Autosomal Dominant Tubulointerstitial Kidney Disease

Abstract

There are three major forms of autosomal dominant tubulo-interstitial kidney disease (ADTKD): ADTKD due to UMOD mutations, MUC1 mutations, and mutations in the REN gene encoding renin. Lack of knowledge about these conditions contributes to frequent non-diagnosis, but with even limited knowledge, nephrologists can easily obtain a diagnosis and improve patient care. There are three cardinal features of these disorders: 1) the conditions are inherited in an autosomal dominant manner and should be considered whenever both a parent and child suffer from kidney disease; the presence of even more affected family members provides further support. 2) These conditions are associated with a bland urinary sediment, ruling out glomerular disorders. 3) There is a variable rate of decline in kidney function. The mean age of ESRD is approximately 45, but the range is from 17 to >75. ADTKD-UMOD is often but not always associated with gout in the teenage years. ADKTKD-REN is associated with signs of hyporeninemia: mild hypotension, mild hyperkalemia, anemia in childhood, and hyperuricemia and gout in the teenage years. The only clinical manifestation of ADTKD-MUC1 is slowly progressive chronic kidney disease. Diagnosis should be made by genetic testing, and kidney biopsy should be avoided.

Novel roles for mucin 1 in the kidney

“…As these patients rarely have cysts, the disease has been appropriately renamed autosomal dominant tubule-interstitial kidney disease due to MUC1 mutations, with an abbreviated name of Mucin 1 Kidney Disease (MKD) [34,35]. The most common causative mutation is a cytosine duplication in a string of seven cytosines within any one of the G-C-rich tandem repeats.…”

“…Although the chimera should be secreted, it is found as intracellular staining by imunohistochemistry in patient kidney tissue and as diffuse and/or fine granular intracellular staining by immunofluorescence microscopy with puncta co-localizing with wild-type MUC1 staining at the apical surface [33]. Patients with MKD present with asymptomatic elevation of serum creatinine, exhibit bland urinary sediment with minimal blood or protein, non-specific tubulointerstitial fibrosis, a gradual decline in glomerular filtration rate, and a need for dialysis between the third and eighth decade of life [35,36]. Most notably, the patients usually have a family history of chronic kidney disease and exhibit only renal disease despite the presence of MUC1-fs in multiple organs.…”

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

“…While there are more than 100 inherited mutations in UMOD described (22)(23)(24)(25)(26)(27), most result in cysteine residue replacement, which disrupts disulfide bridging at critical nodes of protein folding. The majority of reported mutations reside within the portion of the gene that codes for the N-terminus.…”

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

“…Ultimately, these processes result in cell death with tubular atrophy and surrounding interstitial fibrosis . These are the characteristic histological findings in individuals with ADTKD …”

“…At present, there is no specific disease‐modifying treatment available for individuals with ADTKD . Management of other factors, for example, which expedite CKD progression, is appropriate as is treatment of extrarenal manifestations, for example, gout in individuals with mutations in the uromodulin gene …”