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PURPOSE - Nephrolithiasis is an increasingly common ailment in the United States. Ureteroscopic management has supplanted shockwave lithotripsy as the most common treatment of upper tract stone disease. Ureteral stricture is a rare but serious complication of stone disease and its management. The impact of new technologies and more widespread ureteroscopic management on stricture rates is unknown. We describe our experience in managing strictures incurred following ureteroscopy for upper tract stone disease.
MATERIALS AND METHODS - Records for patients managed at four tertiary care centers between December 2006 and October 2015 with the diagnosis of ureteral stricture following ureteroscopy for upper tract stone disease were retrospectively reviewed. Study outcomes included number and type (endoscopic, reconstructive, or nephrectomy) of procedures required to manage stricture.
RESULTS - Thirty-eight patients with 40 ureteral strictures following URS for upper tract stone disease were identified. Thirty-five percent of patients had hydronephrosis or known stone impaction at the time of initial URS, and 20% of cases had known ureteral perforation at the time of initial URS. After stricture diagnosis, the mean number of procedures requiring sedation or general anesthesia performed for stricture management was 3.3 ± 1.8 (range 1-10). Eleven strictures (27.5%) were successfully managed with endoscopic techniques alone, 37.5% underwent reconstruction, 10% had a chronic stent/nephrostomy, and 10 (25%) required nephrectomy.
CONCLUSIONS - The surgical morbidity of ureteral strictures incurred following ureteroscopy for stone disease can be severe, with a low success rate of endoscopic management and a high procedural burden that may lead to nephrectomy. Further studies that assess specific technical risk factors for ureteral stricture following URS are needed.
PURPOSE - Quantitative multi-parametric MRI (mpMRI) methods may allow the assessment of renal injury and function in a sensitive and objective manner. This study aimed to evaluate an array of MRI methods that exploit endogenous contrasts including relaxation rates, pool size ratio (PSR) derived from quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), nuclear Overhauser enhancement (NOE), and apparent diffusion coefficient (ADC) for their sensitivity and specificity in detecting abnormal features associated with kidney disease in a murine model of unilateral ureter obstruction (UUO).
METHODS - MRI scans were performed in anesthetized C57BL/6N mice 1, 3, or 6 days after UUO at 7T. Paraffin tissue sections were stained with Masson trichrome following MRI.
RESULTS - Compared to contralateral kidneys, the cortices of UUO kidneys showed decreases of relaxation rates R and R , PSR, NOE, and ADC. No significant changes in CEST effects were observed for the cortical region of UUO kidneys. The MRI parametric changes in renal cortex are related to tubular cell death, tubular atrophy, tubular dilation, urine retention, and interstitial fibrosis in the cortex of UUO kidneys.
CONCLUSION - Measurements of multiple MRI parameters provide comprehensive information about the molecular and cellular changes produced by UUO. Magn Reson Med 79:2216-2227, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
© 2017 International Society for Magnetic Resonance in Medicine.
Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound α and β subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system is poorly defined. Integrin α3β1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of α6 containing integrins (α6β1 and α6β4), the other major laminin receptors, is unknown. Patients with mutations in α6 containing integrins not only develop epidermolysis bullosa, but also have abnormalities in the kidney collecting system. In this study, we show that selectively deleting the α6 or β4 integrin subunits at the initiation of ureteric bud development in mice does not affect morphogenesis. However, the collecting system becomes dilated and dysmorphic as the mice age. The collecting system in both null genotypes was also highly susceptible to unilateral ureteric obstruction injury with evidence of excessive tubule dilatation and epithelial cell apoptosis. Mechanistically, integrin α6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that α6 integrins are important for maintaining the integrity of the kidney collecting system by enhancing tight adhesion of the epithelial cells to the basement membrane. These data give a mechanistic explanation for the association between kidney collecting system abnormalities in patients and epidermolysis bullosa.
Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagens. DDR1 expression increases following kidney injury and accumulating evidence suggests that it contributes to the progression of injury. To this end, deletion of DDR1 is beneficial in ameliorating kidney injury induced by angiotensin infusion, unilateral ureteral obstruction, or nephrotoxic nephritis. Most of the beneficial effects observed in the DDR1-null mice are attributed to reduced inflammatory cell infiltration to the site of injury, suggesting that DDR1 plays a pro-inflammatory effect. The goal of this study was to determine whether, in addition to its pro-inflammatory effect, DDR1 plays a deleterious effect in kidney injury by directly regulating extracellular matrix production. We show that DDR1-null mice have reduced deposition of glomerular collagens I and IV as well as decreased proteinuria following the partial renal ablation model of kidney injury. Using mesangial cells isolated from DDR1-null mice, we show that these cells produce significantly less collagen compared to DDR1-null cells reconstituted with wild type DDR1. Moreover, mutagenesis analysis revealed that mutations in the collagen binding site or in the kinase domain significantly reduce DDR1-mediated collagen production. Finally, we provide evidence that blocking DDR1 kinase activity with an ATP-competitive small molecule inhibitor reduces collagen production. In conclusion, our studies indicate that the kinase activity of DDR1 plays a key role in DDR1-induced collagen synthesis and suggest that blocking collagen-mediated DDR1 activation may be beneficial in fibrotic diseases.
Copyright © 2016. Published by Elsevier B.V.
PURPOSE - Although reported success rates after pediatric pyeloplasty to correct ureteropelvic junction are high, failure may require intervention. We sought to characterize the incidence and timing of secondary procedures after pediatric pyeloplasty using a national employer based insurance database.
MATERIALS AND METHODS - Using the MarketScan® database we identified patients 0 to 18 years old who underwent pyeloplasty from 2007 to 2013 with greater than 3 months of postoperative enrollment. Secondary procedures following the index pyeloplasty were identified by CPT codes and classified as stent/drain, endoscopic, pyeloplasty, nephrectomy or transplant. The risk of undergoing a secondary procedure was ascertained using Cox proportional hazards models adjusting for demographic and clinical characteristics.
RESULTS - We identified 1,976 patients with a mean ± SD followup of 23.9 ± 19.8 months. Overall 226 children (11.4%) had undergone at least 1 post-pyeloplasty procedure. The first procedure was done within 1 year in 87.2% of patients with a mean postoperative interval of 5.9 ± 11.1 months. Stents/drains, endoscopic procedures and pyeloplasties were noted in 116 (5.9%), 34 (1.7%) and 71 patients (3.1%), respectively. Length of stay was associated with undergoing a secondary procedure. Compared with 2 days or less the HR of 3 to 5 and 6 days or greater was 1.65 and 3.94 (p = 0.001 and <0.001, respectively).
CONCLUSIONS - Following pediatric pyeloplasty 1 of 9 patients undergoes at least 1 secondary procedure with the majority performed within the first year. One of 11 patients undergoes intervention more extensive than placement of a single stent or drain, requiring management strategies that generally signify recurrent or persistent obstruction. Estimates of pyeloplasty success in this national data set are lower than in other published series.
Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
PURPOSE - Radiographic followup after pyeloplasty for the correction of ureteropelvic junction obstruction is not well defined in children. We characterize trends in frequency and modality of postoperative imaging after open and minimally invasive pediatric pyeloplasty.
MATERIALS AND METHODS - Using the MarketScan® database, we identified patients 0 to 18 years old undergoing pyeloplasty between 2007 and 2013. Followup imaging was classified as functional (diuretic renography, excretory urography) or nonfunctional (ultrasound, computerized tomography, magnetic resonance imaging). We excluded patients with less than 24 months of postoperative enrollment in MarketScan. Multivariate logistic regression was performed to determine associations between demographic variables and imaging use patterns.
RESULTS - We identified 926 patients with a mean ± SD followup of 3.6 ± 1.3 years, of whom 30% underwent minimally invasive pyeloplasty. Overall 5.9% of patients had no postoperative imaging available. Within the first 6 months postoperatively 853 patients (91%) underwent at least 1 imaging study and 192 (24%) underwent renography. Within the first 12 months postoperatively 91% of patients underwent at least 1 imaging study, most commonly ultrasound. After 12 months almost a third of the patients were not followed with imaging. Of the 71% undergoing imaging most underwent ultrasound. Younger age and female gender were independently associated with frequent imaging (at least yearly) on multivariate logistic regression.
CONCLUSIONS - Following pediatric pyeloplasty there is variation in modality and frequency of imaging followup. The majority of patients are followed with renal ultrasound, with less frequent use of functional imaging. Almost a third of patients do not undergo followup imaging after 1 year.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insulin-like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress-induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC)-specific IGF-1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE)-cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE-protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin lineage of bone marrow cells had no significant effect on the UUO-induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE-protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.
Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-β mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-β receptor (TβRII), which in turn promotes a TβRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TβRII is considered the principal regulatory mechanism of TβRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TβRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TβRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TβRII tail tyrosine residues, resulting in inhibition of TβR-dependent fibrotic signaling. The collagen-binding receptor integrin α1β1 was required for recruitment of TCPTP to the TβRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TβRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1β1 and TβRII that is essential for TβRII-mediated SMAD activation and fibrotic signaling pathways.