342.1 🎓 醫孞生版

342.1.0.1 📌 䞀頁重點

342.1.0.1.1 Autosomal Dominant Polycystic Kidney Disease (ADPKD)
342.1.0.1.1.1 Epidemiology
  • Most common hereditary kidney disease
  • 1 in 400-1000 globally
  • Adults onset (cysts develop early but progression slow)
  • ~ 50% reach ESKD by 60 yo
342.1.0.1.1.2 Genetics
  • PKD1 (chromosome 16): 85%; polycystin-1; more severe
  • PKD2 (chromosome 4): 15%; polycystin-2; slower progression; ESKD ~ 75 yo
  • GANAB, DNAJB11: rare
  • Family history present in ~ 90%; spontaneous mutations rare
342.1.0.1.1.3 Pathophysiology
  • Mutation → impaired polycystin function
  • Cilia signaling abnormality
  • Tubular dilation → cysts
  • Progressive bilateral cyst formation
  • Compression + interstitial damage
342.1.0.1.1.4 Clinical Features

Renal: - Bilateral renal cysts (variable size + number) - Hypertension (HTN 70-80%) — often early - Hematuria (cyst rupture) - Flank pain (cyst infection, hemorrhage, stones) - Recurrent UTI / pyelonephritis - Stones (10-20% — calcium oxalate, uric acid) - Progressive CKD → ESKD

Extrarenal: - Liver cysts (most common; 70-90%; F > M; estrogen) - Pancreatic cysts (10%) - Spleen cysts - Intracranial aneurysms (Berry, 5-15%) — significantly higher than general population - Cardiac valves (mitral valve prolapse 25%; aortic regurgitation) - Diverticulosis (colonic) - Abdominal hernias - Aortic aneurysm

342.1.0.1.1.5 Diagnosis

Imaging: - Ultrasound: cysts (≥ 3 cysts in each kidney if 30-39 yo; ≥ 2 each kidney 15-29 yo or 40+; modified Ravine criteria) - CT / MRI: more sensitive - Total Kidney Volume (TKV) measurement for risk

Genetic Testing: - For unclear cases (no family history, young onset) - For donor evaluation

Mayo Clinic Classification (1A-1E): - Based on height-adjusted total kidney volume (htTKV) - 1A: slowest; 1E: fastest progression - Guides tolvaptan use

342.1.0.1.1.6 Treatment

General CKD Management (Ch335): - BP control < 130/80 (ACE/ARB first-line) - Statin if indicated - Avoid nephrotoxins

Specific ADPKD Therapy: - Tolvaptan (Jynarque, Samsca) — vasopressin V2 receptor antagonist - TEMPO 3:4 (2012): slowed cyst growth + decline of GFR - REPRISE (2017): confirmed in advanced ADPKD - For rapidly progressing CKD (typical 18-65 yo, eGFR 25-90) - Side effects: polyuria, polydipsia, hepatotoxicity (LFT monitoring), thirst - REMS program

Pain Management: - NSAIDs (cautious — chronic CKD) - Acetaminophen - Cyst aspiration (selected) - Renal denervation (rarely)

Cyst Infections: - Difficult to treat - Fluoroquinolones (penetration) - TMP-SMX

Intracranial Aneurysm Screening: - Family history of aneurysm - High-risk occupation (pilot, military) - MRA or CTA every 5-10 years

Aneurysm Treatment: - Endovascular coiling or surgical clipping - Asymptomatic: > 7 mm typically treated

RRT: - Dialysis or transplant when ESKD - Pre-transplant nephrectomy if very large or symptomatic

342.1.0.1.2 Autosomal Recessive Polycystic Kidney Disease (ARPKD)
342.1.0.1.2.1 Genetics
  • PKHD1 mutation (fibrocystin)
  • Autosomal recessive
342.1.0.1.2.2 Clinical
  • Severe; pediatric (often perinatal)
  • Bilateral enlarged kidneys (palpable abdomen)
  • Hepatic fibrosis (Caroli disease)
  • Pulmonary hypoplasia (severe neonatal)
  • HTN
  • Progressive CKD
342.1.0.1.2.3 Outcome
  • 50% ESKD by 10-20 yo
  • Hepatic complications later
  • Transplant + supportive
342.1.0.1.3 Alport Syndrome
342.1.0.1.3.1 Genetics
  • COL4A5 (X-linked) — most common
  • COL4A3, COL4A4 (autosomal recessive)
  • Defects in type IV collagen → abnormal GBM
342.1.0.1.3.2 Clinical
  • Hematuria (sometimes intermittent)
  • Progressive CKD (especially men)
  • Sensorineural hearing loss (high-frequency)
  • Ocular abnormalities (anterior lenticonus pathognomonic)
  • HTN, eventual ESKD
342.1.0.1.3.3 Diagnosis
  • Genetic testing (definitive)
  • Renal biopsy: thin then thickened GBM; basket-weave appearance on EM
  • Skin biopsy (some — COL4A5 loss on IF)
342.1.0.1.3.4 Treatment
  • ACE/ARB (slow progression; Italian Pediatric Alport Trial)
  • SGLT2i emerging
  • Transplant for ESKD (post-transplant anti-GBM disease in some — Alport in donor kidney)
  • Hearing aids; ocular surveillance
342.1.0.1.4 Thin Basement Membrane Nephropathy (TBMN)
342.1.0.1.4.1 Genetics
  • COL4A3 or COL4A4 heterozygous
  • Autosomal dominant
342.1.0.1.4.2 Clinical
  • Benign familial hematuria
  • Mild proteinuria
  • Generally good prognosis (rare progression)
  • May be carrier for Alport syndrome
342.1.0.1.4.3 Diagnosis
  • Family history
  • Persistent microscopic hematuria
  • Renal biopsy: thin GBM on EM
342.1.0.1.4.4 Treatment
  • Usually no specific
  • Monitor
342.1.0.1.5 Fabry Disease
342.1.0.1.5.1 Genetics
  • X-linked (GLA gene)
  • α-Galactosidase A deficiency
  • Globotriaosylceramide (Gb3) accumulation
342.1.0.1.5.2 Clinical (Multi-Organ)

Renal: - Proteinuria + progressive CKD - FSGS-like, foam cells on biopsy

Cardiovascular: - HCM (concentric hypertrophy) mimics HCM - Arrhythmia - Valvular

Neurologic: - Acroparesthesias (burning pain in hands/feet) - Stroke - Hypohidrosis

Skin: - Angiokeratomas (clustered red papules in “bathing trunk” distribution)

Other: - GI symptoms - Hearing loss - Cataracts - Cornea verticillata

342.1.0.1.5.3 Diagnosis
  • α-Galactosidase A activity (low in males; variable in heterozygous females)
  • Genetic testing (GLA)
  • Lyso-Gb3 biomarker
342.1.0.1.5.4 Treatment
  • Enzyme replacement therapy (ERT):
    • Agalsidase α (Replagal)
    • Agalsidase β (Fabrazyme)
  • Migalastat (Galafold): chaperone for amenable mutations (oral)
  • Pegunigalsidase (PRX-102, Elfabrio): pegylated, longer-acting; FDA 2023
  • Supportive: ACE/ARB, statin, cardiac, neuropathy
342.1.0.1.6 Nephronophthisis (NPHP) + Medullary Cystic Kidney Disease (MCKD)
342.1.0.1.6.1 Genetics
  • Ciliopathy — multiple genes (NPHP1-NPHP22+)
  • Autosomal recessive (NPHP) or dominant (MCKD)
342.1.0.1.6.2 Clinical
  • Juvenile NPHP: most common; ESKD ~ 15 yo
  • Polyuria, polydipsia (early)
  • Anemia, growth failure
  • CKD progressive
  • May have extrarenal (retinitis pigmentosa, hepatic fibrosis)
342.1.0.1.6.3 Diagnosis
  • Genetic testing
  • Imaging: medullary cysts
  • Renal biopsy: tubular atrophy + interstitial fibrosis
342.1.0.1.6.4 Treatment
  • Supportive; transplant for ESKD
342.1.0.1.7 Other Hereditary Kidney Diseases

342.1.1 Tuberous Sclerosis Complex (TSC)

  • TSC1, TSC2 mutations
  • Angiomyolipomas (renal)
  • Cysts
  • Other: skin, brain, heart (rhabdomyoma), lung (LAM)
  • mTOR inhibitor (sirolimus, everolimus)

342.1.2 Von Hippel-Lindau (VHL)

  • VHL mutation
  • Renal cysts + RCC
  • CNS hemangioblastoma
  • Pheochromocytoma
  • Pancreatic + retinal
  • Surveillance + early surgery

342.1.4 Apol1 Risk Genotype

  • G1, G2 in African ancestry
  • ↑ FSGS, hypertensive nephropathy, HIV-AN, lupus nephritis
  • Inaxaplin (AMPLITUDE trial) — emerging
342.1.4.0.1 Genetic Counseling
  • Pre-conception
  • Cascade screening
  • Pre-implantation genetic diagnosis (PGD)
  • Family planning options
  • Insurance/employment considerations
342.1.4.0.2 Pregnancy in Hereditary Kidney Disease
  • ADPKD: increased BP, preeclampsia risk; UTI; cyst hemorrhage rare
  • Alport: variable
  • Fabry: enzyme therapy continuation possible
  • Multidisciplinary management

342.1.4.1 🩺 床邊速查

  • ADPKD: PKD1 (most, severe) > PKD2; bilateral cysts + extrarenal (liver, brain aneurysm); tolvaptan for rapid progressors
  • ARPKD: pediatric severe; PKHD1
  • Alport: type IV collagen; hematuria + hearing loss + ocular; ACE/ARB
  • Fabry: X-linked α-Gal-A deficiency; ERT (agalsidase) or migalastat
  • Thin GBM: benign familial hematuria; COL4A3/4
  • Nephronophthisis: ciliopathy; juvenile ESKD
  • TSC: angiomyolipomas; mTOR inhibitor
  • VHL: cysts + RCC + hemangioblastoma + pheochromocytoma