An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases.

PURPOSE: To evaluate self-referral from the Internet for genetic diagnosis of several rare inherited kidney diseases. METHODS: Retrospective study from 1996 to 2017 analyzing data from an academic referral center specializing in autosomal dominant tubulointerstitial kidney disease (ADTKD). Individuals were referred by academic health-care providers (HCPs) nonacademic HCPs, or directly by patients/families. RESULTS: Over 21 years, there were 665 referrals, with 176 (27%) directly from families, 269 (40%) from academic HCPs, and 220 (33%) from nonacademic HCPs. Forty-two (24%) direct family referrals had positive genetic testing versus 73 (27%) families from academic HCPs and 55 (25%) from nonacademic HCPs (P = 0.72). Ninety-nine percent of direct family contacts were white and resided in zip code locations with a mean median income of $77,316 ± 34,014 versus US median income $49,445. CONCLUSION: Undiagnosed families with Internet access bypassed their physicians and established direct contact with an academic center specializing in inherited kidney disease to achieve a diagnosis. Twenty-five percent of all families diagnosed with ADTKD were the result of direct family referral and would otherwise have been undiagnosed. If patients suspect a rare disorder that is undiagnosed by their physicians, actively pursuing self-diagnosis using the Internet can be successful. Centers interested in rare disorders should consider improving direct access to families.

Quality of life in patients with autosomal dominant tubulointerstitial kidney disease
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AIMS: The reaction to diagnosis and quality of life (QOL) in autosomal dominant tubulointerstitial kidney disease (ADTKD) due to UMOD and MUC mutations from the time of diagnosis until treatment for end-stage kidney disease (ESKD) has not been characterized. It is unclear how asymptomatic patients react to a positive genetic test result. MATERIALS AND METHODS: A cross-sectional survey concerning QOL and genetic testing was delivered to 622 individuals who had undergone genetic testing from families with known ADTKD. RESULTS: 286 of 622 individuals completed the survey, including 61 (21%) genetically unaffected, 36 (12%) with stage 1, 2 chronic kidney disease (CKD), 51 (18%) stage 3, 41 (14%) stage 4 pre-dialysis, 50 (17%) receiving dialysis, and 47 (16%) s/p kidney transplantation. Of 55 respondents who thought they had normal kidney function at the time of testing and were found to have ADTKD, 51 (93%) were happy testing was performed, 3 (5%) neutral, and 1 (2%) neutral/unhappy. 42 of 183 (23%) affected individuals stated that ADTKD "has a substantial effect and I think about it daily," 47 (26%) think about ADTKD weekly, 48 (26%) monthly, and 48 (26%) less than monthly. The mean PROMIS anxiety score was similar between unaffected and affected individuals and the general population. Depression was present in 41% of affected vs. 23% of unaffected individuals (p = 0.01). CONCLUSION: Genetic testing of presymptomatic patients for ADTKD is reasonable when requested. This study provides reassurance regarding the impact on QOL of the increased use of genetic testing to diagnose kidney disease. ADTKD has a significant impact on QOL, with depression, not anxiety, being more prevalent in affected individuals.

Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease.

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations.

INTRODUCTION: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. METHODS: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). RESULTS: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. CONCLUSION: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.