Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Overview

Epidemiology

• Prevalence: 1 in 400 to 1 in 1000 worldwide, in all races
• Annual ESKD incidence: ~8.7/million (men) and 6.9/million (women) in the US
• ~30,000 patients have ESKD due to ADPKD in the United States
• Men have slightly more aggressive disease (gender ratio 1.2–1.3)
• At least 10% of cases arise from apparent de novo mutations

Genetics

• PKD1: ~65% truncating, 35% nontruncating mutations; >1,272 mutations catalogued
• PKD2: ~87% truncating, 13% nontruncating
• Homozygous PKD1/PKD2 loss-of-function → lethal in utero
• Trans-heterozygotes (one PKD1 + one PKD2 mutation) have worse disease than either alone

Pathogenesis

Key Proteins

• Polycystin-1 (PC1) — encoded by PKD1; ~440 kDa; receptor/adhesion molecule with large extracellular N-region, 11 transmembrane domains; located in primary cilia, plasma membrane, focal adhesions, desmosomes
• Polycystin-2 (PC2) — encoded by PKD2; ~110 kDa; transient receptor potential (TRP) channel; mainly in ER, also primary cilium; forms a 1:3 complex with PC1

Two-Hit Model

Downstream Signaling

• ↑ mTOR pathway activation (drives cell proliferation)
• ↑ cAMP (promotes fluid secretion and cell growth)
• Aberrant MAPK/ERK signaling
• Loss of primary cilium mechanosensing function
• Increased cell proliferation + apoptosis

Pathology

• Cysts arise from all nephron segments, predominantly distal tubule and collecting duct
• Cysts grow, dissociate from parent tubule, becoming isolated fluid-filled sacs
• Polycystic kidneys show: afferent arteriole/interlobular artery sclerosis, interstitial fibrosis, tubular hyperplasia — even when GFR is normal
• Histology: papillary hyperplasia of cyst epithelium; microscopic adenomas present (risk of RCC is not increased)

Clinical Features

Renal

• Flank pain / abdominal pain — most common symptom; due to cyst enlargement, hemorrhage, infection, or stone
• Hematuria — gross or microscopic; intracyst hemorrhage is most common cause
• Hypertension — affects >50% early in disease, often precedes GFR decline; driven by intrarenal RAAS activation
• Nephrolithiasis — ~20% of patients; predominantly uric acid and calcium oxalate stones (associated with hypocitraturia, low urine pH)
• Cyst infection — presents with fever, flank/loin pain, elevated CRP; difficult to distinguish from hemorrhage; trimethoprim-sulfamethoxazole or fluoroquinolones (lipophilic agents penetrate cysts)
• CKD progression → ESKD — median age of ESKD: 58.1 (PKD1), 79.7 (PKD2)

Extrarenal

Diagnosis

Ultrasound Criteria (Pei/Ravine, unified criteria)

Imaging

• Ultrasound: first-line; limited by body habitus and large kidney size
• MRI: preferred for monitoring disease progression and identifying solid masses among cysts; superior soft tissue contrast
• CT: good for complications (hemorrhage, infection, malignancy)
• Total Kidney Volume (TKV): key prognostic biomarker; measured by MRI or CT; Mayo Clinic Imaging Classification (MCIC) uses ellipsoid formula for practical risk stratification

Genetic Testing

• Indicated when imaging is equivocal, for living-related donor evaluation, or pre-implantation genetic diagnosis
• Next-generation sequencing (NGS) of PKD1/PKD2 is current standard; PKD1 screening is complex due to segmental duplication

Prognosis / Risk Stratification

Treatment

General / Supportive

• Adequate hydration — high water intake (2.5–3 L/day) suppresses vasopressin/AVP, reducing cAMP-driven cyst growth; goal urine osmolality <280 mOsm/kg
• Hypertension control: RAAS blockade with ACE inhibitors or ARBs first-line; target BP <110/75 mmHg in young patients (HALT-PKD trial data)
• Low-sodium, low-protein diet (standard CKD measures)
• Avoid nephrotoxins: NSAIDs, contrast agents
• Statin therapy: may have modest benefit; used for cardiovascular risk reduction

Pain Management

• Exclude reversible causes (infection, stone, tumor)
• Conservative first: reassurance, lifestyle modification, tricyclic antidepressants
• Narcotic analgesics for acute severe pain only (avoid long-term)
• Cyst decompression: aspiration ± sclerotherapy (95% ethanol, minocycline, sodium tetradecyl sulfate) for large symptomatic cysts; laparoscopic or surgical cyst unroofing for refractory cases

Disease-Modifying / Novel Therapies

• TEMPO 3:4 and REPRISE RCTs showed reduced TKV growth and slowing of GFR decline
• Main side effects: aquaretic (polyuria, polydipsia, nocturia), hepatotoxicity (requires liver function monitoring; REMS program in US)
• Contraindicated in patients who cannot sense/respond to thirst

Cyst Infection

• Fluoroquinolones or TMP-SMX (lipophilic → penetrate cysts)
• Prolonged treatment (4–6 weeks) often required

ESKD Management

• Dialysis or kidney transplantation
• Transplantation outcomes are excellent; pre-emptive transplant preferred
• Native nephrectomy may be needed for massively enlarged kidneys prior to transplant (space issue)

Intracranial Aneurysm Screening

• Prevalence ~8–12% in ADPKD (vs. 2–3% general population)
• Screen with MRA (without gadolinium) in:
  • Family history of intracranial aneurysm or SAH
  • Prior aneurysm rupture
  • High-risk occupation (pilots, surgeons) or preparing for elective surgery under GA
  • Significant anxiety about risk
• If no aneurysm found and no family history: routine screening not generally recommended

Summary

Medullary Kidney Disease

1. Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) — formerly "Medullary Cystic Kidney Disease" (MCKD)
2. Nephronophthisis (NPHP) — the childhood ciliopathy
3. Medullary Sponge Kidney (MSK) — a structural collecting duct anomaly

1. Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

Nomenclature

• Cysts are not invariably present (especially early disease)
• Histology shows predominantly tubulointerstitial fibrosis, not cystic change
• The old MCKD grouping incorrectly lumped it with nephronophthisis, which is a distinct entity

Genetic Subtypes

Pathogenesis — ADTKD-UMOD (Most Common)

Clinical Features

• Onset: typically 4th–7th decade (except FJHN and GCKD, allelic variants presenting in the 1st–3rd decade)
• Slowly progressive CKD with bland urinary sediment — minimal proteinuria, no hematuria
• Hyperuricemia + gout (ADTKD-UMOD, ADTKD-REN; less prominent in ADTKD-MUC1 early on)
• Anemia disproportionate to GFR in ADTKD-REN (↓ Ang II → ↓ erythropoiesis)
• No increased UTI or nephrolithiasis

Investigations

• Urinalysis: bland sediment, minimal or no proteinuria
• Labs: hyperuricemia, ↓ uric acid fractional excretion, mild ↓ urinary concentrating ability
• Imaging: normal to mildly reduced kidney size, ↑ echogenicity, loss of corticomedullary differentiation; medullary cysts visible on US/CT — but may be too small to detect, especially early
• Biopsy: tubulointerstitial fibrosis, tubular atrophy, tubular BM disintegration — not diagnostic of specific subtype
• Genetic testing required for definitive diagnosis (NGS panels available)

Treatment

• Allopurinol or febuxostat for hyperuricemia/gout
• Management of CKD sequelae: anemia, acidosis, MBD, hypertension
• HNF1B: manage pancreatic insufficiency
• ADTKD-REN: manage hypotension and hyperkalemia
• No disease-specific therapy exists; no recurrence after kidney transplantation
• ESKD: age 40–70 years for ADTKD (cf. NPHP, below)

2. Nephronophthisis (NPHP)

Overview

Genetics

Genetic Table (Key Forms)

Clinical Variants

• Infantile NPHP (NPHP2): ESKD in early childhood
• Juvenile NPHP (NPHP1, most common): ESKD by ~13 years; polyuria and polydipsia as first symptoms
• Adolescent NPHP: ESKD in early adulthood

Associated Syndromes

Clinical Features

• Polyuria + polydipsia — earliest symptoms; severe urinary concentrating defect
• Sodium wasting + tubular acidosis
• Bland urinalysis — no proteinuria, no hematuria
• Hypertension — late finding (contrast with ADPKD)
• Progressive CKD → ESKD within 5–10 years of onset

Pathology

• Kidneys: small, contracted granular surface
• Medullary/corticomedullary cysts (1–15 mm); cysts also in cortex
• Histology: tubular BM thickening and disruption, tubular atrophy, interstitial fibrosis, inflammatory infiltrate; glomeruli relatively preserved early

Key pathological distinction: medullary cysts are present, but it is the cortical tubulointerstitial damage that drives renal failure.

Diagnosis

• Medullary cysts may be too small to visualize radiographically
• Suspect in: child/adolescent with unexplained CKD + positive family history + tubulointerstitial nephritis on biopsy
• Genetic panel sequencing is definitive (NGS available clinically)

Treatment

• No curative or targeted therapy exists; no clinical trials for NPHP-specific interventions
• Manage CKD complications: anemia, acidosis, electrolyte imbalance, MBD, growth retardation
• Kidney transplantation — successful, no recurrence; eventually required for most patients

3. Medullary Sponge Kidney (MSK)

Definition

Epidemiology

• General population frequency: ~1 in 5000 (likely underestimated; many asymptomatic)
• Up to 20% of patients with nephrolithiasis have at least mild MSK
• Usually sporadic; rare autosomal dominant familial cases reported
• Associated with: congenital hemihypertrophy, Beckwith-Wiedemann syndrome, CAKUT, Wilms tumor

Pathogenesis

Clinical Features

• Often asymptomatic — incidental finding
• Symptoms in 2nd–3rd decade (sometimes 4th–5th decade)
• Recurrent nephrolithiasis — calcium phosphate (apatite) ± calcium oxalate stones
• Hematuria (microscopic or gross; may be unrelated to stones)
• Recurrent UTI
• Urinary concentrating defect + impaired urinary acidification (incomplete distal RTA)
• Bone mineralization defects from chronic acidification abnormalities
• Renal function usually normal; ESKD is uncommon

Pathology

• Pathology confined to medullary and intrapapillary collecting ducts
• Cysts 1–8 mm (spherical/oval); may contain apatite concretions
• Affected pyramids and calyces enlarged; cortex normal
• Cysts lined by cuboidal or transitional epithelium

Diagnosis

• Plain X-ray: radiopaque medullary concretions (nephrocalcinosis)
• CT urography or IVU: characteristic "bouquet of flowers" / "paintbrush" pooling of contrast in ectatic medullary ducts — historically the gold standard
• Differential: hyperparathyroidism, distal RTA type I, hypervitaminosis D, milk-alkali syndrome, sarcoidosis (all can cause medullary nephrocalcinosis)

Treatment & Prognosis

• Control stone formation: high fluid intake, thiazide diuretics (for hypercalciuria), potassium citrate (for hypocitraturia/acidification defect)
• Treat UTIs promptly
• Long-term prognosis excellent; ESKD is rare

Comparison Table

Medullary Kidney Disease — Summary

1. ADTKD (formerly Medullary Cystic Kidney Disease)

• AD inheritance, adult onset (4th–7th decade)
• Genes: UMOD (most common, hyperuricemia/gout), MUC1, REN, HNF1B, SEC61A1
• Bland urinalysis, slowly progressive CKD → ESKD age 40–70
• Diagnosis by genetic testing; no disease-specific therapy

2. Nephronophthisis (NPHP)

• AR ciliopathy, >90 genes, childhood/adolescent onset
• Most common genetic cause of ESKD in children
• Polyuria/polydipsia earliest symptoms; bland urine; hypertension is late
• Syndromes: Senior-Loken (+ retinitis pigmentosa), Joubert (+ cerebellar vermis hypoplasia), Bardet-Biedl
• No curative therapy; kidney transplant eventually required

3. Medullary Sponge Kidney (MSK)

• Sporadic, collecting duct ectasia, papillary calcifications
• Recurrent stones (calcium), hematuria, UTI; concentrating/acidification defect
• Renal function usually preserved; ESKD rare
• Treatment: hydration, citrate, thiazides