Autosomal Dominant Tubulointerstitial Kidney Disease

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited disorders with bland urine, slowly progressive CKD, and tubular atrophy with interstitial fibrosis, caused by pathogenic variants in UMOD, MUC1, REN, HNF1B, or SEC61A1.

• Accounts for about 1 to 5% of familial CKD, but underdiagnosed.
• ADTKD-UMOD: uromodulin misfolding with retention in the endoplasmic reticulum; early hyperuricaemia and gout, ESKD at age 40 to 70.
• ADTKD-MUC1: frameshift variant producing toxic mucin 1 protein; ESKD at age 30 to 70 with no gout.
• ADTKD-REN: renin deficiency; anaemia in childhood, hyperkalaemia, low blood pressure, early gout.
• ADTKD-HNF1B: renal cysts and diabetes (MODY5), genitourinary malformations, hypomagnesaemia.
• Family history of CKD across generations is the main clue.

• Slowly progressive CKD with minimal proteinuria and bland urinary sediment, from the 2nd to 5th decade.
• Gout in teens or early adulthood (UMOD, REN), low fractional excretion of urate.
• Small kidneys with a few medullary cysts (normal or small size), no hypertension early.
• Anaemia in childhood and hyperkalaemia (REN), hypomagnesaemia, diabetes (HNF1B).
• ESKD often in multiple family members.

• Autosomal dominant family history of CKD without glomerular disease features.
• Urinalysis: bland sediment, proteinuria under 1.5 g/day.
• Kidney ultrasound: normal or small kidneys, medullary cysts in some.
• Serum urate, fractional excretion of urate (under 5% suggestive), magnesium, potassium, renin/aldosterone.
• Genetic testing: UMOD, REN, HNF1B, SEC61A1 sequencing and MUC1 VNTR analysis (special assay such as SNaPshot or long-read sequencing); mandatory for diagnosis.
• Renal biopsy not diagnostic: nonspecific tubular atrophy and fibrosis, immunostaining for uromodulin or MUC1 in specialist labs.
• Exclude ADPKD, Alport syndrome, reflux nephropathy, other familial nephropathies.

• No disease-specific therapy; slow progression with standard CKD care: blood pressure below 130/80 mmHg, ACE inhibitor/ARB when proteinuric, SGLT2 inhibitor, avoid nephrotoxins and dehydration.
• Gout/hyperuricaemia: allopurinol 100 mg increased to 300 mg daily or febuxostat 40 to 80 mg to maintain urate below 6 mg/dL (360 µmol/L); may slow progression modestly; colchicine 0.5 mg daily for flare prophylaxis (renally adjusted).
• ADTKD-REN: fludrocortisone 0.05 to 0.1 mg daily for anaemia, hyperkalaemia and low renin state, erythropoietin if needed.
• ADTKD-HNF1B: manage diabetes (insulin, sulfonylurea), magnesium supplementation, urinary tract malformations.
• Treat CKD complications: anaemia, acidosis, mineral bone disease.
• Genetic counselling and cascade testing; kidney transplantation is curative for the kidney disease; living related donors must be genetically screened.
• Monitor eGFR annually or every 6 months in advanced disease.