Polycystic kidney disease

Polycystic kidney disease (PKD) is an inherited disorder characterized by the development of multiple cysts in the kidneys. It is classified into two distinct disorders: autosomal recessive PKD (ARPKD) and autosomal dominant PKD (ADPKD). ARPKD manifests with severe pulmonary insufficiency and progressive renal failure with onset during infancy or early childhood. If left untreated, ARPKD is typically lethal before adolescence. ADPKD manifests with flank pain, arterial hypertension, and progressive kidney disease with onset in adulthood. Early diagnosis and treatment may prevent or delay end-stage renal disease in both conditions, but kidney transplantation 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 dilation of collecting ducts and bile ducts (intrahepatic and extrahepatic bile ducts) ^[12]

ADPKD

• Symptom onset
  • Symptoms usually occur after 30 years of age, but the disease may also manifest during childhood. ^[1]
  • Symptoms are less severe and tend to manifest later in individuals with the PKD2 mutation compared to those with the PKD1 mutation. ^[13]
• Renal manifestations
  • Gross hematuria
  • Flank or abdominal pain
  • Recurrent urinary tract infections
  • Nephrolithiasis
  • Kidneys might be palpable and enlarged on abdominal exam (they are usually normal at birth)
  • Signs of chronic kidney disease (e.g., hypertension, fluid overload, uremia)
• Extrarenal manifestations
  • Multiple benign hepatic cysts (prevalence increases with age)
  • Cysts may also occur in the pancreas, spleen, ovary, and testicles.
  • Cerebral berry aneurysm (∼8%) ^[14]
    • The risk is higher in patients with a family history positive of ADPKD.
    • May rupture and cause subarachnoid hemorrhage (the risk for growth and rupture is the same in patients with ADPKD as in the general population)
  • Cardiovascular
    • Signs of arterial hypertension; (e.g., morning headaches) through increased renin production
    • Heart valve defects (particularly mitral valve prolapse)
    • Left ventricular hypertrophy
    • Potential association with coronary artery aneurysm and aortic aneurysm
  • Colon diverticula (diverticulosis), abdominal or inguinal hernias

ARPKD

• Symptom onset: Symptoms most commonly manifest in infancy or childhood.
• Renal manifestations
  • Protruding abdomen; (nontender abdominal mass) due to bilateral renal enlargement and/or hepatomegaly
  • Chronic renal failure: frequently hematuria, proteinuria, and oliguria
  • Severe in-utero renal impairment → oliguria in utero → maternal oligohydramnios → Potter sequence
    • Craniofacial abnormalities (retrognathia, low-set ears, flat nose) and clubbed feet
    • Pulmonary hypoplasia → respiratory insufficiency in neonates
• Extrarenal manifestation
  • Hypertension
    • Early manifestation ^[4]
    • Often not responsive to monotherapy
    • Can result in complications if inadequately controlled (e.g., cardiac hypertrophy, heart failure, cerebrovascular diseases, progressive renal impairment)
  • Liver involvement: congenital hepatic and portal fibrosis → progressive liver failure and portal hypertension

Imaging

• Ultrasound ; ^[15]
  • ADPKD
    • In adults: enlarged kidneys with multiple cysts bilaterally of varying sizes (anechoic masses)
    • In children: evidence of cysts in combination with a family history positive of ADPKD
    • Hepatic, pancreatic, and/or splenic cysts may be visible.
  • ARPKD
    • Enlarged kidneys with multiple cysts bilaterally of equal size
    • Diffuse increased echogenicity, despite the presence of liquid-filled cysts (anechoic)
    • Hepatic cysts
    • Hepatic and portal fibrosis
• CT
  • Not the method of choice
  • Should only be used if ultrasound findings are unclear (due to the radiation exposure of CT)
  • Shows
    • Multiple cysts: usually hypodense, well-demarcated, not septated, and thin-walled
    • Bilateral enlargement of the kidneys
• MR angiography: screening for berry aneurysms in patients with ADPKD is recommended in the following scenarios: ^[16]
  • Family history of aneurysm
  • Prior to extensive elective surgeries (e.g., transplantation)
  • Occupations in which unconsciousness represents a public safety risk (e.g., driver)
  • The patient wishes to be screened

Further diagnostic tests

• Genetic testing: DNA linkage analysis to identify ADPKD1 and ADPKD2 (often not necessary) ^[9]
• Laboratory measures: to evaluate and monitor renal function
  • Blood cell count (can show renal anemia)
  • Creatinine clearance
  • Urinalysis (can show proteinuria, hematuria)
• (Diagnostic laparoscopy and) liver biopsy: in ambiguous cases

• ADPKD
  • Progressive cystic dilatation of the kidney tubular system
  • Cystic dilation 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

• See “Renal cysts.”

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
• Diagnostics: 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
• Diagnostics: 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) ^[17]

• 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: ^[18]
    • 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 the 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
• Diagnostics
  • 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 transplantation
  • 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) ^[17]

Medullary sponge kidney

• Definition: calcified cysts originating from the collecting ducts and/or tubules in one or both kidneys
• Epidemiology ^[19]
  • 1/5000 persons
  • 12–20% of patients with calcific renal stones
  • ♀ > ♂
  • The mean age of diagnosed patients is 27 years
• Etiology
  • Most cases are sporadic
  • Some cases are attributed to genetic mutations
• Pathophysiology: disruption at the ureteric bud-metanephric mesenchyme interface → distal tubular acidification defect → ↑ urine pH and urinary stasis in the dilated ducts → calcium phosphate and/or calcium oxalate lithogenesis
• Clinical features
  • Usually asymptomatic (incidental finding)
  • Signs of nephrolithiasis (e.g., colicky flank pain)
  • Signs of urinary tract infection (e.g., polyuria, dysuria)
  • Hematuria
  • Painful excretion of small stones with the urinary flow is common
• Diagnostics
  • Ultrasound: dilatation of collecting ducts, cysts, and/or kidney stones (nonspecific)
  • Contrast CT urography: parallel striations from contrast which extend from the papilla to the medulla and persist on delayed imaging (papillary blush)
  • IVP: irregular ectatic medullary collecting ducts (classic paintbrush-like appearance)
• Treatment
  • Prophylactic treatment of kidney stones with thiazide diuretics, high fluid intake, and/or potassium citrate
  • Extracorporeal shock wave lithotripsy for stones in collecting tubule
  • In rare cases of kidney failure, renal dialysis may be required
• Complications
  • Recurrent UTIs can lead to renal obstruction
  • Dilatation of the collecting ducts → impaired renal filtration → metabolic acidosis
  • Rarely: renal tubular acidosis, ESRD

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
• Diagnostics
  • Renal ultrasound may reveal corticomedullary cysts
  • Genetic analysis allows definitive diagnosis
• Treatment
  • Treatment of chronic kidney disease
  • Curative: kidney transplantation

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
• Diagnostics: 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)

Von Hippel–Lindau disease

• See “von Hippel-Lindau disease.”

The differential diagnoses listed here are not exhaustive.

• Treatment/prevention of renal dysfunction
  • ACE-inhibitors (ACEIs) or angiotensin receptor blockers (ARBs): to prevent/treat hypertension as well as to slow proteinuria and ESRD progression
  • Tolvaptan
    • Indicated in patients with rapidly progressing ADPKD and mild chronic kidney disease (GFR ≥ 25 mL/min/1.73 m² and/or chronic kidney function estimated between 30–90%) ^[23]
    • Slows down the growth of kidney cysts in ADPKD patients
    • Delays progression to ESRD
  • Early treatment of urinary tract infections (to prevent renal cyst infection)
  • High fluid intake to prevent kidney stone formation and to possibly slow cyst progression
  • Avoid nephrotoxic substances (e.g., NSAIDs, sulfonamide antibiotics, aminoglycosides)
  • Avoid ADH (vasopressin may stimulate cyst growth)
• In severe cases: e.g., ESRD
  • Hemodialysis or peritoneal dialysis
  • Kidney transplantation is the only curative option (see also “End-stage renal disease”).
  • Portosystemic shunting or liver transplantation may be required in ARPKD patients with severe hepatic involvement.
  • Treatment of complications (e.g., portal hypertension, subarachnoid hemorrhage)
• General measures
  • Regular sonographic monitoring and laboratory evaluation of renal function
  • Regular sonographic and laboratory monitoring of liver and treatment of hepatic failure
  • Genetic counseling

• ADPKD
  • 50% of ADPKD patients have ESRD requiring dialysis by the age of 60 years ^[24]
  • Chronic hypertension and cerebral aneurysms, in particular, are associated with a poor prognosis.
• ARPKD
  • Neonates with severe cystic dilatation have a poor life expectancy (probability of death within the 1^st year of life is ∼ 30%) ^[25][26]
  • The majority of children who survive infancy have a life expectancy greater than 10 years. ^[25]
  • The prognosis depends on the extent of renal and hepatic impairment:
    • Renal cysts and enlargement lead to systemic hypertension and progressive renal failure.
    • Progressive portal hypertension and hepatic fibrosis lead to liver failure.