The disease
Silent, dominant, and slow.
ADTKD-MUC1 is a tubulointerstitial disease. A frameshifted mucin-1 protein accumulates inside tubular cells rather than reaching the cell surface, driving progressive interstitial fibrosis and tubular atrophy. There is no proteinuric phase, no active sediment, and no imaging signature — the kidney fails quietly.
Presentation
The clinical picture
Autosomal dominant family history
CKD in one parent and, typically, an affected relative in each preceding generation. Penetrance is complete; each child of an affected parent carries a 50% risk. De novo variants do occur, so a negative family history does not exclude the diagnosis.
In plain terms — Kidney failure shows up in every generation — a parent, a grandparent, an aunt, a cousin.
Bland urinary sediment
Minimal or absent hematuria. Proteinuria under 500 mg/24h until advanced CKD. The urinalysis is conspicuously unremarkable relative to the degree of functional loss — this discordance is the single most useful bedside clue.
In plain terms — The urine test looks normal, even though the kidneys are failing. That mismatch is the clue.
Normal or small kidneys on imaging
Ultrasound is normal or shows symmetrically small, echogenic kidneys. Occasional simple cysts may be present but never meet ADPKD criteria. Imaging cannot establish or exclude the diagnosis.
In plain terms — An ultrasound or scan will not find this. The kidneys usually look ordinary.
Slow, relentless decline without a cause
A linear eGFR trajectory over decades, absent diabetes, significant hypertension, glomerulonephritis, or obstruction. Median age at kidney failure is 46 years, with a reported range of 20 to 70 years, and eGFR is already below 90 mL/min/1.73m² in roughly half of carriers by age 15.
In plain terms — Kidney function drops steadily for years with no diabetes, no infection, no explanation.
Subtypes
ADTKD is a family of diseases.
MUC1 and UMOD account for the large majority of solved cases and are clinically indistinguishable in most families. Only MUC1 is invisible to a standard panel — which is precisely why it is the one left undiagnosed.
| Gene | Share | Distinguishing features | Standard panel |
|---|---|---|---|
| MUC1 | ~40% of solved ADTKD | Gout is uncommon before CKD. Indistinguishable from UMOD on clinical grounds alone. | Missed |
| UMOD | ~40% of solved ADTKD | Early gout and hyperuricemia in roughly half of carriers, often preceding CKD by years. | Detected |
| REN | Uncommon | Childhood anemia, hyperkalemia, mild hypotension, acute injury with volume depletion. | Detected |
| HNF1B | Uncommon | Renal cysts, hypomagnesemia, MODY5 diabetes, genital tract anomalies. Often a 17q12 deletion. | Detected |
| SEC61A1 | Rare | Congenital anemia and neutropenia alongside tubulointerstitial disease. | Detected |
| DNAJB11 | Rare | Small kidney cysts and liver cysts; a phenotypic bridge toward ADPKD. | Detected |
Natural history
What families can expect
Kidney function declines along a broadly linear trajectory over decades. Median age at kidney failure is 46 years, though the reported range spans 20 to 70 — including within a single family, so a relative's age at dialysis predicts an individual's only loosely.
Management today
There is no disease-specific therapy. Care is standard CKD care — blood pressure control, avoidance of nephrotoxins, timely planning for kidney replacement therapy. Transplantation works well: the disease does not recur in the graft.
Why a diagnosis matters
It ends the diagnostic odyssey, spares an uninformative biopsy, sets surveillance for at-risk relatives, and — critically — identifies living related donors who should be excluded before they donate a kidney they will need.
On the horizon
A tractable mechanism
The frameshifted protein is retained intracellularly in a TMED9-positive compartment. A small molecule that targets TMED9 promotes lysosomal degradation of the mutant product and reverses the proteinopathy in model systems — the first therapeutic strategy aimed at the cause rather than the consequence.
This work is preclinical. It is not a treatment available to patients today, and no claim here should be read as one. It is, however, the reason a confirmed genetic diagnosis is worth having now: trials recruit from registries of genetically confirmed families. See the citation.