UMOD-related autosomal dominant tubulointerstitial kidney disease (ORPHA:88950)
A form of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to UMOD mutations that is clinically characterized by bland urinalysis (absence of blood or protein in the urine), chronic kidney disease (CKD) leading to end-stage kidney disease (ESKD) between 20 and 80 years, and gout occurring in 50% of affected individuals.
Epidemiology
Whilst prevalence data is limited, it is estimated at approximately 1/600,000 in Austria and 1/110,000 in the UK. The disease has equal prevalence among all studied racial groups.
Clinical description
CKD is usually first evident in the early twenties, though many children will have some evidence of mildly decreased kidney function by 18 years. Ten percent of affected individuals develop gout before age 18 years. Many individuals are first recognized with gout or CKD in their twenties. Patients will have slowly progressive loss of kidney function. The mean age of ESKD is approximately 49 years of age, though the age varies widely from 20 to over 70 years, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear. Gout will develop in approximately 50% of affected individuals over time, often preceding significant loss of kidney function.
Etiology
The disorder is caused by mutations in the UMOD gene, resulting in a mutated uromodulin protein that deposits within the endoplasmic reticulum, leading to cell stress, accelerated apoptosis, and progressive chronic kidney disease.
Diagnostic methods
Diagnosis is suspected in individuals who have chronic kidney disease, a bland urinary sediment, and a family history of kidney disease. Gout presenting in adolescence or in a young woman is suggestive for ADTKD-UMOD. Mutational analysis is the preferred means of diagnosis, either by direct sequencing if the family has a known UMOD mutation or by multi-gene panel or whole exome sequencing, both of which will identify alternative genetic causes.
Differential diagnosis
ADTKD-MUC1 is almost clinically indistinguishable from ADTKD-UMOD except that gout is less prevalent in ADTKD-MUC1 and only occurs after the development of CKD. ADTKD-REN due to mutations in the segment of the gene encoding mature renin is clinically identical to ADTKD-UMOD, with early gout, CKD, and autosomal dominant inheritance. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-UMOD may be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible if there is known mutation in the family.
Genetic counseling
The disorder is autosomal dominant. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing may be performed in children to prevent the risk of gout development with early treatment with allopurinol. If gout is not prevalent in the family, testing in childhood is not recommended. Relatives should be informed of their risk of ADTKD-UMOD, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.
Management and treatment
The only specific treatment for this disease is gout prevention with allopurinol or febuxostat. Gout is lifelong and worsens as CKD worsens, preventative therapy is thus important in patients who develop gout. Patients with ADTKD-UMOD are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial UMOD mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.
Prognosis
Whilst there is wide variation in onset of ESKD, many patients diagnosed today will not develop ESKD for more than two decades, with a current mean age of 49 years. Use of dialysis is variable, ranging from the third decade or as late as the eighth decade of life. Survival post-transplant is comparable to the general ESKD transplant population.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH