Tubulointerstitial kidney disease

ADTKD is a slowly progressive tubulointerstitial disorder that culminates in end-stage renal disease (ESRD), typically between the third and seventh decades of life. Urinalysis shows a bland sediment with minimal hematuria and proteinuria below 250 mg/24 h. Renal ultrasound is usually normal early in the disease course, although kidneys may later become reduced in size with or without medullary cysts. The course and presentation vary considerably both within and between families: in ADTKD-UMOD, hyperuricemia is often present from an early age, with gout developing in approximately 8% of affected individuals during adolescence and in 55% over time. In ADTKD-MUC1, the median age at ESRD is around 46 years, ranging from before age 20 to beyond age 70.

The estimated prevalence of ADTKD-UMOD is approximately 1/110,000 in a British cohort. ADTKD-UMOD accounts for up to 50% of ADTKD cases, so overall ADTKD prevalence is expected to be higher.

Pathogenic variants in any of approximately six genes are currently known to cause ADTKD. The most relevant genes, in descending order of disease burden, are UMOD (~50%), MUC1, REN, HNF1B, SEC61A1 and DNAJB11. ADTKD is caused by heterozygous germline pathogenic variants in genes expressed in renal tubular epithelial cells. ADTKD-UMOD is an endoplasmic reticulum storage disease in which misfolded uromodulin accumulates in the thick ascending limb of Henle’s loop; most UMOD variants are missense, frequently affecting a cysteine residue and thereby disrupting disulfide bond formation. ADTKD-MUC1 results from a frameshifting cytosine insertion in a coding variable-number tandem-repeat region. Each subtype causes progressive tubular injury and interstitial fibrosis.

ADTKD is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis follows the for autosomal dominant tubulointerstitial kidney disease. Meeting the criteria establishes the clinical diagnosis of ADTKD. The consensus definition requires a bland urinary sediment with proteinuria below 250 mg/24 h. Hyperuricemia is characteristic of ADTKD-UMOD and ADTKD-REN, often preceding the decline in eGFR, but is not a primary feature of ADTKD-MUC1. Renal ultrasound is typically normal early on. Kidney biopsy is not recommended because the histological findings of chronic interstitial fibrosis with focal tubular atrophy are non-specific.

Main differential diagnoses include:

• : the most common form of polycystic kidney disease with a prevalence of around 1:2,500 that must be excluded first; numerous cortical and medullary cysts with enlarged kidneys on ultrasound in individuals older than ~25 years
• : microscopic hematuria and proteinuria (in contrast to the bland sediment of ADTKD); frequent extrarenal manifestations (sensorineural hearing loss and ocular changes)
• Isolated nephronophthisis: autosomal recessive tubulointerstitial kidney disease often presenting in childhood with anemia and mild hypotension; earlier progression to ESRD (typically need for dialysis in the teenage years or early twenties)

• Establishing the molecular genetic diagnosis enables confirmation of the suspected clinical diagnosis and provides the basis for informed clinical decision-making.
• Identifying the underlying genetic cause is a prerequisite for targeted medical care, including individualised surveillance and management of affected individuals, decided by the treating physicians in consultation with the affected individual.
• Predictive testing of at-risk relatives clarifies their genetic status and supports family planning and reproductive decision-making.

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