Bilateral Renal Artery Occlusion Research Articles

Renal artery Chronic Total occlusion Angioplasty in a Patient with Bilateral Renal Artery Occlusion and Hypertensive Emergency

Atherosclerotic bilateral renal artery chronic total occlusions (CTOs) as a cause of hypertensive emergency is rare, and other causes such as vasculitis should be ruled out before definitive diagnosis. Successful CTO intervention in such a scenario has only been sparsely reported. A 53-year-old-male smoker with severe resistant hypertension required multiple emergency admissions for flash pulmonary edema and aggressive blood pressure control. He was found to have deranged renal parameters with a serum creatinine of 2.4 mg/dL and an estimated glomerular filtration rate of 25 mL/min. His complete blood picture, metabolic panel, and inflammatory markers were within normal limits. Renal Doppler ultrasonography revealed bilateral severe renal artery stenosis and a contracted left kidney. Renal angiography showed total occlusion of both renal arteries with well-collateralized right kidney. He underwent right renal artery CTO angioplasty with stenting. Left renal artery occlusion was managed conservatively because of the contracted kidney size and poor function. He is doing well for the last 30 months with good hypertension control, well-perfusing and preserved right kidney volume, stable renal function, and significantly fewer medications from baseline. Renal artery stenting is lifesaving in patients with bilateral renal artery occlusion and should be expeditiously performed, particularly in patients with and hypertensive emergency or recurrent unexplained heart failure. Kidney size, function, presence of collateralization, and viable renal parenchymal tissue guide in planning the intervention.

Renal salvage using stent graft placement after acute renal artery occlusion with prolonged ischemic time

PurposeTo describe a patient with acute renal artery occlusion who underwent successful revascularization procedure after experiencing a protracted ischemic period, which resulted in successful retrieval of renal function.Case reportA 58-year-old male with a history of left renal artery stenosis and stent graft placement presented with symptoms of chest pain, shortness of breath, and flank pain. The patient was admitted to the Intensive Care Unit with the diagnosis of multiorgan failure and subsequent anuria that led to the initiation of hemodialysis. Computed tomography angiography demonstrated an aortic occlusion along with bilateral proximal renal artery occlusion with reconstitution of the mid to distal renal arteries via collateralization. The patient underwent angioplasty with bilateral renal artery stent-graft placement and successful revascularization of proximal renal arteries. Post-operatively, his renal function and urine output improved, and the patient was able to be weaned off hemodialysis along with the benefit of concurrent amelioration of his renovascular hypertension.ConclusionFor select patients with renal artery occlusion, revascularization of the renal arteries may result in dialysis independence and stabilization of renovascular hypertension, despite prolonged time of ischemia.

Outcomes after treatment of complex aortic abdominal aneurysms with the fenestrated Anaconda endograft

ObjectiveTo date, information on the fenestrated Anaconda endograft is limited to case series with a small sample size. This study was performed to assess the technical and clinical outcome of this device in a large international case series. MethodsAll worldwide centers having treated more than 15 complex abdominal aortic aneurysms (AAA) or type IV thoracoabdominal aortic aneurysm patients with the fenestrated Anaconda endograft were approached. Main outcome parameters were procedural technical success, postoperative and follow-up clinical outcome for endoleaks, target vessel patency, reintervention rate, and patient survival. ResultsThree hundred thirty-five consecutive cases treated between June 2010 and May 2018 in 11 sites were included. Patients were treated for a short neck infrarenal (n = 98), juxtarenal (n = 191), suprarenal AAA (n = 27), or type IV thoracoabdominal aortic aneurysm (n = 19). Mean age was 73.6 ± 4.6 years (292 male). Endografts contained a total of 920 fenestrations, with a mean of 2.7 ± 0.8 fenestrations per case. Technical success was 88.4% (primary, 82.7%; assisted primary 5.7%). In 6.9% of cases, a procedural type IA endoleak was observed, spontaneously disappearing in 82.6% during early follow-up. The development of a type IA endoleak was associated with greater neck angulation (odds ratio [OR], 0.94; P = .01), three fenestrations (OR, 42.7; P = .01) and the presence of augmented proximal rings (OR, 0.17; P = .03). Median follow-up was 1.2 years (interquartile range, 0.4-2.6). The mean estimated glomerular filtration rate deteriorated from 67.6 ± 19.3 mL/min/1.73 m2 preoperatively to 59.3 ± 22.7 mL/min/1.73 m2 at latest follow-up (P = .00). The freedom from AAA growth were 97.9 ± 0.9% (n = 190) and 86.4 ± 3.0% (n = 68), with a freedom from AAA rupture of 99.7 ± 0.3% (n = 191) and 99.1 ± 0.7% (n = 68), at 1 and 3 years, respectively. The endoleak-free survival, excluding spontaneously resolved procedural endoleaks, at 1 and 3 years was 73.4 ± 2.6 (n = 143) and 65.6 ± 3.4% (n = 45), respectively. The target vessel patency at one and three years were 96.4 ± 0.7% (n = 493) and 92.7 ± 1.4% (n = 156), respectively. A total of 75 reinterventions were done in 64 cases (19.1%), of which 25 cases for an endoleak. The reintervention-free survival at 1 and 3 years were 83.6 ± 2.2% (n = 190) and 71.0 ± 3.7% (n = 68), respectively. No deaths during procedure, extending within 24 hours postoperatively, were observed. Within 30 days 14 patients (4.2%) died and during follow-up another 39 patients (11.6%) died. Three deaths were considered AAA related (one rupture, one endograft infection, and one bilateral renal artery occlusion). The estimated cumulative survival at 1 and 3 years were 89.8 ± 1.8% (n = 191) and 79.2 ± 3.0% (n = 68), respectively. ConclusionsThe custom-made fenestrated Anaconda endograft is a valuable option for the treatment of a complex AAA. A procedural type IA endoleak is seen relatively frequently, but spontaneously resolves in most cases.

The Italian Multi-centre Experience of Fenestrated Anacondatm Endograft for Juxta/Para-renal Aortic Aneurysms

Introduction - Aim of this study is to describe the outcomes of “AnacondaTM-Fenestrated Endograft (Vascutek, Inchinnan, UK) Italian registry” for challenging abdominal aortic aneurysms (AAA), unfit for standard endovascular aortic repair (EVAR). Methods - Between 2012 and 2017, patients with proximal neck unsuitable for standard EVAR were prospectively enrolled. Clinical (demographic, cardiovascular risk factors, co-morbidities) and morphological aortic-iliac features were collected. Intra and peri-operative data were analyzed. Early endpoints were technical success (TS defined as absence of endoleaks (EL) I-III, patency of target visceral vessels (TVV) and iliac legs and 24-hour survival). Late endpoints were survival, endoleaks, TVV patency and limb occlusion/stenosis, freedom from re-interventions and AAA-related mortality during the follow-up. Results - Seventy-eight patients (male 92%(62); mean age 74±4 years, ASA III-IV:73-27%) were submitted to Fenestrated-AnacondaTM in 25 Italian Vascular Surgery Units (73 juxta/para-renal AAA, 4 Type IV TAAA and 1 EL 1A post-EVAR). The mean AAA diameter was 58mm ± 3mm (range: 50-70mm). Configuration with 1, 2, 3 and 4 fenestrations were used in 3 (4%), 40 (51%), 25 (32%) and 10 (13%) cases, respectively for a total of 198 visceral vessels, (3.6±1TVV/patient). Sixty-six (85%) bifurcated and 12 (15%) tube endograft were implanted. The endograft was repositioned during the procedure in 42% (33/78) of cases. From the brachial access, at least 1 TVV was cannulated in 54% (27/52) of cases. TS was 90% (70/78) due to 5 type I EL, 1 type III EL (between fenestration and vessel stent) and 2 renal artery occlusions. All the target visceral vessels were cannulated and stented. The 30-day mortality was 5.1% (4/78). One patient died for a multiple organ disfunction syndrome (MOF) after renal artery ligature ad nephrectomy; one patient died for sepsis after embolization of the renal artery for artery perforation, two patients died for cardiological reasons. Two of the 5 type I EL solved spontaneously at 30-day for adaptation of the sealing ring of the device to the aortic neck. Two type III endoleak detected at the completion angiography were treated by relining of renal artery. At a median follow-up of 20 months (range:1-60) there were 3 type I EL, 2 type III EL and 3 occlusions of renal artery. The reintervention free-survival was 91% and no AAA-related mortality occurred. One patients had a bilateral renal artery occlusion so he has subjected to thrombolysis combined with angioplasty. A patient with type II EL underwent to open hypogastric ligature and another to lumbar embolization. There was an aortic rupture due to a proximal progression of AAA in a patient with two fenestrations for renal arteries; the patient was treated by suprarenal extension with chimney technique for celiac trunk and upper mesenteric artery. The survivor at 36 months was 77% (no AAA-related mortality hasn’t been reported). Conclusion - AnacondaTM-Fenestrated Endograft is an effective treatment of challenging AAA. The repositionability, the brachial access and the adaptation during the follow-up of the proximal ring are useful for complex anatomies and increase the technical success of the procedure.

Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy.

To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine-chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico-medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after acute kidney injury, designed to interdict renal tubular damage. Magn Reson Med 79:3144-3153, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice

AimsWe examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. Main methodsXOR+/+ and XOR+/− mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-α and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. Key findingsThe BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/−IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/−IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-α mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/−IR mice. The histological analysis revealed that the XOR+/−IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SignificanceBoth the disruption of XOR gene in XOR+/− mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR mice attenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target.

Endovascular Repair of Thoracoabdominal and Arch Aneurysms in Patients with Connective Tissue Disease Using Branched and Fenestrated Devices

Prophylactic open surgery is the standard practice in patients with connective tissue and thoracoabdominal aortic aneurysm (TAAA) and aortic arch disease. Branched and fenestrated devices offer a less invasive alternative but there are concerns regarding the durability of the repair and the effect of the stent graft on the fragile aortic wall. The aim of this study is to evaluate mid-term outcomes of fenestrated and/or branched endografting in patients with connective tissue disease. All patients with connective tissue disease who underwent TAAA or arch aneurysm repair using a fenestrated and/or branched endograft in a single, high-volume center between 2004 and 2015 were included. Ruptured aneurysms and acute aortic dissections were excluded from this study, but not chronic aortic dissections. In total, 427 (403 pararenal and TAAAs, and 24 arch aneurysms) endovascular interventions were performed during the study period. Of these, 17 patients (4%) (16 TAAAs, 1 arch) had connective tissue disease. All patients were classified as unfit for open repair. The mean age was 51±8years. Thirteen patients with TAAA were treated with a fenestrated, 1 with a branched, and 2 with a combined fenestrated/branch device. A double inner branch device was used to treat the arch aneurysm. The technical success rate was 100% with no incidence of early mortality, spinal cord ischemia, stroke, or further dissection. Postoperative deterioration in renal function was seen in 3 patients (18.8%) and no hemodialysis was required. The mean follow-up was 3.4years (0.3-7.4). Aneurysm sac shrinkage was seen in 35% of patients (6/17) and the sac diameter remained stable in 65% of patients (11/17). No sac or sealing zone enlargement was observed in any of the patients and there were no conversions to open repair. Reintervention was required in 1 patient at 2 years for bilateral renal artery occlusion (successful fibrinolysis). One type II endoleak (lumbar) is under surveillance and 1 type III (left renal stent) sealed spontaneously. One patient died at 2years after the procedure from nonaortic causes (endocarditis). The favorable mid-term outcomes in this series that demonstrate fenestrated and/or branched endografting should be considered in patients with connective tissue and TAAA and aortic arch disease, which are considered unfit for open surgery. All patients require close lifetime surveillance at a center specializing in aortic surgery, with sufficient experience in both open and endovascular aortic surgery, so that if endovascular treatment failure occurs it can be recognized early and further treatment offered.

Administration of Tempol Improves Renal Autoregulation in Ischemia‐reperfusion Induced Acute Kidney Injury

Renal autoregulation is critical for protecting the kidney from fluctuations in arterial pressure by regulating renal vascular resistance to maintain stable renal perfusion and glomerular filtration rate (GFR). Renal ischemia‐reperfusion (IR) induced acute kidney injury (IR‐AKI) is characterized by reduced renal blood flow and a decline in GFR. We hypothesized that increased reactive oxygen species (ROS) contribute to impairment of renal autoregulatory capability in IR‐AKI. Afferent arteriole autoregulatory behavior was assessed using the in vitro blood‐perfused juxtamedullary nephron preparation. IR‐AKI was induced by 60 minutes of bilateral renal artery occlusion followed by 24 hours of reperfusion. We found that plasma creatinine was increased in IR rats (3.86 ± 0.2 mg/dl) compared to 0.93 ± 0.07 mg/dl in sham rats (n=6–7, p<0.05). Baseline afferent arteriole diameter averaged 13.0 ± 0.4 μm (n=5) in kidneys from sham rats and these arterioles exhibited normal autoregulatory behavior. Decreasing renal perfusion pressure from 100 to 65 mmHg increased arteriole diameter from 13.0 ± 0.4 to 15.1 ± 0.8 μm, corresponding to 116 ± 5% of the baseline diameter. Subsequent stepwise increases in perfusion pressure (15 mmHg) caused pressure‐dependent afferent arteriole vasoconstriction to 66 ± 2% of baseline diameter at 170 mmHg. In contrast, pressure‐mediated afferent arteriole responses were markedly attenuated in IR‐AKI rats. Baseline diameter averaged 11.7 ± 0.6 μm and remained between 91 and 101% of baseline over the 65–170 mmHg pressure range tested, indicating a loss of autoregulatory function. In another set of IR‐AKI rats, acute administration of the ROS scavenger, tempol (10−3 M), to afferent arterioles increased baseline diameter by 10 ± 2% from 11.3 ± 0.8 to 12.2 ± 0.9 μm (n=5). Furthermore, scavenging ROS production improved autoregulatory behavior of afferent arterioles from IR‐AKI rats. During exposure to tempol, decreasing renal perfusion pressure from 100 to 65 mmHg resulted in a diameter increase to 110 ± 2 % of the control diameter while increasing perfusion pressure to 170 mmHg decreased arteriole diameter to 78 ± 1% of control (P<0.05 vs IR). In conclusion, these results suggest that renal ischemia‐reperfusion leads to impaired autoregulatory behavior of afferent arterioles. Acutely scavenging endogenous ROS with tempol improves afferent arteriole autoregulatory responsiveness, suggesting that excessive ROS production contributes to impaired renal autoregulation in IR‐AKI.Support or Funding InformationThis study is supported by a Grant‐in‐Aid (15GRNT25240015) from the American Heart Association for ZG and by grants from NIH (DK044628, HL074167, HL098135 and HL095499) for EWI.

Magnolol Reduces Renal Ischemia and Reperfusion Injury via Inhibition of Apoptosis.

Magnolol, a constituent of the bark of Magnolia officinalis, has been reported to decrease myocardial stunning and infarct size. In this study, we investigated whether magnolol can reduce renal ischemia and reperfusion (I/R) injury. Renal I/R, induced by a 60-min occlusion of bilateral renal arteries and a 24-h reperfusion, significantly increased blood urea nitrogen (BUN) and creatinine levels, and caused histological damage to the kidneys of rats. Apoptosis, as evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and caspase-3 activation, was significantly increased in the kidneys. Furthermore, serum levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were significantly elevated, while the interleukin-10 (IL-10) level was suppressed. However, intravenous pretreatment with magnolol at doses of 0.003[Formula: see text]mg/kg and 0.006[Formula: see text]mg/kg 10[Formula: see text]min before renal I/R significantly limited the increases of BUN, creatinine, the histological damage, and apoptosis in the kidneys. The increases in TNF-[Formula: see text], IL-1β, and IL-6, and the decrease in IL-10 were also significantly inhibited. Additionally, magnolol increased Bcl-2 and decreased Bax in the kidneys. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), was elevated, while phosphorylation of the pro-apoptotic mitogen-activated protein kinases, including p38 and c-Jun N-terminal kinase (JNK), was suppressed. In conclusion, magnolol reduces renal I/R injury. The underlying mechanisms for this effect might be related to the prevention of apoptosis, possibly via the inhibition of both extrinsic and intrinsic apoptotic pathways, including the reduction of TNF-[Formula: see text] production and the modulation of pro- and anti-apoptotic signaling elements.

Abstract 064: Role of Sphingosine-1-phosphate 2 Receptor in Renal Microvascular Function of Renal Ischemia-reperfusion Rats

Renal ischemia-reperfusion (IR) induced acute kidney injury (IR-AKI) is accompanied by increased renal vascular resistance and a dramatic decline in glomerular filtration rate. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, plays a critical role in IR-AKI. Our recent studies established that exogenous S1P is a potent vasoconstrictor in rat afferent arterioles. We postulated that renal IR enhanced sensitivity of afferent arterioles to S1P-induced vasoconstriction via S1P2 receptor activation. The afferent arteriole response to S1P was assessed using the in vitro blood-perfused juxtamedullary nephron preparation. IR rats were induced by 60 min bilateral renal artery occlusion followed by 24 hours reperfusion. Baseline arteriolar diameter decreased significantly in IR (11.9±0.7 vs. 14.7±0.5 μm in sham, n=7, P<0.05). Exogenous S1P evoked concentration-dependent vasoconstriction in sham rats. Increasing S1P (10 -10 -10 -5 M) decreased diameter to 99±1, 95±2, 89±2, 80±3, 58±4, and 34±2% of baseline (n=7), respectively. Renal IR shifted the S1P vasoconstrictor profile to the left. Arteriolar diameter declined to 93±1, 87±1, 76±1, 64±5, 46±5 and 35±4% of baseline (n=7, P<0.05 vs sham at 10 -10 -10 -7 M S1P). S1P2 receptor blockade with JTE-013 markedly increased baseline diameter by 51±13% in IR (P<0.05, vs. 11±3% in shams, n=3-4), suggesting that endogenous S1P exerts a greater influence on arteriolar tonic in IR than in sham. JTE-013 also markedly attenuated the enhanced vasoconstriction to S1P in IR rats. Arteriolar diameter averaged 112±2, 110±1, 114±3, 102±6, 81±6 and 61±10% of control in response to increasing S1P (P<0.05 vs. JTE-013 untreated-IR) similar to JTE-013 treated sham. In contrast, arteriolar responses to Ang II, endothelin-1 or the S1P precursor, sphingosine were unaltered in IR rats. S1P content increased from 1.3±0.4 to 1.9±0.4 pmol/mg protein (~45%) in the cortical tissue of IR rats and 2.2±0.4 to 3.4±0.2 pmol/mg protein (~55%) in the medullary tissue but reduced the plasma S1P concentration from 2.5±0.3 to 1.3±0.1 μM (~50%, P<0.05, n=3). These data establish that renal IR increases sphingolipid metabolites in rat kidneys and enhances renal microvascular S1P signaling, probably via S1P2 receptor activation.

Effect of Intervention in Mast Cell Function Before Reperfusion on Renal Ischemia-Reperfusion Injury in Rats

Background/Aims: Mast cells are sparsely distributed in the kidneys under normal conditions; however, the number of mast cells increases dramatically during renal ischemia/reperfusion injury (RI/RI). When mast cells are stimulated, numerous mediators are released, and under pathological conditions, they produce a wide range of biological effects. The aim of this study was to investigate the effect of intervention in mast cell function before reperfusion on RI/RI. Methods: Sprague-Dawley (SD) rats (n=50) were randomized into five groups: sham group, ischemia/reperfusion (I/R) group, cromolyn sodium treatment group (CS+I/R group), ketotifen treatment group (K+I/Rgroup), and compound 48/80 treatment group (C+I/R group). I/R injury was induced by bilateral renal artery and vein occlusion for 45 min followed by 24 h of reperfusion. The agents were intravenously administered 5 min before reperfusion through the tail vein. The serum levels of blood urea nitrogen(BUN), serum creatinine (Scr) and histamine and the kidney levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were assessed. The expression of intracellular adhesion molecule-1 (ICAM-1) in renal tissue was also measured. Results: I/R injury resulted in severe renal injury, as demonstrated by a large increase in injury scores; serum levels of BUN, Scr and histamine; and kidney levels of MDA, TNF-α, and IL-6; this was accompanied by reduced SOD activity and upregulated ICAM-1 expression. Treatment with cromolyn sodium or ketotifen markedly alleviated I/R-mediated kidney injury, whereas compound 48/80 further aggravated kidney injury. Conclusion: Intervention in mast cell activity prior to reperfusionhas a strong effect on RI/RI.

Effects of palmitoylethanolamide and silymarin combination treatment in an animal model of kidney ischemia and reperfusion

The aim of this study was to investigate the efficacy of PEA+silymarin as a combination treatment in a mouse model of renal I/R and to verify whether PEA+silymarin could exert more potent effects compared to the single substances even if administered at lower doses. Mice were subjected to bilateral renal artery occlusion (30min) and reperfusion (6h) and received intraperitoneally silymarin (100, 30 and 10mg/kg) or PEA (1mg/kg) or PEA (1mg/kg)+silymarin (10mg/kg) 15min before release of clamps. Specific indicators of renal dysfunction, tubular injury, myeloperoxidase activity and malondialdehyde levels were measured. The nuclear factor κB pathway and apoptotic mechanisms were also investigated. The treatment with silymarin reduced kidney dysfunction, histological damage, neutrophil infiltration and oxidative stress in a dose dependent manner. Furthermore, PEA+silymarin showed a significant potentiated effect. Therefore, NF-κB and apoptosis pathways were also significantly inhibited. Our results clearly demonstrate that PEA+silymarin treatment attenuated the degree of renal inflammation.

Effects of Palmitoylethanolamide and Silymarin Combination Therapy in an Animal Model of Kidney Ischemia and Reperfusion

Silymarin, a poliphenolic compound, has multiple pharmacological activities including antioxidant and anti‐inflammatory effects. Palmitoylethanolamide (PEA) has been extensively studied and its capability to reduce inflammatory processes and ischemia/reperfusion (I/R) damage in various organs is well established. The aim of this study was to investigate the efficacy and safety of silymarin combination with PEA in a mouse model of renal I/R. Mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (6 h) and received intraperitoneally silymarin (100, 30 and 10 mg/kg); PEA (1 mg/kg); PEA (1mg/kg)+ silymarin (10mg/kg) as a combination therapy 15 min before release of clamps. The treatment with silymarin reduced kidney dysfunction, histological damage, neutrophil infiltration and oxidative stress in a dose dependent manner. Furthermore, PEA +silymarin combination therapy showed a significant synergistic effect. Therefore, NF‐κB and apoptosis pathways were also significantly inhibited. Our results clearly demonstrate that PEA+silymarin combination therapy significantly attenuated the degree of renal inflammation.

Recombinant human erythropoietin pretreatment attenuates acute renal tubular injury against ischemia-reperfusion by restoring transient receptor potential channel-6 expression and function in collecting ducts.

Acute renal tubular injury is a serious complication in the postoperative period, which is associated with high mortality and increased ICU stay. We aimed to demonstrate the protective effect of rhEPO against acute tubular injury induced by ischemia-reperfusion and to explore the mechanism of canonical transient receptor potential channel-6. Randomized laboratory animal study. Animal research laboratory. Male Sprague-Dawley rats were randomly divided into three groups: the sham group, the control group, and the rhEPO group. Experimental acute tubular injury was established in rats by bilateral renal arterial occlusion for 30 minutes followed by reperfusion. Blood samples were obtained for cystatin-C and neutrophil gelatinase-associated lipocalin measurements by enzyme-linked immunosorbance assays. Seventy-two hours after reperfusion, urine samples were collected for osmolality and fractional excretion of sodium (%) assays on a chemistry analyzer. Kidneys were harvested at 24, 48, and 72 hours after reperfusion. Transient receptor potential channel-6, aquaporin-2, and Na,K-ATPase expression in collecting ducts were studied by immunofluorescence and Western blot. Coimmunoprecipitations were also performed to identify the possible signalplex relation between transient receptor potential channel-6 and aquaporin-2 or Na,K-ATPase channels. RhEPO pretreatment significantly inhibited serum cystatin-C (2 hr: 453 ± 64 μg/L vs 337 ± 28 μg/L, p < 0.01), serum neutrophil gelatinase-associated lipocalin (72 hr: 1,175 ± 107 ng/L vs 1,737 ± 402 ng/L, p < 0.05), and urinary fractional excretion of sodium (%) increase (0.9 ± 0.1 vs 2.2 ± 0.8, p < 0.05) and alleviated the decrease of urinary osmolality (1,293 ± 101 mosmol/kg H2O vs 767 ± 91 mosmol/kg H2O, p < 0.05) induced by ischemia-reperfusion injury. Meanwhile, recombinant human erythropoietin greatly improved the ischemia-reperfusion-induced attenuation of transient receptor potential channel-6 expression (48 hr: 42% ± 2% vs 67% ± 2% and 72 hr: 55% ± 2% vs 66% ± 2%), as well as aquaporin-2 and Na,K-ATPase expression in collecting ducts. Transient receptor potential channel-6 functionally interacted with Na,K-ATPase but not aquaporin-2. Recombinant human erythropoietin pretreatment at the dose of 5,000 IU/kg potently prevented ischemia-reperfusion-induced acute tubular injury, which might be partly attributed to the restoring the effect of transient receptor potential channel-6 expression and collecting duct function.

Abstract 522: Contribution of Reactive Oxygen Species and Rho Kinase in Sphingosine-1-phosphate Mediated Afferent Arteriolar Vasoconstriction of Ischemia-Reperfusion Rats

Our recent studies indicate that sphingosine-1-phosphate (S1P) is a potent vasoconstrictor of afferent arterioles (AA) and is enhanced in renal ischemia-reperfusion (IR) injury. We hypothesized that renal IR-induced increases in reactive oxygen species (ROS) and activation of the rho kinase pathway contribute to the enhanced S1P sensitivity of AA in IR rats. IR injury was induced by bilateral renal artery occlusion for 60 min followed by 24 hrs reperfusion. Renal function was assessed by plasma creatinine (Cr) or glomerular filtration rate (GFR). The AA response to S1P was assessed using the in vitro blood-perfused juxtamedullary nephron preparation with and without superfusion with the ROS scavenger, Tempol, or the rho kinase inhibitor, Y27623. Plasma Cr was markedly increased in IR (3.86±0.20 vs. 0.93±0.07 mg/L in sham, n=5-7, P &lt; 0.05). GFR, calculated from the half time (T 1/2 ) of sinistrin clearance, was significantly reduced in IR rats. The T 1/2 averaged 166±28 min in IR vs. 25±4 min in sham rats corresponding to GFRs of 0.20±0.02 and 1.33±0.23 ml/min (P &lt; 0.05, n=3 each), respectively. The basal AA diameter was significantly decreased in IR compared to sham rats (10.2±0.5 vs. 15.0±0.4 μm, P &lt; 0.05, n=9 each). Superfusion of Tempol (10 -4 M) did not alter the basal AA diameter in sham but increased diameter in IR by 8±1% (P &lt; 0.05, n=6 each). S1P superfusion evoked concentration-dependent AA vasoconstriction in both groups, however, Tempol significantly shifted the S1P response curve to the right in IR. Increasing concentrations of S1P (10 -10 -10 -5 M) reduced AA diameter to 98±2, 96±2, 98±2, 94±3, 81±9 and 59±5% of control in IR rats similar to the response in Tempol-treated sham rats (99±1, 99±2, 96±2, 88±5, 65±6 and 48±4%, respectively, P &gt; 0.05). In contrast, superfusion of Y27632 (10 -5 M) markedly increased the basal AA diameter in both groups. AA diameter increased by 81±17% from 10.6±1.3 to 19.2±3.3 μm in IR vs. a 53±21% increase in sham rats (P &gt; 0.05, n=3 each). Y27632 also significantly blunted S1P-mediated AA vasoconstriction similarly in both groups. These results indicate a significant contribution of ROS and rho kinase to both the elevated afferent arteriolar tone and the enhanced S1P sensitivity of AA in IR induced acute kidney injury.

Effect of dexmedetomidine on myocardial injury induced by renal ischemia-reperfusion in rats

Objective To evaluate the effect of dexmedetomidine on myocardial injury induced by renal ischemia-reperfusion (I/R) injury in rats.Methods Twenty-four male Wistar rats,weighing 280-300 g,were randomly divided into 3 groups (n =8 each):sham operation group (group S),group I/R and dexmedetomidine group (group Dex).Renal ischemia was induced by occlusion of bilateral renal arteries for 45 min followed by reperfusion in I/R and Dex groups.At 20 min before ischemia,dexmedetomidine 50 μg/kg was injected intraperitoneally in group Dex,and the rest procedures were similar to those previously described in group I/R.The rats were sacrificed at 24 h of reperfusion and myocardial specimens were obtained for determination of malondialdehyde (MDA) content and superoxide dismutase (SOD) activity.The apoptosis in cardiomyocytes was examined by flow cytometry.Apoptosis index was calculated.The expression of Bcl-2 and Bax was detected by immunohistochemistry,and Bcl-2/Bax ratio was calculated.Results Compared with group S,apoptosis index and MDA content were significantly increased in I/R and Dex groups,Bcl-2/Bax ratio was decreased in group I/R,and Bcl-2/Bax ratio was increased in group Dex.Compared with group I/R,apoptosis index and MDA content were significantly decreased,and SOD activity and Bcl-2/Bax ratio were increased in group Dex.Conclusion Dexmedetomidine can attenuate myocardial injury induced by renal I/R in rats,and the mechanism may be related to inhibited apoptosis in cardiomyocytes and reduced lipid peroxidation. Key words: Dexmedetomidine ; Myocardial reperfusion injury ; Renal

Abstract 193: Antithrombin Perfluorocarbon Nanoparticles Ameliorate Renal Injury Following Transient Warm Ischemia

Objective: Thrombin mediated microvascular thrombosis plays a crucial role in the pathogenesis of acute renal reperfusion injury following transient ischemia. We hypothesize that anti-thrombin nanoparticles will ameliorate acute renal injury by inhibiting microvascular thrombosis. Methods: Adult, male Sprague Dawley rats were randomized into two groups of 5 to receive tail vein injections of saline or nanoparticles loaded with Phe[D]-Pro-Arg-Chloromethylketone (NP-PPACK). Immediately following injection, all animals underwent operative bilateral renal artery occlusion to create 45 minutes of warm ischemia, followed by restoration of renal blood flow. Blood samples were drawn daily and animals were euthanized on day 1 or 7 for histologic analysis of kidney injury (H&amp;E, TUNEL and thrombin staining). Results: Histologic analysis of renal tissue revealed significant apoptosis, necrosis and thrombin accumulation 1 day after ischemia-reperfusion, confirming acute kidney injury. The peak creatinine (mg/dl) on day 1 was significantly lower in NP-PPACK treated animals (0.57 +/- 0.07 (SEM)) than in saline treated controls (1.40 +/- 0.20 (SEM); p-value &lt;0.01). Furthermore, animals treated with NP-PPACK continued to exhibit less renal dysfunction for 7 days after injury (Figure 1). Conclusion: Histologically confirmed intrarenal thrombosis was detected one day after ischemia-reperfusion injury. Targeted inhibition of thrombin with NP-PPACK prevented a decline in renal function following transient occlusion. Future work will focus on defining the underlying mechanisms of this effect.

Induction of Apelin by Losartan in Renal Ischemia/Reperfusion Injury in Rats - Implication of Endothelial Nitric Oxide Synthase (Enos) Phosphorylation

Apelin and its G-protein-coupled receptor APJ system and renin-angiotensin system have opposing actions on ischemia/reperfusion (I/R) injury. However, changes in renal apelin content after administration of losartan, an angiotensin-II receptor blocker (ARB), in renal I/R injury rat model has not been elucidated. Male Wistat rats were pretreated for 14 days with losartan; losartan+L-NAME, non-selective endothelial nitric oxide synthase (eNOS) inhibitor; or saline, then subjected to bilateral renal artery occlusion for 40 min followed by 2h (early) or 24h (late) of reperfusion (n=10 rats/group at each time point). I/R injury resulted in suppression of renal apelin content, and phosphorylated eNOS (P-eNOS) expression, that were more aggravated after 24h compared to 2h of reperfusion. Losartan pretreatment significantly ameliorated renal insult (as shown by decreased blood urea, serum creatinine, renal malondialdehyde, caspase-3 expression and histopathological scoring), which was concomitant with up regulation of renal tissue apelin levels and P-eNOS expression. Co-administration of L-NAME with losartan completely cancelled its renoprotective effect after 2h of reperfusion. However, some protection was reserved in late reperfusion rats. These findings suggest that the protection offered by losartan against early and late renal I/R injury is associated with induction of renal apelin content and eNOS phosphorylation.

Fenestrated endografting of juxtarenal aneurysms after open aortic surgery

Juxtarenal aneurysms after previous surgical aortic reconstruction constitute a complex clinical scenario. Open redo surgery is technically demanding and usually requires suprarenal or supraceliac clamping. Standard endovascular repair is prohibited due to the lack of a proximal landing zone. We present our experience with fenestrated endovascular aneurysm repair (F-EVAR) in the treatment of juxtarenal aneurysms after previous open surgery. A prospectively maintained database including all patients with juxtarenal abdominal aortic aneurysm after previous surgical reconstruction that underwent F-EVAR within the period from November 2003 to February 2013 under the instruction of the senior author. Evaluated outcomes included initial technical success and operative mortality and morbidity as well as late survival, target vessel patency, aneurysm diameter regression, renal function, and reintervention. A total of 35 patients (33 male; mean age, 71.5 ± 6.2 years) were treated. Median interval from the primary surgical reconstruction was 126 months (range, 48-223 months). All patients had proximal anatomies precluding standard endovascular techniques and were considered high risk for open repair due to their comorbidities and redo nature of the operation. In total, 111 vessels were targeted: 77 with small fenestrations, 33 with scallops, and 1 vessel with a downward branch. The operation was completed by totally endovascular means in 34 patients (97.1%). In one patient, a retroperitoneal approach was needed to gain retrograde access to a renal artery. Operative target vessel perfusion success rate was 100%. Operative mortality was 0% and median hospital stay 6 days (range, 2-40 days). Mean follow-up (FU) was 37.5 ± 25 months. Mean aneurysm maximal diameter decreased from 60 ± 4 mm to 47 ± 8 mm (P < .05). No type I endoleak was diagnosed, and no reintervention was required during FU. There were eight late deaths, all unrelated to the aneurysm. Estimated survival rates at 1, 2, and 4 years were 92.0% ± 5.5%, 82.8% ± 7.9% and 76.9% ± 9.3%, respectively. Three target vessel occlusions occurred during FU. One patient suffered a bilateral renal artery occlusion resulting in dialysis. In a second patient, one renal artery occluded without clinical symptoms. No other cases of renal function deterioration were observed. F-EVAR is a valid treatment option for juxtarenal aneurysms after previous surgical reconstruction. F-EVAR represents a less morbid alternative to redo open surgery, has a high technical success rate, and shows durability in mid-term FU.

Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury

Although recent preclinical and clinical studies have demonstrated that recombinant human relaxin (rhRLX) may have important therapeutic potential in acute heart failure and chronic kidney diseases, the effects of acute rhRLX administration against renal ischaemia/reperfusion (I/R) injury have never been investigated. Using a rat model of 1-hr bilateral renal artery occlusion followed by 6-hr reperfusion, we investigated the effects of rhRLX (5 μg/Kg i.v.) given both at the beginning and after 3 hrs of reperfusion. Acute rhRLX administration attenuated the functional renal injury (increase in serum urea and creatinine), glomerular dysfunction (decrease in creatinine clearance) and tubular dysfunction (increase in urinary excretion of N-acetyl-β-glucosaminidase) evoked by renal I/R. These beneficial effects were accompanied by a significant reduction in local lipid peroxidation, free radical-induced DNA damage and increase in the expression/activity of the endogenous antioxidant enzymes MnSOD and CuZnSOD superoxide dismutases (SOD). Furthermore, rhRLX administration attenuated the increase in leucocyte activation, as suggested by inhibition of myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, interleukin (IL)-1β, IL-18 and tumour necrosis factor-α production as well as increase in IL-10 production. Interestingly, the reduced oxidative stress status and neutrophil activation here reported were associated with rhRLX-induced activation of endothelial nitric oxide synthase and up-regulation of inducible nitric oxide synthase, possibly secondary to activation of Akt and the extracellular signal-regulated protein kinase (ERK) 1/2, respectively. Thus, we report herein that rhRLX protects the kidney against I/R injury by a mechanism that involves changes in nitric oxide signalling pathway.