In a patient with chronic kidney disease and a family history of renal disease, how can I differentiate Autosomal Dominant Polycystic Kidney Disease (ADPKD) from Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)?

Differentiating ADPKD from ADTKD

The key distinction is imaging: ADPKD presents with massively enlarged kidneys filled with numerous bilateral cysts visible on ultrasound, whereas ADTKD shows normal-sized or small kidneys with minimal or absent cysts, bland urinary sediment, and minimal proteinuria. 1, 2

Imaging Characteristics

ADPKD Features

• Bilaterally enlarged kidneys with multiple cysts throughout both cortex and medulla 3, 4
• Cysts increase progressively in size and number with age 3
• Liver cysts frequently present as an extrarenal manifestation 4
• Diagnosis in at-risk adults aged 15-39 requires ≥3 total renal cysts; aged 40-59 requires ≥2 cysts in each kidney 4

ADTKD Features

• Normal-sized or small kidneys with increased echogenicity 2, 5
• Cysts are absent or minimal, appearing only in advanced disease stages and not causing GFR decline 1, 2
• When present, cysts are non-medullary and do not increase with age like ADPKD 2
• Kidney size declines as disease progresses 1

Laboratory Differentiation

ADPKD Pattern

• Variable proteinuria, often more than minimal 6
• Hematuria common, including macroscopic episodes 4
• Hyperuricemia not a defining feature 7

ADTKD Pattern

• Bland urinary sediment with absent or minimal proteinuria (<1 g/day) 1, 2
• Microscopic hematuria only occasionally present 1
• Hyperuricemia with fractional urate excretion <5% highly characteristic of ADTKD-UMOD subtype 2, 5, 7
• Early-onset gout (often teenage years in males) suggests ADTKD-UMOD 2, 5
• Hypomagnesemia and hypokalemia point toward ADTKD-HNF1B 2

Clinical Presentation Patterns

ADPKD

• Flank or abdominal pain common 4
• Macroscopic hematuria episodes 4
• Hypertension develops early, often before significant GFR loss 6
• ESRD typically after age 50-60 in PKD1, later in PKD2 3

ADTKD

• Absence of severe hypertension in early disease; only modest elevation as CKD advances 1, 2
• Minimal symptoms until advanced CKD 1
• ESRD typically between ages 30-50 (range 20-80 years) 1, 2
• Childhood anemia resolving at puberty suggests ADTKD-REN 2

Family History Clues

ADPKD

• Clear autosomal dominant pattern with affected individuals in multiple generations 4
• Penetrance nearly 100% by age 60 6
• Symmetric disease severity within families 4

ADTKD

• Autosomal dominant pattern but may appear sporadic due to variable expressivity, early death of relatives, or misdiagnosis 1, 2
• Three-generation pedigree showing unexplained CKD, early-onset gout (before age 40), childhood anemia, MODY5 diabetes, or dialysis before age 60 strongly suggests ADTKD 2
• De novo mutations occur, particularly in HNF1B 1

Extrarenal Manifestations

ADPKD

• Hepatic cysts in majority of patients 4, 6
• Intracranial aneurysms in 5-10% 6
• Cardiac valve abnormalities 6

ADTKD-HNF1B Specifically

• MODY5-type diabetes 1, 2
• Genital tract anomalies 2
• Pancreatic atrophy or hypoplasia 2
• Abnormal liver function tests 2

Histopathology (When Biopsy Performed)

ADPKD

• Cyst-lined epithelium with focal cyst formation 6
• Relatively preserved intervening parenchyma until late disease 6

ADTKD

• Interstitial fibrosis with tubular atrophy as primary finding 1, 2
• Thickened, lamellated tubular basement membranes 1, 2
• Negative immunofluorescence for complement and immunoglobulins 1, 2
• UMOD subtype: intracellular uromodulin deposits in thick ascending limb cells 2

Diagnostic Algorithm

1. Obtain renal ultrasound as first-line imaging 2

   • Massively enlarged kidneys with numerous bilateral cysts → ADPKD 3, 4
   • Normal or small kidneys with minimal/no cysts → consider ADTKD 2, 5

2. Assess urinalysis and proteinuria 2

   • Active sediment with significant proteinuria → less likely ADTKD 2
   • Bland sediment with <1 g/day proteinuria → ADTKD pattern 2

3. Check serum uric acid and fractional urate excretion 2, 7

   • Fractional excretion <5% with hyperuricemia → strongly suggests ADTKD-UMOD 2, 5

4. Evaluate three-generation pedigree for unexplained CKD, early gout, childhood anemia, MODY5 diabetes 2

5. Consider genetic testing when ADTKD suspected: sequence UMOD and MUC1 first (most common), add HNF1B if extrarenal features present, include REN if childhood anemia documented 2, 8, 9

Common Pitfalls

• Do not assume all inherited cystic kidney disease is ADPKD; ADTKD can have occasional cysts in advanced stages but presents fundamentally differently 1
• Do not exclude ADTKD based on negative family history; affected relatives may have died young, been misdiagnosed, or the patient may have a de novo mutation 1, 2
• Do not rely on presence/absence of hyperuricemia alone; while characteristic of ADTKD-UMOD, it is not universal across all ADTKD subtypes 2, 9
• ADTKD is significantly underdiagnosed; it represents 1% of CKD stages 3-5 patients and is the most common genetic kidney disease after ADPKD 9