Congenital Anomalies of the Kidney and Urinary Tract: A Genetic Disorder?

Congenital anomalies of the kidney and urinary tract (CAKUTs) occur in 3–6 per 1000 live births, account for the most cases of pediatric end-stage kidney disease (ESKD), and predispose an individual to hypertension and cardiovascular disease throughout life. Although CAKUTs are a part of many known syndromes, only few single-candidate causative genes have been implicated so far in nonsyndromic cases of human CAKUT. Evidence from mouse models supports the hypothesis that non-syndromic human CAKUT may be caused by single-gene defects. Because increasing numbers of children with CAKUT are surviving to adulthood, better understanding of the molecular pathogenesis of CAKUT, development of new strategies aiming at prevention of CAKUT, preservation of renal function, and avoidance of associated cardiovascular morbidity are needed. In this paper, we will focus on the knowledge derived from the study of syndromic and non-syndromic forms of CAKUT in humans and mouse mutants to discuss the role of genetic, epigenetic, andin uteroenvironmental factors in the pathogenesis of non-syndromic forms of CAKUT in children with particular emphasis on the genetic contributions to CAKUT.

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Genetic Disorders and Major Extracardiac Anomalies Associated With the Hypoplastic Left Heart Syndrome

PEDIATRICS ◽

10.1542/peds.82.5.698 ◽

1988 ◽

Vol 82 (5) ◽

pp. 698-706 ◽

Cited By ~ 1

Author(s):

Marvin Natowicz ◽

Jane Chatten ◽

Robert Clancy ◽

Katrina Conard ◽

Tracy Glauser ◽

...

Keyword(s):

Hypoplastic Left Heart Syndrome ◽

Chromosomal Abnormalities ◽

Genetic Disorders ◽

Genetic Disorder ◽

Single Gene ◽

Left Heart ◽

Hypoplastic Left Heart ◽

Gene Defects ◽

Insulin Dependent Diabetic ◽

Left Heart Syndrome

All pediatric autopsies of patients with hypoplastic left heart syndrome seen during an 11-year interval were reviewed to determine the frequency of underlying chromosomal and single-gene defects and idiopathic major extracardiac anomalies associated with this common, lethal congenital heart abnormality. Of 83 patients identified, nine had underlying chromosomal abnormalities, four had single-gene defects, ten had one or more major extracardiac anomalies without an identifiable chromosomal or mendelian disorder, and two were infants of insulin-dependent diabetic mothers. Overall, 23 patients (28%) had a genetic disorder and/or major extracardiac anomaly. The substantial prevalence of genetic causes of and major extracardiac anomalies associated with hypoplastic left heart syndrome underscores the need for a detailed genetic evaluation for all patients with hypoplastic left heart syndrome.

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PRIROJENE NEPRAVILNOSTI SEČIL PRI OTROCIH

Slovenian Medical Journal ◽

10.6016/zdravvestn.996 ◽

2015 ◽

Vol 84 (1) ◽

Author(s):

Matjaž Kopač

Keyword(s):

Urinary Tract ◽

Urinary Bladder ◽

Congenital Anomalies ◽

Kidney Diseases ◽

System Structure ◽

Cystic Kidney ◽

Organ Systems ◽

Stage Renal Disease ◽

End Stage ◽

Collecting System

Congenital anomalies of the kidney and urinary tract are the commonest congenital anomalies in children, often detected prenatally with ultrasound. This method is useful for assesing the degree of dilatation of the collecting system, structure of the kidney parenchyma, amount of amniotic fluid and urinary bladder. Hydronephrosis is the most common among them. Anomalies can be bilateral or unilateral and different defects may coexist in an individual child. Anomalies of other organs and organ systems are often associated with anomalies of the kidneys and urinary tract, described in numerous syndromes. Congenital anomalies of the kidney and urinary tract can be divided in anomalies of the renal parencyma development, renal embryonic migration and position, cystic kidney diseases and anomalies of the urinary tract (collecting system of the kidneys, ureters, urinary bladder and urethra). They are the commonest cause of end-stage renal disease in children.

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Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct

AJP Renal Physiology ◽

10.1152/ajprenal.00068.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. F221-F235 ◽

Cited By ~ 63

Author(s):

James A. Schafer

Keyword(s):

Collecting Duct ◽

Single Gene ◽

Extracellular Volume ◽

Prostaglandin E ◽

Salt Wasting ◽

Luminal Membrane ◽

Basal Plasma ◽

Junctional Complexes ◽

Gene Defects

Although the aldosterone-responsive segments of the nephron together reabsorb <10% of the filtered Na+, certain single-gene defects that affect the epithelial Na+ channel (ENaC) in the luminal membrane of the collecting duct (CD) or its regulation by aldosterone cause severe hypertension, whereas others cause salt wasting and hypotension. These rare defects illustrate the key role of the distal nephron in maintaining normal extracellular volume and blood pressure. Genetic defects that increase the Cl− conductance of the junctional complexes may also lead to salt retention and hypertension. Less dramatic alterations in regulatory actions of other hormones such as vasopressin (VP), either alone or with other genetic variations, diet, or environmental factors, may also produce Na+retention or loss. Although VP acts primarily to regulate water balance, it is also an antinatriuretic hormone. Elevated basal plasma VP levels, and/or augmented VP release with increased Na+intake, have been linked to essential hypertension in humans and in animal models of congestive heart failure and cirrhosis. Norepinephrine, dopamine, and prostaglandin E2 can inhibit the antinatriuretic effects of VP, and changes in the actions of these autocrine and paracrine regulators may also be involved in abnormal regulation of Na+ reabsorption.

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Holding Water: Congenital Anomalies of the Kidney and Urinary Tract, CKD, and the Ongoing Role of Excellence in Plumbing

Advances in Chronic Kidney Disease ◽

10.1053/j.ackd.2017.09.012 ◽

2017 ◽

Vol 24 (6) ◽

pp. 357-363 ◽

Cited By ~ 2

Author(s):

Lars J. Cisek

Keyword(s):

Urinary Tract ◽

Congenital Anomalies

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Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfw430 ◽

2017 ◽

Vol 32 (5) ◽

pp. 759-765 ◽

Cited By ~ 9

Author(s):

Tarak Srivastava ◽

Ganesh Thiagarajan ◽

Uri S. Alon ◽

Ram Sharma ◽

Ashraf El-Meanawy ◽

...

Keyword(s):

Urinary Tract ◽

Congenital Anomalies ◽

Glomerular Injury ◽

Biomechanical Forces

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Overexpression of Long Non-coding RNA 4933425B07Rik Causes Urinary Malformations in Mice

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.594640 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lihong Tan ◽

Minghui Yu ◽

Yaxin Li ◽

Shanshan Xue ◽

Jing Chen ◽

...

Keyword(s):

Urinary Tract ◽

Developmental Abnormalities ◽

Expression Levels ◽

Morphogenetic Protein ◽

Non Coding Rna ◽

Genetic And Environmental Factors ◽

Stage Renal Disease ◽

End Stage ◽

Long Non Coding Rna

Congenital anomalies of the kidney and urinary tract (CAKUT) is a common birth defect and is the leading cause of end-stage renal disease in children. The etiology of CAKUT is complex and includes mainly genetic and environmental factors. However, these factors cannot fully explain the etiological mechanism of CAKUT. Recently, participation of long non-coding RNAs (lncRNAs) in the development of the circulatory and nervous systems was demonstrated; however, the role of lncRNAs in the development of the kidney and urinary tract system is unclear. In this study, we used the piggyBac (PB) transposon-based mutagenesis to construct a mouse with lncRNA 4933425B07Rik (Rik) PB insertion (RikPB/PB) and detected overexpression of Rik and a variety of developmental abnormalities in the urinary system after PB insertion, mainly including renal hypo/dysplasia. The number of ureteric bud (UB) branches in the RikPB/PB embryonic kidney was significantly decreased in embryonic kidney culture. Only bone morphogenetic protein 4 (Bmp4), a key molecule regulating UB branching, is significantly downregulated in RikPB/PB embryonic kidney, while the expression levels of other molecules involved in the regulation of UB branching were not significantly different according to the RNA-sequencing (RNA-seq) data, and the results were verified by quantitative real-time polymerase chain reaction (RT-PCR) and immunofluorescence assays. Besides, the expression of pSmad1/5/8, a downstream molecule of BMP4 signaling, decreased by immunofluorescence. These findings suggest that abnormal expression of Rik may cause a reduction in the UB branches by reducing the expression levels of the UB branching-related molecule Bmp4, thus leading to the development of CAKUT.

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