Measurement Of Renal Blood Flow Research Articles

Dynamic Shift Towards Increased O2 Consumption and Reduced Lactate Uptake During Acute Volume Expansion in Sprague Dawley (SD) Rats

Rationale: In a recent study (PMID: 37575482), we established a method to assess alterations in O2 and substance metabolism in the kidneys in conscious free moving rat. This involved the repeated collection of renal arteriovenous blood and urine, alongside continuous measurements (24/7) of renal blood flow (RBF) and blood pressure (BP). Our previous studies demonstrated that in SD rats, there is an augmentation in RBF and GFR following chronic salt loading. Additionally, total renal O2 consumption (VO2) increases while there is a decrease in the net consumption of lactate with a tendency for its increased production. We hypothesize that these changes are not exclusive to the chronic phase of salt-loading but can also manifest during rapid increases of RBF and GFR. The primary aim of this study was to establish an experimental model reflecting these dynamics. Methods: SD rat (male, 10 wk age fed 0.4 NaCl (LS) diet, n=8) were studied. The jugular vein and femoral vein and artery were catheterized together with the renal vein. FITC-inulin (2 mg/mL) dissolved in 2%BSA saline was infused at 1.0 mL/100 g body wt/h from jugular vein. RBF was measured with an ultrasonic flow probe (Transonic, Inc) on the left renal artery and BP was measured through an arterial catheter. Whole blood, collected from donor rats, was diluted by 20% with saline, and a 6 mL volume expansion was performed with this solution over 1 hour. Blood was collected from both the renal venous and arterial catheters and urine from a ureteral catheter before and after volume expansion. O2 content was measured by radiometer and plasma lactate measured with a high sensitivity L-lactate fluorescent assay kit (ab169557, abcam). The same experiment was performed without volume expansion (i.e., sham study). O2 and lactate delivery and consumption were calculated as follows: Delivery = arterial content (A) x RBF; Consumption = (A − renal venous content (RV)) x RBF; Extraction = (A-RV) / A. Results: BP increased from 101 ± 3 to 111 ± 4 mmHg (p<0.05), RBF increased from 5.4 ± 0.5 to 7.9 to 0.6 mL/min/g kidney weight (gkw) (p<0.05) by volume expansion. GFR increased from 0.94 ± 0.06 to 1.19 ± 0.08 mL/min/gkw (p<0.05). O2 delivery increased from 1.06 ± 0.09 to 1.61 ± 0.12 mL/min/gkw (p<0.05). O2 consumption (VO2) increased from 0.06 ± 0.01 to 0.08 ± 0.01 mL/min/gkw (p<0.05). The O2 extraction ratio remained unchanged. Both lactate consumption (0.94 ± 0.11 to 0.47 ± 0.11 mM/gkw, p<0.05) and extraction ratio (0.18 ± 0.01 to 0.11 ± 0.02, p<0.05) were reduced by volume expansion. Conclusion: The increase of O2 consumption and reduction of lactate consumption with acute volume expansion model appear to be similar to those that we observed when SD rats were subjected to a chronic step increase of salt intake (from 0.4 to 4.0% NaCl). In contrast, however, an increase in O2 extraction was not observed with acute volume expansion as was the case with a high salt diet in which our studies have indicated that a prolonged tubular reabsorptive workload leads to enhanced oxidative stress with an uncoupling of oxidative phosphorylation. R01 HL151587, AHA 23POST1008714. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physiological confounders of renal blood flow measurement.

Renal blood flow (RBF) is controlled by a number of physiological factors that can contribute to the variability of its measurement. The purpose of this review is to assess the changes in RBF in response to a wide range of physiological confounders and derive practical recommendations on patient preparation and interpretation of RBF measurements with MRI. A comprehensive search was conducted to include articles reporting on physiological variations of renal perfusion, blood and/or plasma flow in healthy humans. A total of 24 potential confounders were identified from the literature search and categorized into non-modifiable and modifiable factors. The non-modifiable factors include variables related to the demographics of a population (e.g. age, sex, and race) which cannot be manipulated but should be considered when interpreting RBF values between subjects. The modifiable factors include different activities (e.g. food/fluid intake, exercise training and medication use) that can be standardized in the study design. For each of the modifiable factors, evidence-based recommendations are provided to control for them in an RBF-measurement. Future studies aiming to measure RBF are encouraged to follow a rigorous study design, that takes into account these recommendations for controlling the factors that can influence RBF results.

Abstract 040: Evidence Of Increased Glycolysis In Renal Cortex Of High Salt Fed Sprague Dawley Rats

To determine whole kidney O 2 and substance metabolism in an unanesthetized state, arterial (A), renal venous (Vr) blood and urine (U) were analyzed together with measurements of renal blood flow (RBF), blood pressure (BP) and GFR in conscious freely moving male SD rats. RBF and BP were measured continuously (24/7) via chronically implanted ultrasonic flow probe and A-line respectively. A and Vr blood through chronically implanted catheters and urine (U) were sampled intermittently when rats were fed a 0.4% NaCl (LS) diet and on days 7, 14, and 21 after switching to a 4.0% NaCl (HS) diet (HS7, HS14, HS21). A and Vr O 2 contents were determined by radiometer and a global metabolomic analysis was performed at the JAX Laboratory (LC-MS-MS). GFR was determined in another group of rats by transcutaneous detection of the attenuation of i.v. injected FITC sinistrin. Cortical (Cx) and outer medullary (OM) tissues were obtained from the other group of rats and underwent metabolomic and mRNAseq analyses (Novogene). From another group of rats, glomeruli (Glo), proximal tubules (PT) and non-PT were isolated for RT-PCR. BP and RBF slightly increased by HS3 (P<0.05) and were sustained at these levels. O 2 extraction rose progressively from 0.10 ± 0.01 at LS to 0.14 ± 0.01 at HS21 (P<0.05). GFR increased from 0.64 to 0.83 mL/min/100 g (P<0.05) at HS7 and sustained. Na + reabsorption and O 2 consumption were positively correlated. Clear distinctions were observed in a sparse partial least squares discriminant analysis of tissue metabolomics among LS, HS14, and HS21. The mRNAseq analysis found that the HS diet resulted in the activation of immune system-related genes in both Cx and OM and the downregulation of genes related to the TCA cycle and metabolism of amino acids and fatty acids in Cx only. In contrast, glycolysis-related genes including hexokinase ( Hk ) and pyruvate kinase ( Pkm ) were upregulated in Cx. Metabolic fluxes (A-Vr-U) showed the increased release of lactate and pyruvate from the kidney when fed HS. Increased mRNA expression of Hk and Pkm in HS21 was observed only in PT but not in Glo and non-PT. In summary, SD rats fed a HS diet underwent changes in RBF, O 2 extraction, and utilization of substrates with evidence of increased glycolysis.

GABAergic and glutamatergic transmission reveals novel cardiovascular and urinary bladder control features in the shell nucleus accumbens

The shell Nucleus Accumbens (NAcc) projects to the lateral preoptic area, which is involved in the central micturition control and receives inputs from medullary areas involved in cardiovascular control. We investigated the role of GABAergic and glutamatergic transmission in the shell NAcc on intravesical pressure (IP) and cardiovascular control. Male Wistar rats with guide cannulas implanted bilaterally in the shell NAcc 7 days prior to the experiments were anesthetized with 2% isoflurane in 100% O2 and subjected to cannulation of the femoral artery and vein for mean arterial pressure (MAP) and heart rate recordings (HR) and infusion of drugs, respectively. The urinary bladder (UB) was cannulated for IP measurement. A Doppler flow probe was placed around the renal arterial for renal blood flow (RBF) measurement. After the baseline MAP, HR, IP and RBF recordings for 15 min, GABA or bicuculline methiodate (BMI) or L-glutamate or kynurenic acid (KYN) or saline (vehicle) were bilaterally injected into the shell NAcc and the variables were measured for 30 min. Data are as mean ± SEM and submitted to Student́s t test. GABA injections into the shell NAcc evoked a significant fall in MAP and HR and increased IP and RC compared to saline. L-glutamate in the shell NAcc increased MAP, HR and IP and reduced RC. Injections of BMI and KYN elicited no changes in the variables recorded. Therefore, the GABAergic and glutamatergic transmissions in neurons in the shell NAcc are involved in the neural pathways responsible for the central cardiovascular control and UB regulation.

Point-of-care Ultrasound to Assess Hemodynamic Contributors to Acute Kidney Injury in Pediatric Patients With Cerebral Malaria: A Pilot Study.

Acute kidney injury is common in severe malaria and is independently associated with mortality. The pathogenesis of acute kidney injury (AKI) in severe malaria remains incompletely understood. Ultrasound-based tools such as point-of-care ultrasound (POCUS), ultrasound cardiac output monitors (USCOMs) and renal arterial resistive index (RRI) can be used to detect hemodynamic and renal blood flow abnormalities contributing to AKI in malaria. We conducted a prospective study of Malawian children with cerebral malaria to determine the feasibility of using POCUS and USCOM to characterize hemodynamic contributors to severe AKI (Kidney Disease: Improving Global Outcomes stage 2 or 3). The primary outcome was feasibility (completion rate of study procedures). We also assessed for differences in POCUS and hemodynamic variables for patients with or without severe AKI. We enrolled 27 patients who had admission cardiac and renal ultrasounds and USCOM. Completion rates were high for cardiac (96%), renal (100%) and USCOM studies (96%). Severe AKI occurred in 13 of 27 patients (48%). No patients had ventricular dysfunction. Only 1 patient in the severe AKI group was determined to be hypovolemic ( P = 0.64). No significant differences in USCOM, RRI or venous congestion parameters were detected among patients with and without severe AKI. Mortality was 11% (3/27) with the 3 deaths occurring in the severe AKI group ( P = 0.056). Ultrasound-based cardiac, hemodynamic and renal blood flow measurements appear to be feasible in pediatric patients with cerebral malaria. We were unable to detect hemodynamic or renal blood flow abnormalities contributing to severe AKI in cerebral malaria. Larger studies are needed to corroborate these findings.

Metabolic Responses of Normal Rat Kidneys to a High Salt Intake.

In this study, novel methods were developed, which allowed continuous (24/7) measurement of arterial blood pressure and renal blood flow in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O2 and metabolites. Specifically, the study determined the effects of a high salt (HS; 4.0% NaCl) diet upon whole kidney O2 consumption and arterial and renal venous plasma metabolomic profiles of normal Sprague-Dawley rats. A separate group of rats was studied to determine changes in the cortex and outer medulla tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to 4.0% NaCl diet. In addition, targeted mRNA expression analysis of cortical segments was performed. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O2 consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. A novel finding was the increased expression of glycolysis-related genes in Cx and isolated proximal tubular segments in response to an HS diet, consistent with increased release of pyruvate and lactate from the kidney to the renal venous blood. Data suggests that aerobic glycolysis (eg, Warburg effect) may contribute to energy production under these circumstances. The study provides evidence that kidney metabolism responds to an HS diet enabling enhanced energy production while protecting from oxidative stress and injury. Metabolomic and transcriptomic analysis of kidneys of Sprague-Dawley rats fed a high salt diet.

Renal blood flow during exercise: understanding its measurement with Doppler ultrasound.

The sympathetic nervous system (SNS) has a critical role in continuously coordinating responses to stimuli internal and external to the human body by appropriately modulating the activity of the organs it innervates. The SNS is activated in response to various physiological stressors, including exercise, which can involve a significant increase in SNS activity. An increase in SNS activity directed toward the kidneys causes vasoconstriction of afferent arterioles within the kidneys. This sympathetically mediated renal vasoconstriction decreases renal blood flow (RBF), causing significant blood flow redistribution toward active skeletal muscles during exercise. In research studies, different modes, intensities, and durations of exercise have been used to investigate the sympathetically mediated RBF response to exercise, and several methodological approaches have been used to quantify RBF. Doppler ultrasound provides noninvasive, continuous, real-time measurements of RBF and has emerged as a valid and reliable technique to quantify RBF during exercise. This innovative methodology has been applied in studies in which the RBF response to exercise has been examined in healthy young and older adults and patient populations such as those with heart failure and peripheral arterial disease. This valuable tool has enabled researchers to produce clinically relevant findings that have furthered our understanding of the effect of SNS activation on RBF in populations of health and disease. Therefore, the focus of this narrative review is to highlight the use of Doppler ultrasound in research studies that have provided important findings furthering our knowledge of the impact of SNS activation on RBF regulation in humans.

GLP-1 Promotes Cortical and Medullary Perfusion in the Human Kidney and Maintains Renal Oxygenation During NaCl Loading.

Background GLP-1 (glucagon-like peptide-1) receptor agonists exert beneficial long-term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is accompanied by suppression of angiotensin II, and is independent of changes in renal plasma flow. In rodents, angiotensin II constricts vasa recta and lowers medullary perfusion. The current randomized, controlled, crossover study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans. Methods and Results Healthy male participants (n=10, aged 27±4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg per minute) or placebo together with infusion of 0.9% NaCl (750 mL/h). Interleaved measurements of renal arterial blood flow, oxygenation (R2*), and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. GLP-1 infusion increased medullary perfusion (32±7%, P<0.001) and cortical perfusion (13±4%, P<0.001) compared with placebo. Here, NaCl infusion decreased medullary perfusion (-5±2%, P=0.007), whereas cortical perfusion remained unchanged. R2* values increased by 3±2% (P=0.025) in the medulla and 4±1% (P=0.008) in the cortex during placebo, indicative of decreased oxygenation, but remained unchanged during GLP-1. Blood flow in the renal artery was not altered significantly by either intervention. Conclusions GLP-1 increases predominantly medullary but also cortical perfusion in the healthy human kidney and maintains renal oxygenation during NaCl loading. In perspective, suppression of angiotensin II by GLP-1 may account for the increase in regional perfusion. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04337268.

Divergent roles of angiotensin II upon the immediate and sustained increases of renal blood flow following unilateral nephrectomy.

Although the molecular and functional responses related to renal compensatory hypertrophy after unilateral nephrectomy (UNX) has been well described, many aspects of these events remain unclear. One question is how the remaining kidney senses the absence of the contralateral organ, and another is what the role of the renin-angiotensin system is in these responses. Both acute anesthetized and chronic unanesthetized experiments were performed using the angiotensin II type 1 receptor blocker losartan and the renin inhibitor aliskiren to determine the contribution of the renin-angiotensin system to immediate changes and losartan for chronic changes of renal blood flow (RBF) and the associated hypertrophic events in male Sprague-Dawley rats. Chronic experiments used implanted RBF probes and arterial catheters for continuous data collection, and the glomerular filtration rate was determined by noninvasive transcutaneous FITC-sinistrin measurements. The results of the acute experiments found that RBF increased nearly 25% (4.6 ± 0.5 to 5.6 ± 0.6 mL/min/g kidney wt) during the first 15 min following UNX and that this response was abolished by losartan (6.7 ± 0.7 to 7.0 ± 0.7 mL/min/g kidney wt) or aliskiren (5.8 ± 0.4 to 6.0 ± 0.4 mL/min/g kidney wt) treatment. Thereafter, RBF increased progressively over 7 days, and kidney weight increased by 19% of pre-UNX values. When normalized to kidney weight determined at day 7 after UNX, RBF was not significantly different from pre-UNX levels. Semiquantification of CD31-positive capillaries revealed increases of the glomeruli and peritubular capillaries that paralleled the kidney hypertrophy. None of these chronic changes was inhibited by losartan treatment, indicating that neither the compensatory structural nor the RBF changes were angiotensin II type 1 receptor dependent.NEW & NOTEWORTHY This study found that the immediate increases of renal blood flow (RBF) following unilateral nephrectomy (UNX) are a consequence of reduced angiotensin II type 1 (AT1) receptor stimulation. The continuous monitoring of RBF and intermittent measurement of glomerular filtration rate (GFR) in conscious rats during the 1-wk period of rapid hypertrophy following UNX provided unique insights into the regulation of RBF and GFR when faced with increased metabolic loads. It was found that neither kidney hypertrophy nor the associated increase of capillaries was an AT1-dependent phenomenon.

Long-Term Continuous Measurement of Renal Blood Flow in Conscious Rats.

The kidneys play a crucial role in maintaining the homeostasis of body fluids. The regulation of renal blood flow (RBF) is essential to the vital functions of filtration and metabolism in kidney function. Many acute studies have been carried out in anesthetized animals to measure RBF under various conditions to determine mechanisms responsible for the regulation of kidney perfusion. However, for technical reasons, it has not been possible to measure RBF continuously (24 h/day) in unrestrained unanesthetized rats over prolonged periods. These methods allow the continuous determination of RBF over many weeks while also simultaneously recording blood pressure (BP) with implanted catheters (fluid-filled or by telemetry). RBF monitoring is carried out with rats placed in a circular servo-controlled rat cage that enables the unrestrained movement of the rat throughout the study. At the same time, the tangling of cables from the flow probe and arterial catheters is prevented. Rats are first instrumented with an ultrasonic flow probe placement on the left renal artery and an arterial catheter implanted in the right femoral artery. These are routed subcutaneously to the nape of the neck, and connected to the flowmeter and pressure transducer, respectively, to measure RBF and BP. Following surgical implantation, rats are immediately placed in the cage to recover for at least one week and stabilize the ultrasonic probe recordings. Urine collection is also feasible in this system. The surgical and post-surgical procedures for continuous monitoring are demonstrated in this protocol.

Long-Term Continuous Measurement of Renal Blood Flow in Conscious Rats

Long-Term Continuous Measurement of Renal Blood Flow in Conscious Rats

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

BACKGROUND: Reactive oxygen species and cytokines are the main players in the development of renal ischemia-reperfusion (I/R) injury. AIM: The current study aimed to evaluate the effects of carvedilol and/or glibenclamide and the interaction between autophagy and oxidative stress. METHODS: 50 male rats were divided into five groups: Control, IR injury (IRI), carvedilol pretreated, glibenclamide pretreated, and combined carvedilol and glibenclamide pretreated. Measurements of renal blood flow (RBF), creatinine clearance, serum blood urea nitrogen (BUN), histopathological, and immunohistochemical evaluation of autophagy marker Becl-1 in the rat kidney were performed. Beclin-1and light chain 3 (LC3) Mrna expression was detected by real time polymerase chain reaction. RESULTS: IRI was associated with significant increases in BUN, tumor necrosis factor-alpha, nuclear factor κB, and histo (H) score value of Becl-1. However, there was a significant decrease in RBF, creatinine clearance, and glutathione peroxidase compared to the control group. There was significant increase in Beclin-1 and LC3 mRNA gene expression in carvedilol, glibenclamide, and combined treatment groups as compared to IRI and control groups. Combination of carvedilol and glibenclamide significantly restored IRI changes when compared with the other pretreated groups. CONCLUSION: This study suggests that carvedilol and glibenclamide are promising reno-protective drugs to reduce renal injury induced by I/R through their antioxidant and autophagy stimulation.

Renal hemodynamics across the adult lifespan: Relevance of flow pulsatility to chronic kidney disease.

Elevated renal flow pulsatility may contribute to the pathogenesis of chronic kidney disease (CKD). The purpose of this study was to investigate the associations among age, renal flow pulsatility, and CKD biomarkers in non-CKD adults and CKD patients. Non-CKD adults (n=415) and CKD patients (n=136) aged between 22 and 83years underwent the renal blood flow measurement using duplex ultrasonography. Pulsatility index (PI) and resistive index (RI) were calculated to assess renal flow pulsatility. The CKD biomarkers such as urinary liver-type fatty acid-binding protein (L-FABP) and serum fibroblast growth factor 23 (FGF23) were measured from each participant. Aortic hemodynamic parameters were measured by applanation tonometry. In non-CKD adults, advancing age was associated with elevations of renal PI and RI which slowly increased during middle-aged (PI: β=0.14, RI: β=0.17) and accelerated in older adults (PI: β=0.34, RI: β=0.33). In CKD patients, age-related increases in renal PI and RI were observed only in the middle age group (PI: β=0.23, RI: β=0.26). Multivariate analysis demonstrated that renal PI and RI were independently associated with CKD biomarkers, including urinary L-FABP and serum FGF23, and aortic pulse pressure. Advancing age is associated with a progressive elevation of renal flow pulsatility which manifests during middle age and accelerates in later life. Moreover, elevated renal flow pulsatility is associated with the presence of CKD in each age group and also with biomarker levels that reflect CKD progression.

Fetal renal artery blood flow - Normal ranges.

The study objectives were to develop standard charts for fetal renal artery blood flow to define normal ranges and to assess the reliability of the measurements. This prospective, longitudinal study reviewed 72 low-risk singleton pregnancies who had serial ultrasound examinations. Pulse wave Doppler was used to obtain the resistivity and pulsatility indices of the fetal renal arteries. Standard charts of the fetal renal arteries were created using mixed effects modelling and the intra- and interobserver reliability for the renal blood flow measurements was analysed. Standard charts of the normal ranges of the renal artery resistive index (RI) and pulsatility index (PI) of the fetal renal arteries were created. The 3rd, 5th, 10th, 50th, 90th, 95th and 97th centiles were calculated. The intraclass correlation coefficient was acceptable for intraobserver reliability (RI = 0.66, PI = 0.88) and poor for interobserver reliability (RI = 0.11, PI = -0.56). These novel charts demonstrate the change of the fetal renal artery blood flow during pregnancy. These may be used in clinical practice to detect variations from these normal ranges and be useful in future studies of kidney function projection.

High Salt Diet Increases Renal Oxygen Consumption in Sprague‐Dawley Rats

The physiological relationships between kidney O2 delivery and consumption and metabolism have been studied only under conditions of anesthesia and stressful surgical procedures. We report here techniques developed in our laboratory enabling determination of kidney O2 utilization over many days in instrumented unanesthetized rats in which the effects of a high salt diet were determined in normal Sprague Dawley (SD) rats. Male SD rats (10 weeks of age) fed a 0.4% NaCl diet were instrumented with a left renal artery flow probe (Transonic) for continuous (24 hr/day) measurement of renal blood flow (RBF). An indwelling intra-renal vein catheter (MRE 025) was inserted through the femoral vein and tip fixed close to the renal pelvis. An aortic catheter inserted though the femoral artery was implanted to sample blood and continuously (24 hr/day) measure arterial blood pressure (BP). Catheters and flow probe cables which exited from the neck were attached to a custom designed swivel and a servo-controlled circular cage system (BASi cage) enabling the rat to move freely throughout the study. Following 7 days of recovery from surgery, continuous monitoring of RBF and BP began and continued throughout the study. Following a 3 day control period with rats fed a 0.4% NaCl diet, renal venous and arterial blood were samples (250 ul) and blood gas was measured immediately by a radiometer (ABL800 FLEX). The diet was switch to 4% NaCl and blood sampling was performed at days 7, 14 and 21 of the high salt diet. O2 content, O2 consumption, and O2 extraction were determined as: O2 content (mL/dL): 0.31 × Hemoglobin (Hb) (g/dL) × HbO­2 (%) + 0.003 × PaO2 (mmHg). O2 consumption (ml/min): RBF (ml/min) × (arterial-renal venous O2 content difference). O2 extraction (% of arterial supply): 1-(renal venous O2 content/arterial O2 content) × 100. Daily average mean arterial pressure (MAP) increased moderately soon after switching to the 4% NaCl diet from 113 ± 2 to 120 ± 2 mmHg by day 3 (p=0.03, n=9) and remain elevated at this level throughout the study (120 ± 3 mmHg at day 13). Renal blood flow also rose soon after switching to the 4% salt diet from 9.4 ± 0.8 to 10.3 ± 0.8 ml/min during day 2 (p=0.03, n=9) . Thereafter, it also remained elevated throughout the study (10.7 ± 0.8 ml/min at day 13). Changes in O2 consumption occurred more gradually increasing from 0.21 ± 0.04 and rising to 0.27 ± 0.03 (ml/min) at day 14 of 4% salt diet (p=0.02, n=5). The calculated O2 extraction ratio remained unchanged ranging from 12.1 ± 0.1 (%) to 12.8 ± 0.1 (%) (p=0.48, n=5) throughout the study. It appears that in normal SD rats, the increased tubular metabolic work associated with a high salt diet is initially accommodated by increased perfusion (RBF) and a gradual increase of O2 consumption while extraction remains unchanged for a two-week period.

DETECTION OF CHANGES IN RENAL BLOOD FLOW USING ARTERIAL SPIN LABELING MRI

Objective: Alteration in kidney perfusion is an early marker of renal damage. Magnetic resonance imaging (MRI) with arterial spin labeling (ASL) is a noninvasive approach to measure renal blood flow (RBF) without the use of contrast media. The purpose of this study consisting of two experiments was to evaluate whether both acute and short-term changes in RBF could be detected using ASL-MRI technique. Design and method: RBF as assessed by cortical (CRBF), medullary, and total renal blood flow (TRBF) were measured by ASL-MRI using FAIR True-FISP sequence. In the first experiment with 11 normotensive healthy individuals (NT) and 11 hypertensive patients (HT), RBF was measured at baseline and after both feet were covered with cold ice packs (cold pressor test) that activates the sympathetic nervous system. In the second experiment, RBF was measured in patients with chronic kidney disease (CKD) before and after a pharmacological intervention. Results: A significant reduction in CRBF (p = 0.042) and a trend in TRBF (p = 0.053) were observed in response to the activation of the sympathetic nervous system in both NT individuals and HT patients (Table 1). In the second experiment, a trend towards reduction of CRBF (p = 0.051) and TRBF (p = 0.059) has been detected after pharmacological intervention. An evaluation of RBF measurements between three different study populations reveals that TRBF were significantly lower in patients with HT (309.5 ± 17.3 mL/100 g/min) and CKD patients (260.4 ± 29.1 mL/100 g/min) compared to NT individuals (338.7 ± 30.0 mL/100 g/min) (NT vs. HT-p = 0.014, NT vs. CKD-p = 0.004). TRBF was also lower in patients with CKD compared to HT (p = 0.047). Conclusions: Our data indicate that both acute and short-term changes in RBF could be detected using ASL-MRI. Moreover, we were able to detect differences in RBF between healthy and diseased individuals by needing only small sample size per group. Thus, ASL-MRI offers an advantage in conducting clinical trials compared to other technologies.

Detection of Changes in Renal Blood Flow Using Arterial Spin Labeling MRI

Background: Alteration in kidney perfusion is an early marker of renal damage. The purpose of this study was to evaluate if changes in renal blood flow (RBF) could be detected using MRI with arterial spin labeling (ASL) technique. Methods: RBF as assessed by cortical (CRBF), medullary, and total renal blood flow (TRBF) were measured by MRI with arterial spin labeling (ASL-MRI) using flow-sensitive alternating inversion recovery true fast imaging with steady-state precession sequence. In 11 normotensive healthy individuals (NT) and 11 hypertensive patients (HT), RBF was measured at baseline and after both feet were covered with cold ice packs (cold pressor test) that activates the sympathetic nervous system. In another experiment, RBF was measured in 10 patients with CKD before and after a pharmacological intervention. We compared RBF measurements between the 3 study populations. Results: A significant reduction in CRBF (p = 0.042) and a trend in TRBF (p = 0.053) were observed in response to the activation of the sympathetic nervous system. A trend toward reduction of CRBF (p = 0.051) and TRBF (p = 0.059) has been detected after pharmacological intervention. TRBF was significantly lower in patients with HT and CKD patients compared to NT individuals (NT vs. HT, p = 0.014; NT vs. CKD, p = 0.004). TRBF was lower in patients with CKD compared to HT (p = 0.047). Conclusion: Our data indicate that both acute and short-term changes in RBF could be detected using ASL-MRI. We were able to detect differences in RBF between healthy and diseased individuals by needing only small sample size per group. Thus, ASL-MRI offers an advantage in conducting clinical trials compared to other technologies.

Consensus-Based Technical Recommendations for Clinical Translation of Renal Phase Contrast MRI.

BackgroundPhase‐contrast (PC) MRI is a feasible and valid noninvasive technique to measure renal artery blood flow, showing potential to support diagnosis and monitoring of renal diseases. However, the variability in measured renal blood flow values across studies is large, most likely due to differences in PC‐MRI acquisition and processing. Standardized acquisition and processing protocols are therefore needed to minimize this variability and maximize the potential of renal PC‐MRI as a clinically useful tool.PurposeTo build technical recommendations for the acquisition, processing, and analysis of renal 2D PC‐MRI data in human subjects to promote standardization of renal blood flow measurements and facilitate the comparability of results across scanners and in multicenter clinical studies.Study TypeSystematic consensus process using a modified Delphi method.PopulationNot applicable.Sequence Field/StrengthRenal fast gradient echo‐based 2D PC‐MRI.AssessmentAn international panel of 27 experts from Europe, the USA, Australia, and Japan with 6 (interquartile range 4–10) years of experience in 2D PC‐MRI formulated consensus statements on renal 2D PC‐MRI in two rounds of surveys. Starting from a recently published systematic review article, literature‐based and data‐driven statements regarding patient preparation, hardware, acquisition protocol, analysis steps, and data reporting were formulated.Statistical TestsConsensus was defined as ≥75% unanimity in response, and a clear preference was defined as 60–74% agreement among the experts.ResultsAmong 60 statements, 57 (95%) achieved consensus after the second‐round survey, while the remaining three showed a clear preference. Consensus statements resulted in specific recommendations for subject preparation, 2D renal PC‐MRI data acquisition, processing, and reporting.Data ConclusionThese recommendations might promote a widespread adoption of renal PC‐MRI, and may help foster the set‐up of multicenter studies aimed at defining reference values and building larger and more definitive evidence, and will facilitate clinical translation of PC‐MRI.Level of Evidence1Technical Efficacy Stage1

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol

BackgroundDiabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim).MethodsiBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes.DiscussioniBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D.Trial registrationClinicaltrials.gov (NCT03716401).

P0544INHIBITION OF 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE (15-PGDH) PROTECTS MICE AGAINST CONTRAST-INDUCED ACUTE KIDNEY INJURY

Abstract Background and Aims Although the mechanism of contrast-induced acute kidney injury (CI-AKI) is not fully known, the imbalance of vasoconstrictive and vasodilative mediators plays a major role. Prostaglandin E2 (PGE2) is one of the vasodilators involved in this process. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) causes elevation of PGE2 level in tissue by delaying the rapid degradation of PGE2 by the enzyme. We tested the hypothesis that the 15-PGE2 inhibitor would protect against CI-AKI in a mouse model and attempted to elucidate the mechanism involved. Method 10-week aged male C57/BL6 Mice were injected with 10gI/kg of iodixanol by tail vein. Renal blood flow measurement, right nephrectomy, and blood sampling were taken at 48 hours after iodixanol injection. The 15-PGDH inhibitor was injected before and after iodixanol administration. Plasma creatinine, NGAL, KIM-1 were measured as biomarkers for renal function. Histological evaluation was analyzed by the necrosis scoring system and TUNEL assay. Arteriolar area of outer medulla was analyzed by α-smooth muscle actin stain. Renal blood flow was measured by the non-invasive laser doppler. Results Plasma creatinine (1.94±0.75 vs 1.11±0.44 mg/dL, p=0.005), NGAL (299.7±115.87 vs 140.4±76.56 ng/mL, p=0.004), and KIM-1 (2.09±2.34 vs 0.43±0.89 ng/mL, p=0.024) levels were significantly lower when the 15-PGDH inhibitor was injected before and after iodixanol administration than the vehicle group. But no significant renal protective effect was shown when the 15-PGDH inhibitor was injected before or after iodixanol administration. The 15-PGDH inhibitor administration before and after iodixanol injection showed a significantly wider renal arteriolar area (683.63±248.46 vs 1132.97±357.46 μm2, p=0.039) and larger renal blood flow (360.0±49.72 vs 635.1±27.20, p=0.011) than vehicle administration. Conclusion The 15-PGDH inhibitor has a renal protective effect against CI-AKI in mice by increasing renal blood flow when injected intravenously before and after iodine contrast media administration.