20 results on '"Kendrah Kidd"'
Search Results
2. Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases
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Victoria Robins, Maegan Harden, Anna Greka, Miroslav Votruba, Alese Hunt, Petr Vyleťal, Sri Vidya, Hana Hartmannová, Shahriar Moossavi, Georgeanna Tsoumas, Brendan Blumenstiel, Kateřina Hodaňová, Anthony J. Bleyer, Kendrah Kidd, Martina Živná, Annie Santi, Marwan Abbas, Lauren Martin, Stanislav Kmoch, Elizabeth Swain, Abbigail Taylor, and Ebun Akinbola
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Referral ,uromodulin ,education ,Medical laboratory ,rare disease ,030105 genetics & heredity ,Zip code ,Article ,03 medical and health sciences ,Rare Diseases ,medicine ,Humans ,Genetic Testing ,Referral and Consultation ,Genetics (clinical) ,Retrospective Studies ,Genetic testing ,Internet ,Self Referral ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,autosomal dominant tubulo-interstitial kidney disease ,3. Good health ,030104 developmental biology ,Family medicine ,Female ,Kidney Diseases ,business ,mucin-1 ,Kidney disease ,Rare disease - Abstract
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.
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- 2020
3. The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project
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Elhussein A. E. Elhassan, Susan L. Murray, Dervla M. Connaughton, Claire Kennedy, Sarah Cormican, Cliona Cowhig, Caragh Stapleton, Mark A. Little, Kendrah Kidd, Anthony J. Bleyer, Martina Živná, Stanislav Kmoch, Neil K. Fennelly, Brendan Doyle, Anthony Dorman, Matthew D. Griffin, Liam Casserly, Peter C. Harris, Friedhelm Hildebrandt, Gianpiero L. Cavalleri, Katherine A. Benson, and Peter J. Conlon
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Adult ,Young Adult ,TRPP Cation Channels ,Nephrology ,Mutation ,Humans ,Genetic Testing ,Prospective Studies ,Middle Aged ,Renal Insufficiency, Chronic ,Kidney ,Polycystic Kidney, Autosomal Dominant - Abstract
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 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. Graphical abstract
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- 2021
4. Ultrabright plasmonic fluor nanolabel-enabled detection of a urinary ER stress biomarker in autosomal dominant tubulointerstitial kidney disease
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Jeremiah J. Morrissey, Ying Maggie Chen, Chuang Li, Zheyu Wang, Stanislav Kmoch, Jeremy S. Duffield, Yeawon Kim, Kendrah Kidd, Yixuan Wang, Bryce G. Johnson, Srikanth Singamaneni, and Anthony J. Bleyer
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0301 basic medicine ,Physiology ,Urinary system ,030232 urology & nephrology ,Disease ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Western blot ,Uromodulin ,medicine ,Animals ,Humans ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Immunosorbent Techniques ,biology ,medicine.diagnostic_test ,business.industry ,Endoplasmic reticulum ,medicine.disease ,Endoplasmic Reticulum Stress ,030104 developmental biology ,Cancer research ,biology.protein ,Unfolded protein response ,Innovative Methodology ,Biomarker (medicine) ,Nephritis, Interstitial ,Antibody ,business ,Biomarkers ,Kidney disease - Abstract
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.
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- 2021
5. Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland
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Katherine A. Benson, Brendan Doyle, Claire Kennedy, C. Foley, Anthony Dorman, Neil K. Fennelly, Patrick O'Kelly, Peter J. Conlon, Dervla M. Connaughton, Mark A. Little, Eoin T. Conlon, Anthony J. Bleyer, Peter Lavin, Stanislav Kmoch, Sarah Cormican, Kendrah Kidd, Gianpiero L. Cavalleri, Susan L. Murray, and Martina Živná
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Male ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,medicine.disease_cause ,0302 clinical medicine ,Prevalence ,urinary smear ,Exome sequencing ,Genes, Dominant ,Mutation ,medicine.diagnostic_test ,General Medicine ,Middle Aged ,HNF1B ,3. Good health ,Kidney Tubules ,Nephrology ,Cohort ,Female ,Adult ,medicine.medical_specialty ,Urinary system ,frameshift ,Frameshift mutation ,03 medical and health sciences ,muc-1 ,Internal medicine ,adtkd ,Uromodulin ,medicine ,Humans ,Genetic Testing ,Genetic testing ,Aged ,Hepatocyte Nuclear Factor 1-beta ,business.industry ,Mucin-1 ,hnf-1b ,medicine.disease ,Diseases of the genitourinary system. Urology ,Cross-Sectional Studies ,Clinical Study ,Kidney Failure, Chronic ,RC870-923 ,genetic ,business ,Ireland ,umod ,chronic kidney disease ,Kidney disease - Abstract
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.
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- 2019
6. Autosomal dominant tubulointerstitial kidney disease: more than just HNF1β
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Martina Zivna, Stanislav Kmoch, Anthony J. Bleyer, Matthias T.F. Wolf, and Kendrah Kidd
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Nephrology ,Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Tamm–Horsfall protein ,Hyperkalemia ,Adolescent ,Gout ,Anemia ,030232 urology & nephrology ,Renal function ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Uromodulin ,medicine ,Humans ,Renal Insufficiency, Chronic ,Child ,Kidney ,Polycystic Kidney Diseases ,biology ,business.industry ,medicine.disease ,female genital diseases and pregnancy complications ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Mutation ,biology.protein ,Female ,medicine.symptom ,business ,Kidney disease - Abstract
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 end-stage kidney disease. HNF1β mutations often presents in childhood with anatomic abnormalities such as multicystic or dysplastic kidneys, in addition to 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.
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- 2021
7. Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations
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Petr, Vylet'al, Kendrah, Kidd, Hannah C, Ainsworth, Drahomíra, Springer, Alena, Vrbacká, Anna, Přistoupilová, Rebecca P, Hughey, Seth L, Alper, Niall, Lennon, Steven, Harrison, Maegan, Harden, Victoria, Robins, Abbigail, Taylor, Lauren, Martin, Katrice, Howard, Ibrahim, Bitar, Carl D, Langefeld, Veronika, Barešová, Hana, Hartmannová, Kateřina, Hodaňová, Tomáš, Zima, Martina, Živná, Stanislav, Kmoch, and Anthony J, Bleyer
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Adult ,Male ,Patient-Oriented, Translational Research: Research Article ,Mucin-1 ,Middle Aged ,Prognosis ,digestive system ,biological factors ,digestive system diseases ,Healthy Volunteers ,Cross-Sectional Studies ,Case-Control Studies ,Mutation ,Uromodulin ,Humans ,Nephritis, Interstitial ,Female ,skin and connective tissue diseases ,neoplasms ,Alleles ,Biomarkers ,Aged - Abstract
INTRODUCTION: Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1. METHODS: This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals. RESULTS: Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were 20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate. DISCUSSION/CONCLUSIONS: Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.
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- 2020
8. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes
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Veronika Baresova, Miroslav Votruba, Kálmán Tory, Aleš Hnízda, Jakub Sikora, Matthias T.F. Wolf, Marisa Santostefano, Neila Belghith, Lídia Balogh, Jan Živný, Tal Kopel, Robert M. Haws, Bertrand Knebelmann, Andrea Wenzel, Bodo B. Beck, Lawrence R. Shoemaker, Laurent Mesnard, Anna Jakubowska, Kendrah Kidd, Charles Shaw-Smith, Christoforos Stavrou, Mayssa Abdelwahed, Constantinos Deltas, John A. Sayer, Claudio Graziano, Rhian L Clissold, Petr Vyleťal, Stanislav Kmoch, Victoria Robins, Howard Trachtman, Michael E. Bleyer, Marie Matignon, Anthony J. Bleyer, Kathleen Claes, Jana Sovová, Irene Capelli, Philippe Grimbert, Sharon M. Moe, Luca Rampoldi, Ivana Jedličková, Karsten Häeffner, Stéphane Decramer, Kateřina Hodaňová, Helena Trešlová, Matthew R. Sinclair, Raj Munshi, Gregory Papagregoriou, Hana Hartmannová, Albert C.M. Ong, Mohamad Zaidan, Agnieszka Łaszkiewicz, Amy N. Sussman, Claudia Izzi, Martina Živná, Helena Hůlková, Francesco Scolari, Živná, M, Kidd, K, Zaidan, M, Vyleťal, P, Barešová, V, Hodaňová, K, Sovová, J, Hartmannová, H, Votruba, M, Trešlová, H, Jedličková, I, Sikora, J, Hůlková, H, Robins, V, Hnízda, A, Živný, J, Papagregoriou, G, Mesnard, L, Beck, Bb, Wenzel, A, Tory, K, Häeffner, K, Wolf, Mtf, Bleyer, Me, Sayer, Ja, Ong, Acm, Balogh, L, Jakubowska, A, Łaszkiewicz, A, Clissold, R, Shaw-Smith, C, Munshi, R, Haws, Rm, Izzi, C, Capelli, I, Santostefano, M, Graziano, C, Scolari, F, Sussman, A, Trachtman, H, Decramer, S, Matignon, M, Grimbert, P, Shoemaker, Lr, Stavrou, C, Abdelwahed, M, Belghith, N, Sinclair, M, Claes, K, Kopel, T, Moe, S, Deltas, C, Knebelmann, B, Rampoldi, L, Kmoch, S, and Bleyer, Aj
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0301 basic medicine ,Signal peptide ,Adult ,Male ,medicine.medical_specialty ,Mutant ,030232 urology & nephrology ,Chromosomal translocation ,autosomal dominant tubulointerstitial kidney disease ,characterization ,mutation ,prosegment ,renin ,signal peptide ,medicine.disease_cause ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,Renin ,medicine ,Humans ,Secretion ,Child ,Mutation ,Polycystic Kidney Diseases ,business.industry ,Endoplasmic reticulum ,Anemia ,medicine.disease ,030104 developmental biology ,Endocrinology ,Nephrology ,Female ,business ,Kidney disease - Abstract
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.
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- 2020
9. Clinical and Genetic Spectra of Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in UMOD and MUC1
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Nathalie Demoulin, Eric Goffin, Yves Pirson, Anna Greka, Patrick Hofmann, Uyen Huynh-Do, Olivier Devuyst, Olivier Bonny, Johann Morelle, Gregory Papagregoriou, Roser Torra, Karin Dahan, Hendrica Belge, Bruno Vogt, Constantinos Deltas, John A. Sayer, Anthony J. Bleyer, Céline Schaeffer, Kendrah Kidd, Daniel Guido Fuster, Luca Rampoldi, Eric Olinger, Stanislav Kmoch, Kateřina Hodaňová, Anne Kipp, Inès Dufour, Reto Martin Venzin, Thomas Fehr, Andreas D. Kistler, Christina Venzin, Martina Živná, Daniel P. Gale, Richard Sandford, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Olinger, E, Hofmann, P, Kidd, K, Dufour, I, Belge, H, Schaeffer, C, Kipp, A, Bonny, O, Deltas, C, Demoulin, N, Fehr, T, Fuster, Dg, Gale, Dp, Goffin, E, Hodanova, K, Hyunh-Do, U, Kistler, Ad, Morelle, J, Papagregoriou, G, Pirson, Y, Sandford, R, Sayer, Ja, Torra, R, Venzin, C, Venzin, R, Vogt, B, Živná, M, Greka, A, Dahan, K, Rampoldi, L, Kmoch, S, Bleyer AJ, Sr, and Devuyst, O
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0301 basic medicine ,Nephrology ,medicine.medical_specialty ,Tamm–Horsfall protein ,Gout ,Urinary system ,030232 urology & nephrology ,610 Medicine & health ,medicine.disease_cause ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Diagnostic score ,Internal medicine ,Uromodulin ,Humans ,Medicine ,Genetic Testing ,Genetic testing ,Mutation ,Kidney ,medicine.diagnostic_test ,biology ,business.industry ,Mucin-1 ,Middle Aged ,Polycystic Kidney, Autosomal Dominant ,medicine.disease ,Dominant kidney disease ,Europe ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,business ,Kidney disease - Abstract
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized. cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. To expand on this, we analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
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- 2020
10. Chronic tubulointerstitial kidney disease in untreated adenine phosphoribosyl transferase (APRT) deficiency: A case report
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Kendrah Kidd, Benjamin Cochran, Angela G Niehaus, Stanislav Kmoch, Alex Bonnecaze, Anthony J. Bleyer, Tereza Kovačíková, Gowrie Balasubraminiam, Amret T. Hawfield, Martina Živná, Aleš Hnízda, Kateřina Hodaňová, and Irene Ceballos-Picot
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Male ,medicine.medical_specialty ,Antimetabolites ,Allopurinol ,medicine.medical_treatment ,Adenine Phosphoribosyltransferase ,030232 urology & nephrology ,Adenine phosphoribosyltransferase ,Urology ,Renal function ,030204 cardiovascular system & hematology ,Nephropathy ,Kidney Calculi ,03 medical and health sciences ,0302 clinical medicine ,Urolithiasis ,medicine ,Humans ,Renal Insufficiency, Chronic ,Dialysis ,Kidney ,business.industry ,Phosphoribosyl transferase ,General Medicine ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Nephrology ,Nephritis, Interstitial ,business ,Metabolism, Inborn Errors ,Glomerular Filtration Rate ,medicine.drug ,Kidney disease - Abstract
Adenine phosphoribosyltransferase (APRT) deficiency (OMIM #614723) is a rare autosomal recessive defect in the purine salvage pathway that causes excessive production of 2,8-dihydroxyadenine, leading to nephrolithiasis and chronic kidney disease (CKD). This case report describes the natural history of CKD in untreated APRT deficiency. We describe a novel APRT mutation (chr16:88877985 G / C; c.195 C>/G; p.His54Asp) presenting with CKD without nephrolithiasis. The patient initially required dialysis, but kidney function improved with allopurinol. We reviewed APRT deficiency reported in the literature to determine the loss of kidney function in individuals with untreated APRT deficiency and its relationship to nephrolithiasis. We identified 95 individuals in whom kidney function was assessed prior to treatment. There was a bimodal distribution of kidney failure. AKI occurred frequently in childhood due to obstructing nephrolithiasis or crystalline nephropathy and was usually reversible. CKD developed after age 20 in all patients irrespective of nephrolithiasis history, with 36/42 patients > 40 years of age having at least stage 3 CKD, and 24/42 having an eGFR > 10 mL/min/1.73m2 or being on dialysis. There were 13 adults without nephrolithiasis and 50 adults with nephrolithiasis. The mean age of end-stage renal diesease (ESRD) was 50.52 ± 13.9 for those without nephrolithiasis and 43.4 ± 15.8 years for those with nephrolithiasis (p = 0.24). APRT deficiency is associated with slowly progressive CKD that occurs independently of nephrolithiasis. Diagnosis should be considered in all individuals with chronic tubulointerstitial kidney disease, with or without the presence of nephrolithiasis. In our patient, allopurinol 300 mg/day resulted in improvement of kidney function. .
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- 2018
11. Utility of genomic testing after renal biopsy
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Sarah Cormican, Peter J. Conlon, Brendan Doyle, Claire Kennedy, Anthony Dorman, Kendrah Kidd, Neil K. Fennelly, Mark A. Little, Caragh P. Stapleton, Ciara A. McDonnell, Peter Lavin, Susan L. Murray, Gianpiero L. Cavalleri, Katherine A. Benson, Friedhelm Hildebrandt, Dervla M. Connaughton, Anthony J. Bleyer, and Louise A. Ryan
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Adult ,Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Adolescent ,Biopsy ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Kidney ,Gastroenterology ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Internal medicine ,Medicine ,Humans ,Genetic Testing ,Alport syndrome ,Child ,Genetic testing ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Glomerulonephritis ,Middle Aged ,medicine.disease ,Nephrology ,Female ,Kidney Diseases ,Renal biopsy ,business ,Kidney disease - Abstract
Background: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment. Methods: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared. Results: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39). Conclusions: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.
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- 2019
12. Quality of life in patients with autosomal dominant tubulointerstitial kidney disease
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Bowline I, Kim N, Martina Živná, Johnson E, Stanislav Kmoch, Hana Hartmannová, Robins, Taylor Kb, Kendrah Kidd, Petr Vyleťal, Anthony J. Bleyer, Frankova, Kateřina Hodaňová, Pinder Aj, Martin L, Taylor A, Miroslav Votruba, and Baek Jj
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Renal function ,Young Adult ,Quality of life ,Internal medicine ,Uromodulin ,Medicine ,Humans ,Genetic Testing ,education ,Kidney transplantation ,Dialysis ,Depression (differential diagnoses) ,Genetic testing ,Aged ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Mucin-1 ,General Medicine ,Middle Aged ,medicine.disease ,Cross-Sectional Studies ,Nephrology ,Mutation ,Quality of Life ,Female ,Kidney Diseases ,business ,Kidney disease - Abstract
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.
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- 2019
13. Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease
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Patrick O'Kelly, Claire Kennedy, Peter J. Conlon, Katherine A. Benson, Stanislav Kmoch, Sarah Cormican, Gianpiero L. Cavalleri, Susan L. Murray, Anthony Dorman, Kendrah Kidd, Peter Lavin, Neil K. Fennelly, Brendan Doyle, Dervla M. Connaughton, Martina Živná, Mark A. Little, Eoin T. Conlon, Anthony J. Bleyer, and Claire Foley
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medicine.medical_specialty ,Population ,Disease ,030230 surgery ,urologic and male genital diseases ,Second transplant ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Uromodulin ,medicine ,Humans ,In patient ,education ,Transplantation ,education.field_of_study ,business.industry ,Graft Survival ,Patient survival ,medicine.disease ,Polycystic Kidney, Autosomal Dominant ,Kidney Transplantation ,surgical procedures, operative ,Renal transplant ,Mutation ,Kidney Failure, Chronic ,030211 gastroenterology & hepatology ,business ,Kidney disease - Abstract
INTRODUCTION Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure. METHODS Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non-ADTKD renal transplant recipients. RESULTS We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite-ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow-up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty-five transplant biopsies were performed during follow-up, and none of these showed signs of recurrent ADTKD post-transplant. CONCLUSION In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.
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- 2019
14. Development and Validation of a Mass Spectrometry–Based Assay for the Molecular Diagnosis of Mucin-1 Kidney Disease
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Todd A. Carter, Matthew DeFelice, Heidi L. Rehm, Stanislav Kmoch, Lucienne Ronco, Brendan Blumenstiel, Niall J. Lennon, Stacey Gabriel, Kendrah Kidd, Andreas Gnirke, Ozge Birsoy, Eric S. Lander, Anthony J. Bleyer, Massachusetts Institute of Technology. Department of Biology, and Lander, Eric Steven
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Genotype ,030232 urology & nephrology ,Disease ,Biology ,medicine.disease_cause ,Medullary cystic kidney disease ,Sensitivity and Specificity ,Mass Spectrometry ,Workflow ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,MUC1 ,Genetics ,Mutation ,Mucin-1 ,Mucin ,Reproducibility of Results ,Polycystic Kidney, Autosomal Dominant ,medicine.disease ,Variable number tandem repeat ,030104 developmental biology ,Molecular Diagnostic Techniques ,Molecular Medicine ,Kidney disease - Abstract
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. The inherently difficult nature of this mutation required an alternative method for routine detection and clinical diagnosis of the disease. We therefore developed and validated a mass spectrometry–based probe extension assay with a series of internal controls to detect the insertion event using 24 previously characterized positive samples from patients with mucin-1 kidney disease and 24 control samples known to be wild type for the variant. Validation results indicate an accurate and reliable test for clinically establishing the molecular diagnosis of mucin-1 kidney disease with 100% sensitivity and specificity across 275 tests called., Carlos Slim Foundation. Slim Initiative for Genomic Medicine
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- 2016
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15. Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease
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Andrea Alice da Silva, Jorge Reis Almeida, F. Aguiar-Alves, Stanislav Kmoch, L.B. Lopes, L.E.R. Guimaraes, Kendrah Kidd, C.C. Abreu, Cintia Fernandes de Souza, and Anthony J. Bleyer
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0301 basic medicine ,Tamm–Horsfall protein ,Physiology ,medicine.medical_treatment ,Biopsy ,030232 urology & nephrology ,Genetic mutation ,medicine.disease_cause ,Biochemistry ,0302 clinical medicine ,Chronic kidney disease ,Genotype ,Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,lcsh:QH301-705.5 ,Research Articles ,Uromodulin kidney disease ,Genetics ,lcsh:R5-920 ,Mutation ,biology ,medicine.diagnostic_test ,General Neuroscience ,General Medicine ,Genetic kidney diseases ,Middle Aged ,Polycystic Kidney, Autosomal Dominant ,3. Good health ,Pedigree ,Female ,lcsh:Medicine (General) ,Immunology ,Biophysics ,Ocean Engineering ,Peritoneal dialysis ,UMOD ,03 medical and health sciences ,Uromodulin ,Humans ,Genetic testing ,business.industry ,Cell Biology ,medicine.disease ,Gout ,030104 developmental biology ,lcsh:Biology (General) ,Tubulointerstitial fibrosis ,biology.protein ,business ,Kidney disease - Abstract
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.
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- 2018
16. Noninvasive Immunohistochemical Diagnosis and Novel
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Martina, Živná, Kendrah, Kidd, Anna, Přistoupilová, Veronika, Barešová, Mathew, DeFelice, Brendan, Blumenstiel, Maegan, Harden, Peter, Conlon, Peter, Lavin, Dervla M, Connaughton, Hana, Hartmannová, Kateřina, Hodaňová, Viktor, Stránecký, Alena, Vrbacká, Petr, Vyleťal, Jan, Živný, Miroslav, Votruba, Jana, Sovová, Helena, Hůlková, Victoria, Robins, Rebecca, Perry, Andrea, Wenzel, Bodo B, Beck, Tomáš, Seeman, Ondřej, Viklický, Sylvie, Rajnochová-Bloudíčková, Gregory, Papagregoriou, Constantinos C, Deltas, Seth L, Alper, Anna, Greka, Anthony J, Bleyer, and Stanislav, Kmoch
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Male ,Incidence ,Biopsy, Needle ,Mucin-1 ,Polycystic Kidney, Autosomal Dominant ,Prognosis ,Immunohistochemistry ,Risk Assessment ,Pedigree ,Case-Control Studies ,Mutation ,Humans ,Female ,Genetic Predisposition to Disease ,Registries ,Erratum ,Retrospective Studies - Abstract
Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-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 novelWe 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
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- 2018
17. A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis
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Timmy Lee, Barry J. Browne, Steven K. Burke, C. Keith Ozaki, Vincent A. Scavo, Eric K. Peden, Brian L. Ferris, Timothy P. O'Connor, Bradley S. Dixon, Rick E Mishler, Samuel E. Wilson, Anthony J. Bleyer, and Kendrah Kidd
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Fistula ,Administration, Topical ,Arteriovenous fistula ,030204 cardiovascular system & hematology ,Placebo ,law.invention ,Veins ,Upper Extremity ,03 medical and health sciences ,0302 clinical medicine ,Arteriovenous Shunt, Surgical ,Randomized controlled trial ,Double-Blind Method ,law ,Renal Dialysis ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Vein ,Vascular Patency ,Aged ,Pancreatic Elastase ,business.industry ,Graft Occlusion, Vascular ,Thrombosis ,Middle Aged ,medicine.disease ,United States ,Surgery ,medicine.anatomical_structure ,Treatment Outcome ,Radial Artery ,Female ,Hemodialysis ,Cardiology and Cardiovascular Medicine ,business ,Carrier Proteins ,Kidney disease - Abstract
Objective Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. Methods PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n = 210) or placebo (n = 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. Results The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P = .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P = .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P = .035) with unassisted use for hemodialysis and 64% and 44% (P = .006) with unassisted plus assisted use. Conclusions Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.
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- 2017
18. Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease
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Kendrah Kidd, Sun-Ji Park, Stanislav Kmoch, Chirag R. Parikh, Rebecca J. Perry, Scott R. Manson, Heather Thiessen-Philbrook, Ying Maggie Chen, Yeawon Kim, Helen Liapis, Carlos A.F. Molina, and Anthony J. Bleyer
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0301 basic medicine ,Nephrology ,Male ,medicine.medical_specialty ,Pathology ,Nephrotic Syndrome ,Urinary system ,03 medical and health sciences ,Postoperative Complications ,Internal medicine ,Uromodulin ,medicine ,Animals ,Humans ,Cardiac Surgical Procedures ,Child ,Kidney ,Extracellular Matrix Proteins ,business.industry ,Podocytes ,Acute kidney injury ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Endoplasmic Reticulum Stress ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Unfolded protein response ,Biomarker (medicine) ,Nephritis, Interstitial ,business ,Nephrotic syndrome ,Cell Adhesion Molecules ,Biomarkers ,Kidney disease ,Research Article - Abstract
ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress-mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress-induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion-induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.
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- 2017
19. Autosomal Dominant Tubulointerstitial Kidney Disease
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Martina Živná, Kendrah Kidd, Stanislav Kmoch, and Anthony J. Bleyer
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Pathology ,Hyperkalemia ,Anemia ,030232 urology & nephrology ,Renal function ,Nephritis, Hereditary ,Article ,03 medical and health sciences ,0302 clinical medicine ,Renin ,Uromodulin ,medicine ,Humans ,Hyperuricemia ,Genetic testing ,Hepatocyte Nuclear Factor 1-beta ,Kidney ,medicine.diagnostic_test ,business.industry ,Mucin-1 ,medicine.disease ,Gout ,030104 developmental biology ,medicine.anatomical_structure ,Nephrology ,Mutation ,medicine.symptom ,business ,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.
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- 2016
20. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia
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Hana Hartmannová, Christelle Golzio, Nicholas Katsanis, Lut Van Laer, Geert Vandeweyer, Nikhita Ajit Bolar, Igor Pediaditakis, Christine Van Hemelrijk, Bart Loeys, Jana Sovová, Kendrah Kidd, Martina Živná, Geert Mortier, Guy Van Camp, Han G. Brunner, Kateřina Hodaňová, Richard Spong, Alexander Hoischen, Jeroen R. Huyghe, Gaëlle Hayot, Anna Přistoupilová, Myriam Azou, Erve Matthys, Viktor Stránecký, Ann Raes, Stanislav Kmoch, Marie Claire Gubler, Emiel Sys, Veronika Baresova, Dorien Schepers, Ivana Jedličková, Marleen Praet, Aleš Hnízda, Johan Vande Walle, Petr Vyleťal, Anthony J. Bleyer, Helena Hůlková, and Kelsey McFadden
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Male ,Models, Molecular ,0301 basic medicine ,Pathology ,Biopsy ,medicine.medical_treatment ,PRONEPHROS ,030232 urology & nephrology ,Golgi Apparatus ,Endoplasmic Reticulum ,0302 clinical medicine ,ENDOPLASMIC-RETICULUM STRESS ,Medicine and Health Sciences ,Exome ,Genetics(clinical) ,Child ,SIGNAL SEQUENCE ,Zebrafish ,Genetics (clinical) ,Kidney transplantation ,Genes, Dominant ,Genetics ,Kidney ,Fetal Growth Retardation ,medicine.diagnostic_test ,Anemia ,Syndrome ,Middle Aged ,ER STRESS ,Pedigree ,TRANSLOCATION ,3. Good health ,GENOME ,Phenotype ,medicine.anatomical_structure ,Disease Progression ,Female ,Kidney Diseases ,Renal biopsy ,Adult ,Heterozygote ,medicine.medical_specialty ,Neutropenia ,NEPHROPATHY ,Tubular atrophy ,Mutation, Missense ,DNA-SEQUENCING DATA ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Biology ,Article ,Nephropathy ,Young Adult ,03 medical and health sciences ,GENE MUTATION ,medicine ,Animals ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Alleles ,Dialysis ,Aged ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,LINKAGE ANALYSIS ,Infant, Newborn ,Biology and Life Sciences ,Glomerulosclerosis ,medicine.disease ,030104 developmental biology ,Chronic Disease ,Mutation ,Human medicine ,SEC Translocation Channels ,Kidney disease - Abstract
Contains fulltext : 167296.pdf (Publisher’s version ) (Open Access) Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.
- Published
- 2016
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