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Polycystic Kidney Disease and Other Inherited Disorders ofTubule Growth and Development

Chapter 327 | Harrison's 22e · Part 9 – Renal & Urinary Tract Disorders · Chapter 327

Key Clinical Points

  1. ADPKD is the most common life-threatening monogenic disease, affecting 12 million people worldwide.
  2. ARPKD is a rarer form primarily affecting the pediatric population.
  3. Cystic kidney diseases are part of a broad group of disorders called ciliopathies, characterized by defects in primary cilia.
  4. The PC1/PC2 protein complex acts as both a mechanosensor and chemical sensor, regulating calcium (Ca2+) and G-protein signaling.
  5. Cellular defects in ADPKD include increased cell proliferation and fluid secretion, decreased cell differentiation, and abnormal extracellular matrix.
  6. Cyst growth occurs in only 5% of the tubules but leads to significant loss of surrounding tissue and renal function.
  7. Clinical severity is determined by whether ciliary signaling defects occur during 'development morphogenesis' (severe/early) or 'post-development maintenance' (mild/late).
  8. ADPKD patients frequently present with hypertension, subarachnoid hemorrhage, and flank pain (reported in ~60% of cases).
  9. PC1 is a large 11-transmembrane protein (G protein-coupled receptor type); PC2 is a calcium-permeable 6-transmembrane protein (TRP family).
  10. The PC1/PC2 complex maintains a 1:3 stoichiometry and regulates cell cycle, actin cytoskeleton, and planar cell polarity (PCP).

DEFINITION & CLASSIFICATION

• Polycystic Kidney Diseases: A group of genetically heterogeneous disorders and a leading cause of kidney failure. • Autosomal Dominant Polycystic Kidney Disease (ADPKD): The most common life-threatening monogenic disease, affecting 12 million people worldwide. • Autosomal Recessive Polycystic Kidney Disease (ARPKD): A rarer form primarily affecting the pediatric population. • Ciliopathies: A broad group of genetic diseases characterized by defects in the structure or function of primary cilia; kidney cysts are a common phenotype shared by many ciliopathies.

ETIOLOGY & PATHOPHYSIOLOGY

• Cyst Development: ◦ Although cysts occur in only 5% of the tubules, their growth leads to loss of surrounding tissue and renal function. • Cellular Defects in ADPKD: ◦ Increased cell proliferation ◦ Increased fluid secretion ◦ Decreased cell differentiation ◦ Abnormal extracellular matrix • Primary Cilium Function: ◦ Structure: A hair-like structure on the apical membrane of cells, also present on cell membranes and cell–cell junctions. ◦ Organization: 9+0 organization of microtubule doublets. ◦ Transport: Proteins are transported into the cilium by motor protein kinesin 2 and out by dynein. ◦ Role: Acts as a mechanosensor and chemical sensor; regulates calcium (Ca2+) and G-protein signaling. ◦ Regulation: Regulates cell cycle, actin cytoskeleton, planar cell polarity (PCP), and cell migration. • Protein Complex (PC1/PC2): ◦ Polycystin-1 (PC1): A large 11-transmembrane protein; functions like a G protein–coupled receptor. Expression is high in development and low in the adult. ◦ Polycystin-2 (PC2): A calcium-permeable six-transmembrane protein; belongs to the transient receptor potential (TRP) cation channel family. Expression is relatively constant. ◦ Interaction: PC1 and PC2 bind via their respective C-terminal tails to form a complex with a 1:3 stoichiometry of PC1:PC2. ◦ Signaling Pathways: Regulates Wnt, mTOR, STAT3, cMET, and PI3K/Akt. • Genetic Landscape (Table 327-1): ◦ ADPKD: Caused by mutations in PKD1 or PKD2. ◦ AD PKD-like: Associated with GANAB and DNAJB11. ◦ ARPKD: Associated with PKHD1. ◦ Tubulointerstitial Kidney Disease: Associated with UMOD, MUC1, REN, HNF1b, and SEC61A1. ◦ Renal Cysts and Diabetes Syndrome: Associated with HNF1B. ◦ Nephronophthisis (NPHP): Associated with NPHP1-20, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, SDCCAG8, TMEM67, and TTC21B. ◦ Senior-Loken Syndrome: Associated with NPHP1-6 and SDCCAG8. ◦ Leber Congenital Amaurosis: Associated with GUCY2D, RPE65, and LCA3-14. ◦ Meckel-Gruber Syndrome: Associated with MKS1, TMEM216, TMEM67, TMEM231, TMEM107, CEP290, RPGRIP1L, CC2D2A, TCTN2, B9D1, B9D2, NPHP3, and KIF14. ◦ Bardet-Biedl Syndrome: Associated with BBS1, 2, ARL6, BBS4,5, MKKS, BBS7, TTC8, BBS9, 10, TRIM32, BBS12, MKS1, CEP290, and C2ORF86. ◦ Oral-facial-digital Syndrome Type I: Associated with OFD1. ◦ Tuberous Sclerosis: Associated with TSC1 and TSC2. ◦ Von Hippel-Lindau (VHL) Disease: Associated with VHL.

Molecular Details of Polycystin Proteins

• PC2 Gene Structure: ◦ Single-copy gene with 15 exons. ◦ Produces a ~5.3 kb mRNA transcript. ◦ Encodes a protein of 968 amino acids.

CLINICAL FEATURES

• General Symptoms: ◦ Flank pain: Frequent in ~60% of patients with ADPKD. ◦ Causes of pain: Renal cyst infection, hemorrhage, or nephrolithiasis. ◦ Gross hematuria: Resulting from cyst rupture. • ADPKD Specifics: ◦ Hypertension ◦ Subarachnoid hemorrhage ◦ Liver and pancreatic cysts. • ARPKD Specifics: ◦ Oligohydramnios (if severe) ◦ Ascending cholangitis ◦ Liver fibrosis. • Other Syndromic Features: ◦ Bardet-Biedl: Obesity, polydactyly, retinitis pigmentosa, anosmia, congenital heart defects, intellectual disability. ◦ Meckel-Gruber: CNS anomalies, polydactyly, congenital heart defects. ◦ Tuberous Sclerosis: Angiomyolipomas, renal cell carcinoma, facial angiofibromas, CNS hamartomas. ◦ Von Hippel-Lindau: Renal cell carcinoma, retinal angiomas, CNS hemangioblastomas, pheochromocytomas.

KEY PEARLS & HIGH-YIELD POINTS

• Ciliary Signaling Logic: The severity of the cystic phenotype is determined by the timing of the defect. ◦ Defect during "Development Morphogenesis" → Severe disease / Early quick onset. ◦ Defect during "Post-development Maintenance" → Mild disease / Late slow onset.

PATHOPHYSIOLOGY OF CILIARY SIGNALING (Flowchart 1)

The following logic describes the progression from ciliary signaling to clinical outcomes as shown in Figure 327-1:

  1. Initial Signaling: Receptors → Ca^{2+}, Wnt, SHH, cAMP and other signaling events.
  2. Cellular Response: Signal leads to "Defective Planar cell polarity (PCP) cell orientation".
  3. Temporal/Developmental Branching: ◦ Path A: If defect occurs during "Development morphogenesis" → Severe disease / Early quick onset. ◦ Path B: If defect occurs during "Post development maintenance" → Mild disease / Late slow onset.
  4. Clinical Correlation of Syndromes: ◦ ADPKD (PKD1/PKD2): Associated with Polycystin-1 and Polycystin-2. ◦ ARPKD (PKHD1): Associated with the protein FPC. ◦ Nephronophthisis (NPHP): Linked to specific ciliary proteins (e.g., NPHP1-6, SDCCAG8). ◦ Meckel & Bardet-Biedl: Linked to specific ciliary defects and associated with multisystem involvement.

Reference Tables

TABLE 327-1 Inherited Diseases Commonly Associated with a Cystic Phenotype DISEASE Autosomal dominant polycystic kidney…

Harrison's 22e, p.2430

DISEASE MODE OF
INHERITANCE		 RENAL ABNORMALITIES OTHER CLINICAL FEATURES GENES
Autosomal dominant
polycystic kidney
disease		 AD Bilaterally enlarged kidneys with
cortical and medullary cysts		 Liver, pancreatic cysts, hypertension,
subarachnoid hemorrhage		 PKD1, PKD2
AD Normal to smaller sized kidneys with
fewer cortical and medullary cysts		 Liver cysts at variable degree (from absent
to severe)
Autosomal recessive
polycystic kidney
disease		 AR Distal and collecting duct cysts Oligohydramnios if severe, hypertension,
ascending cholangitis, liver fibrosis		 PKHD1
AD Small fibrotic kidneys; medullary cysts In adults, gout
Renal cysts and
diabetes syndrome		 AD Kidney cysts, aberrant nephrogenesis,
irregular collecting systems, abnormal
renal calyces, hyperuricemic
nephropathy. Highly variable.		 Diabetes HNF1B
AR Small fibrotic kidneys; medullary cysts Growth retardation, anemia
(In syndromic forms: visual loss, liver fibrosis,
cerebellar ataxia, other)
Senior-Loken syndrome AR Renal cysts Juvenile nephronophthisis, Leber amaurosis NPHP1-6, SDCCAG8
AR Renal cysts Visual impairment in first year of life;
pigmentary retinopathy
Meckel-Gruber
syndrome		 AR Cortical and medullary cysts CNS anomalies, polydactyly, congenital
heart defects		 MKS1, TMEM216, TMEM67,
TMEM231, TMEM107, CEP290,
RPGRIP1L, CC2D2A, TCTN2,
B9D1, B9D2, NPHP3, KIF14
AR Renal cysts Obesity, polydactyly, retinitis pigmentosa,
anosmia, congenital heart defects,
intellectual disability
Oral-facial-digital
syndrome type I		 X-linked
dominant		 Renal cysts Oral cavity, face, and digit anomalies; CNS
abnormalities; cystic kidney disease; X-linked
with male lethality, primary ciliary dyskinesia		 OFD1
AD Renal cysts Angiomyolipomas; renal cell carcinoma
Facial angiofibromas; CNS hamartomas
Von Hippel-Lindau
disease		 AD Renal cysts Renal cell carcinoma, retinal angiomas; CNS
hemangioblastomas; pheochromocytomas		 VHL