Bile duct epithelium forms a barrier to the backflow of bile into the liver parenchyma. However, the structure and regulation of the tight junctions in bile duct epithelium is not well understood. In the present study, we evaluated the effect of lipopolysaccharide on tight junction integrity and barrier function in normal rat cholangiocyte monolayers. Lipopolysaccharide disrupts barrier function and increases paracellular permeability in a time- and dose-dependent manner. Lipopolysaccharide induced a redistribution of tight junction proteins, occludin, claudin-1, claudin-4, and zonula occludens (ZO)-1 from the intercellular junctions and reduced the level of ZO-1. Tyrosine kinase inhibitors (genistein and PP2) prevented lipopolysaccharide-induced increase in permeability and subcellular redistribution of ZO-1. Reduced expression of c-Src, TLR4, or LBP by specific small interfering RNA attenuated lipopolysaccharide-induced permeability and redistribution of ZO-1. ML-7, a myosin light chain kinase inhibitor, attenuated LPS-induced permeability. Lipopolysaccharide treatment rapidly increased the phosphorylation of occludin and ZO-1 on tyrosine residues, which was prevented by genistein and PP2. Occludin and ZO-1 were found to be highly phosphorylated on threonine residues in intact cell monolayers. Threonine-phosphorylation of occludin was rapidly reduced by lipopolysaccharide administration. Lipopolysaccharide-induced dephosphorylation of occludin on Thr residues was prevented by genistein and PP2. In conclusion, lipopolysaccharide disrupts the tight junction of a bile duct epithelial monolayer by a c-Src-, TLR4-, LBP-, and myosin light chain kinase-dependent mechanism.
Objectives Wilms tumor (WT) is the most common renal cancer in children. Approximately 5% of children with WT present with disease in both kidneys. The treatment challenge is to achieve a high cure rate while maintaining long-term renal function. We retrospectively reviewed our institutional experience with nephron-sparing surgery (NSS) in patients with synchronous bilateral Wilms tumor (BWT) operated on between 2001-2014. Methods Imaging studies, surgical approach, adjuvant therapy and pathology reports were reviewed. Outcomes evaluated included surgical complications, tumor recurrence, patient survival and renal function, as assessed by estimated glomerular filtration rate (eGFR). Results Forty-two patients with BWT were identified. Thirty-nine (92.9%) patients underwent bilateral NSS; only three patients (7.1%) underwent unilateral nephrectomy with contralateral NSS. Post-operative complications included prolonged urine leak (10), infection (6), intussusception (2) and transient renal insufficiency (1). Three patients required early (within four months) repeat NSS for residual tumor. Long-term, seven (16.7%) patients had local tumor recurrence (managed with repeat NSS in 6 and completion nephrectomy in 1) and three had an episode of intestinal obstruction requiring surgical intervention. Overall survival was 85.7% (mean follow-up, 4.1 years). Of the 6 patients who died, 5 had diffuse anaplastic histology. All patients had an eGFR>60mL/min/1.73m2 at last follow-up; no patient developed end-stage renal disease. Conclusions In patients with synchronous, bilateral Wilms tumor, bilateral nephron-sparing surgery is safe and almost always feasible, there by preserving maximal renal parenchyma. With this approach, survival was excellent, as was maintenance of renal function.
Purpose Partial nephrectomy is being considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. We evaluated the prevalence of hypertension and impaired renal function in long-term survivors of non-syndromic UWT treated without nephrotoxic chemotherapy or ionizing radiation. Patients and Methods Eligibility included: age ≤15 years at diagnosis of non-syndromic UWT, treatment prior to 2002 and maintenance of remission following unilateral nephrectomy without abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients on anti-hypertensive medication or with blood pressure >140/90mmHg were defined as hypertensive. Results Seventy-five patients with median age at diagnosis of 3.2 (range: 0.2-12.1) years met eligibility criteria. The median length of follow-up was 19.6 (range: 10.0-32.8) years. All but one patient had stage 1/2 disease. Sixty-eight (90.7%) patients had favorable histology WT; seven had anaplastic histology. Sixteen (21.3%) patients had an eGFR <90 ml/min/1.73m2, two of whom also had proteinuria (12.5%). No patient had an eGFR<60 ml/min/1.73m2. Five (6.7%) patients had hypertension, three of whom were taking anti-hypertensive medications. No patient has developed end-stage renal disease. Conclusions Patients with UWT treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation are at low risk for significant long-term renal dysfunction. For this patient population, routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and so might be at increased risk for adverse cardiovascular sequelae.
ABSTRACT. We evaluated the response of individuals with metabolic syndrome to lifestyle modification intervention and examined the influence of the 48867A>C (Asp358Ala) IL6R (rs2228145) polymorphism on this response. Participants were randomly divided into two groups: NI, nutritional intervention; NIE, nutritional intervention and exercise practice. Intervention lasted three months and participants completed a comprehensive evaluation and had blood collected for biochemical measurements. Eighty-two sedentary individuals with at least three criteria for metabolic syndrome were included. Comparing metabolic syndrome parameters before and after intervention, a reduction of waist circumference was observed, although significant only for AA and AC genotypes. Also, a decrease in triglyceride levels was observed (significant for AA genotype individuals; for the AC genotype, only in the NIE group). Significant reduction of fasting glucose level was observed in all AA genotype individuals; for the AC genotype, only in the NI group. Systolic blood pressure showed significant reduction in AA and AC genotype individuals. After three months of lifestyle modification intervention, improvement in some of the metabolic syndrome parameters was observed, some associated with the IL6R genotype. At enrollment, participants with genotypes AA and AC showed more severe conditions regarding metabolic syndrome inclusion criteria, supporting previous reports that the A allele is a genetic risk factor. These individuals, however, had a better response to intervention compared to individuals with the CC genotype, suggesting that nutritional control and exercise practice could prevent risks associated with metabolic syndrome more efficiently in individuals bearing the A allele.
Objectives The purpose of this study was to perform a comprehensive assessment of long-term renal function in patients treated at our institution for synchronous bilateral Wilms tumor (BWT) and to determine the optimal method for estimating glomerular filtration rate (eGFR). Methods Surgical approach, adjuvant therapy, and pathology reports were reviewed for patients with at least six months follow-up from definitive surgery. eGFRs, as assessed by the Schwartz and Chronic Kidney Disease in Children (CKiD) formulas, were compared to measured GFR (mGFR) determined by 99mTc-DTPA scanning. Urine studies, including microalbumin, β-microglobulin, and FENa were also reviewed. Results Forty-two patients were identified. Of 36 living patients, 28 (77.8%) had greater than 6 months follow-up, with a median overall follow-up of 5.2 years (range: 1.4-13.4). The median mGFR was 97mL/min/1.73m2, while the median eGFRSchwartz and eGFRCKiD were 103.3mL/min/1.73m2 and 79.7mL/min/1.73m2, respectively, (p=0.13 and p=0.75, compared to mGFR). Eleven (39.3%) patients had at least one abnormal urine study (microalbumin >30μg/g creatinine, n=3; β-2 microglobulin >133μg/g creatinine, n=9; FENa >1%, n=4). Conclusions In our series, few patients had an abnormally low GFR. Neither method for estimating GFR gave a significantly different result from measured GFR, suggesting that the Schwartz equation is adequate, although specific urine tests may be more sensitive for detecting subtle renal dysfunction.
IntroductionVesicoureteral reflux is a common disorder in children but can result in kidney scarring following acute pyelonephritis. The gold standard diagnostic to detect renal scars in children is 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. DMSA has a number of limitations including radiation exposure, need for sedation, and radiotracer supply shortages. Contrast-enhanced ultrasound (CEUS) is a technique whereby biocompatible microspheres of inert gas are administered i.v. that reflect ultrasonography sound waves and do not involve radiation. Because the contrast agent is rapidly cleared, contrast images must be obtained within minutes of administration. CEUS has been used in a variety of organ systems, but its use in pediatric kidney diseases is limited.MethodsIn this study, we performed CEUS in 7 children with documented renal scars by radiographic imaging consistent with reflux nephropathy.ResultsIn all subjects, CEUS detected all previously known radiologic abnormalities as well as detecting new areas of hypoenhancing renal parenchyma. None of the patients experienced any serious adverse events.DiscussionThis study represents the first report of using CEUS to characterize renal scars in children with reflux nephropathy. We conclude that CEUS is a highly sensitive, rapid, and cost-effective diagnostic imaging modality for detecting and monitoring renal scars in children with vesicoureteral reflux.
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