NephrologyTier 2Disease (DEADMAN)

Inherited and genetic renal disease - polycystic kidney disease

Description

Progressive bilateral cyst formation from all nephron segments -> massive kidney enlargement, loss of functioning parenchyma
Commonest inherited kidney disease; 5-10% of ESKD

ADPKD vs ARPKD

	ADPKD	ARPKD
Gene	*PKD1 (~78%), PKD2 (~15%), GANAB, DNAJB11, IFT140*	*PKHD1* (fibrocystin)
Presentation	Adult, 3rd-5th decade	Neonatal/infancy
Kidneys	Large, irregular, macrocysts	Large, echogenic, radial microcysts
Liver	Polycystic liver disease	Congenital hepatic fibrosis -> portal HTN
Other	Intracranial aneurysm	Potter sequence, pulmonary hypoplasia

**PKD1 is ~20 years worse than PKD2** - median ESKD ~55 vs ~75 yrs
- Truncating PKD1 worst of all

1:400-1:1000 live births - commonest monogenic kidney disease
~10% of dialysis population in Australia
~10-25% have no family history (de novo mutation or mild parental phenotype)
ARPKD 1:20,000

Polycystin-1 (PKD1) and polycystin-2 (PKD2) - primary cilium mechanosensory complex
- Loss of function -> dec intracellular Ca2+ -> inc cAMP
- -> inc tubular cell proliferation + inc luminal fluid secretion (CFTR-mediated Cl-)
- -> cyst growth, detachment from the nephron, interstitial fibrosis
Vasopressin acts through V2 receptor -> inc cAMP - the target of tolvaptan; also why water intake matters
Two-hit model: germline mutation + somatic second hit in the tubular cell
- Explains why only a minority of nephrons form cysts

Presentation

HTN - earliest manifestation, often before eGFR falls, and LVH
Haematuria - cyst rupture into collecting system
Flank/loin pain - cyst haemorrhage, rupture, infection, stone, or simple mass effect
Nephrolithiasis (~20%, uric acid and calcium oxalate; low urine citrate)
Recurrent UTI, cyst infection
Bilaterally palpable, enlarged, irregular kidneys
Progressive CKD -> ESKD

Imaging criteria - Ravine (US), by age, positive family history

Exclusion in an at-risk person: <2 cysts if age >=40
US insensitive under 30, especially for PKD2 - use MRI, or genetic testing, if a definitive negative is needed (e.g. living donation)

Prognostication

Mayo Imaging Classification - height-adjusted total kidney volume by age, classes 1A-1E
- Validated only in PKD1/PKD2
PROPKD score - sex, genotype, HTN <35, urological event <35
Genetic testing where prognosis, family planning or donor assessment depends on it

Intracranial aneurysm screening

Prevalence ~6% without family history, ~16% with family history of aneurysm/SAH
MRA screen if: family history of aneurysm/SAH/stroke, new or changed headache, neurological symptoms, high-risk occupation (pilot), or before major elective surgery
Not routine in everyone

Slow progression

Tolvaptan - V2 receptor antagonist; suppresses cAMP-driven proliferation and fluid secretion
- Eligible: Mayo class 1C-1E or documented eGFR decline >=3 mL/min/1.73m2/yr; eGFR >25
- Evidence: TEMPO 3:4 (TKV >750 mL, eGFR >60) slowed TKV growth; REPRISE (eGFR 25-65) slowed eGFR decline in later disease
- Aquaresis: polyuria, nocturia, thirst - the main reason for discontinuation
- *Hepatotoxicity - LFTs monthly for 18 months then 3-monthly; idiosyncratic, potentially fatal*
BP control - ACEi/ARB first-line, especially if proteinuria >1 g/day
- HALT-PKD: target 95/60-110/75 in young patients with preserved eGFR (age 15-49, eGFR >60) slowed TKV growth
- Otherwise standard CKD target
High water intake (~3 L/day) to suppress vasopressin; dietary Na restriction; avoid caffeine excess
SGLT2i: not established in ADPKD - excluded from the major CKD trials

Pain

Simple analgesia, avoid NSAIDs; cyst aspiration/sclerotherapy for a dominant cyst; laparoscopic cyst fenestration; coeliac plexus block

Cyst infection

Lipophilic antibiotics penetrate cysts: ciprofloxacin, trimethoprim, chloramphenicol
- Beta-lactams penetrate poorly
4-6 weeks; consider drainage if no response by 72 h

Nephrectomy

Indications: severe recurrent bleeding, recurrent/severe cyst infection, infected stones, intractable pain, suspected malignancy, no room for a graft
Costs: transfusion and allosensitisation, loss of residual renal function, loss of pre-emptive transplant
TKV usually falls after transplantation - so defer where possible

Reproductive

Avoid oestrogen-containing contraception and HRT - worsens polycystic liver disease
Preimplantation genetic diagnosis available
Screening asymptomatic children is generally not done - no treatment changes, insurance implications

Vascular

Non-vascular

Polycystic liver disease - most common extrarenal feature; usually asymptomatic
- Worse with: female sex, exogenous oestrogen, multiple pregnancies
- Complications: mass effect, cyst infection, hepatic venous outflow obstruction; liver function preserved
Pancreatic and seminal vesicle cysts, arachnoid cysts
Diverticular disease, abdominal wall and inguinal hernia
Bronchiectasis

Differential - other cystic kidney disease

Tuberous sclerosis (TSC2/PKD1 contiguous deletion - severe early disease), VHL, acquired cystic disease of dialysis, medullary sponge kidney, nephronophthisis, ADTKD

GFR stays normal for decades despite massive kidney enlargement - surviving nephrons hyperfilter and mask nephron loss
- By the time creatinine rises, most of the parenchyma is gone
TKV and its rate of growth are the best early progression markers
- Normal combined kidney volume ~300 mL (F) / ~400 mL (M); polycystic kidneys often >1000 mL
- Typical growth ~5-6%/yr
Median ESKD: **PKD1 ~55 yrs, PKD2 ~75 yrs**
Poor prognostic factors: male sex, truncating PKD1, HTN before 35, urological event before 35, large TKV for age, gross haematuria

Complications

ESKD; HTN and cardiovascular death exceed ESKD as causes of mortality
Cyst haemorrhage, infection, stones
SAH from aneurysm rupture
Renal cell carcinoma risk is NOT clearly increased in native ADPKD kidneys (unlike acquired cystic disease)

Post-transplant

Outcomes at least as good as other causes of ESKD; lower rates of post-transplant cardiovascular death

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