What are the key differentials and management strategies for a patient presenting with symptoms suggestive of polycystic kidney disease (PKD), including abdominal pain, hematuria, and impaired renal function, with a relevant family history and associated conditions such as hypertension, kidney stones, and liver cysts?

Differential Diagnosis of Polycystic Kidney Disease

When evaluating a patient with bilateral renal cysts, abdominal pain, hematuria, and impaired renal function, the primary differential includes autosomal recessive PKD (ARPKD), acquired cystic kidney disease (ACKD), multiple simple cysts, tuberous sclerosis complex (TSC), and autosomal dominant tubulointerstitial kidney disease (ADTKD), with diagnosis guided by age of presentation, family history, imaging characteristics, and presence of extrarenal manifestations. 1

Key Differentials to Consider

Hereditary Cystic Kidney Diseases

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

• Presents in neonates or early childhood with bilaterally enlarged echogenic kidneys and hepatic fibrosis 2, 3
• Cysts develop primarily in collecting ducts due to maturation failure 3
• Associated with Potter's syndrome, respiratory dysfunction from massive kidney enlargement, and early hypertension 3
• Requires genetic testing of chromosome 6 for definitive diagnosis when clinical presentation is atypical 1

PKD1/TSC2 Contiguous Gene Syndrome

• Presents with severe polycystic kidney disease in infancy or early childhood combined with tuberous sclerosis features 2
• Look for subependymal giant cell astrocytomas, cardiac rhabdomyomas, facial angiofibromas, and renal angiomyolipomas 1
• Requires referral to specialized centers for multidisciplinary management 2
• May reach end-stage renal disease in young adulthood 2

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

• Characterized by bland urinary sediment, minimal proteinuria, and progressive CKD without significant cyst burden 1
• Cysts are fewer and smaller compared to ADPKD 1
• Requires genetic testing to differentiate from ADPKD in atypical presentations 1

Acquired and Non-Hereditary Conditions

Acquired Cystic Kidney Disease (ACKD)

• Occurs exclusively in patients with end-stage renal disease on dialysis 4, 1
• Cyst number increases with duration of hemodialysis 4
• More common in males 4
• Distinguished by history of chronic kidney disease preceding cyst development 1

Multiple Simple Renal Cysts

• Extremely common, affecting ~50% of individuals over age 50 4
• Cysts are typically few in number, unilateral or asymmetric, and non-progressive 1
• No family history of kidney disease 1
• Normal kidney size and preserved renal function 1

Multicystic Dysplastic Kidney (MCDK)

• Unilateral involvement with non-functioning kidney 1
• Typically diagnosed in infancy or childhood 1
• Contralateral kidney is normal 1

Neoplastic Cystic Diseases

Von Hippel-Lindau (VHL) Syndrome

• Multiple bilateral renal cysts with clear cell renal carcinomas 1
• Associated with retinal and CNS hemangioblastomas, pheochromocytomas 1
• Requires genetic testing of VHL gene for diagnosis 1

Tuberous Sclerosis Complex (TSC)

• Renal angiomyolipomas are more characteristic than cysts 1
• Look for seizures, intellectual disability, facial angiofibromas, cardiac rhabdomyomas 1

Diagnostic Approach Algorithm

Step 1: Age and Presentation Pattern

• Neonatal/early childhood with massive kidneys: Consider ARPKD or PKD1/TSC2 contiguous gene syndrome 2, 3
• Young adult (15-39 years) with ≥3 total renal cysts and positive family history: Likely ADPKD 5
• Middle-aged/elderly with few cysts: Consider simple cysts or ACKD if on dialysis 4, 1

Step 2: Family History Assessment

• Positive family history with similar phenotype: ADPKD is most likely 2, 5
• Negative family history: Requires imaging characteristics and extrarenal manifestations to guide differential 5
• Family history of tuberous sclerosis or VHL: Consider syndromic cystic diseases 1

Step 3: Imaging Characteristics

• Bilateral, symmetric, numerous cysts with enlarged kidneys: Classic for ADPKD 5, 6
• Asymmetric or focal cystic disease: Consider ADTKD, simple cysts, or atypical ADPKD requiring genetic testing 5
• Unilateral cystic disease: MCDK or unilateral renal cystic disease 1
• Small kidneys with end-stage disease: ACKD if on dialysis 4, 1

Step 4: Extrarenal Manifestations

• Liver cysts (present in 44-80% of ADPKD patients): Strongly supports ADPKD diagnosis 2, 7
• Hepatic fibrosis in child: Pathognomonic for ARPKD 3
• Cardiac valvular abnormalities, intracranial aneurysms: Associated with ADPKD 2, 3
• Retinal/CNS hemangioblastomas: VHL syndrome 1
• Subependymal nodules, facial angiofibromas: TSC or PKD1/TSC2 1

Step 5: Laboratory and Clinical Features

• Hypertension (present in 69% of ADPKD patients >50 years): Common in ADPKD but non-specific 7
• Hematuria (31% of older ADPKD patients): Occurs in ADPKD but also simple cysts with hemorrhage 2, 7
• Recurrent UTIs (41% of ADPKD patients): More common in ADPKD than simple cysts 2, 7
• Nephrolithiasis: Associated with ADPKD 2, 6
• Normal creatinine in older patient with cysts: Does not exclude ADPKD (31% of older ADPKD patients have normal creatinine) 7

Step 6: When to Pursue Genetic Testing

• Atypical imaging findings (asymmetric, focal, or discordant disease within family) 5
• Negative family history with bilateral cysts 5
• Early-onset disease with ESRD before age 30 5
• Need to differentiate ADPKD from ADTKD, ARPKD, or syndromic diseases 1

Critical Pitfalls to Avoid

Do not exclude ADPKD based solely on preserved renal function - 31% of older ADPKD patients maintain normal creatinine 7

Do not rely on absence of family history to rule out ADPKD - spontaneous mutations occur, and family history may be unclear due to variable penetrance or early death from other causes 5

Do not assume all bilateral cysts in dialysis patients are ACKD - patients with pre-existing ADPKD who develop ESRD will have both conditions 1

Do not perform routine intracranial aneurysm screening in children with ADPKD - rupture is exceedingly rare in childhood; screen only with positive family history of aneurysm or high-risk profession 2

Avoid chronic NSAID use for pain management - potential for accelerating renal decline in ADPKD 2

Management Implications Based on Differential

Once ADPKD is confirmed, blood pressure control with ACE inhibitors or ARBs is cornerstone therapy targeting 110/75 mmHg for ages 18-49 with CKD G1-G2, or systolic <120 mmHg for age ≥50 or CKD G3-G5 8, 9

Tolvaptan should be considered for adults at high risk of rapid progression based on Mayo Imaging Classification and total kidney volume, slowing eGFR decline by 1.3 mL/min/1.73m²/year 8

Do not use mTOR inhibitors in classical ADPKD - lack of eGFR benefit with significant adverse effects 8, 9

For ARPKD, focus shifts to managing hepatic fibrosis complications and preparing for earlier renal replacement therapy 3

For TSC/VHL, surveillance for malignancy becomes paramount alongside cystic disease management 1