Vesicoureteric reflux and reflux nephropathy: from mouse models to childhood disease

Fillion, Marie-Lyne; Watt, Christine L.; Gupta, Indra R.

doi:10.1007/s00467-014-2761-3

Cited by 32 publications

(29 citation statements)

References 74 publications

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“…It is frequently found at the time of transplant in kidney grafts from older donors 25 and may be aggravated or induced by other nonimmunologic factors involving one or more of the following: CNI, 21,22,[26][27][28] recurrent native kidney diseases, viral infections, and reflux nephropathy. [29][30][31][32][33] Chronic rejection, however, represents a common cause of IFTA, 29,30,34,35 but the exact contribution of each of these insults, combined with the overall IFTA load, remains unknown. Interstitial fibrosis, tubular atrophy, and glomerulosclerosis also are commonly observed along with other lesions of both immune and nonimmune origin, such as arterial fibrointimal hyperplasia, medial arteriolar hyalinosis, and TIV.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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“…These children are at risk of pyelonephritis or renal scarring, which may progress to reflux nephropathy (RN) and end-stage renal damage (3, 4). The main histopathological findings of RN are tubular atrophy with prominent mononuclear inflammatory cellular infiltrate and interstitial fibrosis (5). The main biomolecular mechanisms responsible for its progression still under investigation are genetic, pro-inflammatory and pro-apoptotic.…”

Section: Introductionmentioning

confidence: 99%

Urinary excretion of EGF and MCP-1 in children with vesico-ureteral reflux

Pastore

Bartoli

2017

Int. braz j urol.

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Purpose The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR).Materials and methods A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI.Results In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls.Conclusions Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

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“…VUR is a congenital urinary tract defect associated with the anomalous development of the UVJ, and is observed in ~1 % of general population, and in at least 30 % of children presenting with urinary tract infection [1–3]. However, the prevalence of VUR is likely underreported due to the invasive nature of the test used for diagnosis: the voiding cystourethrogram.…”

Section: Clinical Spectrum Of Vur and Reflux Nephropathymentioning

confidence: 99%

“…However, the prevalence of VUR is likely underreported due to the invasive nature of the test used for diagnosis: the voiding cystourethrogram. VUR is highly heritable and a number of genes and susceptibility loci have been identified [3]. In addition to the genetic heterogeneity of the disorder, it is also phenotypically heterogeneous and loosely classified as primary and secondary VUR.…”

Section: Clinical Spectrum Of Vur and Reflux Nephropathymentioning

confidence: 99%

Vesicoureteral reflux and the extracellular matrix connection

et al. 2016

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Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes.

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Vesicoureteric reflux and reflux nephropathy: from mouse models to childhood disease

Cited by 32 publications

References 74 publications

Untitled

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Urinary excretion of EGF and MCP-1 in children with vesico-ureteral reflux

Vesicoureteral reflux and the extracellular matrix connection

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