The portal for rare diseases and orphan drugs

Autosomal dominants tubulointerstitial kidney (ADTKD) is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. In the Caucasian population, no geographic or sex differences are reported.

There are four clinical subtypes, classified due to the genetic mutation involved: UMOD-, MUC1-, REN- and HNF1B-related ADTKD. The typical clinical findings in ADTKD are a progressive loss of kidney function with bland urinary sediment, absent-to-mild proteinuria, urinary concentrating defects with low morning urine osmolality, normal or slightly elevated blood pressure, normal or small kidney size and a family history of CKD that is compatible with an autosomal dominant inheritance pattern. Presentation and age of onset varies according to clinical subtype. For ADTKD-UMOD, presentation may occur in adolescence with gout; hyperuricemia and gout are highly prevalent. CKD is often first diagnosed in the late adolescence or early adulthood. ADTKD-MUC1 typically presents with CKD in the early twenties. ADTKD-REN may present as early as infancy with anemia, hyperkalemia and CKD. ADTKD-HNF1B may present in childhood with genitourinary abnormalities, in the teenage years with gout or diabetes, and in the third decade of life with CKD; extrarenal anomalies are possible. All subtypes lead to progressive ESKD, occurring generally between 25 and 70 years of age. Renal cysts may occur but are not typical.

Pathogenic variants are detected in 50-60% of cases and most commonly involve UMOD (16p12.3) and MUC1 (1q22). More rare variants include REN (1q32.1) and HNF1B (17q12), and different genes may be identified in the future.

Diagnosis can be difficult due to the lack of distinct clinical features but should be suspected in individuals with a family history of CKD, gout and/or hyperuricemia, a bland urinary sediment and a renal ultrasound that excludes autosomal dominant polycystic disease (ADPKD). If available, kidney biopsy from the patient or an affected family member showing predominant tubulointerstitial fibrosis are supportive of a diagnosis. Genetic testing for a pathogenic variant in the patient or a family member can also be useful.

The differential diagnoses include atypical ADPKD (DNAJB11-related), nephronophthisis (NPHP1-related), renal coloboma syndrome, tubulointerstitial nephritis and uveitis syndrome, and Sjögren syndrome. Mutations in SEC61A1 have been reported in a few cases with congenital anemia, neutropenia (in one family) and tubulointerstitial kidney disease; mitochondrial mutations have also been associated with an ADTKD phenotype.

Genetic prenatal diagnosis may be possible where pathogenic variants have previously been identified in a family member.

The disease is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that for each conception there is 50% risk of disease transmission. However, penetrance is incomplete and disease expression may vary between affected family members.

There is no specific treatment for ADTKD; affected individuals should be treated according to established CKD guidelines, noting that specific recommendations are based on limited evidence in ADTKD. Children with ADTKD-HNF1B and ADTKD-REN disease are likely to benefit from early management by a pediatric nephrologist. Diuretics should be used with caution as they may aggravate salt loss, volume depletion and hyperuricemia. A low-salt diet is not recommended. NSAIDS are contraindicated in ADTKD patients. In patients with gout, urate-lowering treatment may prevent future attacks. Kidney transplantation is the preferred option for ESKD, and ADTKD does not recur in the renal transplant.

The quality of life in patients with ADTKD largely depends on the severity of CKD the presence of CKD-associated comorbidities and the existence of extrarenal manifestations.