Device-assisted Enteroscopy for Obscure Gastrointestinal Bleeding in the Setting of Thienopyridine Antiplatelet Therapy.

BACKGROUND: Current guidelines recommend suspending thienopyridine therapy 5 to 7 days before therapeutic endoscopy to reduce the risk of bleeding-related complication. However, interruption of antiplatelet therapy may increase the risk of a cardiovascular event. The aim of this study was to evaluate the safety and diagnostic yield of device-assisted enteroscopy (DAE) with endoscopic therapy in patients receiving thienopyridine antiplatelet therapy. MATERIALS AND METHODS: A retrospective chart review was performed for patients treated in the LSU Health Sciences Gastroenterology Clinics between the dates of October 4, 2007 and February 15, 2015. A total of 774 enteroscopy procedures were reviewed to identify patients on active thienopyridine therapy at the time of DAE. RESULTS: During the study period, a total of 68 patients underwent DAE while on thienopyridine therapy. Confirmed or suspected small bowel bleeding was the most common procedural indication. A total of 143 endoscopic interventions were performed, primarily argon plasma coagulation for ablation of intestinal angioectasias. There were no significant bleeding-related complications associated with these procedures. In addition, the diagnostic yield for these procedures was high (77%) with a significant percentage of patients in the thienopyridine group found to have an active bleeding source at the time of DAE. CONCLUSIONS: The performance of DAE procedures with endoscopic intervention such as argon plasma coagulation may be safe in patients on thienopyridine therapy. Continuing thienopyridines may also increase the diagnostic yield of these procedures by promoting active bleeding from the culprit source.

Clinical Case Of the Month: A 35 Year Old Woman with Abdominal Pain.

A 35 year old woman with past medical history of hypertension presented to the emergency department with chief complaint of severe abdominal pain for one week. The abdominal pain was located in the epigastrium and described as "cramping" and "intermittent". The pain intensity was quantified initially as 6 out of 10 on the pain scale. As the week progressed the pain became constant and radiated to the back. The intensity of the abdominal pain increased to 10 out of 10. The patient reported some relief from her pain while lying in the prone position. Initially the pain was associated with loose stools for several days. The loose stools resolved spontaneously and then the patient began to experience nausea and vomiting. Her medications included lisinopril-hydrochlorothiazide which she had been taking for the past five months. She had no history of alcohol, tobacco or illicit drug use.

Angiotensin II-induced activation of c-Ret signaling is critical in ureteric bud branching morphogenesis.

The renin-angiotensin system (RAS) plays a critical role in ureteric bud (UB) and kidney morphogenesis. Mutations in the genes encoding components of the RAS cause a spectrum of congenital abnormalities of the kidney and urinary tract (CAKUT). However, the mechanisms by which aberrations in the RAS result in CAKUT are poorly understood. Given that c-Ret receptor tyrosine kinase (RTK) is a major inducer of UB branching, the present study tested the hypothesis that angiotensin (Ang) II-induced activation of c-Ret plays a critical role in UB branching morphogenesis. E12.5 mice metanephroi were grown for 24h in the presence or absence of Ang II, Ang II AT(1) receptor (AT(1)R) antagonist candesartan, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or ERK1/2 inhibitor PD98059. Ang II increased the number of UB tips (61+/-2.4 vs. 45+/-4.3, p<0.05) compared with control. Quantitative RT-PCR analysis demonstrated that Ang II increased c-Ret mRNA levels in the kidney (1.35+/-0.05 vs. 1.0+/-0, p<0.01) and in the UB cells (1.28+/-0.04 vs. 1.0+/-0, p<0.01) compared to control. This was accompanied by increased Tyr(1062)Ret phosphorylation by Ang II (5.5+/-0.9 vs. 1.8+/-0.4 relative units, p<0.05). In addition, treatment of UB cells with Ang II (10(-5)M) increased phosphorylation of Akt compared to control (213+/-16 vs. 100+/-20%, p<0.05). In contrast, treatment of metanephroi or UB cells with candesartan decreased c-Ret mRNA levels (0.72+/-0.06 vs. 1.0+/-0, p<0.01; 0.68+/-0.07 vs. 1.0+/-0, p<0.05, respectively) compared with control. Ang II-induced UB branching was abrogated by LY294002 (24+/-2.6 vs. 37+/-3.0, p<0.05) or PD98059 (33+/-2.0 vs. 48+/-2.2, p<0.01). These data demonstrate that Ang II-induced UB branching depends on activation of Akt and ERK1/2. We conclude that cross-talk between the RAS and c-Ret signaling plays an important role in the development of the renal collecting system.

Angiotensin II AT2 receptor regulates ureteric bud morphogenesis.

ANG II AT2 receptor (AT2R)-deficient mice exhibit abnormal ureteric bud (UB) budding, increased incidence of double ureters, and vesicoureteral reflux. However, the role of the AT2R during UB morphogenesis and the mechanisms by which aberrant AT2R signaling disrupts renal collecting system development have not been fully defined. In this study, we mapped the expression of the AT2R during mouse metanephric development, examined the impact of disrupted AT2R signaling on UB branching, cell proliferation, and survival, and investigated the cross talk of the AT2R with the glial-derived neurotrophic factor (GDNF)/c-Ret/Wnt11 signaling pathway. Embryonic mouse kidneys express AT2R in the branching UB and the mesenchyme. Treatment of embryonic day 12.5 (E12.5) metanephroi with the AT2R antagonist PD123319 or genetic inactivation of the AT2R in mice inhibits UB branching, decreasing the number of UB tips compared with control (34 +/- 1.0 vs. 43 +/- 0.6, P < 0.01; 36 +/- 1.8 vs. 48 +/- 1.3, P < 0.01, respectively). In contrast, treatment of metanephroi with the AT2R agonist CGP42112 increases the number of UB tips compared with control (48 +/- 1.8 vs. 39 +/- 12.3, P < 0.05). Using real-time quantitative RT-PCR and whole mount in situ hybridization, we demonstrate that PD123319 downregulates the expression of GDNF, c-Ret, Wnt11, and Spry1 mRNA levels in E12.5 metanephroi grown ex vivo. AT(2)R blockade or genetic inactivation of AT2R stimulates apoptosis and inhibits proliferation of the UB cells in vivo. We conclude that AT2R performs essential functions during UB branching morphogenesis via control of the GDNF/c-Ret/Wnt11 signaling pathway, UB cell proliferation, and survival.

Downregulation of Spry-1, an inhibitor of GDNF/Ret, causes angiotensin II-induced ureteric bud branching.

Mutations of genes in the renin-angiotensin system are associated with congenital abnormalities of the kidney and urinary tract. The major signaling pathway for branching morphogenesis during kidney development is the c-Ret receptor tyrosine kinase whose ligand is GDNF and whose downstream target is Wnt11. We determined whether angiotensin II, an inducer of ureteric bud branching in vitro, influences the GDNF/c-Ret/Wnt11 pathway. Mouse metanephroi were grown in the presence or absence of angiotensin II or an angiotensin type 1 receptor (AT1R) antagonist and gene expression was measured by whole mount in situ hybridization. Angiotensin II induced the expression of c-Ret and Wnt11 in ureteric bud tip cells. GDNF, a Wnt11-regulated gene expressed in the mesenchyme, was also upregulated by angiotensin II but this downregulated Spry1, an endogenous inhibitor of Ret tyrosine kinase activity in an AT1R-dependent manner. Angiotensin II also decreased Spry1 mRNA levels in cultured ureteric bud cells. Exogenous angiotensin II preferentially stimulated ureteric bud tip cell proliferation in vivo while AT1R blockade increased cell apoptosis. Our findings suggest AT1R-mediated inhibition of the Spry1 gene increases c-Ret tyrosine kinase activity leading to upregulation of its downstream target Wnt11. Enhanced Wnt11 expression induces GDNF in adjacent mesenchyme causing focal bursts of ureteric bud tip cell proliferation, decreased tip cell apoptosis and branching.