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Mechanistic Deep Dive
Polycystin Function
- Cilia signaling
- Cell polarity
- Apoptosis
- Calcium signaling
- Tubular morphogenesis
Type IV Collagen
- α3, α4, α5 chains form GBM
- Triple helix
- Cross-linking
- Multiple tissues (kidney, ear, eye)
- Mutations â multi-organ disease
Fabry Pathophysiology
- α-Gal-A cleaves Gb3
- Mutation â enzyme deficiency
- Gb3 accumulates in lysosomes
- Affects multiple cell types
- Endothelium, podocytes, cardiomyocytes, smooth muscle
Recent Trials & Updates
TEMPO 3:4 (2012) â Tolvaptan
- N = 1445 ADPKD
- Tolvaptan vs placebo
- â Cyst growth + slower GFR decline
- Practice-changing
REPRISE (2017) â Tolvaptan in Advanced ADPKD
- eGFR 25-65
- Confirmed benefit
- Extended FDA approval
Venglustat for ADPKD (2024)
- Glucosylceramide synthase inhibitor
- Phase 3 trials
- Promising
Pegunigalsidase (PRX-102) for Fabry â 2023
- Pegylated long-acting α-Gal-A
- BALANCE study
- FDA 2023
Migalastat (Galafold)
- Oral chaperone
- For amenable GLA mutations (~ 50% of Fabry patients)
- Long-term outcomes data
Inaxaplin (VX-147) for APOL1 Nephropathy
- AMPLITUDE Phase 3 ongoing
High-Yield Specialist Points
Tolvaptan Practical Management
- Start low, titrate
- Daily fluid intake 3-4 L
- Avoid dehydration
- LFT monitoring
- Hepatotoxicity â discontinue
- REMS pharmacy
ADPKD Imaging Frequency
- Annual ultrasound or MRI for TKV
- Mayo classification
- More frequent if treatment changes
ADPKD Pre-Transplant
- Bilateral nephrectomy sometimes for very large kidneys
- Pre or post transplant
- Bleeding risk
Pregnancy + ADPKD
- Increased preeclampsia
- HTN management
- UTI prophylaxis
- Multidisciplinary
- ACE/ARB switched
Alport Donor Selection
- Affected female may be appropriate donor
- Need genetic counseling
- Long-term outcomes
Fabry ERT Practical
- IV every 2 weeks
- Compatibility (humanized vs not)
- Antibodies in some
- Long-term outcomes excellent
Fabry Pegunigalsidase
- Once monthly
- Better convenience
- Comparable efficacy
- FDA 2023
Migalastat Eligibility
- Amenable mutation tested in vitro
- Oral every other day
- Convenient
- ~ 50% of Fabry patients
TSC + Angiomyolipomas
- Larger > 4 cm at risk for bleeding
- Everolimus (or sirolimus) reduces size
- Embolization for bleeding
- Surgery if large
Long-Term Follow-Up Hereditary CKD
- Multidisciplinary (nephrology + genetics + cardiology + ophtho for Alport/Fabry)
- Pre-conception counseling
- Genetic testing offered to children + siblings
- Quality of life support
Renal Transplant in Hereditary CKD
- Living donor consideration (genetic implications)
- Disease recurrence (most hereditary donât recur except some)
- Alport: anti-GBM disease risk in donor kidney
- Long-term outcomes good
Stones in ADPKD
- 10-20% develop
- Calcium oxalate, uric acid common
- Hydration, dietary modifications
Cyst Infections in ADPKD
- Difficult to penetrate
- Fluoroquinolones, TMP-SMX
- Long-duration antibiotics
- Drainage sometimes needed
Cyst Hemorrhage
- Common
- Self-limited typically
- Pain control
- Stop ASA / anticoagulant transiently
- Severe: angioembolization
Pearls
- ADPKD: PKD1 (85%, severe) > PKD2 (15%); bilateral cysts + extrarenal; tolvaptan (TEMPO 3:4, REPRISE) for rapid progressors
- ARPKD: pediatric severe (PKHD1)
- Alport: type IV collagen (COL4A5 X-linked); hematuria + hearing + ocular; ACE/ARB
- Fabry: X-linked α-Gal-A deficiency; multi-organ + angiokeratomas; ERT or migalastat or pegunigalsidase
- Thin GBM: benign familial hematuria
- Nephronophthisis: ciliopathy juvenile CKD
- TSC + VHL: angiomyolipomas vs cysts/RCC/hemangioblastoma
- Mayo Classification 1A-1E for ADPKD progression
- Berry aneurysm screening in ADPKD with family history
- Genetic counseling + cascade screening