Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
Overview and Clinical Significance
ADTKD should be strongly considered in this 56-year-old patient with tubulointerstitial kidney disease lacking diabetes or hypertension, particularly if there is a family history of unexplained CKD, early-onset gout, or kidney failure before age 60. ADTKD represents the third most common monogenic cause of kidney failure worldwide, yet remains significantly underdiagnosed because its clinical presentation mimics other forms of chronic tubulointerstitial disease 1.
Key Clinical Features That Distinguish ADTKD
Core Diagnostic Characteristics
Autosomal dominant inheritance pattern with progressive kidney function decline, typically requiring renal replacement therapy between ages 30-50 years, though the range extends from 20-80 years 2, 1.
Bland urinary sediment with absent or minimal proteinuria (typically <1 g/day), occasionally with microhematuria 2, 3.
Absence of severe hypertension during early disease stages; blood pressure may increase modestly only with progressive CKD 2.
Normal or small-sized kidneys on ultrasound with increased echogenicity; kidney size declines as disease advances 2, 3.
Renal histology demonstrates interstitial fibrosis with tubular atrophy, thickened and lamellated tubular basement membranes, and negative immunofluorescence for complement and immunoglobulins 2.
Genetic Subtypes and Distinguishing Features
ADTKD-UMOD (Uromodulin Gene)
Most common subtype along with ADTKD-MUC1; characterized by inappropriately low fractional urate excretion (<5%) causing hyperuricemia and early-onset gout 2.
Gout often begins in teenage years, particularly in males, and frequently affects multiple family members—this is a key diagnostic clue 2.
Hyperuricemia occurs in 87% of ADTKD-UMOD patients versus 54% in ADTKD-MUC1 4.
Histology may reveal intracellular uromodulin deposits in thick ascending limb cells 2.
ADTKD-MUC1 (Mucin-1 Gene)
Second most common subtype; presents with no characteristic extrarenal findings or specific laboratory abnormalities 2.
The c.(428)dupC frameshift mutation is particularly prevalent in certain populations 4.
May have worse renal survival than ADTKD-UMOD, with higher risk for ESRD (HR 2.24) and median ESRD onset at age 51 years 4.
Histology shows intracellular accumulation of MUC1-fs protein in distal tubules 2.
ADTKD-REN (Renin Gene)
Less common; characterized by childhood anemia unrelated to GFR that resolves at puberty but may recur with progressive CKD 2.
Patients exhibit mild hypotension and heightened risk for acute kidney injury due to renin-angiotensin system dysfunction 2.
Hyperuricemia and hyperkalemia may be present 2.
Histology demonstrates reduced renin staining in juxtaglomerular apparatus cells 2.
ADTKD-HNF1B (Hepatocyte Nuclear Factor-1β Gene)
Presents with extensive extrarenal manifestations: MODY5-type diabetes, bilateral renal cysts, genital abnormalities, pancreatic atrophy 2.
Laboratory findings include hypomagnesemia, hypokalemia, and liver function abnormalities 2.
Often detected prenatally or in childhood on ultrasound 2.
Only cases with tubulointerstitial fibrosis as the leading manifestation should be classified as ADTKD-HNF1B 2.
Recommended Diagnostic Work-Up
Step 1: Detailed Family History
Obtain a three-generation pedigree specifically querying unexplained kidney disease, early-onset gout (especially before age 40), childhood anemia, MODY5-type diabetes, and dialysis requirement before age 60 3.
Do not exclude ADTKD based on negative family history alone; affected relatives may have died young, been misdiagnosed, or the condition exhibits incomplete penetrance 3, 5.
Step 2: Laboratory Evaluation
Serum creatinine and eGFR (CKD-EPI equation) to establish baseline kidney function 3.
Urinalysis with microscopy: bland sediment favors ADTKD; pyuria or cellular casts suggest alternative diagnoses 3.
Urine albumin-to-creatinine ratio: expect absent-to-mild proteinuria (<1 g/day) 3.
Serum uric acid and fractional urate excretion: fractional excretion <5% strongly suggests ADTKD-UMOD 2, 3.
Serum magnesium and potassium: hypomagnesemia and hypokalemia point toward ADTKD-HNF1B 2, 3.
Urinary uromodulin excretion (if available): low levels support ADTKD-UMOD or ADTKD-REN 3.
Complete blood count: childhood anemia suggests REN mutation 3.
Serum complement (C3, C4) and immunoglobulins to exclude immune-complex disease 3.
Serum and urine protein electrophoresis with immunofixation to rule out monoclonal gammopathy 3.
Step 3: Imaging
Renal ultrasound as first-line imaging: ADTKD typically shows normal or small kidneys with increased echogenicity and occasional non-medullary cysts 2, 3.
Avoid iodinated contrast due to underlying renal impairment 3.
Non-contrast MRI if HNF1B-related extrarenal abnormalities (pancreatic or genital) are suspected 3.
Step 4: Kidney Biopsy Indications
Perform biopsy when the underlying cause remains unclear after initial work-up and a definitive diagnosis would alter management 3.
Also biopsy if atypical features are present: proteinuria >1 g/day, active urinary sediment with cellular casts, or early severe hypertension 3.
Expected findings: interstitial fibrosis, tubular atrophy, thickened tubular basement membranes, negative immunofluorescence 2, 3.
Biopsy is particularly valuable when ADTKD overlaps with other conditions (e.g., Sjögren's syndrome) that can cause tubulointerstitial disease 6.
Step 5: Genetic Testing Strategy
Pursue genetic testing when family history demonstrates autosomal dominant CKD with bland sediment and minimal proteinuria 3.
Early-onset hyperuricemia or gout (especially before age 40 in males) further supports testing 3.
Testing sequence:
Refer to specialized centers for MUC1 testing due to technical complexity 3.
Critical Diagnostic Pitfalls
Do not assume genetic etiology automatically; drug-induced tubulointerstitial nephritis (proton pump inhibitors, NSAIDs, immune checkpoint inhibitors) is more prevalent and potentially reversible 3.
Do not overlook ADTKD in "sporadic" cases; affected relatives may have been misdiagnosed or died young 3, 5.
Do not misattribute renal cysts to autosomal dominant polycystic kidney disease; cysts in ADTKD occur in advanced stages and do not cause the GFR decline 2, 3.
Do not rely solely on hyperuricemia or gout to distinguish ADTKD-UMOD from other causes; values overlap with other CKD etiologies 2.
Review all medications thoroughly, including over-the-counter NSAIDs and supplements, to exclude drug-induced causes 3.
Management Principles
General CKD Management
Standard CKD care applies: blood pressure control, avoidance of nephrotoxins, management of metabolic complications 3.
Monitor renal function serially over three months to confirm chronicity if prior data are unavailable 3.
Subtype-Specific Considerations
ADTKD-UMOD: Treat hyperuricemia and gout with urate-lowering therapy; fractional urate excretion <5% confirms diagnosis 2.
ADTKD-REN: Careful fluid management is essential due to heightened susceptibility to volume depletion and acute kidney injury 3.
ADTKD-HNF1B: Manage diabetes, hypomagnesemia, and hypokalemia; monitor for pancreatic and hepatic complications 2.
Transplantation
ADTKD does not recur in transplanted kidneys; renal transplantation is an excellent option for ESRD 7.
Median age at ESRD is approximately 45 years, with most patients requiring renal replacement therapy between ages 30-50 years 2, 1.
Prognosis and Disease Trajectory
Rate of GFR decline averages -3.0 to -3.9 mL/min/1.73m² per year, with no significant difference between ADTKD-UMOD and ADTKD-MUC1 4.
ADTKD-MUC1 may have worse renal survival than ADTKD-UMOD, with earlier onset of ESRD (median age 51 vs. 56 years) 4.
Age at ESRD varies widely among and within families, ranging from 20 to 80 years 2.