What causes renal cysts?

What Causes Renal Cysts

Renal cysts develop through multiple distinct mechanisms: genetic mutations affecting primary cilia function in hereditary diseases (most notably ADPKD from PKD1/PKD2 mutations), acquired processes in end-stage renal disease, developmental abnormalities during nephrogenesis, or as simple sporadic cysts with unclear etiology.

Hereditary/Genetic Causes

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

• PKD1 and PKD2 gene mutations are the primary causes, with PKD1 mutations causing more severe disease than PKD2 1
• These mutations lead to defects in primary cilia structure and function of renal tubular epithelial cells 2
• The disease shows autosomal dominant inheritance with near 100% penetrance if patients live long enough, though up to 50% of cases may represent de novo mutations 1, 3
• Environmental factors including obesity and salt intake can modify disease severity 1
• Male sex is associated with more severe disease progression 1

Other Hereditary Cystic Diseases

• Autosomal Recessive Polycystic Kidney Disease (ARPKD) results from mutations in PKHD1, DZIP1L, CYS1, or PKD1 genes 1
• Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) caused by mutations in UMOD, MUC1, REN, or SEC61A genes 1
• HNF1B-related kidney disease from HNF1B mutations, with up to 50% appearing as de novo cases 1
• Tuberous sclerosis complex from TSC1 or TSC2 mutations 1
• Von Hippel-Lindau syndrome from VHL gene mutations 1, 2

Acquired Causes

Acquired Cystic Disease (ACD)

• End-stage renal disease is the primary driver, occurring exclusively in this setting 1
• Duration of hemodialysis directly correlates with increased cyst occurrence 1
• Male gender is associated with higher risk of developing ACD 1
• Cysts in ACD can show proliferative changes with multilayered epithelium and harbor cytogenetic alterations 1, 4
• Recent genetic studies identified recurrent mutations in KMT2C (4 of 5 cases) and TSC2 (3 of 5 cases) in ACD-associated renal cell carcinoma 1

Developmental Causes

Disrupted Nephrogenesis

• Cystic maldevelopment occurs when normal nephrogenesis processes are disrupted during fetal development 5
• This results from genetic mutations or environmental insults triggering epithelial hyperplasia, abnormal protein sorting, altered fluid transport, and abnormal extracellular matrix-cell interactions 5
• Developmental conditions include multicystic dysplastic kidney, localized renal cystic disease, and medullary sponge kidney 2
• Renal dysplasia represents disturbed renal histogenesis that gives rise to morphologically characteristic cysts 6

Cellular Mechanisms Common to Multiple Etiologies

Primary Cilia Dysfunction

• Genetic mutations in hereditary diseases lead to defects in primary cilia structure and function of renal tubular epithelial cells 2
• This ciliary dysfunction triggers abnormal proliferation of tubular epithelium 2
• Increased fluid secretion into developing cysts follows 2

Proliferative Changes

• Even in "non-proliferative" conditions, cysts often demonstrate proliferative changes with multilayered epithelium, particularly in acquired cystic kidney disease 4
• These proliferative cysts can harbor cytogenetic alterations indicating active cellular processes rather than passive formation 4
• The cyst lining may show sieve-like growth patterns and short papillary projections 4

Simple/Sporadic Cysts

• Simple cysts are acquired and sporadic with no clear hereditary pattern 1, 7
• The precise mechanism of simple cyst formation remains unclear 1
• These typically follow an indolent course without significant size changes, though reasons for variable growth patterns are not well understood 4

Important Clinical Pitfalls

• A normal fetal or childhood ultrasound does not exclude ADPKD in at-risk children, as cysts develop gradually and may not be detectable early in milder phenotypes 3
• Approximately 3% of children with ADPKD-causing mutations have very-early-onset or unusually rapid progressive disease 4
• Assuming all simple-appearing cysts are truly non-proliferative is a critical error, as many harbor proliferative changes at the microscopic level 4
• Multiple inherited disorders can mimic ADPKD with kidney and/or liver cysts, including collagen disorders (COL4A genes), nephrolithiasis-associated conditions, and syndromic ciliopathies 1