Iyad Khamaysi

Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury

Background Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFβ-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models. Methods Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies. Results In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48–72 h. Noteworthy, these effects were absent in WT animals. Conclusions In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.

Late Complication of Laparoscopic Sleeve Gastrectomy

Laparoscopic sleeve gastrectomy (LSG) is gaining popularity for the treatment of morbid obesity. It is a simple, low-cost procedure resulting in significant weight loss within a short period of time. LSG is a safe procedure with a low complication rate. The complications encountered nevertheless can result in morbidity and even mortality. The most significant complications are staple-line bleeding, stricture, and staple-line leak. The purpose of this paper is to present a patient who suffered from a staple-line leak presenting 16 months after LSG. Review of the current literature regarding this complication as well as outline of a strategy for the management of post-LSG gastric leaks is suggested.

Phosphodiesterase 5 inhibition protects against increased intra-abdominal pressure-induced renal dysfunction in experimental congestive heart failure.

Congestive heart failure (CHF) is associated with impaired renal function. Previously, we have demonstrated that rats with decompensated CHF exhibited exaggerated sensitivity to the adverse renal effects of increased increased intra‐abdominal pressure (IAP) as compared with normal controls. This study tested whether phosphodiesterase 5 (PDE5) inhibition protects against the adverse renal effects of increased IAP in rats with CHF.

Pneumoperitoneum Aggravates Renal Function in Cases of Decompensated But Not Compensated Experimental Congestive Heart Failure: Role of Nitric Oxide

PURPOSE Congestive heart failure is associated with impaired renal function. Previously we noted that increased intra-abdominal pressure (pneumoperitoneum) in normal rats induced renal dysfunction. In this study we investigated the renal effects of pneumoperitoneum in rats with compensated (urinary Na(+) excretion greater than 1,200 μEq per 24 hours) and decompensated (urinary Na(+) excretion less than 200 μEq per 24 hours) congestive heart failure, and the possible involvement of nitric oxide in these effects. MATERIALS AND METHODS After a baseline period rats with congestive heart failure induced by aorto-caval fistula and sham operated controls underwent consecutive intra-abdominal pressures of 7, 10 or 14 mm Hg for 45 minutes each. Urinary flow, urinary Na(+) excretion, glomerular filtration rate, renal plasma flow and urinary nitric oxide metabolites were determined. RESULTS There were no changes in urinary flow, urinary Na(+) excretion, glomerular filtration rate or renal plasma flow during 7 mm Hg insufflation in controls. However, significant decreases in these parameters were observed during 10 and 14 mm Hg in correlation with intra-abdominal pressure. Baseline renal function and hemodynamics were lower in rats with congestive heart failure in correlation with disease severity. Rats with decompensated congestive heart failure that underwent 10 and 14 mm Hg showed aggravated decreases in urinary flow, urinary Na(+) excretion, glomerular filtration rate and renal plasma flow. In contrast, no adverse renal effects were observed in rats with compensated congestive heart failure under identical intra-abdominal pressure conditions. Despite unaltered baseline urinary nitric oxide metabolites in the 2 congestive heart failure subgroups, the decompensated group showed decreased urinary nitric oxide metabolites after 14 mm Hg. Finally, rats with compensated congestive heart failure pretreated with the nitric oxide synthase inhibitor L-NAME showed worse renal function in response to pneumoperitoneum. CONCLUSIONS Decompensated congestive heart failure renders rats susceptible to the adverse renal effects of pneumoperitoneum, a phenomenon that may involve alterations in the renal nitric oxide system.

Accuracy and Quality Assessment of EUS-FNA: A Single-Center Large Cohort of Biopsies

Introduction. Thorough quality control (QC) study with systemic monitoring and evaluation is crucial to optimizing the effectiveness of EUS-FNA. Methods. Retrospective analysis was composed of investigating consecutive patient files that underwent EUS-FNA. QC specifically focused on diagnostic accuracy, impacts on preexisting diagnoses, and case management. Results. 268 patient files were evaluated. EUS-FNA cytology helped establish accurate diagnoses in 92.54% (248/268) of patients. Sensitivity, specificity, PPV, NPV, and accuracy were 83%, 100%, 100%, 91.6%, and 94%, respectively. The most common biopsy site was the pancreas (68%). The most accurate location for EUS-FNA was the esophagus, 13/13 (100%), followed by the pancreas (89.6%). EUS-FNA was least informative for abdominal lymph nodes (70.5%). After FNA and followup, eight false negatives for tumors were found (3%), while 7.5% of samples still lacked a definitive diagnosis. Discussion. QC suggests that the diagnostic accuracy of EUS-FNA might be improved further by (1) taking more FNA passes from suspected lesions, (2) optimizing needle selection (3) having an experienced echo-endoscopist available during the learning curve, and (4) having a cytologist present during the procedure. QC also identified remediable reporting errors. In conclusion, QC study is valuable in identifying weaknesses and thereby augmenting the effectiveness of EUS-FNA.

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

Acute pancreatitis (AP) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specific or effective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains of HS sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Heparanase, therefore, emerges as a potential new target in AP, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove beneficial also in AP.

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI. Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction, attesting heparanase inhibition as a promising therapeutic approach for AKI.

Differentiation of Pancreatic Cyst Types by Analysis of Rheological Behavior of Pancreatic Cyst Fluid

Differentiation between mucinous and non-mucinous pancreatic cysts is exceedingly important and challenging, particularly as the former bears malignant transformation potential. Pancreatic cyst fluid (PCF)-based diagnostics, including analyses of biochemical markers, as well as cytology, has shown inadequate accuracy. Herein, a preliminary single-center study of 22 PCF samples, collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), assessed the rheological behavior of PCF and its correlation with lesion type. The dependence of PCF shear viscosity on shear rate was found to follow a power law and could be fitted using Ostwald–de Waele model. Three types of flow curves were identified, where two types correlated with non-mucinous cysts, differing by their power law exponent, and the third type corresponding to mucinous cysts. Viscosity measured at a high shear rate was shown to serve as an accurate and independent marker distinguishing between mucinous and non-mucinous cysts, with an optimal cutoff value of ηc = 1.3 cP The accuracy of this novel technique proved superior to string-sign, cytology, carcinoembryonic antigen, and amylase assessments. Moreover, the combined predictive value of ηc and patient age provided for sensitivity and specificity of 100% and 95.5%, respectively. This simple and rapid diagnostic tool can be immediately implemented after EUS-FNA sampling.

Self-expandable metallic stents for the palliation of malignant dysphagia: a single center experience

Introduction: Self-expandable metallic stents (SEMS) for the palliation of unresectable esophageal cancer (EC) is now standard of care. We evaluated the technical success, clinical outcomes, and safety of endoscopic SEMS placement in patients with unresectable EC. Methods: Retrospective cohort analysis of endoscopy data on all patients with unresectable EC referred for stent placement. Dysphagia scores, pre and post SEMS placement, were calculated in order to define clinical success of SEMS treatment. Results: A total of 42 patients (28 male, mean age = 73.1 years) underwent endoscopic SEMS placement: 38 (90.5%) with primary esophageal tumor and 4 (9.5%) with an extra-esophageal mass. Tumors were located in the distal n=33 (78.5%), mid n=7 (16.7%), and proximal n=2 (4.8%) esophagus. Technical success of stent placement was 41/42 (97.6%). One technical failure required a second stent placement. Clinical success was achieved in all patients (100%) with significant improvement in dysphagia score. The mean pre-SEMS dysphagia score was 2.88 and the post-SEMS dysphagia score was 1.04 (p<0.00001). A total of 13 (30.9%) patients required re-stenting within a mean of 32 weeks due to tumor ingrowth/overgrowth (n=8), stent migration (n=4), or stent degradation (n=1). No immediate adverse events (AE) occurred. Early AE (within 1 week of stent placement) occurred in 6 (14.3%) patients: vomiting (n=3), stent migration (n=2) and chest pain (n=1). Late AE occurred in n=11 patients: death (n=6) unrelated to stent placement, globus sensation /recurrent dysphagia / food impaction (n=5), and stent migration (n=1). Median survival was 17 weeks. Conclusions: Endoscopic placement of SEMS for palliation of dysphagia due to unresectable EC is technically feasible, effective, and safe.