Pathology of Polycystic Kidney Disease (PKD)

Comparison Overview

Part I: Autosomal Dominant PKD (ADPKD)

Genetics

• PKD1 (chromosome 16p13.3): accounts for ~78% of pedigrees. Encodes polycystin-1 (PC1, ~4,303 amino acids). PKD1 mutations cause more severe disease; mean age at ESKD = 58.1 years.
• PKD2 (chromosome 4q21): accounts for ~15%. Encodes polycystin-2 (PC2, ~968 amino acids). Mean age at ESKD = 79.7 years.
• Rarer genes: GANAB and DNAJB11 (ER maturation defects) cause ADPKD-like phenotypes.

The Polycystin Proteins

• Extensive extracellular N-terminal region (leucine-rich repeats, C-type lectin, LDL-A, PKD repeats, REJ module, GAIN domain)
• 11 transmembrane domains
• Short intracellular C-terminal tail (G-protein binding, coiled-coil)
• Found in primary cilia, focal adhesions, desmosomes, adherens junctions, ER, and nucleus

• 6 transmembrane domains
• Short N-terminal cytoplasmic region
• C-terminal portion with EF-hand calcium-binding motif and ER retention signal
• Localized primarily in ER, but also in primary cilium, centrosome, and mitotic spindles
• The two proteins interact via coiled-coil domains in a 1 PC1 : 3 PC2 stoichiometry (cryo-EM data)

The "Two-Hit" Hypothesis

• Loss of heterozygosity (LOH) detected in cyst-lining cells
• Cystic cells have reduced or absent PC1/PC2
• Experimental Pkd1 or Pkd2 knockout studies confirm two hits needed

Molecular Pathogenesis of Cyst Formation

1. Primary ciliary signaling - PC1 and PC2 in cilia detect flow-induced bending; loss abolishes calcium influx response
2. Intracellular calcium - Reduced resting [Ca²⁺], depleted ER calcium stores, impaired store-operated calcium entry
3. Elevated cAMP - Reduced intracellular calcium disinhibits adenylyl cyclase (AC6) and impairs PDE activity → raised cAMP in kidneys, liver, and vasculature. cAMP activates:
   • B-Raf/MEK/ERK proliferation pathway (via AMPK inhibition)
   • PKA → phosphorylates CFTR and other chloride transporters → fluid secretion into cyst lumen
4. mTOR pathway activation - mTORC1 is activated via PC1's interaction with TSC2. mTORC1 drives tubular cell hypertrophy and proliferation
5. Planar cell polarity (PCP) loss - Normal tubulogenesis requires oriented cell division along the tubule axis; polycystin deficiency disrupts this, causing tubule dilation
6. Increased proliferation - Cyst-lining cells show abnormally high rates of mitosis
7. Abnormal fluid secretion - Instead of absorbing like normal tubular epithelium, cyst epithelium secretes Cl⁻ and fluid via CFTR-driven trans-epithelial transport, enlarging the cyst
8. Extracellular matrix (ECM) remodeling - Altered collagen composition and increased matrix metalloproteinase activity promotes cyst expansion

Gross Pathology of ADPKD

• Bilateral, diffuse cyst distribution (no dominant side)
• Kidneys can reach weights of 4,000 g or more per kidney at end-stage (normal ~150 g each)
• Kidney reniform shape may be maintained initially but lost at end-stage
• Cysts range from millimeters to several centimeters
• Cyst contents: clear serous fluid, or hemorrhagic (brown/red) - hemorrhage is a common complication
• At end-stage: only scant islands of normal parenchyma visible; fibrous tissue beneath capsule; fibrous bands encapsulating cysts on cut section
• Tubulointerstitial fibrosis and arteriolar sclerosis are cardinal end-stage features

Microscopic Pathology of ADPKD

• Cyst origins: Cysts begin as outpouchings from preexisting tubules; most detach from the parent tubule once they exceed a few millimeters
• Segment of origin: The majority (especially large cysts >1 mm) stain for collecting duct markers; distal nephron/collecting duct origin predominates. Proximal tubule cysts occur early. Cysts can also arise from Bowman's capsule (parietal epithelium)
• Cyst epithelium: Not typical of mature, fully differentiated tubular epithelium - cells are partially dedifferentiated/immature; some show a flat, attenuated lining; others show cuboidal or low columnar cells
• Majority of cysts (75%) have high luminal Na⁺ (~plasma level) and leaky apical junctions, consistent with poorly differentiated/secretory epithelium; minority have low Na⁺ (more differentiated, absorptive-type)
• Interstitium: Progressive interstitial fibrosis; lymphocytic infiltration; arteriolar sclerosis
• Apoptosis is prominent in noncystic parenchyma adjacent to expanding cysts - this is the primary mechanism of progressive nephron loss and GFR decline

Extrarenal Pathology of ADPKD

• Up to 90% of adults have liver cysts
• Cysts are lined by biliary-type epithelium (single layer)
• Arise from proliferation/dilation of biliary ductules (biliary microhamartomas/von Meyenburg complexes) and peribiliary glands
• Macroscopic cysts usually do not communicate with the biliary system
• Clinically more severe in women (estrogen effect); can cause massive hepatomegaly

• Prevalence ~8% (higher in families with a history)
• Rupture is a major cause of mortality; risk increases with hypertension

• Mitral valve prolapse (~25% of patients)
• Aortic regurgitation
• Left ventricular hypertrophy (often before hypertension)

• Pancreatic cysts (~10%)
• Seminal vesicle cysts (men)
• Arachnoid cysts
• Colonic diverticula

Part II: Autosomal Recessive PKD (ARPKD)

Genetics

• PKHD1 gene (chromosome 6p21.1-p12): one of the largest human genes (~470 kb, 67 exons)
• Encodes fibrocystin/polyductin (~460 kDa)
• No mutation hot spots; most mutations are private (single-family)
• Two truncating mutations → lethal neonatal phenotype; at least one missense/hypomorphic mutation required for survival
• Carrier frequency ~1 in 70; disease prevalence ~1 in 10,000-20,000

Fibrocystin (Polyductin)

• Single-pass transmembrane protein
• Large extracellular region with IPT/TIG (immunoglobulin-like) and PbH1 (parallel beta-helix) repeats
• Expressed in primary cilia (like polycystins), kidney, liver, and pancreas
• Expressed during embryogenesis in ureteric bud branches, intrahepatic/extrahepatic biliary ducts, and pancreatic ducts - explaining the renal and hepatic phenotype

Gross Pathology of ARPKD

• Kidneys are symmetrically and bilaterally enlarged (combined weight up to 300 g vs. normal ~25 g in neonates - up to 20x normal)
• May cause dystocia due to size
• External surface: lobulated but smooth; kidney shape maintained
• Cut section: radially oriented, fusiform dilations of collecting ducts, 1-2 mm in diameter, throughout cortex and medulla - the classic "sponge-like" or "sunburst" pattern
• No discrete rounded cysts (unlike ADPKD) - the dilations are elongated/fusiform
• Almost 100% of collecting ducts are affected in severe perinatal cases

Microscopic Pathology of ARPKD

• Collecting ducts are lined by typical cuboidal epithelium (well-differentiated, unlike ADPKD)
• Glomeruli and proximal tubular elements appear histologically normal initially
• Proximal tubule cysts may occur in early fetuses (14-24 weeks) but resolve by 34 weeks
• In older children with milder renal involvement: medullary ductal ectasia is prominent; macroscopic cysts can develop
• Renal calcifications are common

• Characteristic feature of ARPKD (inverse relationship with renal severity)
• Ductal plate malformation - failure of remodeling of primitive bile duct precursors
• Dense periportal fibrosis with proliferating, poorly formed bile ducts (biliary dysgenesis)
• Portal hypertension → esophageal varices, splenomegaly
• Caroli disease (non-obstructive intrahepatic bile duct dilation) variably present

Pathogenetic Summary: The Ciliopathy Concept

Key Differences: ADPKD vs. ARPKD at a Glance