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"Autosomal dominant tubulointerstitial kidney disease"

Sian E Piret, Eric Olinger, Anita A C Reed, M Andrew Nesbit, Tertius A Hough, Liz Bentley, Olivier Devuyst, Roger Cox, Rajesh V Thakker
Renal fibrosis is a common feature of renal failure resulting from multiple aetiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation, and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R)...
March 21, 2017: Disease Models & Mechanisms
Anthony J Bleyer, Kendrah Kidd, Martina Živná, Stanislav Kmoch
There are 3 major forms of autosomal dominant tubulointerstitial 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 nondiagnosis, but with even limited knowledge, nephrologists can easily obtain a diagnosis and improve patient care. There are 3 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...
March 2017: Advances in Chronic Kidney Disease
Elisabeth Kemter, Thomas Fröhlich, Georg J Arnold, Eckhard Wolf, Rüdiger Wanke
'Autosomal dominant tubulointerstitial kidney disease - UMOD' (ADTKD-UMOD) is caused by impaired maturation and secretion of mutant uromodulin (UMOD) in thick ascending limb of Henle loop (TAL) cells, resulting in endoplasmic reticulum (ER) stress and unfolded protein response (UPR). To gain insight into pathophysiology, we analysed proteome profiles of TAL-enriched outer renal medulla samples from ADTKD-UMOD and control mice by quantitative LC-MS/MS. In total, 212 differentially abundant proteins were identified...
February 21, 2017: Scientific Reports
Robin Satanovskij, Alhaddad Bader, Matthias Block, Victor Herbst, Wolfgang Schlumberger, Tobias Haack, Wolfgang Andreas Nockher, Uwe Heemann, Lutz Renders, Christoph Schmaderer, Susanne Angermann, Ming Wen, Thomas Meitinger, Jürgen Scherberich, Dominik Steubl
BACKGROUND: Uromodulin-associated Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD) belongs to a group of autosomal dominant inherited diseases caused by mutations in the UMOD gene, which codes for uromodulin, a protein exclusively expressed in renal tubular cells of the ascending limb of the loop of Henle. The diagnosis is hampered by non-specific clinical, laboratory and histological findings. In this study, we evaluated serum uromodulin as diagnostic marker for ADTKD-UMOD in a family with a novel mutation in UMOD...
February 2017: Clinical Biochemistry
Thomas G Hammond, Suzette Moes, Sonia Youhanna, Paul Jennings, Olivier Devuyst, Alex Odermatt, Paul Jenö
BACKGROUND: Uromodulin is the most abundant protein in healthy human urine. Recently it has been suggested as a specific biomarker of renal tubular damage. We have developed a novel pseudo multiple reaction monitoring (pseudo MRM) for the protein's quantification in human urine. RESULTS: Selection of two peptides allowed quantification of uromodulin in human urine. The pseudo MRM quantified uromodulin in healthy individuals between 21 and 1344 nM and in autosomal dominant tubulointerstitial kidney disease-UMOD patients between 2 and 25 nM...
June 2016: Bioanalysis
Brendan Blumenstiel, Matthew DeFelice, Ozge Birsoy, Anthony J Bleyer, Stanislav Kmoch, Todd A Carter, Andreas Gnirke, Kendrah Kidd, Heidi L Rehm, Lucienne Ronco, Eric S Lander, Stacey Gabriel, Niall J Lennon
Mucin-1 kidney disease, previously described as medullary cystic kidney disease type 1 (MCKD1, OMIM 174000), is an autosomal dominant tubulointerstitial kidney disease recently shown to be caused by a single-base insertion within the variable number tandem repeat region of the MUC1 gene. Because of variable age of disease onset and often subtle signs and symptoms, clinical diagnosis of mucin-1 kidney disease and differentiation from other forms of hereditary kidney disease have been difficult. The causal insertion resides in a variable number tandem repeat region with high GC content, which has made detection by standard next-generation sequencing impossible to date...
July 2016: Journal of Molecular Diagnostics: JMD
Mingzhu Nie, Manjot S Bal, Zhufeng Yang, Jie Liu, Carolina Rivera, Andrea Wenzel, Bodo B Beck, Khashayar Sakhaee, Denise K Marciano, Matthias T F Wolf
Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1 (MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused by UMOD mutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis...
November 2016: Journal of the American Society of Nephrology: JASN
Claudio Musetti, Deepak Babu, Ileana Fusco, Simona Mellone, Andrea Zonta, Marco Quaglia, Vincenzo Cantaluppi, Piero Stratta, Mara Giordano
INTRODUCTION: Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD). CASE REPORT: A specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report...
June 2016: Journal of Nephrology
Gopalakrishnan Venkat-Raman, Christine Gast, Anthony Marinaki, Lynnette Fairbanks
Familial juvenile hyperuricaemic nephropathy (FJHN) is a diagnosis that is easily missed. It has taken a long time to clarify the pathophysiology and prevalence of this disease entity which has been shown to be genetically identical to medullary cystic kidney disease (MCKD) type II. The initial suspicion that uric acid was the noxious agent has been replaced by the recognition that a mutant uromodulin (UMOD) is the real culprit-although the exact mechanisms of pathogenicity remain uncertain. The mutation has been traced to the UMOD gene in chromosome 16...
November 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Gabriele Raffler, Emanuel Zitt, Hannelore Sprenger-Mähr, Mato Nagel, Karl Lhotta
BACKGROUND: Uromodulin (UMOD)-associated kidney disease belongs to the group of autosomal dominant interstitial kidney diseases and is caused by mutations in the UMOD gene. Affected patients present with hyperuricemia, gout, and progressive renal failure. The disease is thought to be very rare but is probably underdiagnosed. METHODS: Two index patients from two families with tubulointerstitial nephropathy and hyperuricemia were examined, including blood and urine chemistry, ultrasound, and mutation analysis of the UMOD gene...
April 2016: Wiener Klinische Wochenschrift
Cas I van der Made, Ewout J Hoorn, Renaud de la Faille, Huseyin Karaaslan, Nine V A M Knoers, Joost G J Hoenderop, Rosa Vargas Poussou, Jeroen H F de Baaij
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes. CASES: The current case series describes 3 patients in whom hypomagnesemia proved to be the first clinical manifestation of ADTKD-HNF1B. All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria...
2015: American Journal of Nephrology
Kai-Uwe Eckardt, Seth L Alper, Corinne Antignac, Anthony J Bleyer, Dominique Chauveau, Karin Dahan, Constantinos Deltas, Andrew Hosking, Stanislav Kmoch, Luca Rampoldi, Michael Wiesener, Matthias T Wolf, Olivier Devuyst
Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion...
October 2015: Kidney International
Laura Labriola, Eric Olinger, Hendrica Belge, Yves Pirson, Karin Dahan, Olivier Devuyst
Mutations in the UMOD gene coding for uromodulin cause autosomal dominant tubulointerstitial kidney disease. Uromodulin is known to regulate transport processes in the thick ascending limb, but it remains unknown whether UMOD mutations are associated with functional tubular alterations in the early phase of the disease. The responses to furosemide and to a water deprivation test were compared in a 32-year-old female patient carrying the pathogenic UMOD mutation p.C217G and her unaffected 31-year-old sister...
February 2015: Nephrology, Dialysis, Transplantation
Anthony J Bleyer, Stanislav Kmoch
Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of conditions characterized by autosomal dominant inheritance, a bland urinary sediment with minimal blood and protein, pathologic changes of tubular and interstitial fibrosis, and slowly progressive chronic kidney disease. This commentary discusses recent advances in our medical knowledge of these conditions, including the recent identification of mutations in the MUC1 gene as a cause of ADTKD and changes in terminology proposed by Ekici et al...
September 2014: Kidney International
Arif B Ekici, Thomas Hackenbeck, Vincent Morinière, Andrea Pannes, Maike Buettner, Steffen Uebe, Rolf Janka, Antje Wiesener, Ingo Hermann, Sina Grupp, Martin Hornberger, Tobias B Huber, Nikky Isbel, George Mangos, Stella McGinn, Daniela Soreth-Rieke, Bodo B Beck, Michael Uder, Kerstin Amann, Corinne Antignac, André Reis, Kai-Uwe Eckardt, Michael S Wiesener
For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis...
September 2014: Kidney International
Anthony J Bleyer
Autosomal dominant tubulointerstitial kidney disease is characterized by the poorly recognized inheritance of slowly progressive renal failure leading to ESRD in later life. Patients with this condition have bland urinary sediment, and renal ultrasound typically reveals normal to small kidneys, with occasional individuals having small medullary cysts. Diagnosis relies on the clinical acumen of the nephrologist. Obtaining a thorough family history and records of affected family members is especially helpful...
January 2009: Journal of the American Society of Nephrology: JASN
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