Reduction In Renal Blood Flow Research Articles

Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated ata pump flow of 80 mL kg-1min-1 and target MAP of70mmHg. Pump flow was then set at 60 and 100mLkg-1min-1, while MAP was maintained at approximately 70mmHg.MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg-1min-1.CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po2 from 43 to 27 mmHg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mmHg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mmHg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mmHg, RBF (47%), and medullary Po2 from 19 to 39 mmHg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.

Effect of exercise intensity on renal blood flow in patients with chronic kidney disease stage 2.

Acute exercise reduces renal blood flow (RBF). However, the effect of exercise intensity on RBF in patients with chronic kidney disease (CKD) stage 2 is not known. We investigated the association between RBF and exercise intensity in patients with CKD stage 2 using pulsed Doppler ultrasonography. Eight men with CKD stage 2 (cystatin C-based estimate of glomerular filtration rate: 60-89ml/min/1.73m2) participated in this study. Using a bicycle ergometer, participants undertook a maximal graded exercise test (MGET) (experiment 1) and a multi-stage exercise test (experiment 2) to determine their lactate threshold (LT). Participants undertook a multi-stage exercise test for 4-min each. Workloads of 60%, 80%, 100%, 120%, and 140% of LT were used in experiment 3. RBF was measured by pulsed Doppler ultrasonography at rest, immediately after exercise, and 1h after exercise in experiment 1, and at rest and immediately after each exercise bout in experiment 3. Renal blood flow after the MGET was 52% lower than at rest, and did not recover as well as after the exercise test. Cross-sectional area (CSA) was significantly lower after graded exercise. RBF tended to be lower at 100% of LT and was significantly lower at 120% of LT. CSA was significantly lower at 100% of LT. Renal blood flow does not change during exercise until the LT is reached. These findings may assist in making appropriate exercise recommendations to patients with CKD stage 2.

A rat model of acute kidney injury through systemic hypoperfusion evaluated by micro-US, color and PW-Doppler.

To create an animal model of acute renal ischemia induced by systemic hypoperfusion, controllable and reproducible to study, in real time, hemorrhagic shock changes with micro-imaging. Hemorrhagic shock was induced in rats activating a syringe pump setup to remove 1mL/min of blood, through the femoral artery catheter. The withdrawal was continued until the mean arterial pressure (MAP) dropped to 25-30mmHg. For the next 60min, the MAP was maintained at a constant pressure value, by automatic pump infusion and withdrawal. Micro-ultrasound imaging was performed using the Vevo 2100 system with the MS250 transducer (13-24MHz). Renal size, morphology and echogenicity were evaluated in B-mode. Renal blood flow was evaluated using color and PW-Doppler. After 1h of ischemia, B-mode images documented slight changes in kidney echogenicity. Color and PW-Doppler analysis showed a reduction in renal blood flow in kidneys during the hypoperfusion with a progressive and significant change from baseline values of resistive index (RI). At the histological evaluation, 60min of hypoperfusion resulted in ischemic changes in the kidneys. The results of this experimental study encourage the use of the described model to study acute renal ischemia trough severe hypoperfusion. The histological data confirmed that the model was able to produce injury in renal parenchyma. It can be used to assess acute ischemic damage not only in the kidney but also in other organs by using all available dedicated small animals imaging techniques.

A1651 TAURINE IMPROVES REDUCED RENAL MEDULLARY BLOOD FLOW IN SPONTANEOUSLY HYPERTENSIVE RATS

Objectives: Present study was carried out to clarify the effect of renal nerve stimulation on renal cortical and medullary blood flow and the effects of chronic treatment of taurine on altered renal cortical and medullary blood flow distribution by renal nerve stimulation in spontaneously hypertensive rats (SHR). Methods: We used 6–7 (young) and 16–17 week old (adult) SHR and divided to taurine treated group and control group. Renal nerve surround left renal artery was stimulated electrically by 2, 5, 10 and 15 Hz under the anesthesia of isoflurane. Renal blood flow was measured using laser tissue flow meter using noncontact prove for cortical blood flow and contact glass-fiber needle type of prove for medullary flow. After a series of electrical stimulation, 1 mg of LNAME was injected and same protocol was repeated. Results: High frequency stimulation caused transient cortical blood flow elevation and which was followed by decrease of blood flow in young and adult WKY. In contrast, blood flow in renal medulla showed no significant changes compared with that in cortex. Young SHR showed a decrease of cortical and medullary blood flow by nerve stimulation. In adult SHP, blood flow reduction was similar to young SHR and medullary blood flow was more reduced than that in young rats. In adult WKY and young SHR, LNAME augmented the reduction of medullary blood flow by electrical stimulation. In adult SHR, LNAME showed no effects on blood flow reduction in medulla. Chronic treatment of taurine blunted the reduction of blood flow by electrical stimulation in medulla but not in cortex of adult SHR. Conclusion: Medullary blood flow is protected through the nitric oxide production in normotensive rats but this mechanism is blunted in SHR. Taurine could improve the reduction of renal medullary blood flow in aged SHR.

Abstract 124: Nadph Oxidase 4 and Mitochondrial Abnormalities Contribute to Oxidative Stress and Endothelial Dysfunction in Young Normotensive Patients With Autosomal Dominant Polycystic Kidney Disease

Background: Fifty percent of patients with autosomal dominant polycystic kidney disease (ADPKD) present hypertension (HTN) early on, which increases to nearly 100% at end-stage, and is associated with faster renal functional decline. Endothelial dysfunction (ED) accompanied by oxidative stress (OS) precedes the development of HTN, but the mechanisms responsible remain unknown. The aim of this study was to determine whether NADPH oxidase (NOX4) and mitochondrial dysfunction contribute to OS and ED preceding HTN in early ADPKD. Methods: We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes COX3 and ND1 in young normotensive (without BP medication) ADPKD patients, and age-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI. Results: BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD, and correlated directly with HtTKV (p<0.05, Figure), but the correlation with RBF was not significant. Plasma mtDNA copy number were lower in ADPKD compared to controls, and correlated inversely with HtTKV(R 2 0.397 and 0.392 respectively). Conclusion: Early ADPKD is associated with elevation in Hcy, 8-isoprostane, and NOX4 levels, and decreased mtDNA copy numbers, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. NOX4 and mitochondrial abnormalities may contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD.

Diabetes Mellitus: a risk factor for drug toxicity.

To assess the effect of the antibiotic Gentamicin in an experimental model in the presence of Diabetes Mellitus through renal function and oxidative profile. Adult male Wistar rats were distributed into groups: Citrate; Gentamicin (Genta), (intraperitoneal, i.p. gentamicin, 100 mg/kg of body weight, once a day,5 days); DM (60 mg/kg of STZ (Streptozotocin), single dose, intravenously, i.v., diluted in citrate buffer); and DM+Genta. Physiological parameters, renal function (creatinine clearance), oxidative damage (peroxides and thiobarbituric acid reactive substances - urinary TBARS) and renal hemodynamics were evaluated. The Diabetes Mellitus group presented chronic hyperglycemia associated with loss of body weight, polyphagia, polydipsia and polyuria, in addition to reduced renal function and with an increase in oxidative metabolite excretion. Administration of gentamicin induced a reduction in renal blood flow and increased renal vascular resistance in healthy rats. The association of Diabetes Mellitus with gentamicin resulted in an additional reduction in renal function and elevation of oxidative metabolites, with increased renal vascular resistance. The existence of Diabetes Mellitus resulted in an elevation of gentamicin nephrotoxicity, thus confirming the risk factor for drug nephrotoxicity.

Peripheral Chemoreceptor Ablation Modulates Renal MiR‐155/KLF4 Expression in Chronic Heart Failure

Background and SignificanceRecent evidence suggests aberrant carotid body chemoreceptor (CBC) function contributes to tonic elevation of renal nerve activity and reductions in renal blood flow in chronic heart failure (CHF). These changes combined with anemia and capillary rarefaction likely contribute to tissue hypoxia, and may drive renal fibrosis and attendant dysfunction. Previous work indicates that stable expression of hypoxia‐inducible factor 1‐α (HIF1α) and down regulation of MiR‐155 drive gene programs that mediate epithelial‐mesenchymal transition (EMT) in renal tubular epithelial cells, including increases in Krüppel‐like factor 4 (KLF4) and matrix metalloproteinase 9 (MMP9). To date, no studies have examined this signaling pathway in CHF, thus our objective was to determine the influence of CBC on renal cortical expression of HIF1α, KLF4, MiR‐155, MMP9, and α‐smooth muscle actin (SMA) in CHF.HypothesisWe hypothesize that CBC‐mediated reductions in renal blood flow activate EMT pathways in CHF by exacerbating tissue hypoxia, leading to sustained accumulation of HIF1α, downregulation of MiR‐155, and KLF4/MMP9/SMA induction.MethodsTo address this hypothesis, we measured expression of HIF1α, MiR‐155, KLF4, MMP9, and SMA in renal cortical tissue from sham, and CHF animals (n=4–8 per group) with and without ablation of the CBC (CBA). CHF was induced in rats by coronary artery ligation (CAL) and CBA was performed (4 weeks post‐CAL) by cryogenic ablation. CHF was confirmed via echocardiography under isoflurane anesthesia (1–1.5%). At 8‐weeks post‐CAL, rats were humanely euthanized and renal cortical tissue was collected and analyzed for HIF1α, KLF4, MMP9, and SMA expression via western blot and MiR‐155 expression by RT‐qPCR.ResultsEjection fraction was 72±2% in sham animals, 34±2% in CHF animals, and 32±2% in CHF‐CBA animals (p<0.05 sham vs. CHF and CHF‐CBA). Expression of HIF1α was 1.37±0.33 in CHF rats relative to sham, and 1.25±0.15 in CHF‐CBA relative to sham. KLF4 was 1.64±0.25 in CHF rats relative to sham, and this effect was attenuated in CHF‐CBA (1.06±0.16 relative to sham, p<0.05 vs. CHF). MMP9 expression in CHF rats was 1.79±0.43 relative to sham and 1.092±0.23 in CHF‐CBA relative to sham. SMA expression in CHF rats was 0.58±0.17 relative to sham and 0.83±0.15 relative to sham in CHF‐CBA. MiR‐155 expression in CHF rats was 0.48±0.11 relative to sham, and this effect was attenuated by CBA (0.73±0.12 relative to sham, p<0.05 vs. CHF).ConclusionThese results suggest a novel relationship between CBC function and expression of renal cortical MiR‐155 and KLF4 in CHF, and that CBA has the potential to influence EMT pathways in the kidney in this pathophysiological setting.Support or Funding InformationThis work was supported by a grant from NHLBI (1 R15 HL138600‐01)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impairment of renal organic anion transport mediated by organic anion transporter 1 (Oat1) and 3 (Oat3) in acute myocardial ischemic and reperfusion injury in rats

Acute kidney injury (AKI) is frequently associated with acute myocardial infarction (AMI). Kidney plays a crucial role in the clearance of uremic toxins, produced from organ dysfunctions, mainly through organic anion transporters 1 (Oat1) and 3 (Oat3). This study aims to examine the effects of acute myocardial ischemia and ischemic/reperfusion (I/R) on renal transporter functions, and identify the mechanisms involved in the impairment of these transporters. Myocardial ischemia and I/R were induced in rats by either 30‐minute left anterior descending coronary artery occlusion or 30‐minute occlusion followed by 120‐minute of reperfusion, respectively. The renal hemodynamic parameters and renal transporter functions were subsequently determined along with renal biochemical markers. Results showed that myocardial ischemia led to reduction in renal blood flow, perfusion pressure, and kidney function by approximately 40%, while the reperfusion phase partially recovered renal hemodynamic parameters. Moreover, myocardial ischemia and I/R progressively induced renal oxidative stresses and mitochondria dysfunction, all of which directly deteriorated renal Oat1 and Oat3 functions. Thus, this study indicates that myocardial ischemia and I/R conditions leads to a progressively declined renal transport function, which could potentially worsen AKI. Renal Oat1 and Oat3 transporters, therefore, might be potential therapeutic targets for reversing such injury.Support or Funding InformationThis research was supported by the Thailand Research Fund (RSA5980009 to CS), Faculty of Medicine Endowment Fund, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal Nitric Oxide‐Dependent Mechanisms in Early Sunitinib‐Induced Hypertension

Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used in cancer treatment. A major adverse effect of sunitinib is a rapidly developing hypertension associated with reduced renal nitric oxide (NO) availability and increased renal fractional sodium reabsorption (FRNa). We tested if NO‐dependent regulation of renal hemodynamics and FRNa are compromised and if nitrate supplementation has antihypertensive effects in early sunitinib‐induced hypertension.Male Wistar rats were treated with sunitinib at 15 mg/(kg*d). Four days after initiation of sunitinib treatment, renal hemodynamics and renal sodium excretion were investigated. Radiotelemetric experiments were performed to study the effects of nitrate supplementation and soluble guanylate cyclase (sGC) activation on arterial pressure. Nitric oxide synthase (NOS) as well as sGC mRNA and protein abundances were studied in renal tissue.Within four days, sunitinib elicited a 20–25 mmHg arterial pressure rise. NOS inhibition elicited similar reductions in total and renal medullary blood flow in sunitinib‐ and vehicle‐treated rats. NO‐dependent and independent components of endothelium‐dependent renal vasodilation were not compromised in early sunitinib‐induced hypertension. Low dose intrarenal NOS inhibition did not differentially affect FRNa in sunitinib‐ and vehicle‐treated rats. In sunitinib‐treated rats, renal nitrite/nitrate excretion was 60 per cent less than in controls (p < 0.05). However, nitrate supplementation did not reduce arterial pressure and renal sodium balance in sunitinib‐treated rats. While sunitinib treatment had no effects on renal NOS mRNA abundances, it significantly reduced renal cortical sGC α‐ and β‐subunit mRNA abundances as well as renal cortical guanylate cyclase protein expression. Pharmacological sGC activation caused a rapid 15–20 mmHg arterial pressure fall in sunitinib‐treated rats (p < 0.05).We conclude that the NO‐dependent regulation of renal hemodynamics is largely unaltered in early sunitinib‐induced hypertension despite evidence for reduced NO formation. Reduced renal sGC expression and activity may contribute to the early arterial pressure rise in sunitinib‐induced hypertension and cause its nitrate resistance.Support or Funding InformationSupported by the German Research Foundation, Grant‐No. KO 4936/2‐1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Association between exercise intensity and renal blood flow evaluated using ultrasound echo.

High-intensity exercise reduces renal blood flow (RBF) and may transiently exacerbate renal dysfunction. RBF has previously been measured invasively by administration of an indicator material; however, non-invasive measurement is now possible with technological innovations. This study examined variations in RBF at different exercise intensities using ultrasound echo. Eight healthy men with normal renal function (eGFRcys 114 ± 19mL/min/1.73m2) participated in this study. Using a bicycle ergometer, participants underwent an incremental exercise test using a ramp protocol (20W/min) until exhaustion in Study 1 and the lactate acid breaking point (LaBP) was calculated. Participants underwent a multi-stage test at exercise intensities of 60, 80, 100, 120, and 140% LaBP in Study 2. RBF was measured by ultrasound echo at rest and 5min after exercise in Study 1 and at rest and immediately after each exercise in Study 2. To determine the mechanisms behind RBF decline, a catheter was placed into the antecubital vein to study vasoconstriction dynamics. RBF after maximum exercise decreased by 51% in Study 1. In Study 2, RBF showed no significant decrease until 80% LaBP, and showed a significant decrease (31%) at 100% LaBP compared with at rest (p < 0.01). The sympathetic nervous system may be involved in this reduction in RBF. RBF showed no significant decrease until 80% LaBP, and decreased with an increase in blood lactate. Reduction in RBF with exercise above the intensity at LaBP was due to decreased cross-sectional area rather than time-averaged flow velocity.

The Role of Renal Vascular Reactivity in the Development of Renal Dysfunction in Compensated and Decompensated Congestive Heart Failure

Background/Aims: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of the renal vasculature to endogenous vasoactive agents. Methods: To evaluate the role of this mechanism, we assessed by an ultrasonic transient-time flow probe maximum RBF responses to renal artery infusion of angiotensin II (ANG II), norepinephrine (NE) and acetylcholine (Ach) in healthy male rats and animals with compensated and decompensated CHF. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) in Hannover Sprague-Dawley rats. Results: Maximum responses in RBF to ANG II were similar in rats studied five weeks (compensated phase) and 20 weeks (decompensated phase) after ACF creation when compared to sham-operated rats. On the other hand, NE elicited larger maximum decreases in RBF in rats with CHF (five and 20 weeks post-ACF) than in sham-operated controls. We observed greater maximum vasodilatory responses to Ach only in rats with a compensated stage of CHF (five weeks post-ACF). Conclusion: Greater renal vasoconstrictor responsiveness to ANG II or reduced renal vasodilatation in response to Ach do not play a decisive role in the development of renal dysfunction in ACF rats with compensated and decompensated CHF. On the other hand, exaggerated renal vascular responsiveness to NE may be here a contributing causative factor, active in either CHF phase.

Two-stage Operation for Stanford Type B Acute Aortic Dissection with Renal Blood Flow Reduction

Two-stage Operation for Stanford Type B Acute Aortic Dissection with Renal Blood Flow Reduction

New Developments in Hepatorenal Syndrome

Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFRmore accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance ofthis remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed thevalue of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remainsthe definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation.

The unsuitability of implantable Doppler probes for the early detection of renal vascular complications - a porcine model for prevention of renal transplant loss.

BackgroundVascular occlusion is a rare, but serious complication after kidney transplantation often resulting in graft loss. We therefore aimed to develop an experimental porcine model for stepwise reduction of the renal venous blood flow and to compare an implantable Doppler probe and microdialysis for fast detection of vascular occlusion.MethodsIn 20 pigs, implantable Doppler probes were placed on the renal artery and vein and a microdialysis catheter was placed in the renal cortex. An arterial flowprobe served as gold standard. Following two-hour baseline measurements, the pigs were randomised to stepwise venous occlusion, complete venous occlusion, complete arterial occlusion or controls.ResultsAll parameters were stable through baseline measurements. Glutamate and lactate measured by microdialysis increased significantly (p = 0.02 and p = 0.03 respectively) 30 minutes after a 2/3 (66%) reduction in renal blood flow. The implantable Doppler probe was not able to detect flow changes until there was total venous occlusion. Microdialysis detected changes in local metabolism after both arterial and venous occlusion; the implantable Doppler probe could only detect vascular occlusions on the vessel it was placed.ConclusionsWe developed a new model for stepwise renal venous blood flow occlusion. Furthermore, the first comparison of the implantable Doppler probe and microdialysis for detection of renal vascular occlusions was made. The implantable Doppler probe could only detect flow changes after a complete occlusion, whereas microdialysis detected changes earlier, and could detect both arterial and venous occlusion. Based on these results, the implantable Doppler probe for early detection of vascular occlusions cannot be recommended.

Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8–10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18–20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

Protective role of cGMP in early sepsis

Septic shock, which is triggered by microbial products, is mainly characterised by inadequate tissue perfusion, which can lead to multiple organ dysfunction and death. An intense release of vasoconstrictors agents occurs in the early stages of shock, which can lead to ischemic injury. In this scenario, cGMP could play a key role in counterbalancing these agents and preventing tissue damage. Sildenafil, which is a phosphodiesterase-5 inhibitor, increases cGMP in smooth muscle cells and promotes vasodilation. Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male rats were submitted to either cecal ligation and puncture (CLP) or a sham procedure. Eight h after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10mg/kg, gavage) or vehicle, and twelve or twenty-four h later the inflammatory, biochemical and haemodynamic parameters were evaluated. Sepsis significantly increased levels of plasma nitrate/nitrite (NOx), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatine kinase and lactate. Additionally, sepsis led to hypotension, hyporesponsiveness to vasoconstrictor, renal blood flow reduction and also increased lung and kidney myeloperoxidase. Sildenafil increased renal blood flow and reduced the plasma levels of creatinine, lactate and creatine kinase, as well as reducing lung myeloperoxidase. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper time.

Internal dysregulation of the renin system in patients with stable liver cirrhosis

Sodium retention in cirrhosis is associated with changes in the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and the glomerular filtration rate (GFR). We hypothesized that in cirrhosis the acute reactions of RAAS and SNS to volume expansion are qualitatively intact, but occurring from elevated baseline levels. Acute cardiovascular, neurohumoral and renal responses to central blood volume changes were studied in cirrhotic patients and healthy controls. In patients, baseline plasma renin concentration (PRC) was elevated 5-fold compared to controls (p < .001); it increased during standing (+144%, p < .001) and remained elevated during subsequent sitting (+118%, p < .001). At baseline, plasma angiotensin II (pANGII) was not elevated significantly (14 ± 2 vs. 9 ± 2 pg/mL) in contrast to plasma aldosterone (pAldo, +160%, p < .001). During orthostatic RAAS activation, the rise in pAngII per unit increase in PRC was 0.04 pg AngII/mIU and 0.48 pg AngII/mIU in patients and controls, respectively (p < .001); similarly, the change in pAldo per unit change in pANGII was 3.6 in patients and 14.5 pg/pg in controls (p < .001). Plasma noradrenaline was elevated in the patients, but the dynamic changes were virtually identical to those of controls. During standing, abrupt decreases in renal blood flow (−63%, p < .001) and GFR (−42% p < .04) occurred only in patients. In conclusion, in stable cirrhosis, static and dynamic dysregulation exists within the RAAS; in the supine position pAngII levels are inappropriately low, and the AngII-mediated regulation of aldosterone secretion is severely impeded. In cirrhotic patients, profound reductions in renal blood flow and GFR occur during standing.

Arterial spin labeling MRI is able to detect early hemodynamic changes in diabetic nephropathy.

To investigate whether arterial spin labeling (ASL) MRI could detect renal hemodynamic impairment in diabetes mellitus (DM) along different stages of chronic kidney disease (CKD). Three Tesla (3T) ASL-MRI was performed to evaluate renal blood flow (RBF) in 91 subjects (46 healthy volunteers and 45 type 2 diabetic patients). Patients were classified according to their estimated glomerular filtration rate (eGFR) as group I (eGFR > 60 mL/min/1.73 m2 ), group II (60 ≥ eGFR>30 mL/min/1.73 m2 ), or group III (eGFR ≤ 30 mL/min/1.73 m2 ), to determine differences depending on renal function. Studies were performed at 3T using a 12-channel flexible body array combined with the spine array coil as receiver. A 28% reduction in cortical RBF was seen in diabetics in comparison with healthy controls (185.79 [54.60] versus 258.83 [37.96] mL/min/100 g, P < 3 × 10-6 ). Differences were also seen between controls and diabetic patients despite normal eGFR and absence of overt albuminuria (RBF [mL/min/100 g]: controls=258.83 [37.96], group I=208.89 [58.83], P = 0.0018; eGFR [mL/min/1.73 m2 ]: controls = 95.50 [12.60], group I = 82.00 [20.76], P > 0.05; albumin-creatinine ratio [mg/g]: controls = 3.50 [4.45], group I = 17.50 [21.20], P > 0.05). A marked decrease in RBF was noted a long with progression of diabetic nephropathy (DN) through the five stages of CKD (χ2 = 43.58; P = 1.85 × 10-9 ). Strong correlation (r = 0.62; P = 4 × 10-10 ) was obtained between RBF and GFR estimated by cystatin C. ASL-MRI is able to quantify early renal perfusion impairment in DM, as well as changes according to different CKD stages of DN. In addition, we demonstrated a correlation of RBF quantified by ASL and GFR estimated by cystatin C. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1810-1817.

Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury.

Damage to endothelial cells contributes to acute kidney injury (AKI) by leading to impaired perfusion. Endothelial colony-forming cells (ECFC) are endothelial precursor cells with high proliferative capacity, pro-angiogenic activity, and in vivo vessel forming potential. We hypothesized that ECFC may ameliorate the degree of AKI and/or promote repair of the renal vasculature following ischemia-reperfusion (I/R). Rat pulmonary microvascular endothelial cells (PMVEC) with high proliferative potential were compared with pulmonary artery endothelial cells (PAEC) with low proliferative potential in rats subjected to renal I/R. PMVEC administration reduced renal injury and hastened recovery as indicated by serum creatinine and tubular injury scores, while PAEC did not. Vehicle-treated control animals showed consistent reductions in renal medullary blood flow (MBF) within 2 h of reperfusion, while PMVEC protected against loss in MBF as measured by laser Doppler. Interestingly, PMVEC mediated protection occurred in the absence of homing to the kidney. Conditioned medium (CM) from human cultured cord blood ECFC also conveyed beneficial effects against I/R injury and loss of MBF. Moreover, ECFC-CM significantly reduced the expression of ICAM-1 and decreased the number of differentiated lymphocytes typically recruited into the kidney following renal ischemia. Taken together, these data suggest that ECFC secrete factors that preserve renal function post ischemia, in part, by preserving microvascular function.

Lower blood pressure and risk of cisplatin nephrotoxicity: a retrospective cohort study

BackgroundThe pathophysiological mechanisms of cisplatin nephrotoxicity include the reduction of renal blood flow, as well as tubular epithelial cell toxicity. The objective of this study was to investigate the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.MethodsWe conducted a retrospective cohort study at a university hospital between 2011 and 2012. We identified hospitalized adult patients with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration. The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times from baseline.ResultsThe study participants included 182 patients, in whom we observed a total of 442 cycles of cisplatin chemotherapy. The incidence of cisplatin nephrotoxicity was observed in 41 of 182 cycles with initial administration. Multivariate logistic regression analysis showed that systolic blood pressure was independently associated with cisplatin nephrotoxicity (adjusted odds ratio 0.75, 95% confidence interval 0.57 to 0.95 for each 10 mmHg). The use of renin-angiotensin system (RAS) inhibitors was also associated with cisplatin nephrotoxicity (3.39, 1.30 to 8.93). Among quartiles of systolic blood pressure in all cycles of chemotherapy, the incidence of nephrotoxicity in the lower blood pressure group was significantly higher than that in the higher blood pressure group for patients taking non-solid food (P = 0.037), while there was no significant difference for patients taking solid food (P = 0.67).ConclusionsLower blood pressure and the use of RAS inhibitors were associated with the incidence of cisplatin nephrotoxicity, and lower blood pressure had a greater influence on nephrotoxicity in patients who could not take solid food. Discontinuation of antihypertensive medication including RAS inhibitors before cisplatin chemotherapy should be considered, which may be beneficial for patients with lower blood pressure.