INTRODUCTION: Patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) usually present with nonspecific progressive chronic kidney disease (CKD) with mild to negative proteinuria and a family history. ADTKD-MUC1 leads to the formation of a frameshift protein that accumulates in the cytoplasm, leading to tubulointerstitial damage. ADTKD-MUC1 prevalence remains unclear because MUC1 variants are not routinely detected by standard next-generation sequencing (NGS) techniques. METHODS: We developed a bioinformatic counting script that can detect specific genetic sequences and count the number of occurrences. We used DNA samples from 27 patients for validation, 11 of them were patients from the Lille University Hospital in France and 16 were from the Wake Forest Hospital, NC. All patients from Lille were tested with an NGS gene panel with our script and all patients from Wake Forest Hospital were tested with the snapshot reference technique. Between January 2018 and February 2023, we collected data on all patients diagnosed with MUC1 variants with this script. RESULTS: A total of 27 samples were tested anonymously by the BROAD Institute reference technique for confirmation and we were able to get a 100% concordance for MUC1 diagnosis. Clinico-biologic characteristics in our cohort were similar to those previously described in ADTKD-MUC1. CONCLUSION: We describe a new simple and cost-effective method for molecular testing of ADTKD-MUC1. Genetic analyses in our cohort suggest that MUC1 might be the first cause of ADTKD. Increasing the availability of MUC1 diagnosis tools will contribute to a better understanding of the disease and to the development of specific treatments.

• Keywords
• ADTKD, MUC1, VNTR,
• Publication type
• Journal Article MeSH

• Publication type
• Journal Article MeSH
• Case Reports MeSH

BACKGROUND AND AIMS: Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. METHODS: In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. RESULTS: Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P < 0.001) of a positive genetic diagnosis. CONCLUSIONS: A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients.

• Keywords
• Chronic kidney disease, Genetic kidney disease, Inherited kidney diseases, Next-generation sequencing, Polycystic kidney genetics,
• MeSH
• Renal Insufficiency, Chronic * diagnosis   epidemiology   genetics   MeSH
• Adult MeSH
• Genetic Testing methods   MeSH
• TRPP Cation Channels genetics   MeSH
• Kidney MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation MeSH
• Polycystic Kidney, Autosomal Dominant * diagnosis   MeSH
• Prospective Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• TRPP Cation Channels MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of disorders with a bland urinary sediment, slowly progressive chronic kidney disease (CKD), and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD in both children and adults. ADTKD-REN presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-UMOD is associated with gout and CKD that may present in adolescence and slowly progresses to kidney failure. HNF1β mutations often present in childhood with anatomic abnormalities such as multicystic or dysplastic kidneys, as well as CKD and a number of other extra-kidney manifestations. ADTKD-MUC1 is less common in childhood, and progressive CKD is its sole clinical manifestation, usually beginning in the late teenage years. This review describes the pathophysiology, genetics, clinical characteristics, diagnosis, and treatment of the different forms of ADTKD, with an emphasis on diagnosis. We also present data on kidney function in children with ADTKD from the Wake Forest Rare Inherited Kidney Disease Registry.

• Keywords
• Autosomal dominant, Chronic kidney disease, HNF1β, Inherited, Mucin-1, Pediatric, Renin, Uromodulin,
• MeSH
• Renal Insufficiency, Chronic * MeSH
• Child MeSH
• Gout * MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• Polycystic Kidney Diseases * MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Uromodulin MeSH

The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD-SEC61A1). Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD-SEC61A1 patients as well.

• MeSH
• Endoplasmic Reticulum metabolism   MeSH
• Phenylbutyrates metabolism   pharmacology   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Molecular Chaperones metabolism   MeSH
• Kidney Diseases physiopathology   MeSH
• Polycystic Kidney Diseases MeSH
• Renin genetics   metabolism   MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism   MeSH
• SEC Translocation Channels chemistry   genetics   metabolism   MeSH
• Protein Transport genetics   MeSH
• Calcium metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4-phenylbutyric acid MeSH Browser
• ATP2A2 protein, human MeSH Browser
• Phenylbutyrates MeSH
• Molecular Chaperones MeSH
• Renin MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases MeSH
• SEC61A1 protein, human MeSH Browser
• SEC Translocation Channels MeSH
• Calcium MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin (UMOD) is the most common nonpolycystic genetic kidney disease, but it remains unrecognized due to its clinical heterogeneity and lack of screening test. Moreover, the fact that the clinical feature is a poor predictor of disease outcome further highlights the need for the development of mechanistic biomarkers in ADTKD. However, low abundant urinary proteins secreted by thick ascending limb cells, where UMOD is synthesized, have posed a challenge for the detection of biomarkers in ADTKD-UMOD. In the CRISPR/Cas9-generated murine model and patients with ADTKD-UMOD, we found that immunoglobulin heavy chain-binding protein (BiP), an endoplasmic reticulum chaperone, was exclusively upregulated by mutant UMOD in the thick ascending limb and easily detected by Western blot analysis in the urine at an early stage of disease. However, even the most sensitive ELISA failed to detect urinary BiP in affected individuals. We therefore developed an ultrasensitive, plasmon-enhanced fluorescence-linked immunosorbent assay (p-FLISA) to quantify urinary BiP concentration by harnessing the newly invented ultrabright fluorescent nanoconstruct, termed "plasmonic Fluor." p-FLISA demonstrated that urinary BiP excretion was significantly elevated in patients with ADTKD-UMOD compared with unaffected controls, which may have potential utility in risk stratification, disease activity monitoring, disease progression prediction, and guidance of endoplasmic reticulum-targeted therapies in ADTKD.NEW & NOTEWORTHY Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin (UMOD) is an underdiagnosed cause of chronic kidney disease (CKD). Lack of ultrasensitive bioanalytical tools has hindered the discovery of low abundant urinary biomarkers in ADTKD. Here, we developed an ultrasensitive plasmon-enhanced fluorescence-linked immunosorbent assay (p-FLISA). p-FLISA demonstrated that secreted immunoglobulin heavy chain-binding protein is an early urinary endoplasmic reticulum stress biomarker in ADTKD-UMOD, which will be valuable in monitoring disease progression and the treatment response in ADTKD.

• Keywords
• autosomal dominant tubulointerstitial kidney disease, biomarker, endoplasmic reticulum stress, plasmon-enhanced fluorescence-linked immunosorbent assay,
• MeSH
• Biomarkers urine   MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• Immunosorbent Techniques * MeSH
• Nephritis, Interstitial genetics   urine   MeSH
• Humans MeSH
• Mice MeSH
• Heat-Shock Proteins urine   MeSH
• Endoplasmic Reticulum Stress physiology   MeSH
• Uromodulin genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Biomarkers MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• Heat-Shock Proteins MeSH
• Uromodulin MeSH

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.

• Keywords
• autosomal dominant tubulointerstitial kidney disease, internet, mucin-1, rare disease, uromodulin,
• MeSH
• Adult MeSH
• Genetic Testing MeSH
• Internet MeSH
• Referral and Consultation classification   statistics & numerical data   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Diseases diagnosis   genetics   MeSH
• Retrospective Studies MeSH
• Rare Diseases diagnosis   genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

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.

• Keywords
• ADTKD, HNF-1B, MUC-1, UMOD, chronic kidney disease, frameshift, genetic, urinary smear,
• MeSH
• Kidney Failure, Chronic epidemiology   genetics   pathology   MeSH
• Genes, Dominant * MeSH
• Adult MeSH
• Genetic Testing statistics & numerical data   MeSH
• Hepatocyte Nuclear Factor 1-beta genetics   MeSH
• Kidney Tubules pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-1 genetics   MeSH
• Mutation MeSH
• Prevalence MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Ireland epidemiology   MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-beta MeSH
• HNF1B protein, human MeSH Browser
• MUC1 protein, human MeSH Browser
• Mucin-1 MeSH
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

• MeSH
• White People MeSH
• Genome-Wide Association Study MeSH
• Renal Insufficiency, Chronic genetics   physiopathology   urine   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Association Studies methods   MeSH
• Glomerular Filtration Rate MeSH
• Polymorphism, Single Nucleotide MeSH
• Quantitative Trait, Heritable * MeSH
• Humans MeSH
• Quantitative Trait Loci * MeSH
• Chromosome Mapping MeSH
• Inheritance Patterns MeSH
• Uromodulin urine   MeSH
• Kidney Function Tests MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Uromodulin MeSH

BACKGROUND: HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. METHODS: Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. RESULTS: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m2 (± 13.2), in the total cohort - 1.0 ml/min/1.73m2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. CONCLUSIONS: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.

• Keywords
• Cystic kidney disease, GFR decline, HNF1B, Hypomagnesemia, MODY,
• MeSH
• Kidney Failure, Chronic genetics   MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Association Studies MeSH
• Hepatocyte Nuclear Factor 1-beta genetics   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Infant, Newborn MeSH
• Polycystic Kidney Diseases genetics   pathology   physiopathology   MeSH
• Child, Preschool MeSH
• Disease Progression MeSH
• Registries MeSH
• Age of Onset MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Germany MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-beta MeSH
• HNF1B protein, human MeSH Browser