Search

The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.

Purpose To evaluate self-referral from the Internet for genetic diagnosis of several rare inherited kidney diseases. Methods Retrospective study from 1996–2017 analyzing data from an academic referral center specializing in autosomal dominant tubulo-interstitial kidney disease (ADTKD). Individuals were referred by academic health care providers (HCPs) non-academic 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 non-academic HCPs. 42(24%) of direct family referrals had positive genetic testing vs 73(27%) of families from academic HCPs and 55(25%) from non-academic HCPs (P=.72). 99% of direct family contacts were white and resided in zip code locations with a mean median income of $77,316±34,014 vs. US median income $49,445. Conclusions 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 per cent of all families diagnosed with ADTKD were the result of direct family referral and would otherwise have been un-diagnosed. If patients suspect a rare disorder that is un-diagnosed 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.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

Objectives Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity is an X-linked disorder characterized by urate overproduction Online Mendelian Inheritance in Man (OMIM) gene reference 300661. This condition is thought to rarely affect women, and when it does, the clinical presentation is mild. We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction. Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout. The main aim of this study was to describe the clinical manifestations of PRPS1 superactivity in women. Methods Whole exome sequencing was performed in affected females and their fathers. Results Mutational analysis revealed a new c.520 G > A (p.G174R) mutation in the PRPS1 gene. The mutation resulted in decreased PRPS1 inhibition by ADP. Conclusion Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl [506 (247) μmol/l] and a high prevalence of gout. These findings indicate that all women in families with PRPS1 superactivity should be genetically screened for a mutation (for clinical management and genetic counselling). In addition, women with tophaceous gout, gout presenting in childhood, or a strong family history of severe gout should be considered for PRPS1 mutational analysis.

Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.