Angiotensin II and the Renal Hemodynamic Response to an Isolated Increased Renal Venous Pressure in Rats

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min, p<0.05) and GFR (−0.77±0.18ml/min, p<0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (−22.4±4.1 vs. −9.9±2.3mmHg, p<0.05), whereas the decrease in heart rate (HR) was less (−5±6bpm vs. −23±4bpm, p<0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (−0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction.

Case Report On Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a potentially reversible renal impairment where the kidney function is stopped due to renal vasoconstriction resulting from extreme vasodilation. This case report describes a 64 year old female with Decompensated Chronic Liver Disease. Her clinical history and physical findings shows a decreased renal function secondary to chronic liver disease and was later diagnosed as HRS. HRS can be managed effectively with Terlipressin, Midodrine, Albumin. Such combination therapy at the early stage of diagnosis can prevent further complications. Keywords: HRS, CLD, Albumin, Terlipressin, Midodrine.

Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs

Angiotensin II (AngII) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma AngII levels and is associated with increased risk of acute kidney injury. We hypothesized that AngII antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared and randomized to intravenous losartan (1.5 mg kg-1 h-1, n=8) or an equal volume of intravenous Ringer's acetate (vehicle-treated, n=8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial blood pressure of <50 mmHg for 30 minutes. Plasma AngII levels, hemodynamics and oxygenation were assessed 60 minutes pre-hemorrhage, 30-minutes after the start of hemorrhage and 60 minutes post-hemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma AngII levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, AngII antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications

The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1–D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.

Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs

Hypotensive events are strongly correlated to the occurrence of perioperative acute kidney injury, but the underlying mechanisms for this are not completely elucidated. We hypothesised that anaesthesia-induced hypotension causes renal vasoconstriction and decreased oxygen delivery via angiotensin II-mediated renal vasoconstriction. Pigs were anaesthetised, surgically prepared and randomised to vehicle/losartan treatment (0.15 mg*kg−1). A deliberate reduction in arterial blood pressure was caused by infusion of propofol (30 mg*kg−1) for 10 min. Renal function and haemodynamics were recorded 60 min before and after hypotension. Propofol induced hypotension in all animals (p < 0.001). Renal blood flow (RBF) and renal oxygen delivery (RDO2) decreased significantly regardless of treatment but more so in vehicle-treated compared to losartan-treated (p = 0.001, p = 0.02, respectively). During recovery RBF and RDO2 improved to a greater extent in the losartan-treated compared to vehicle-treated (+ 28 ml*min−1, 95%CI 8–50 ml*min−1, p = 0.01 and + 3.1 ml*min−1, 95%CI 0.3–5.8 ml*min−1, p = 0.03, respectively). Sixty minutes after hypotension RBF and RDO2 remained depressed in vehicle-treated, as renal vascular resistance was still increased (p < 0.001). In losartan-treated animals RBF and RDO2 had normalised. Pre-treatment with losartan improved recovery of renal blood flow and renal oxygen delivery after propofol-induced hypotension, suggesting pronounced angiotensin II-mediated renal vasoconstriction during blood pressure reductions caused by anaesthesia.

Latest Clinical Evidence About Effect of Acetylcysteine on Preventing Contrast-Induced Nephropathy in Patients Undergoing Angiography: A Meta-Analysis

Contrast-induced nephropathy (CIN) is a serious complication of angiographic procedures. It is the third most common cause of hospital acquired acute renal injury. As there are currently no approved therapies for CIN, prevention could be the best strategy to address this issue. Acetylcysteine may indirectly play an antioxidant role by inducing the synthesis of glutathione. Acetylcysteine can also reduce renal vasoconstriction induced by contrast medium stimulation by stabilizing nitric oxide and acting directly or indirectly on renal cortex and medulla microcirculation. To evaluate the effect of acetylcysteine on the prevention of CIN in patients after angiography, we systematically searched and analyzed the clinical data of patients including the incidence of CIN and change in serum creatinine (SCr) at 48 hours after angiography from selected articles. The result showed that acetylcysteine significantly reduces the incidence of CIN (risk ratios: 0.78, 95% CI: 0.68-0.90, I 2 = 37.3%) and the level of SCr (standardized mean difference: −0.53, 95% CI: −0.93 to −0.12, I 2 = 91.5%) after angiography compared with the control group. Overall, the use of acetylcysteine in patients after angiography was associated with a significant reduction of CIN and the level of SCr.

The Role of P2X7 Purinergic Receptors in the Renal Inflammation Associated with Angiotensin II-Induced Hypertension

Purinergic receptors play a central role in the renal pathophysiology of angiotensin II-induced hypertension, since elevated ATP chronically activates P2X7 receptors in this model. The changes induced by the P2X antagonist Brilliant blue G (BBG) in glomerular hemodynamics and in tubulointerstitial inflammation resulting from angiotensin II infusion were studied. Rats received angiotensin II (435 ng kg−1 min−1, 2 weeks) alone or in combination with BBG (50 mg/kg/day intraperitoneally). BBG did not modify hypertension (214.5 ± 1.4 vs. 212.7 ± 0.5 mmHg), but restored to near normal values afferent (7.03 ± 1.00 to 2.97 ± 0.27 dyn.s.cm−5) and efferent (2.62 ± 0.03 to 1.29 ± 0.09 dyn.s.cm−5) arteriolar resistances, glomerular plasma flow (79.23 ± 3.15 to 134.30 ± 1.11 nL/min), ultrafiltration coefficient (0.020 ± 0.002 to 0.036 ± 0.003 nL/min/mmHg) and single nephron glomerular filtration rate (22.28 ± 2.04 to 34.46 ± 1.54 nL/min). Angiotensin II induced overexpression of P2X7 receptors in renal tubular cells and in infiltrating T and B lymphocytes and macrophages. All inflammatory cells were increased by angiotensin II infusion and reduced by 20% to 50% (p < 0.05) by BBG administration. Increased IL-2, IL-6, TNFα, IL-1β, IL-18 and overexpression of NLRP3 inflammasome were induced by angiotensin II and suppressed by BBG. These studies suggest that P2X7 receptor-mediated renal vasoconstriction, tubulointerstitial inflammation and activation of NLRP3 inflammasome are associated with angiotensin II-induced hypertension.

P0545DPP-4 INHIBITOR ATTENUATED RENAL VASOCONSTRICTION FOLLOWING ISCHEMIA-REPERFUSION INJURY IN CIRRHOTIC RATS

Background and Aims Cirrhotic patients may develop gastroesophageal varices to cope with portal hypertension. Annual risk of variceal bleeding among small and large varices is 5% and 15%, respectively. Bleeding from varices is a medical emergency and is associated with a high morbidity and mortality. In those who survive the initial bleeding event, the risks of further bleeding and other serious complications remain high, such as hypotension and ischemia-reperfusion injury. Ischemia-reperfusion injury is a leading cause of acute kidney injury. In patients with advanced liver cirrhosis, variceal bleeding associated hypotension and ischemia-reperfusion injury may activated endogenous vasoconstrictors, leading to severe renal vasoconstriction and subsequent renal failure (so called hepatorenal syndrome). There was not effective treatment yet. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, have shown potential pleiotropic effects, such as anti-inflammatory and anti-oxidant properties. Previous studies reported that inhibition of DPP-4 could attenuate the development of ischemia-reperfusion injury in kidney. Cumulated evidences indicates that DPP-4 inhibitors could attenuate the endothelin-1 induced contraction and increase endothelial-dependent vasodilation related to activation of endothelial nitric oxide synthase and increased production of nitric oxide. In addition, DPP-4 inhibitors may suppress inflammation and fibrosis in the kidneys independently of glycemic control. The aim of this study is to delineate the effect of DPP-4 inhibitors in renal vascular reactivity of cirrhotic rats following ischemia-reperfusion injury. Method Male Sprague-Dawley rats weighing 240-270 g were used for experiments. Secondary biliary cirrhosis were created by common bile duct ligation (CBDL). Rats receiving sham surgery (SHAM) were used as the control group. Linagliptin (3 mg/kg/day) or distilled water (DW) was administered via oral gavage since the 1st day throughout the 28th day after surgery. On the 29th day, all rats were randomized to control group or ischemia-reperfusion injury. Bilateral renal pedicles of rats in the ischemia-reperfusion injury group were clamped for 45 minutes with microvascular clamps. Thereafter, the clamps were removed and reperfusion was allowed by visual control. After 60 minutes of reperfusion period, kidneys were perfused in situ via right renal artery for continuous monitoring of renal perfusion pressure using a non-recirculating system. Results There was no significant difference in mean arterial pressure, heart rate, and portal pressure between DW and DPP-4 inhibitor treated groups in both SHAM and CBDL rats. Ischemia-reperfusion injury enhanced renal vascular reactivity to endothelin-1 in both SHAM (p = 0.027) and CBDL (p = 0.016) rats, implying renal vasoconstriction. Compared with corresponding DW-treated rats, DPP-4 inhibitor treatment abrogated renal hyper-reactivity following ischemia-reperfusion injury in BDL rats (p = 0.038), but not in SHAM rats (p = 0.17). Conclusion We concluded that DPP-4 inhibitors may attenuate the development of renal vasoconstriction following ischemia-reperfusion injury in cirrhotic rats. The potentially mechanisms remained to be elucidated.

Pathophysiology of Contrast-Induced Acute Kidney Injury (CIAKI)

: Contrast-induced acute kidney injury (CIAKI) is a severe complication associated with the use of iodinated contrast media (CM); a sudden but potentially reversible fall in glomerular filtration rate (GFR) typically occurring 48-72 hours after CM administration. Principal risk factors related with the presentation of CIAKI are preexisting chronic kidney disease and diabetes mellitus. Studies on CIAKI present considerable complexity because of differences in CM type and dose, controversies in definition and baseline comorbidities. Despite that, it should be noted that CIAKI poses a serious health problem because it is a very common cause of hospitalacquired AKI, linked to increased morbidity and mortality and utilizing growing healthcare resources. The pathogenesis of CIAKI is heterogeneous and, thus, is incompletely understood. Three basic mechanisms appear to simultaneously occur for CIAKI development: Renal vasoconstriction and medullary hypoxia, tubular cell toxicity and reactive oxygen species formation. The relative contribution of each one of these mechanisms is unknown but they ultimately lead to epithelial and endothelial cell apoptosis and GFR reduction. Further research is needed in order to better clarify CIAKI pathophysiology and accordingly introduce effective preventive and therapeutic strategies.

Spironolactone but not Eplerenone Exacerbates Cisplatin Nephrotoxicity

Cisplatin is a highly successful chemotherapeutic agent used for the treatment of solid tumors. However, nephrotoxicity is a limiting factor that occurs in 30% of patients under treatment. Many mechanisms are involved in cisplatin-induced nephrotoxicity, such as epithelial and endothelial injury, inflammation, oxidative stress, and renal vasoconstriction. The mineralocorticoid receptor (MR) has an important role in inflammation and vascular function. MR blockage and ablation have been shown to be effective in preventing renal ischemia-reperfusion injury and cyclosporine A-induced nephrotoxicity. We investigated whether MR antagonism with spironolactone or eplerenone could prevent cisplatin-induced nephrotoxicity. Here, we show that spironolactone treatment exacerbates nephrotoxicity in mice treated with acute and long-term cisplatin regimes. Moreover, spironolactone potentiated the toxicity induced by cisplatin treatment in a cell viability assay in human embryonic kidney cells. In contrast, eplerenone neither prevented nor increased cisplatin toxicity in mice or cultured cells. Thus, our studies support recent findings showing that spironolactone potentiates cisplatin-induced cytotoxicity, independently of mineralocorticoid receptor inhibition.