Polycystic kidney disease

Polycystic kidney disease (PKD) is an inherited disorder characterized by the development of multiple cysts in the kidneys. There are two forms of PKD: autosomal dominant (ADPKD) and autosomal recessive (ARPKD). Both disorders have a wide range of clinical presentations. ADPKD manifests with flank pain, arterial hypertension, and end-stage renal disease (ESRD) with symptom onset in adulthood. Patients with severe ARPKD and onset during infancy or early childhood have a mortality rate of up to 40% and typically present with respiratory failure and progressive renal impairment. Early diagnosis and treatment may prevent or delay ESRD in both conditions, but kidney transplant is the only curative treatment option.

• Incidence
  • ADPKD: ∼ 1/1,000 ^[1]
    • The most common inherited cause of chronic kidney disease ^[2]
    • Responsible for 5–10% of end-stage renal disease (ESRD) ^[3]
  • ARPKD: ∼ 1/20,000 ^[4]
• Prevalence: ∼ 140,000 patients with polycystic kidney disease in the US ^[5]
• Sex: ♂ = ♀ ^[6]

Epidemiological data refers to the US, unless otherwise specified.

• ADPKD ^[7]
  • Autosomal dominant inheritance
  • Complete penetrance but variable expressivity
  • Mutation in: ^[8][9]
    • PKD1 on chromosome 16 (85% of cases); , the gene that encodes polycystin-1 OR
    • PKD2 on chromosome 4 (15% of cases); , the gene that encodes polycystin-2
  • Positive family history ^[1]
• ARPKD
  • Autosomal recessive inheritance
  • Mutation in PKHD1 gene on chromosome 6, the gene that encodes for fibrocystin, a protein involved in the maintenance of primary cilia of the renal collecting duct and biliary epithelial cells

ADPKD

• Two-hit hypothesis
  • Inherited mutation in one allele of PKD1 (polycystin-1) or PKD2 (polycystin-2) genes ^[10]
    • Polycystin-1: involved in cell-cell and/or cell-matrix interactions
    • Polycystin-2: a nonselective cation channel transporting Ca²⁺
  • Additional second somatic acquired mutation in tubule epithelial cells
• Abnormal cilia-mediated signaling pathways →; formation and expansion of cysts in the renal cortex and medulla → compression of renal vessels with activation of the renin-angiotensin-aldosterone system (RAAS), ischemia, and destruction of the kidney parenchyma ^[11]

ARPKD

• Inherited mutation in the PKHD1 gene → defective fibrocystin (also called polyductin) → cystic dilatation of collecting ducts and bile ducts (intrahepatic and extrahepatic bile ducts) ^[12]

ADPKD ^[1][11]

Clinical manifestations of ADPKD usually directly correlate with the progression of cystic degeneration.

Symptom onset

• Symptom onset most commonly occurs after 30 years of age but can develop earlier, occasionally even in childhood. ^[1]
• Patients with the PKD2 mutation often have less severe symptoms and later onset than patients with the PKD1 mutation. ^[1][13]

Renal manifestations

• Mild polyuria
• Macroscopic hematuria
• Flank and/or abdominal pain
• Recurrent UTIs
• Nephrolithiasis
• Signs of CKD (e.g., fluid overload, uremia)
• Palpable, enlarged kidneys (usually normal at birth)

Extrarenal manifestations

• Digestive
  • Hepatic cysts: multiple, benign, mostly asymptomatic, and more prevalent with age
  • Pancreatic cysts
  • Colonic diverticulosis
  • Abdominal or inguinal hernias
• Cardiovascular
  • Symptoms of hypertension; , e.g., morning headaches due to increased renin production
  • Heart valve defects (commonly mitral valve prolapse)
  • Pericardial effusion
  • Left ventricular hypertrophy
  • Coronary artery aneurysm and aortic aneurysm
• Neurological: intracranial saccular aneurysm (in ∼ 8% of patients with ADPKD) ^[1]
  • Higher risk if positive ADPKD family history
  • Aneurysm rupture: clinical features of SAH
• Other manifestations
  • Bronchiectasis
  • Cysts in the spleen, ovaries, or seminal vesicles

Hypertension, hematuria, and UTIs often precede kidney function decline. ^[1]

ARPKD ^[1]

Symptom onset occurs most commonly in utero, infancy, or childhood.

Renal manifestations

• In severe cases, fetal renal impairment and oliguria leading to oligohydramnios and Potter sequence
  • Craniofacial abnormalities (e.g., retrognathia, low-set ears, flat nose) and talipes equinovarus
  • Pulmonary hypoplasia leading to respiratory failure in neonates
• Protruding abdomen; due to bilateral renal enlargement and/or hepatomegaly ^[1]
• Signs of CKD, e.g., hematuria, proteinuria, oliguria

Renal manifestations are typically more severe in patients with perinatal onset than those with onset in childhood, adolescence, or adulthood. ^[1]

Extrarenal manifestations

• Hypertension
  • Early manifestation ^[4]
  • Often resistant to monotherapy
  • Complications often occur, e.g., heart failure, cerebrovascular disease, progressive renal impairment.
• Congenital hepatic and portal fibrosis
  • Progressive liver failure
  • Signs of portal hypertension or cholangitis

General principles ^[1][13]

• Consult nephrology for all patients.
• Preferred initial study: abdominal ultrasound
• If ultrasound findings are unclear or presentation is atypical, consider CT or MRI and/or genetic testing.
• Screen for extrarenal complications (e.g., hypertension, intracranial aneurysms) in patients with ADPKD.
• Monitor kidney function and CKD complications.

Imaging

Abdominal ultrasound ^[1][13][14]

• Indications
  • Screening for adults who have first-degree relatives with ADPKD ^[13]
  • Preferred initial study for all patients with clinically suspected PKD
• Diagnostic criteria for patients with first-degree relatives with ADPKD: ^[13]
  • Children < 15 years old: ≥ 1 cyst (unilateral or bilateral) ^[14]
  • Patients 15–39 years old: ≥ 3 cysts (unilateral or bilateral)
  • Patients 40–59 years old: ≥ 2 cysts in each kidney
  • Patients > 60 years old: ≥ 4 cysts in each kidney ^[14]
• ADPKD findings ; ^[14]
  • Renal cysts: multiple, bilateral, anechoic, round lesions of varying sizes
  • Bilateral renal enlargement
  • Hepatic, pancreatic, and/or splenic cysts ^[11]
  • Kidney stones (i.e., hyperechoic signal with acoustic shadowing) may be observed.
• ARPKD findings ^[1]
  • Renal cysts: multiple, bilateral, anechoic, round lesions of equal size
  • Bilateral renal enlargement with diffuse increased echogenicity and poor corticomedullary differentiation
  • Hepatic cysts
  • Hepatic and portal fibrosis

CT or MRI abdomen ^[1][14]

• Indications
  • Equivocal findings on abdominal ultrasound
  • To measure height-adjusted total kidney volume (htTKV), an important prognostic marker used to assess for risk of rapid progression
• Findings ^[14]
  • Bilateral renal enlargement
  • Renal cysts: multiple, hypodense, well-demarcated, nonseptated, and thin-walled

Laboratory studies ^[1][13]

• CBC: may show anemia of chronic disease
• Kidney function tests: ↑ creatinine and BUN, ↓ estimated GFR (may be normal even in patients with severe disease) ^[1]
• Urine studies: may show proteinuria (> 300 mg/24 h), hematuria ^[1][13]
• CRP: ↑ in cyst infection
• Genetic testing
  • ADPKD: Sanger sequencing of PKD1 and PKD2 (usually not required)
    • May be considered for:
      • Atypical clinical presentation or imaging findings ^[14]
      • Potential kidney donors
  • ARPKD: gold standard for diagnosis ^[1]

Additional studies in ADPKD ^[1][13]

• MR angiography brain ^[13][15]
  • Use: screen for intracranial saccular aneurysms
  • Indications
    • Family history of aneurysm or SAH
    • Planned extensive surgery (e.g., transplant)
    • High-risk occupations (e.g., driver)
• Blood pressure measurement
  • Indication: patients with family history of ADPKD
  • Frequency: every 3 years starting at 5 years of age ^[1][13]
• Echocardiography
  • Indications
    • Cardiovascular signs and/or symptoms
    • Family history of idiopathic dilated cardiomyopathy
  • Findings may include:
    • Valvular heart disease (e.g., mitral valve prolapse)
    • Pericardial effusion
    • Idiopathic dilated cardiomyopathy

• ADPKD
  • Progressive cystic dilatation of the kidney tubular system
  • Cystic dilatation in other organs such as liver and pancreas
  • Left ventricular hypertrophy
  • Vascular dolichoectasias (elongations and distentions of the arteries caused by weakening of the vessel walls)
  • Cardiac valvular abnormalities (e.g., defects of the mitral valve and the aortic root, annulus, and/or valve)
• ARPKD
  • Cystic dilatation of the collecting ducts (other nephron segments are usually not affected)
  • Hepatic fibrosis (see “Pathology” section in “Cirrhosis”)

• Renal cysts
• Acquired cystic kidney disease
• Multicystic dysplastic kidneys
• Autosomal dominant tubulointerstitial kidney disease
• Medullary sponge kidney
• Nephronophthisis
• Obstructive cystic dysplasia
• von Hippel-Lindau syndrome

Acquired cystic kidney disease

• Etiology
  • No gene mutation
  • Typically seen in advanced chronic kidney disease, especially in patients on renal replacement therapy
• Clinical features
  • Small, usually bilateral cysts
  • Multiple cysts (> 4 cysts per kidney)
  • Small-to-normal size kidney
• Complications: cyst infection or bleeding, renal cell carcinoma
• Diagnosis: ultrasound
• Treatment: See “Treatment” in “Renal cysts.”
• Prevention: Prevent or delay progression to ESRD (see “Treatment” below).

Multicystic dysplastic kidneys

• Definition: renal dysplasia with multiple cystic dilatations of nephrons during embryonic development
• Etiology: predominantly nonhereditary
• Pathophysiology
  • Sporadic occurrence during embryonic development of the ureter and nephrons
  • Defective interaction of the ureteric bud and the metanephric mesenchyme → nonfunctional kidney with multiple cysts and connective tissue
• Clinical features
  • Onset: birth to childhood
  • Rarely symptomatic
  • Large cysts might impair urinary output (due to constriction of the urinary tract).
  • Usually unilateral cysts
  • In the case of bilateral involvement
    • Potter sequence (due to oligohydramnios)
    • Spontaneous abortion in case of failure of amniotic fluid production
  • Renal insufficiency is rare.
  • Extrarenal manifestations:
    • Congenital heart defects
    • Esophageal or intestinal atresia
    • Spinal anomalies
    • VACTERL association
• Diagnosis: ultrasound showing unilateral (rarely bilateral) cysts of varying size
• Treatment
  • Surveillance in most cases
  • Nephrectomy is indicated in severe cases (e.g., hypertension, progression of cyst growth)
• Prognosis
  • Most cases regress spontaneously.
  • The nondysplastic kidney usually functions properly and takes over the function of two kidneys.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) ^[16]

• Definition: a group of rare kidney diseases characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions
• Etiology
  • The 3 major genetic causes include autosomal dominant mutation of one of the following genes: ^[17]
    • UMOD, encoding uromodulin (∼ 70% of cases)
    • MUC1, encoding mucin–1 (∼ 30% of cases)
    • REN, encoding renin (< 5% of cases)
• Pathophysiology
  • ADTKD due to UMOD mutation
    • Accumulation of uromodulin within the cells of the thick ascending loop of Henle → mitochondrial dysregulation → tubular cell death → chronic kidney disease
    • ↓ Uromodulin production → ↓ apical expression of the Na-K-2Cl cotransporter → ↑ natriuresis → compensatory proximal tubular sodium reabsorption → secondary increase in proximal urate reabsorption → hyperuricemia
  • ADTKD due to MUC1 mutation: possible dominant-negative or gain-of-function effect of MUC1 mutation
  • ADTKD due to REN mutation: accumulation of preprorenin in the renal tubular cells → apoptosis → chronic kidney disease
• Clinical features
  • Small-to-normal size kidney
  • Signs of chronic kidney disease (e.g., hypertension, fluid overload, uremia)
  • ESRD usually develops between 30–60 years of age.
  • Occasional bilateral cysts, mostly medullary
  • Absent or minimal proteinuria with a bland urine sediment
  • ADTKD due to UMOD mutation: gout since adolescence
  • Clinical findings associated with low renin in ADTKD due to REN mutation
    • Low-to-normal blood pressure
    • Hypoproliferative anemia in childhood
    • Mild hyperkalemia
    • Hyperuricemia
• Diagnosis
  • Ultrasound
    • Small kidneys in advanced stages of CKD
    • Medullary cysts can rarely be seen.
  • Genetic analysis provides a definitive diagnosis.
• Pathology: tubulointerstitial fibrosis
• Treatment
  • Curative: kidney transplant
  • Treatment of chronic kidney disease
  • ADTKD due to UMOD mutation: allopurinol for gout
  • ADTKD due to REN mutation: Fludrocortisone or high-sodium diet may be used for low blood pressure, hyperkalemia, and to potentially preserve kidney function.
• Prognosis: poor (due to progression of chronic kidney disease) ^[16]

Medullary sponge kidney ^[18]

• Definition: a rare congenital disorder characterized by calcified cysts in the collecting ducts in one or both kidneys
• Epidemiology ^[18]
  • Prevalence: occurs in ∼ 1% of the general population and 12–20% of patients with recurrent calcium nephrolithiasis ^[18]
  • ♀ = ♂
  • Mostly diagnosed in young adults
• Etiology
  • Most cases are sporadic.
  • Some cases are associated with genetic mutations.
• Pathophysiology: disruption at the ureteric bud-metanephric mesenchyme interface → distal tubular acidification defect → ↑ urine pH and urinary stasis in the dilated collecting ducts → calcium phosphate and/or calcium oxalate lithogenesis
• Clinical features
  • Usually asymptomatic (incidental finding)
  • Signs of nephrolithiasis (e.g., colicky flank pain)
  • Painful excretion of small stones with urine passage is common.
  • Signs and symptoms of UTI (e.g., polyuria, dysuria)
  • Hematuria
• Diagnosis ^[19]
  • Ultrasound abdomen and pelvis: cysts and/or neprholithiasis, dilatation of the collection ducts, hyperechoic renal papillae
  • Contrast CT urography: parallel striations from contrast that extend from the papilla to the medulla and persist on delayed imaging (papillary blush), nephrocalcinosis
  • Intravenous urography (rarely used): irregular ectatic medullary collecting ducts (classic paintbrush or bouquet appearance)
• Treatment
  • Prevention of nephrolithiasis: high fluid intake, potassium citrate, thiazide diuretics
  • Management of complications: e.g., extracorporeal shock wave lithotripsy, renal replacement therapy for ESRD
• Complications
  • Recurrent UTIs can cause urinary tract obstruction.
  • Rare: renal tubular acidosis, ESRD
  • Defective bone mineralization secondary to renal tubular acidosis

Nephronophthisis (NPHP)

• Definition: a hereditary cystic kidney disease that typically manifests in childhood, characterized by renal ciliopathy, reduced renal concentration ability, and progression to ESRD
• Epidemiology ^[20]
  • Incidence: ∼ 1/1,000,000 in the U.S.
  • One of the most common genetic disorders leading to ESRD in children
• Etiology
  • Autosomal recessive inheritance pattern
  • Mutations in genes encoding nephrocystin protein
• Clinical features
  • Similar clinical and histopathological features as ADTKD
  • Renal manifestations
    • Multiple, bilateral, mostly corticomedullary, kidney cysts
    • Polyuria, polydipsia (due to impaired ability to concentrate urine)
    • Signs of chronic tubulointerstitial nephritis
    • Signs of chronic kidney disease (e.g., hypertension, fluid overload, anemia, uremia)
    • ESRD usually develops before the age of 20 years ^[21]
  • Extrarenal manifestations (10–20% of cases) include: retinal defects, liver fibrosis, skeletal abnormalities, cardiac defects, or brain developmental disorders
• Diagnosis
  • Renal ultrasound may reveal corticomedullary cysts
  • Genetic analysis allows definitive diagnosis
• Treatment
  • Treatment of chronic kidney disease
  • Curative: kidney transplant

Obstructive cystic dysplasia

• Definition: renal dysplasia and cystic dilatation secondary to obstruction in the urinary tract (e.g., ureteral stenosis, urethral agenesis) during fetal development
• Etiology
  • Ureteral stenosis
  • Posterior urethral valves
  • Bladder outlet obstruction
  • Urethral agenesis
  • Duplex collecting system with obstructing ureterocele
  • Congenital vesicoureteric junction obstruction
• Pathophysiology: urinary tract obstruction → urine retention in functioning nephrons → formation of glomerular cysts in the nephrogenic zone
• Clinical features
  • Onset: birth to childhood
  • During pregnancy: oligohydramnios
  • The cause, the severity, and the timing of the obstruction determine the extent of symptoms
    • Asymptomatic in mild cases
    • Acute renal failure in severe cases
  • Extrarenal manifestations
    • Congenital heart defects
    • CNS anomalies
    • VACTERL association
• Diagnosis: ultrasound showing unilateral or bilateral cysts of varying size (cysts are usually smaller than those seen in patients with multicystic dysplastic kidneys) ^[22]
• Treatment: elimination of the obstruction as a curative approach (e.g., urethral valve ablation)

The differential diagnoses listed here are not exhaustive.

Specialist consultation (e.g., nephrologist, hepatologist) is required for all patients.

Supportive measures ^[1][13]

The following are evidence-based recommendations for ADPKD that may also benefit patients with ARPKD.

• Management of blood pressure
  • Goal: to prevent or treat hypertension and proteinuria and slow estimated GFR decline
  • Agents: ACE inhibitors or ARBs
• ASCVD risk reduction
  • Smoking cessation
  • Management of hyperlipidemia
  • Maintaining a healthy weight
• Lifestyle modifications
  • High fluid intake: to prevent nephrolithiasis and potentially slow cyst progression
  • Dietary sodium and protein restriction
• General measures
  • Early treatment of UTIs to prevent renal cyst infection
  • Avoidance of nephrotoxic substances and vasopressin agonists, e.g., NSAIDs, sulfonamide antibiotics, aminoglycosides
  • Genetic counseling during family planning as available

Tolvaptan ^[1][13]

• Indications
  • ADPKD at risk of rapid progression, e.g.: ^[1]
    • Patients with rapid decline in estimated GFR and/or higher than expected htTKV
    • Individuals < 35 years of age with onset of hypertension, hematuria, or cyst infection
  • Not recommended for use in patients with ARPKD
• Tolvaptan slows cyst progression and estimated GFR decline in ADPKD.
• Obtain liver chemistries before and during treatment to monitor for liver injury (may be irreversible).

Management of complications ^[1][13]

• Hematuria and cyst hemorrhage
  • Typically self-limited, i.e., 2–7 days
  • Supportive care, e.g., oral fluids, rest
  • Consider temporary discontinuation of anticoagulants, diuretics, and RAAS inhibitors.
  • Extensive bleeding and/or retroperitoneal or subcapsular hematoma: Inpatient management is often required.
  • Persistent hematuria: Consider evaluation for renal cell carcinoma.
• Renal cyst infection ^[23]
  • Management of sepsis as indicated
  • First-line: IV antibiotics, e.g., fluoroquinolones
  • If antibiotic treatment failure: percutaneous or surgical drainage
• ESRD
  • Kidney transplant is the only curative option.
  • Other renal replacement therapies may be considered for patients awaiting transplant.
• Other complications
  • Severe polycystic liver disease: Surgical excision, percutaneous aspiration, or sclerotherapy may be considered.
  • Management of SAH
  • Management of portal hypertension
  • Management of nephrolithiasis

• ADPKD
  • 50% of patients with ADPKD develop ESRD by 60 years of age. ^[1]
  • Chronic hypertension and intracranial aneurysms are associated with a poor prognosis.
• ARPKD
  • Perinatal and infant mortality rates are high. ^[1]
  • Neonates with severe kidney disease have a mortality rate of up to 40%. ^[1]
  • ∼ 80% of patients who survive infancy have a life expectancy > 10 years. ^[1]
  • 60% of patients with ARPKD develop ESRD by 20 years of age. ^[1]

ESRD occurs in 60% of patients with ARPKD by 20 years of age and in 50% of patients with ADPKD by 60 years of age. ^[1]