a) Diagnosis and management of ADTKD (Autosomal dominant tubulointerstitial kidney diseases). [6] b) Role of uromodulin in health and kidney disease. [4]
- ADTKD is an autosomal dominant disorder causing CKD due to tubular interstitial fibrosis with key mutations in UMOD, MUC1, REN, and HNF1B (Brenner).
- Genetic testing is essential for definitive diagnosis; kidney biopsy is nonspecific.
- Management is supportive: control hypertension, treat gout (UMOD mutation), and eventual RRT.
- Uromodulin is a renal tubular protein critical for TAL function, innate immunity, and is implicated in ADTKD pathogenesis.
- Low urinary uromodulin levels serve as early markers of tubular disease and CKD progression.
Mnemonic for ADTKD genes: "UMORehNaH"
U - UMOD
M - MUC1
O - [Omitted]
R - REN
Na - [Sodium transport, TAL]
H - HNF1B
Definition
ADTKD is a hereditary kidney disorder characterized by progressive tubulointerstitial fibrosis leading to chronic kidney disease (CKD) and eventual end-stage renal disease (ESRD). It follows an autosomal dominant inheritance pattern (Brenner & Rector's The Kidney, 11th ed, Ch. 35).
Etiopathogenesis
ADTKD is caused by mutations affecting proteins involved in tubular function and integrity, leading to tubular atrophy and interstitial fibrosis. The main genetically defined subtypes include mutations in UMOD, MUC1, REN, HNF1B, and SEC61A1.
| Subtype | Gene | Protein affected | Pathophysiology | Clinical hallmark |
|---|---|---|---|---|
| ADTKD-UMOD | UMOD | Uromodulin | Defective protein folding → ER stress → tubular damage | Hyperuricemia, gout |
| ADTKD-MUC1 | MUC1 | Mucin-1 | Frameshift mutant protein aggregates → tubular injury | Normal uric acid, progressive CKD |
| ADTKD-REN | REN | Renin | Abnormal renin synthesis → hypotension, anemia | Early anemia, low BP |
| ADTKD-HNF1B | HNF1B | Hepatocyte nuclear factor | Developmental cystic kidney disease | Renal cysts, diabetes |
(Major features from Harrison's 21e, Ch. 20; Brenner & Rector's The Kidney, 11e)
Clinical Features
- Slowly progressive CKD presenting in adulthood (20–60 years)
- Mild to moderate proteinuria (usually <1 g/day)
- Tubulointerstitial nephritis features: sterile pyuria, bland urine sediment
- Hyperuricemia and gout (especially in ADTKD-UMOD)
- Hypertension, anemia (especially in ADTKD-REN)
- Family history positive in 50–75% cases
- Renal cysts uncommon but seen in HNF1B mutations
Diagnosis
Clinical criteria for suspecting ADTKD
| Criteria | Finding |
|---|---|
| Family history | Autosomal dominant pattern |
| CKD | Slowly progressive with bland urine sediment |
| Uric acid level | Elevated (UMOD mutations) or normal (MUC1) |
| Extrarenal features | Diabetes, renal cysts (HNF1B) |
| Genetic testing | Confirmatory for mutations in UMOD, MUC1, REN, HNF1B |
Investigations:
- Serum creatinine and urinalysis showing bland sediment
- Serum uric acid levels
- Renal ultrasound (may show normal/small kidneys or renal cysts)
- Genetic testing is gold standard (next-gen sequencing panels for UMOD, MUC1, REN, HNF1B)
- Kidney biopsy: nonspecific interstitial fibrosis, tubular atrophy; sometimes proteinaceous casts
(Diagnosis algorithms: first suspect based on family history + clinical features → genetic confirmation; Harrison's 21e, Ch. 20)
Management
- No disease-specific therapy currently available; management is mainly supportive
- Control hypertension (RAAS blockers preferred)
- Address complications: gout managed via allopurinol/febuxostat (especially in UMOD mutations)
- Avoid nephrotoxic drugs
- Monitor renal function periodically
- Preparation for renal replacement therapy at ESRD stage
- Genetic counseling for family planning
| Therapeutic Aspect | Recommendation |
|---|---|
| Hypertension | ACE inhibitors/ARBs |
| Gout | Xanthine oxidase inhibitors (allopurinol, febuxostat) |
| ESRD management | Dialysis / renal transplantation |
| Genetic counseling | Mandatory for affected families |
(Brenner & Rector's The Kidney, 11e; Harrison's 21e, Ch. 20)
Recent Advances
- Identification of MUC1-associated ADTKD as a distinct subtype via novel frameshift mutation detection (long-read sequencing)
- Development of synthetic small molecule chaperones targeting mutant UMOD protein to reduce ER stress (early phase research)
- Improved genetic panels increasing diagnostic yield
- Kidney transplantation outcomes appear favorable with no disease recurrence
(Harrison's 21e, Ch 20; recent nephrology journals 2020-2023)