Decrease In Renal Blood Flow Research Articles

Abstract 631: Maternal Separation (msep) Alters Baroreflex Function And Renal Blood Flow Responsiveness

An impairment of the baroreflex buffering has been shown to precede the development of hypertension. Formerly, we reported that MSep, a model of behavioral stress during early life, impairs chronic blood pressure control and renal filtration capacity. Thus, the aim of this study was to study the baroreflex function and renal blood flow regulation in MSep rats. We used 3 month-old MSep male rats, anesthetized with isoflurane. Femoral vein catheter was fitted to infuse saline (3 ml/hr, baseline), PE (phenylephrine, 1 ug/ml, 9 ml/hr) or SNP (sodium nitroprusside, 0.5 ug/ml, 9 ml/hr). Femoral artery catheter was fitted to collect blood pressure and HR data (ADInstruments). In addition, a flow probe was placed in the left renal artery for renal blood flow (RBF) assessment (Transonic). After 45 minutes of baseline, PE infusion (2 min) was performed. Following 30-minute recovery period, SNP infusion (2 min) was achieved. Delta heart rate (HR)/Delta mean arterial pressure (MAP) relationship shows a significant difference in the slopes between MSep vs. control rats (-0.5 ±0.07 vs. -1.08 ±0.08, p<0.05). PE-induced decrease in RBF was attenuated in a dose dependent manner in MSep rats (max. delta RBF -4.8±0.8 ml/min) compared to controls (max. delta RBF -7±1.5 ml/min, p<0.05, respectively). Yet, renal vascular resistance (MAP/RBF) was not different between MSep and control rats along the 2-min period (slope: 0.43±0.02 vs. 0.42±0.03 mmHg/ml/min, respectively). These data suggest that MSep rats fail to increase HR in response to a vasodilatory agent and lower HR in response to vasoactive stimulus. Furthermore, attenuated alpha-adrenergic-induced renal vascular responses support the existence of a compensatory mechanism in response to an increased sympathetic outflow to the kidney, as previously suggested. The contribution of the different components of the autonomic nervous system is the focus of ongoing studies.

Effects of hydrogen sulphide on cyclosporin induced nephrotoxicity at reperfusion

Effects of hydrogen sulphide on cyclosporin induced nephrotoxicity at reperfusion

Renal vascular reactivity to AVP in wild type and CD38‐/‐ mice: modulation by nitric oxide, prostanoids, and superoxide (692.9)

Renal vascular responses to AVP were tested in anesthetized wild‐type (WT) and CD38‐/‐ mice that lack the calcium mobilizing second messenger cyclic ADP ribose. Iv injections of AVP (3‐25ng) produced a dose‐dependent decrease in renal blood flow with a minimum of 25±2% below control in WT and 27±2% in CD38‐/‐ mice at the 25ng dose. Renal vascular resistance (RVR) increased by 75±6% in WT and 78±6% in CD38‐/‐ mice. Inhibition of NO synthase with L‐NAME increased the maximum RVR response to AVP from 71±7 to 308±76% in WT and from 86±7 to 388±81% in CD38‐/‐. Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125±15% in WT and 120±14% in CD38‐/‐ mice (P<0.001, <0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains (p<0.005). All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. Thus, vasoconstriction by AVP in the mouse is caused by V1a receptor activation with no concomitant vasodilatation by V2 receptors. However, renal vasoconstrictor responses to AVP are strongly buffered by vasodilatory actions of NO and prostanoids and augmented by the vasoconstrictor actions of superoxide. Unlike AVP, other vasoconstrictor agents show attenuated vasoconstrictor activity in CD38‐/‐ mice which points to a distinct activation mechanism for AVP that appears to be independent of CD38 and its downstream calcium signaling pathway.Grant Funding Source: Supported by HL‐02334

Renal vasoconstriction by vasopressin V1a receptors is modulated by nitric oxide, prostanoids, and superoxide but not the ADP ribosyl cyclase CD38

Renal blood flow (RBF) responses to arginine vasopressin (AVP) were tested in anesthetized wild-type (WT) and CD38(-/-) mice that lack the major calcium-mobilizing second messenger cyclic ADP ribose. AVP (3-25 ng) injected intravenously produced dose-dependent decreases in RBF, reaching a maximum of 25 ± 2% below basal RBF in WT and 27 ± 2% in CD38(-/-) mice with 25 ng of AVP. Renal vascular resistance (RVR) increased 75 ± 6% and 78 ± 6% in WT and CD38(-/-) mice. Inhibition of nitric oxide (NO) synthase with nitro-L-arginine methyl ester (L-NAME) increased the maximum RVR response to AVP to 308 ± 76% in WT and 388 ± 81% in CD38(-/-) (P < 0.001 for both). Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125 ± 15% in WT and 120 ± 14% in CD38(-/-) mice (P < 0.001, <0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains (P < 0.005) but was ineffective when administered after L-NAME. The rate of RBF recovery (relaxation) after AVP was slowed by L-NAME and indomethacin (P < 0.001, <0.005) but was unchanged by tempol. All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. A V2 receptor agonist or antagonist had no effect on AVP-induced renal vasoconstriction. Taken together, the results indicate that renal vasoconstriction by AVP in the mouse is strongly buffered by vasodilatory actions of NO and prostanoids. The vasoconstriction depends on V1a receptor activation without involvement of CD38 or concomitant vasodilatation by V2 receptors. The role of superoxide is to enhance the contractile response to AVP, most likely by reducing the availability of NO rather than directly stimulating intracellular contraction signaling pathways.

Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension.

This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle-treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 ± 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 ± 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 ± 0.14). Compared with normotensive sham-vehicle-treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 ± 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 ± 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II-induced hypertension, possibly by reducing renal T cell infiltration.

Acute Kidney Injury

Acute Kidney Injury

Acute Kidney Injury

1. David T. Selewski, MD* 2. Jordan M. Symons, MD† 1. *Department of Pediatrics and Communicable Diseases, Division of Nephrology, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI. 2. †Department of Pediatrics, Division of Nephrology, University of Washington School of Medicine, Seattle, WA. * Abbreviations: ACE: : angiotensin-converting enzyme AKI: : acute kidney injury AKIN: : Acute Kidney Injury Network ANCA: : antineutrophil cytoplasmic antibody ATN: : acute tubular necrosis ECG: : electrocardiogram FEurea: : fractional excretion of urea FENa: : fractional excretion of sodium KDIGO: : Kidney Disease: Improving Global Outcomes NSAID: : nonsteroidal anti-inflammatory drug RIFLE: : Risk, Injury, Failure, Loss, and End-stage The term acute kidney injury has replaced acute renal failure and represents a spectrum of clinically meaningful kidney damage. After completing this article, readers should be able to: 1. Recognize and define the spectrum of acute kidney injury (AKI). 2. Understand the diagnostic approach and be able to differentiate the main causes of AKI. 3. Understand the complications of AKI and the treatment of a child with AKI. Acute kidney injury (AKI), formerly called acute renal failure, is characterized by multiple abnormalities, including increases in serum creatinine and blood urea nitrogen, electrolyte abnormalities, acidosis, and difficulties with fluid management. We have come to realize that what was previously thought to be relatively minor damage to the kidney can have significant short-term effects on morbidity and mortality and potential long-term implications for the development of chronic kidney disease. Thus, the term acute kidney injury has replaced acute renal failure , suggesting the spectrum of kidney damage that can occur. ### Definition AKI is classically defined as an acute decrease in glomerular filtration rate, which results in an increase in serum creatinine. It is important to recognize the limitations of creatinine as a marker of AKI because an increase in creatinine can be delayed by as much as 48 hours after damage to the kidney has occurred. Despite this limitation, change in creatinine remains the gold standard for the diagnosis of AKI. An evolution in the definition of AKI to better understand, characterize, and study the disease spectrum, has occurred, which has sought to capture the clinical importance of even small variations in kidney function. In addition, previous definitions used in the literature were widely disparate; this …

Effect of reactive oxygen species and nitric oxide in the neural control of intrarenal haemodynamics in anaesthetized normotensive rats

This study examined the interaction between reactive oxygen species and nitric oxide (NO) in mediating the decrease in renal blood flow (RBF) evoked by sympathetic renal nerve stimulation (RNS). Groups of male Wistar rats were subjected to RNS at different frequencies prior to, and following, an infusion of: (i) tempol, the superoxide dismutase (SOD) mimetic, (ii) tempol plus the hydrogen peroxide-degrading enzyme catalase (tem + cat), (iii) diethyldithiocarbamic acid (DETC), a SOD inhibitor, (iv) the nitric oxide synthase (NOS) inhibitor, L-nitro-arginine methyl ester (L-NAME) alone, or (v) L-NAME followed by tempol, into the kidney cortico-medullary border (CMB). Blood perfusion within the cortical (CBP) and medullary (MBP) regions of the kidney was measured using Laser-Doppler flowmetry. Infusion of tempol CMB significantly attenuated RNS-evoked reductions in CBP (by 22% at 8 Hz; P < 0.05), but not MBP. When tempol and catalase were co-infused to reduce both ROS and hydrogen peroxide (H2 O2 ), respectively, there was a significantly greater attenuation of the RNS-evoked reduction in CBP compared with that of tempol alone. Infusion of either DETC or L-NAME alone did not significantly affect the CBP or MBP responses to RNS. Similarly, RNS following tempol infusion with L-NAME also had no effect on CBP and MBP over and above the group that received tempol alone. These results suggest that reactive oxygen species such as superoxide and H2 O2 have a direct role in reducing renal vascular compliance in response to RNS, rather than indirectly through scavenging NO.

Improvement in renal hemodynamics following combined angiotensin II infusion and AT1R blockade in aged female sheep following fetal unilateral nephrectomy.

Renin-angiotensin system (RAS) is a powerful modulator of renal hemodynamic and fluid homeostasis. Up-regulation in components of intra-renal RAS occurs with ageing. Recently we reported that 2 year old uninephrectomised (uni-x) female sheep have low renin hypertension and reduced renal function. By 5 years of age, these uni-x sheep had augmented decrease in renal blood flow (RBF) compared to sham. We hypothesised that this decrease in RBF in 5 year old uni-x sheep was due to an up-regulation in components of the intra-renal RAS. In this study, renal responses to angiotensin II (AngII) infusion and AngII type 1 receptor (AT1R) blockade were examined in the same 5 year old sheep. We also administered AngII in the presence of losartan to increase AngII bioavailability to the AT2R in order to understand AT2R contribution to renal function in this model. Uni-x animals had significantly lower renal cortical content of renin, AngII (∼40%) and Ang 1–7 (∼60%) and reduced cortical expression of AT1R gene than sham animals. In response to both AngII infusion and AT1R blockade via losartan, renal hemodynamic responses and tubular sodium excretion were significantly attenuated in uni-x animals compared to sham. However, AngII infusion in the presence of losartan caused ∼33% increase in RBF in uni-x sheep compared to ∼14% in sham (P<0.05). This was associated with a significant decrease in renal vascular resistance in the uni-x animals (22% vs 15%, P<0.05) without any changes in systemic blood pressure. The present study shows that majority of the intra-renal RAS components are suppressed in this model of low renin hypertension. However, increasing the availability of AngII to AT2R by AT1R blockade improved renal blood flow in uni-x sheep. This suggests that manipulation of the AT2R maybe a potential therapeutic target for treatment of renal dysfunction associated with a congenital nephron deficit.

The conundrum of protection from AKI by adenosine in rodent clamp ischemia models

Kim et al. show that isoflurane uses a tubule-based transforming growth factor-β/CD73-dependent process that generates adenosine to protect mice from ischemic acute kidney injury (AKI) with effects to prevent the 'no-reflow phenomenon' and decrease inflammation. While direct cytoprotection occurred in culture, extensive research suggests that in vivo adenosine protection from rodent ischemic AKI is mediated by a mutually cooperative mechanism involving blood flow, inflammation, and innate immunity through multiple adenosine receptors with promiscuous actions on diverse cell types.

ADP‐ribosyl cyclase (CD38) and superoxide mediate renal vasoconstriction due to thromboxane receptor (TpR) activation

The calcium mobilizing second messenger, cyclic ADP ribose (cADPR, the product of ADP‐ribosyl cyclase) is an important component in the renal vasoconstrictor response to G‐protein coupled receptor stimulation. The role of cADPR in TpR‐mediated renal vasoconstriction was tested with the stable thromboxane mimetic U‐46619 in wild type (WT) and CD38 −/− mice. Arterial blood pressure (ABP) and renal blood flow (RBF) were not different between WT and CD38−/− mice during basal conditions. Bolus injections of U‐46619 (10–50ng in 10μl) caused a dose‐dependent decrease in RBF and increase in ABP in both strains but to a lesser extent for both in CD38−/− mice. Compared to control, 50 ng of U‐46619 reduced RBF by 37±4% and 22±3% and increased ABP by 36±6% and 22±6% in WT and CD38−/− mice, respectively (p&lt;0.05 n=7). Intravenous infusion of Tempol to scavenge superoxide reduced renal vasoconstrictor response to U‐46619 by 40–45% in both strains of mice. The data show that the renal vasoconstriction produced by TpR stimulation is mediated by ADP‐ribosyl cyclase activity and depends upon superoxide for full expression. The comparable inhibition of the RBF response by Tempol in both strains of mice indicates that the vasoconstrictor action of superoxide is independent of CD38 and cannot explain the attenuated response to TpR activation in CD38−/− mice. Funded by NIH grant RO1 HL‐02334

Losartan retards the development of Chronic Kidney Disease (CKD) after an Acute Kidney Injury (AKI) episode

We studied if preventing AKI with Losartan (Lo) stops CKD development. Fifty rats were divided in: Sham‐operated (S), Lo‐treated group (50 mg/kg) (Lo+S), rats underwent bilateral ischemia of 45 min (I), rats receiving Lo before I (Lo+I), and rats receiving Lo, 3 h after I (I+Lo). All groups were observed 270 days. Proteinuria (Prot), creatinine clearance (CrCl), renal blood flow (RBF), tubulo‐interstitial fibrosis (TIF) and glomerular diameter were measured. In addition, interleukin 6 and monocyte chemo attracting protein mRNA levels, as well as urinary kidney injury molecule and H2O2 were measured. Rats underwent ischemia developed CKD characterized by a progressive increase in Prot and a decrease in CrCl and RBF. Glomerular hypertrophy, extensive TIF, and Kim‐1 up‐regulation were also observed, all these findings were associated with an increase in oxidative stress and with greater inflammation. Losartan treatment avoided the progression of CKD evidenced by CrCl and renal architecture preservation without increased inflammation or oxidative stress. We show in this model of renal injury induced by AKI that angiotensin receptor antagonism reduced CKD progression. However, prophylactic treatment was more effective than after the ischemic insult. The mechanisms activated after AKI episode and the angiotensin II involvement could give us the knowledge for designing therapeutic strategies to prevent CKD.

Novel targets for sepsis‐induced kidney injury: the glomerular arterioles and the sympathetic nervous system

Sepsis and septic shock are the most common causes of acute kidney injury (AKI) in the intensive care unit, and mortality remains high despite improvements in our ability to support vital organs. The lack of development of effective treatments is partly because there has been little advance in our understanding of the pathophysiology of septic AKI, owing to the difficulty in conducting experiments on critically ill patients and use of inappropriate experimental models. Recently, however, a number of new concepts have emerged that challenge existing dogma and give insights into the causes of AKI. Traditionally, renal ischaemia has been proposed as the main cause of AKI, but it is becoming apparent that in sepsis with a hyperdynamic circulation, the most common situation in septic patients, there is an increase or at least no decrease in renal blood flow. In this review, the possible role of changes in pre- and postglomerular resistance in setting the increased level of renal blood flow in the presence of a decreased glomerular filtration rate is discussed. New evidence also indicates that the increased sympathetic nerve activity that occurs in sepsis may contribute to the induction of organ failure. Experimental studies indicate that inhibition of central sympathetic outflow with α(2)-adrenoceptor agonists or treatment with β(1)-adrenoceptor antagonists might reduce mortality in experimental endotoxaemia and sepsis. The possibility that these beneficial actions are partly dependent on a reduction in the excessive cytokine release caused by marked and prolonged sympathetic activation is discussed.

Acute Effects of Calcineurin Inhibitors on Kidney Allograft Microperfusion Visualized by Contrast-Enhanced Sonography

Calcineurin inhibitors induce detrimental vascular remodeling, which may be one cause of chronic allograft failure. Real-time contrast-enhanced sonography (CES) is a relatively new technique in providing quantitative information on microvascular tissue perfusion in kidney allografts in more detail. The purpose of the study was to explore whether acute changes of kidney allograft microperfusion due to the administration of cyclosporine A (CsA) and tacrolimus (Tac) can be evidenced using real-time CES. In an explorative single-center clinical trial, renal parenchymal tissue perfusion of 32 stable kidney allograft recipients was evaluated with CES before and 2 hr after the intake of CsA or Tac. In addition to laboratory and clinical parameters, Doppler indices and estimated glomerular filtration rate were measured. Although systolic and diastolic blood pressure and color Doppler indices did not significantly differ, there was a significant decrease of renal blood flow 2 hr after the intake of CsA compared with baseline (4.78±2.31 dB/s, 49%, respectively). In contrast, kidney allograft microperfusion was neither significantly reduced in patients receiving CsA paralleled by calcium channel blockers nor significantly reduced in patients receiving Tac. Furthermore, there was a significant correlation between renal blood flow obtained before drug administration and kidney function. CES revealed a 49% reduction of kidney allograft microperfusion 2 hr after the intake of CsA, which might be abrogated by calcium channel blockers. In comparison to CsA, Tac did not result in a significant decrease of kidney blood flow.

Page kidney in a patient with granulomatosis with polyangiitis (Wegener's)

Page kidney results from a perirenal haematoma or a mass around the kidney, which causes extrinsic compression on the renal parenchyma and is a very rare cause of secondary hypertension.1...

Arterial spin labeling blood flow magnetic resonance imaging for evaluation of renal injury

A multitude of evidence suggests that iodinated contrast material causes nephrotoxicity; however, there have been no previous studies that use arterial spin labeling (ASL) blood flow functional magnetic resonance imaging (fMRI) to investigate the alterations in effective renal plasma flow between normointensive and hypertensive rats following injection of contrast media. We hypothesized that FAIR-SSFSE arterial spin labeling MRI may enable noninvasive and quantitative assessment of regional renal blood flow abnormalities and correlate with disease severity as assessed by histological methods. Renal blood flow (RBF) values of the cortex and medulla of rat kidneys were obtained from ASL images postprocessed at ADW4.3 workstation 0.3, 24, 48, and 72 h before and after injection of iodinated contrast media (6 ml/kg). The H&E method for morphometric measurements was used to confirm the MRI findings. The RBF values of the outer medulla were lower than those of the cortex and the inner medulla as reported previously. Iodinated contrast media treatment resulted in decreases in RBF in the outer medulla and cortex in spontaneously hypertensive rats (SHR), but only in the outer medulla in normotensive rats. The iodinated contrast agent significantly decreased the RBF value in the outer medulla and the cortex in SHR compared with normotensive rats after injection of the iodinated contrast media. Histological observations of kidney morphology were also consistent with ASL perfusion changes. These results demonstrate that the RBF value can reflect changes of renal perfusion in the cortex and medulla. ASL-MRI is a feasible and accurate method for evaluating nephrotoxic drugs-induced kidney damage.

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution regarding antioxidant strategies in RAS.

Differential adrenergic signaling in the regulation of renal blood flow in rats with heart failure

Chronic heart failure (CHF) is a disease characterized by an overactive sympathetic nervous system. The kidney is especially vulnerable to these adaptations, and responds, in part, with a decrease in renal blood flow (RBF). The purpose of this study was to determine the effects of the α1 adrenergic receptor agonist phenylephrine (PE) and the nonselective adrenergic receptor agonist norepinephrine (NE) on RBF in sham and CHF animals. CHF was induced by coronary artery ligation. Anesthetized animals were instrumented with a renal flow probe and a catheter in the aorta close to the renal bifurcations. Changes in RBF were measured in response to intra‐aortic infusions of increasing doses of PE (5, 10, and 20 μg/kg) and NE (8 and 16 μg/kg). Renal cortices from CHF and sham animals were sieved to obtain a vascular‐enriched preparation. CHF animals exhibited a blunted change in RBF in response to intra‐aortic infusion of PE compared to sham animals at all concentrations. Conversely, CHF animals exhibited an increased sensitivity to NE. To determine if the changes in blood flow in response to ligand correlated to differential expression of the targeted receptors western blotting on sieved lysate was performed. Preliminary western blotting data indicate that relative amounts of β1 adrenergic receptor were significantly decreased in CHF animals compared to sham. Results of this study suggest that changes in RBF during CHF are due in part to alterations in adrenergic receptor signaling.

Pathophysiology of acute kidney injury.

Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia, or nephrotoxicity. An underlying feature is a rapid decline in glomerular filtration rate (GFR) usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or chronic kidney disease (CKD) patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.

Inhibition of KV7 channels causes rat renal vasoconstriction in vivo

We investigated the possible role of KV7 (KCNQ)‐channels in the control of rat renal vascular hemodynamics. We also investigated whether this family of K+ channels participated in the acetylcholine (ACh) mediated renal vasodilation.We measured renal blood flow (RBF) in vivo in Sprague Dawley rats using an ultrasonic flow probe. Basal RBF was 6.0 ± 0.38 ml/min (n=5). Intrarenal infusion of XE991 (a potent blocker of KV7.1‐7.5) at rates of 0.6 nmol/min and 6 nmol/min did not affect RBF (n=5). However, intrarenal infusion of XE991 for 1.5 min at rates of 15 nmol/min and 30 nmol/min (estimated plasma concentrations ~2.5 μM and 5 μM, respectively) significantly decreased RBF by 2.2 ± 0.6 % and 3.1 ± 0.8 %, respectively (n=5). After 4 min XE991 infusion the corresponding RBF decreases were 3.5 ± 0.8 % and 4.6 ± 0.8 %, respectively (n=5). Intrarenal ACh infusion at a rate of 3 nmol/min (estimated plasma concentration ~ 0.5 μM) increased RBF by 26 ± 2.8 % (n=3). Pretreatment with XE991 (30 nmol/min) for 1.5 min did not affect the response to ACh as RBF increased by 28 ± 2.9 % (n=3). In summary, we show that KV7 channels have a potential role in the regulation of renal hemodynamics. Furthermore, we find no indication that these channels play a role in ACh induced renal vasodilation. This study is supported by the Danish National Research Foundation, the Danish Heart Foundation, and the Lundbeck Foundation.