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DCHS1 DNA copy number loss associated with pediatric urinary tract infection risk.

ABSTRACT: Urinary tract infections (UTI), associated with vesicoureteral reflux (VUR), can lead to chronic kidney disease. Genetic alterations in the innate immune defenses contribute to UTI risk. We investigated a novel gene, Dachsous Cadherin-Related 1 (DCHS1), in children with UTI. We determined absolute DNA copy number (CN) of DCHS1 in children with UTI. In this case-control study, we utilized multiple complementary methods to determine the genomic CN of DCHS1. Children with (n?=?370) and without (n?=?71) VUR from two well-phenotyped clinical trials of UTI were copy-typed and compared to 491 healthy controls with no known history of VUR or UTI. Less than 1% of controls had a single copy of DCHS1, while 31% of children with UTI and no VUR and 7% of children with UTI and VUR had a single copy of the DCHS1 gene. Using immunostaining, we localized expression postnatally to the bladder and renal epithelia. Mice were also challenged with two uropathogenic Escherichia coli strains, and Dchs1 mRNA was quantified. This study represents the first report of DCHS1 in association with pediatric UTI. We hypothesize that its role in innate immunity is critical to lower urinary tract defense. Further investigation is required to determine the role of DCHS1 in innate immunity.

SUBMITTER: Qureshi AH

PROVIDER: S-EPMC7491237 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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DCHS1 DNA copy number loss associated with pediatric urinary tract infection risk.

Qureshi Aslam H AH Liang Dong D Canas Jorge J Hooks Jenaya J Arrregui Samuel W SW Saxena Vijay V Rooney Robert R Nolan Vikki V Schwaderer Andrew L AL Hains David S DS

Innate immunity 20200415 6

Urinary tract infections (UTI), associated with vesicoureteral reflux (VUR), can lead to chronic kidney disease. Genetic alterations in the innate immune defenses contribute to UTI risk. We investigated a novel gene, Dachsous Cadherin-Related 1 (DCHS1), in children with UTI. We determined absolute DNA copy number (CN) of DCHS1 in children with UTI. In this case-control study, we utilized multiple complementary methods to determine the genomic CN of DCHS1. Children with (n ...[more]

PMID: 32295462

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Project description:Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level-dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.

Project description:INTRODUCTION:Concerns regarding the quality, credibility, and applicability of recently published pediatric urinary tract infection (UTI) clinical practice guidelines have been raised due to the inconsistencies of recommendations between them. We aimed to determine the quality of the recent clinical practice guidelines on pediatric UTI by using the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument, and summarize the standard of care in diagnosis and management of pediatric UTI from the top three clinical practice guidelines. METHODS:A systematic literature search was performed on medical literature electronic databases and international guideline repository websites. English language-based clinical practice guidelines from 2007-2016 endorsed by any international society or government organization providing recommendations for the management of pediatric UTI were considered. Eligible clinical practice guidelines were independently appraised by six reviewers using the AGREE II tool. Clinical practice guidelines were assessed for standardized domains and summarized for overall quality. Inter-rater reliability was assessed using inter-class coefficient (ICC). RESULTS:Thirteen clinical practice guidelines were critically reviewed. The Spanish clinical practice guidelines, American Academy of Pediatrics, and National Institute for Health and Clinical Excellence clinical practice guidelines consistently scored high on all AGREE domains (total averaged domain scores 90, 88, and 88, respectively). Among the six reviewers, there was a high degree of inter-rater reliability (average measure ICC 0.938; p<0.0001). There is reasonable consensus among the top three clinical practice guidelines in their major recommendations. CONCLUSIONS:The clinical practice guidelines from Spain, American Academy of Pediatrics, and National Institute for Health and Clinical Excellence, with their major recommendations being similar, have scored highly on the AGREE II indicators of quality for the clinical practice guidelines development process.

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DCHS1 DNA copy number loss associated with pediatric urinary tract infection risk.

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<i>DCHS1</i> DNA copy number loss associated with pediatric urinary tract infection risk.

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