Use of High-Dose Phenylephrine in the Treatment of Ischemic Priapism: Five-Year Experience at a Single Institution.

INTRODUCTION: Ischemic priapism is an uncommon urologic emergency characterized by a compartment syndrome-like ischemic insult to the corpora cavernosa of the penis. The goal of treatment in ischemic priapism is rapid detumescence to prevent long-term erectile dysfunction. Non-surgical treatment options include aspiration, irrigation, and intracavernous injections of sympathomimetic agents. At our institution, phenylephrine is used in the treatment of ischemic priapism at concentrations and doses that are higher than those recommended in established guidelines. AIM: To characterize our experience with high-concentration intracavernous phenylephrine in the treatment of ischemic priapism at an urban tertiary care center. METHODS: A retrospective chart review identified 58 unique patients presenting to the emergency department on 136 occasions and receiving the diagnosis of ischemic priapism by urologic physicians. Patients' charts were reviewed to record the dosing of phenylephrine and the outcomes and circumstances of the presentation. MAIN OUTCOME MEASURES: Success rates of different treatment strategies for different circumstances of presentation. RESULTS: Successful detumescence was achieved with non-surgical management in 86% of unique patients and the overall resolution rate when including repeat visits was 94%. All patients presenting within less than 36 hours of priapism were successfully treated with non-surgical management. There were no reported complications or associated symptoms related to the use of intracavernous phenylephrine during the 5-year period. CONCLUSION: The use of high concentration and dosing of intracavernous phenylephrine demonstrates a high success rate in the treatment of ischemic priapism. Future prospective studies are needed to further characterize appropriate phenylephrine dosing for its efficacy and safety.

Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver.

Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild-type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b(-/-) mice. Subsequent studies in mice with Adora2b deletion in different tissues--including vascular endothelia, myeloid cells, and hepatocytes--revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-κB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury.

CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy.

Nucleotide phosphohydrolysis by the ecto-5'-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b(-/-) mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

Endothelial nitric oxide synthase mediates the first and inducible nitric oxide synthase mediates the second window of desflurane-induced preconditioning.

OBJECTIVES: Nitric oxide synthases (NOSs) mediate the first window of anesthetic-induced preconditioning (APC). The authors tested the hypothesis that endothelial NOS (eNOS) mediates the first window and inducible NOS (iNOS) mediates the second window of APC. DESIGN: Randomized, prospective, blinded laboratory investigation. SETTING: Experimental laboratory. PARTICIPANTS: Mice. INTERVENTIONS: Mice were subjected to a 45-minute coronary artery occlusion (CAO) and a 180-minute reperfusion. C57BL/6 mice received desflurane, 1.0 minimum alveolar concentration, for 30 minutes or 12, 24, 48, or 96 hours before CAO. In eNOS(-/-) and iNOS(-/-) mice, desflurane was given 30 minutes and 48 hours before CAO. In the control groups, no desflurane was administered. Myocardial infarct size (IS) was determined after staining with Evans blue and triphenyltetrazolium chloride. MEASUREMENTS AND MAIN RESULTS: The second window of APC was detectable at 48 hours but not at 12, 24, and 96 hours after preconditioning. In the control groups, IS was not different among the wild-type (50 ± 10%), eNOS(-/-) (52 ± 14%), and iNOS(-/-) (46 ± 10%) mice. The IS decreased significantly (p < 0.05) when desflurane was administered 30 minutes (10 ± 6%) or 48 hours (16 ± 7%) before CAO in wild-type mice, 48 hours (21 ± 13%) before CAO in eNOS(-/-) mice, and 30 minutes (13 ± 6%) before CAO in iNOS(-/-) mice. Desflurane given 30 minutes before CAO in eNOS(-/-) mice (60 ± 10%) and 48 hours before CAO in iNOS(-/-) mice (48 ± 21%) did not decrease the IS significantly compared with controls. CONCLUSIONS: Endothelial NOS and iNOS work independently to mediate the first and second windows of APC, respectively. Endothelial NOS is not necessary to trigger the second window of APC.

The Current State of Adjuvant Therapy Following Surgery for High-risk Renal Cell Carcinoma.

Cancer recurs in up to 40% of patients following surgery for high-risk, locoregional renal cell carcinoma (RCC). To date, little progress has been made in identifying systemic adjuvant treatment options to reduce the mortality risk after surgery for high-risk RCC. Several randomized trials exploring the efficacy of adjuvant targeted therapies in the postoperative setting have recently reported results. We examine these trials to assess the contemporary role of targeted therapy following surgery in high-risk RCC and briefly consider trials that are currently accruing with a focus on immunotherapy agents in the adjuvant setting. PATIENT SUMMARY: Kidney cancer often recurs despite initial surgery in patients with high-risk tumors. So far, adding systemic treatments such as targeted therapies after surgery has not resulted in improved survival outcomes. Future studies that include immunotherapy after surgery to reduce the risk of recurrence in patients with high-risk disease are eagerly anticipated.

From novelty to the every-day: the evolution of ureteroscopy.

Ureteroscopy revolutionized the surgical approach to the upper urinary tract, and is well recognized as a cornerstone of modern urology. Although now commonplace, ureteroscopic equipment and techniques were truly revolutionary. A review of the innovations and innovators that developed ureteroscopic surgery sets the stage for a more thorough understanding of what can be done ureteroscopically, and may additionally better inform what limitations remain. Given that future advancements in urologic therapy will be dependent upon a similar pursuit of paradigm shifting improvements in disease management, an overview of the development of modern ureteroscopy may inspire such change.

Caprini venous thromboembolism risk assessment permits selection for postdischarge prophylactic anticoagulation in patients with resectable lung cancer.

OBJECTIVE: Postoperative venous thromboembolism (VTE) creates an 8-fold increase in mortality after lung resection. About one third of postoperative VTEs occur after discharge. The Caprini risk assessment model has been used by other specialties to calculate the risk of a VTE. Patients deemed high risk by the model are candidates for prophylactic anticoagulation after discharge, reducing the VTE risk by 60%. Our primary aims were to determine the frequency of VTE events and evaluate whether the Caprini model could risk-stratify patients. METHODS: Patients undergoing lung cancer resections during 2005 to 2013 were evaluated. Exclusion criteria were preoperative filter and therapeutic anticoagulation. A total of 232 patients were reviewed and Caprini scores calculated. Subjects were risk stratified into groups of low risk (0-4), moderate risk (5-8), and high risk (≥ 9). Occurrence of VTE events (deep vein thrombosis; pulmonary embolism) were identified by imaging. RESULTS: The 60-day VTE incidence was 5.2% (12 of 232); 33.3% occurred postdischarge (n = 4). Half (6 of 12) were pulmonary emboli, 1 of which caused a death, in an inpatient with a score of 16. The VTE incidence increased with Caprini score. Scores in the low, moderate, and high risk groups were associated with a VTE incidence of 0%, 1.7%, and 10.3%, respectively. With a high risk score cutoff of 9, the sensitivity, specificity, and accuracy are 83.3%, 60.5%, and 61.6%, respectively. CONCLUSIONS: One third of VTE events occurred after discharge. Postoperative VTE incidence was correlated with increasing Caprini scores. Patients in the high risk group had an incidence of 10.3%. Elevated scores may warrant extended chemoprophylaxis for patients after discharge.

Protective role for netrin-1 during diabetic nephropathy.

Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney-protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at the age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary, and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1(+/-) mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease.

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.

A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) - a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1-/- mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications.

Use of a hanging-weight system for isolated renal artery occlusion.

In hospitalized patients, over 50% of cases of acute kidney injury (AKI) are caused by renal ischemia. A recent study of hospitalized patients revealed that only a mild increase in serum creatinine levels (0.3 to 0.4 mg/dl) is associated with a 70% greater risk of death than in persons without any increase. Along these lines, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a renal failure rates of up to 30%. Similarly, AKI after cardiac surgery occurs in over 10% of patients under normal circumstances and is associated with dramatic increases in mortality. AKI are also common complications after liver transplantation. At least 8-17% of patients end up requiring renal replacement therapy. Moreover, delayed graft function due to tubule cell injury during kidney transplantation is frequently related to ischemia-associated AKI. Moreover, AKI occurs in approximately 20% of patients suffering from sepsis. The occurrence of AKI is associated with dramatic increases of morbidity and mortality. Therapeutic approaches are very limited and the majority of interventional trials in AKI have failed in humans. Therefore, additional therapeutic modalities to prevent renal injury from ischemia are urgently needed. To elucidate mechanisms of renal injury due to ischemia and possible therapeutic strategies murine models are intensively required. Mouse models provide the possibility of utilizing different genetic models including gene-targeted mice and tissue specific gene-targeted mice (cre-flox system). However, murine renal ischemia is technically challenging and experimental details significantly influence results. We performed a systematic evaluation of a novel model for isolated renal artery occlusion in mice, which specifically avoids the use of clamping or suturing the renal pedicle. This model requires a nephrectomy of the right kidney since ischemia can be only performed in one kidney due to the experimental setting. In fact, by using a hanging-weight system, the renal artery is only instrumented once throughout the surgical procedure. In addition, no venous or urethral obstruction occurs with this technique. We could demonstrate time-dose-dependent and highly reproducible renal injury with ischemia by measuring serum creatinine. Moreover, when comparing this new model with conventional clamping of the whole pedicle, renal protection by ischemic preconditioning is more profound and more reliable. Therefore his new technique might be useful for other researchers who are working in the field of acute kidney injury.

Partial netrin-1 deficiency aggravates acute kidney injury.

The netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes beyond their functions in the brain, incluing the ochrestration of inflammatory events. Particularly netrin-1 has been implicated in dampening hypoxia-induced inflammation. Here, we hypothesized an anti-inflammatory role of endogenous netrin-1 in acute kidney injury (AKI). As homozygous deletion of netrin-1 is lethal, we studied mice with partial netrin-1 deletion (Ntn-1(+/-) mice) as a genetic model. In fact, Ntn-1(+/-) mice showed attenuated Ntn-1 levels at baseline and following ischemic AKI. Functional studies of AKI induced by 30 min of renal ischemia and reperfusion revealed enhanced kidney dysfunction in Ntn-1(+/-) mice as assessed by measurements of glomerular filtration, urine flow rate, urine electrolytes, serum creatinine and creatinine clearance. Consistent with these findings, histological studies indicated a more severe degree kidney injury. Similarly, elevations of renal and systemic inflammatory markers were enhanced in mice with partial netrin-1 deficiency. Finally, treatment of Ntn-1(+/-) mice with exogenous netrin-1 restored a normal phenotype during AKI. Taking together, these studies implicate endogenous netrin-1 in attenuating renal inflammation during AKI.