Evolving Concepts in Human Renal Dysplasia

Nephro-Urology and Molecular Medicine Units, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 05/2004; 15(4):998-1007.
Source: PubMed


Human renal dysplasia is a collection of disorders in which kidneys begin to form but then fail to differentiate into normal nephrons and collecting ducts. Dysplasia is the principal cause of childhood end-stage renal failure. Two main theories have been considered in its pathogenesis: A primary failure of ureteric bud activity and a disruption produced by fetal urinary flow impairment. Recent studies have documented deregulation of gene expression in human dysplasia, correlating with perturbed cell turnover and maturation. Mutations of nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which renal dysplasia can feature, including Fraser, renal cysts and diabetes, and Kallmann syndromes. Here, it is possible to begin to understand the normal nephrogenic function of the wild-type proteins and understand how mutations might cause aberrant organogenesis.

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Available from: Karen L Price, Aug 28, 2014
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    • "involvement, suggesting that kidney damage may result not from a primary single constitutional gene mutation but rather from defective local gene control of renal outgrowth (Woolf et al. 2004). Recently, mutations in individual single genes, such as TCF2/hepatocyte nuclear factor 1β (HNF1β), PAX2, RET, and ROB02, were described, but these are very rare (Winyard and Chitty 2008). "
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    ABSTRACT: Congenital renal dysplasia (RD) is a severe form of congenital renal malformation characterized by disruption of normal renal development with cyst formation, reduced or absent nephrons, and impaired renal growth. The authors previously identified that matrilysin (matrix metalloproteinase-7) was overexpressed in a microarray gene expression analysis of human RD compared to normal control kidneys. They now find that active matrilysin gene transcription and protein synthesis occur within dysplastic tubules and epithelial cells lining cysts in human RD by RT-PCR and immunohistochemistry. Similar staining patterns were seen in obstructed kidneys of pouch opossums that show histological features similar to that of human RD. In vitro, matrilysin inhibits formation of branching structures in mIMCD-3 cells stimulated by bone morphogenetic protein-7 (BMP-7) but does not inhibit hepatocyte growth factor-stimulated branching. BMP-7 signaling is essential for normal kidney development, and overexpression of catalytically active matrilysin in human embryonic kidney 293 cells reduces endogenous BMP-7 protein levels and inhibits phosphorylation of BMP-7 SMAD signaling intermediates. These findings suggest that matrilysin expression in RD may be an injury response that disrupts normal nephrogenesis by impairing BMP-7 signaling.
    Journal of Histochemistry and Cytochemistry 01/2012; 60(3):243-53. DOI:10.1369/0022155411435152 · 1.96 Impact Factor
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    • "Current research is being undertaken to better understand the genetic predisposition and embryologic mechanisms underlying CAKUT in addition to factors that might further complicate acquired pyelonephritic scarring, such as genes involved in inflammation and fibrosis as well as hypertension [24-27]. Embryologic studies suggest abnormal laterally displaced ureteral budding from the bladder wall may predispose to a dysplastic refluxing ureter that makes contact with a reduced amount of mesenchyme forming a smaller hypo-dysplastic poorly functioning kidney. "
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    ABSTRACT: Studies undertaken in recent years have improved our understanding regarding the consequences and management of febrile urinary tract infections (UTIs), which are amongst the most common serious bacterial infections in childhood, with renal scarring a frequent outcome. In the past pyelonephritic scarring of the kidney, often associated with vesico-ureteral reflux (reflux nephropathy) was considered a frequent cause of chronic renal insufficiency in children. Increasing recognition as a consequence of improved antenatal ultrasound, that the majority of these children had congenital renal hypo-dysplasia, has resulted in a number of studies examining treatment strategies and outcomes following UTI. In recent years there is a developing consensus regarding the need for a less aggressive therapeutic approach with oral as opposed to intravenous antibiotics, and less invasive investigations, cystourethrography in particular, following an uncomplicated first febrile UTI. There does remain a concern that with this newer approach we may be missing a small subgroup of children more prone to develop severe kidney damage as a consequence of pyelonephritis, and in whom some form of intervention may prove beneficial. These concerns have meant that development of a universally accepted diagnostic protocol remains elusive.
    Italian Journal of Pediatrics 11/2011; 37(1):57. DOI:10.1186/1824-7288-37-57 · 1.52 Impact Factor
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    • "A transient embryonic kidney, the mesonephros, then forms along the long axis of the nephric duct (2) with the definitive kidney or metanephros forming via an outgrowth of the distal nephric duct, the ureteric bud, which then undergoes extensive branching and induces the surrounding mesoderm to form glomeruli and nephrons (3,4). The first 6–10 generations of ureteric branching events will form the pelvis and calyces and are not associated with nephrogenesis (5). The molecules determining the position of the boundaries between ureter and renal pelvis or between renal papilla and collecting duct fate have not yet been identified. "
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUTs) are common disorders of human development affecting the renal parechyma, renal pelvis, ureter, bladder and urethra; they show evidence of shared genetic aetiology, although the molecular basis of this remains unknown in the majority of cases. Breakpoint mapping of a de novo, apparently balanced, reciprocal translocation associated with bilateral renal agenesis has implicated the gene encoding the nuclear steroid hormone receptor ESRRG as a candidate gene for CAKUT. Here we show that the Esrrg protein is detected throughout early ureteric ducts as cytoplasmic/sub-membranous staining; with nuclear localization seen in developing nephrons. In 14.5-16.5 dpc (days post-conception) mouse embryos, Esrrg localizes to the subset of ductal tissue within the kidney, liver and lung. The renal ductal expression becomes localized to renal papilla by 18.5 dpc. Perturbation of function was performed in embryonic mouse kidney culture using pooled siRNA to induce knock-down and a specific small-molecule agonist to induce aberrant activation of Esrrg. Both resulted in severe abnormality of early branching events of the ureteric duct. Mouse embryos with a targeted inactivation of Esrrg on both alleles (Esrrg(-/-)) showed agenesis of the renal papilla but normal development of the cortex and remaining medulla. Taken together, these results suggest that Esrrg is required for early branching events of the ureteric duct that occur prior to the onset of nephrogenesis. These findings confirm ESRRG as a strong candidate gene for CAKUT.
    Human Molecular Genetics 03/2011; 20(5):917-26. DOI:10.1093/hmg/ddq530 · 6.39 Impact Factor
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