm rupture. Elective repair may be considered for large aneurysms (>7 mm).

ADPKD:
Progressive decline in renal function is common, with 50% of patients developing ESRD by age 60. Early blood pressure control and management of complications can slow progression.
ARPKD:
Prognosis is poor, especially in severe cases presenting at birth. Many infants die from respiratory failure, but those who survive may develop progressive liver and kidney disease.

Key Points

Polycystic kidney disease (PKD) is an inherited disorder characterized by the development of renal cysts, leading to progressive kidney dysfunction.
ADPKD is the most common form, associated with PKD1 and PKD2 mutations, and typically presents in adulthood with hypertension, flank pain, hematuria, and renal failure.
ARPKD affects infants and children, with severe kidney and liver involvement, often leading to early mortality.
Diagnosis is based on family history, clinical findings, and imaging, with ultrasound as the first-line diagnostic tool.
Management focuses on controlling hypertension (ACE inhibitors/ARBs), managing pain, treating infections, preventing kidney stones, and providing renal replacement therapy as needed.
Screening for intracranial aneurysms is recommended in ADPKD patients with a family history or personal risk factors.
Prognosis varies, with ADPKD leading to ESRD in 50% of patients by age 60, while ARPKD has a poorer prognosis, especially in severe neonatal cases.