Effects of glucagon-like peptide-1 on systemic hemodynamics, kidney function, and intrarenal oxygenation in sheep with sepsis-associated acute kidney injury

Effects of glucagon-like peptide-1 on systemic hemodynamics, kidney function, and intrarenal oxygenation in sheep with sepsis-associated acute kidney injury | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effects of glucagon-like peptide-1 on systemic hemodynamics, kidney function, and intrarenal oxygenation in sheep with sepsis-associated acute kidney injury Abraham H. Hulst, Connie P.C. Ow, Clive N May, Sally G Hood, Mark P. Plummer, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7445170/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce chronic kidney disease progression in people with type 2 diabetes mellitus. Sepsis is the leading cause of acute kidney injury (AKI). This study investigated whether GLP-1 is renoprotective in an ovine model of gram-negative septic AKI. Methods Sixteen healthy merino ewes were surgically instrumented to measure mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion and oxygenation, and renal function. After a 5-day recovery period, sepsis was induced via continuous intravenous infusion of live Escherichia coli for 30 hours. After 24 hours, the sheep were randomized to receive an intravenous infusion of 3.6 pmol/kg/min GLP-1 (n = 8) or a fluid-matched vehicle (n = 8) for 6 hours. Results After 24 hours of sepsis, 7/8 sheep in each group developed oliguria, which was consistent with the criteria for AKI. Compared with vehicle, GLP-1 significantly increased renal blood flow (p = 0.0054), renal oxygen delivery (p = 0.0032), and renal cortical oxygenation (p < 0.001) and improved renal medullary perfusion (p = 0.029) during the intervention period. However, GLP-1 did not significantly improve the primary endpoint of renal medullary oxygenation (p = 0.115). Conclusion In an ovine model of gram-negative sepsis-associated AKI, GLP-1 infusion improved global renal perfusion, renal oxygen delivery, and cortical oxygenation but failed to improve renal medullary oxygenation and kidney function. Health sciences/Diseases Health sciences/Medical research Health sciences/Nephrology Biological sciences/Physiology glucagon-like peptide-1 Sepsis Acute kidney injury Medullary oxygenation Sheep Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Sepsis is the leading cause of acute kidney injury (AKI) in intensive care units (ICUs). 1 Compared with either disease alone, sepsis-associated AKI (SA-AKI) has a worse prognosis. 1 , 2 SA-AKI is associated with a prolonged length of stay in the ICU, increased mortality, increased likelihood of developing chronic kidney disease, and reduced quality of life. 3 – 6 The consensus among intensivists for managing patients at risk of AKI due to sepsis is as follows: preservation of tissue oxygenation, correction of hypovolemia and hypotension, and avoidance of nephrotoxins. However, apart from these generalized interventions, no specific targeted protective therapies exist to treat or prevent AKI in patients with sepsis. 7 Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is an established therapy for patients with type 2 diabetes that improves glucose control, induces weight loss, and reduces major adverse cardiovascular events. In these studies, GLP-1 RAs also reduced the incidence of important kidney events and kidney failure. 8 In addition, a mechanistic imaging study revealed that GLP-1 increases the perfusion and oxygenation of healthy human kidneys. 9 The effects of GLP-1 have been evaluated clinically in patients admitted to the ICU for their effects on blood glucose and gastric emptying. 10 To date, the effects of GLP-1 on renal macro- and microcirculation, kidney function and renal histopathology have not been studied in the context of sepsis-associated AKI. We aimed to investigate whether GLP-1 infusion could alleviate renal tissue hypoperfusion and hypoxia in an ovine model of live gram-negative SA-AKI. We hypothesized that GLP-1 would improve renal cortical and medullary tissue perfusion, oxygenation and kidney function in sheep with established septic AKI. Materials and methods Animals Sixteen healthy female merino ewes (35–45 kg body weight) were housed in individual metabolic cages with free access to water and 800 g/day oaten chaff. The animals were procured from a farm in Central Victoria, Australia, and delivered into our facility at the Florey Institute for acclimatization before any experimentation. The Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health (Ethics identification number: 21-030-FINMH) approved these experiments under the guidelines of the National Health and Medical Research Council of Australia. All methods and procedures were performed according to these guidelines and regulations. This report was written in accordance with the ARRIVE 2.0 guidelines. 11 The ewes underwent two aseptic surgical procedures under general anesthesia, described in detail previously 12 – 21 and summarized below. Anesthesia was induced with intravenous sodium thiopentone (15 mg/kg, Jurox Pty Ltd, Rutherford, NSW, Australia) and maintained with isoflurane (2.0–2.5% v/v oxygen/air/isoflurane) following intubation. Prior to incision, the sheep was given 900 mg of the antibiotic procaine penicillin (Ilium Propercillin, Troy Laboratories, Glendenning, NSW, Australia) and 1 mg/kg of the analgesic flunixin meglumine (Ilium Flunixil, Troy Laboratories). First, the left carotid artery was exteriorized into a skin fold to form a carotid arterial loop for subsequent access to arterial cannulation. 15 , 19 A 20-mm transit-time flow probe (Transonic Systems, Ithaca, NY) for cardiac output (CO) measurement was placed around the pulmonary artery. 15 Three weeks later, the carotid artery was cannulated and connected to a pressure transducer for measurement of systolic, diastolic, and mean arterial pressure (SBP, DBP, and MAP), heart rate and blood sampling. 19 Three catheters were inserted into the right jugular vein: one for delivery of treatment, one for administering E. coli , and one for fluid resuscitation and vasopressors, as needed. The arterial and venous catheters were continuously infused with heparinized saline (10 U heparin/mL at 3 mL/hr) to maintain patency. During the second surgical procedure, a 4-mm transit-time flow probe (Transonic Systems) was placed around the left renal artery to measure renal blood flow (RBF), 15 and the left renal vein was cannulated for blood sampling. Two fiber-optic probes (Oxford Optronix, Abingdon, United Kingdom) were inserted into the renal cortex and medulla to measure renal cortical and medullary oxygenation (PrcO 2 , RrmO 2 ) and perfusion (RCP, RMP). 13 , 20 A Foley catheter was inserted into the bladder with a fiber-optic probe inserted into the tip to measure partial urinary oxygen pressure (PuO 2 ). 12 , 13 For both surgical procedures, the animals were injected with intramuscular antibiotics (900 mg procaine penicillin, Ilium Propen, Troy Laboratories, Smithfield, NSW, Australia) and analgesics (Flunixin meglumine, 1 mg/kg; Troy Laboratories or Mavlab) at the start of surgery and 24 and 48 hours after surgery. 13 , 16 , 21 The animals were allowed at least five days after the second surgical procedure to recover prior to experimental intervention. Experimental Protocol Experimental Protocol A schematic representation of the experimental protocol and data collection time points is depicted in Fig. 1 . Following a 24-hour baseline period, sepsis was induced in nonanesthetized sheep with an intravenous dose of live E. coli (2.8×10 9 colony-forming units [CFUs] over 30 min) as a bolus, followed by a continuous infusion (1.26 × 10 9 CFU/hr for the rest of the experiment). At 23.5 hours of sepsis, fluid bolus therapy with Hartmann’s solution (Baxter Australia, 30 mL/kg over 30 min) was administered. 21 At 24 h after sepsis, the animals were randomized via online software built into electronic data capture software (Castor EDC, Castor B.V., Amsterdam, Netherlands). The animals in the intervention group received an IV GLP-1 infusion of 3.6 pmol/kg/min for six hours (Bachem AG., Bubendorf, Switzerland) dissolved in 20% Albumin (CSL Behring, Broadmeadows, VIC, Australia). This is a clinically effective dose, as indicated by previous studies in critically ill patients in which no major adverse events were reported. 22 The animals in the comparator group received an equal volume of vehicle solution with 20% Albumin. At the end of the protocol, the animals were euthanized with a lethal dose of sodium pentobarbitone (100 mg/kg, IV). The positions of the renal fiber-optic probes were confirmed at autopsy, and kidney biopsies were taken for histopathological assessment. 21 Data collection A computer with a CED 1401 interface running a data acquisition system (Spike 2 Software, Cambridge Electronic Design, Cambridge, United Kingdom) continuously recorded analog signals (MAP, heart rate, CO, renal blood flow, RCP, RMP, PrcO 2, and RrmO 2 , temperature, and PuO 2 ) at 100 Hz. Renal vascular conductance (RVC) was calculated as RBF/MAP. Stroke volume (SV) was calculated as CO/heart rate. We calculated the body surface area (BSA) as 0.09*weight (0.67) , and the cardiac index (CI) and stroke volume index (SVI) were calculated as the CO/BSA and SV/BSA, respectively. We recorded the hourly urine flow and collected 1-hourly urine samples at baseline and at 24, 26, 28, and 30 h after the induction of sepsis, corresponding to before the start of the intervention and 2, 4, and 6 h after the intervention, respectively. Urine samples were collected for measurement of creatinine and sodium concentrations and subsequent analysis of renal excretory function. Arterial and renal venous blood samples were collected at baseline, just prior to the infusion of E. coli , and subsequently at 24, 26, 28, and 30 hours of sepsis for the measurement of blood oximetry (ABL System 625, Radiometer Medical, Copenhagen, Denmark), creatinine, and glucose. The occurrence of AKI was based on the “Kidney Disease: Improving Global Outcomes (KDIGO)” clinical criteria; stage 1 AKI is characterized by a > 1.5-fold increase in plasma creatinine or oliguria of 0.5 ml/kg/h for > 6 hours. Statistical analysis Data are reported as the mean ± SD, and between-group differences are reported as the difference with a 95% confidence interval (95% CI). All outcome measurements are reported as the absolute changes from the start of the intervention period. 23 The data were analyzed via repeated-measures analysis of variance (ANOVA) with the factors intervention (P Intervention : vehicle or GLP-1) and time (P Time ). The treatment effect was evaluated on the basis of the interaction term P Intervention*Time . Given its critical role in the development of AKI, we defined renal medullary tissue oxygenation as the primary outcome. 17 On the basis of previous studies, detecting a 50% improvement in medullary tissue oxygenation (mean pO 2 = 10 ± 9) with 90% power and α = .05 required a sample size of eight sheep per group. 17 The histological assessment of kidney tissues was performed according to the semiquantitative histological scoring system 24 by a pathologist blinded to group allocation and analyzed with Fisher’s exact test. Statistical analysis was performed via GraphPad PRISM 6.0 (GraphPad Software, La Jolla, CA). All variables were assessed for normality and log-transformed where appropriate. A two-sided P value less than or equal to 0.05 was considered statistically significant without correction for multiple comparisons. Results The body weights of sheep treated with GLP-1 (38.9 ± 4.5 kg; n = 8) were similar to those of sheep treated with vehicle (39.4 ± 3.5 kg; n = 8). During the 24-hour period of sepsis induction, the sheep in both groups developed changes in hemodynamics and organ dysfunction consistent with sepsis, including hyperdynamic circulation with reductions in blood pressure, arterial oxygenation, and renal medullary oxygenation. Creatinine clearance and urine output decreased as plasma creatinine increased, which is consistent with the development of acute kidney injury (Table 1 ). No animals died during the 30-hour period after the infusion of E. coli commenced. No animals were excluded from the analysis. Table 1 Changes in systemic hemodynamics, global and regional kidney perfusion, oxygenation, and renal function from baseline (premorbid) to 24 hours of gram-negative sepsis in nonanesthetized sheep in both treatment groups. GLP-1 group (n = 8) Vehicle group (n = 8) Systemic and renal variables Before sepsis (0 h) End sepsis (23.5 h) Before sepsis (0 h) End sepsis (23.5 h) Mean arterial pressure (MAP, mmHg) 90 ± 14 75 ± 7.9 * 88 ± 13 83 ± 9.9 * Heart rate (HR, bpm) 75 ± 5.8 106 ± 21 * 77 ± 16 138 ± 28 * Cardiac output (CO, l/min) 4.0 ± 0.4 5.3 ± 0.8 * 4.6 ± 0.7 5.8 ± 1.9 * Systemic vascular resistance (SVR, mmHg/ml/min) 22 ± 4.4 15 ± 2.9 * 20 ± 2.8 17 ± 11 * Urine Output (UO, ml/kg/h) 1.5 ± 0.6 0.9 ± 0.9 * 1.3 ± 0.6 0.9 ± 0.3 * Urinary Oxygenation (PuO 2 , mmHg) 37 ± 12 23 ± 14 * 27 ± 11 16 ± 16 * AKI grade 1 (UO 6 h) 0/8 7/8 * 0/8 7/8 * Creatinine clearance (ml/min) 86 ± 31 52 ± 14 * 85 ± 14 58 ± 26 * Plasma creatinine (µmol/l) 65.5 ± 11.3 109.3 ± 34.1 * 63.6 ± 8.7 101.4 ± 16.4 * Plasma lactate (mmol/l) 0.6 ± 0.1 1.1 ± 0.5 * 0.5 ± 0.1 1.4 ± 0.6 * Arterial oxygen tension (PaO 2, mmHg) 106 ± 18 95 ± 9.3 * 95 ± 9.5 91 ± 9.3 Renal blood flow (RBF, ml/min) 278 ± 73 283 ± 130 335 ± 75 397 ± 64 Renal oxygen delivery (RDO 2 , ml O 2 /min) 37 ± 11 31 ± 16 * 40 ± 9.4 52 ± 10 * Renal oxygen consumption (RVO 2 , ml O 2 /min) 5.0 ± 1.4 3.1 ± 2.3 * 5.2 ± 1.9 4.6 ± 1.6 * Renal cortical tissue perfusion (RCP, BPU) 2067 ± 773 1367 ± 1231 1861 ± 902 2406 ± 1105 Renal medullary tissue perfusion (RMP, BPU) 1211 ± 858 512 ± 371 * 817 ± 358 563 ± 279 * Renal cortical oxygen tension (PrcO 2 , mmHg) 24 ± 9.0 30 ± 19 * 32 ± 11 45 ± 6.1 * Renal medullary oxygen tension (PrmO 2 , mmHg) 30 ± 12.7 26 ± 19 35 ± 15 26 ± 19 *P < 0.05 comparison of measurements before with end of sepsis. Systemic hemodynamic function After 24 hours of E. coli infusion, the sheep developed a hypotensive hyperdynamic circulatory state, with an increased heart rate and a reduced stroke volume and systemic vascular resistance (Table 1 ). During sepsis induction, arterial lactate increased from 0.48 ± 0.10 to 1.35 ± 0.63 mmol/L. Following fluid resuscitation, the intervention period did not result in significant between-group differences in systemic hemodynamics, and the interaction effect of intervention*time did not reach statistical significance for any of these systemic hemodynamic parameters when GLP-1 infusion was compared with vehicle. (Fig. 2 A-F). Kidney function At 24 hours after the commencement of E. coli infusion, 7 out of 8 sheep in each group had developed stage 1 AKI. During the induction of sepsis, plasma creatinine increased, and creatinine clearance decreased (Table 1 ). During the intervention period, plasma creatinine decreased, and creatinine clearance increased without any differences between the groups (Fig. 3 A + B). While the fractional excretion of sodium was stable in the vehicle group, it decreased during the intervention period in the GLP-1-treated group, with P intervention*time = 0.032 (Fig. 3 C). Glycemia Blood glucose levels remained stable and within normal ranges during the study period (0 h = 3.0 ± 0.45, 24 h = 2.9 ± 1.5, 30 h = 3.3 ± 1.6 mmol/l). Normal ovine glycemia ranges from 1.4 to 3.6 mmol/l. 25,26 Glucose measurements are summarized per group in supplementary figure S1, without any between-group differences. Global kidney perfusion and oxygen handling During the induction of sepsis, renal blood flow and renal vascular conductance increased, whereas urine output and urinary oxygenation decreased (Table 1 ). During the intervention period, renal blood flow increased in the GLP-1 group compared with a further decrease in the placebo group (Fig. 4 A). This was also reflected in a significant between-group difference in renal oxygen delivery (Fig. 4 C), which was maintained in the GLP-1 group but decreased in the placebo group during the intervention period. In contrast, renal oxygen consumption was stable during the intervention period, without between-group differences (Fig. 4 D). Urine output (Fig. 4 E) decreased between baseline and the end of sepsis induction (Table 1 ). During the intervention period, urine output remained relatively stable, without significant differences between the groups. Similarly, urinary oxygenation did not differ significantly between the groups (Fig. 4 F). Intrarenal perfusion and oxygenation During sepsis, renal cortical perfusion and oxygenation increased, whereas medullary perfusion and oxygenation decreased (Table 1 ). During the intervention period, renal cortical perfusion (Fig. 5 A) did not differ between the groups, whereas renal cortical oxygenation increased in the GLP-1 group compared with a decrease in the placebo group (P Intervention*Time < 0.001). The GLP-1 group maintained renal medullary perfusion throughout the intervention period, whereas this decreased in the placebo group (P Intervention*Time = 0.029). We observed a similar profile in renal medullary oxygenation, although the between-group difference was not statistically significant (P Intervention*Time = 0.101). Renal histopathology Histopathological examination of renal biopsies revealed diffuse tubular injury in three sheep in the GLP-1 group and one in the vehicle group (Table 2 ). In addition, focal tubular injury was present in one sheep in each group. The incidence of tubular injury was not significantly different between the groups (4/8 vs. 2/8, respectively, P = 0.6). Inflammatory changes were present in three of the sheep in each treatment group. Tubular casts were observed in 4/8 of the GLP-1-treated group and in 5/8 of the vehicle-treated group ( P = 0.32). Between-group comparisons of inflammatory changes and the presence of tubular casts revealed no significant differences between the GLP-1 and vehicle groups (Table S1). Table 2 Renal pathological changes in GLP-1 and vehicle-treated groups. GLP-1 (n = 8) Vehicle (n = 8) G1 G2 G3 G4 G5 G6 G7 G8 V1 V2 V3 V4 V5 V6 V7 V8 Tubular injury + 0 ++ ++ ++ 0 0 0 0 0 + 0 0 0 ++ 0 Interstitial inflammation 0 0 ++ ++ ++ 0 0 0 ++ 0 + 0 0 0 ++ 0 Tubular casts 0 0 ++ ++ ++ 0 + 0 0 0 + ++ 0 ++ + + Zero (0), no histological renal tubular injury, inflammation, or tubular casts; (+) = mild or focal histological renal tubular injury, inflammation, or tubular casts; (++) = significant histological renal tubular injury, inflammation, or tubular casts. Discussion In an ovine model of gram-negative SA-AKI, we studied the acute effects of GLP-1 on systemic hemodynamics, renal function, and intrarenal perfusion and oxygenation. GLP-1 infusion did not result in a significant difference between groups in the primary endpoint of renal medullary oxygenation or kidney function. However, GLP-1 increasedincreases renal blood flow, renal oxygen delivery, cortical oxygenation, and medullary perfusion. Relationship to previous studies Clinical research on GLP-1 in critically ill patients has focused mainly on its effects on glycemia, glucose-regulating hormones, and gastric emptying. 10 These studies revealed that GLP-1 significantly attenuated hyperglycemia in the ICU but also delayed gastric emptying. 10 Currently, the literature concerning GLP-1 treatment is conflicting regarding the associated risk of AKI. A meta-analysis including 11 large (> 500 participants) randomized trials studying the effects of GLP-1 receptor agonists on kidney outcomes reported 16% lower rates of kidney failure (HR = 0.84, 95% CI = 0.72–0.99). 8 In addition, real-world data analysis of the outcomes of GLP-1 RA users revealed significantly lower incidences of major adverse kidney events (HR = 0.66, 95% CI = 0.60–0.73). 27 In contrast, concerns have been raised that GLP-1 RAs could be associated with kidney injury on the basis of case reports of acute interstitial nephritis following GLP-1 RA treatment, likely in the context of reduced intake during illness. 28 While our study revealed improvements in renal blood flow, cortical oxygenation, and medullary perfusion, histopathology revealed tubular injury in four of the eight sheep in the GLP-1 group compared with two in the vehicle group. Therefore, GLP-1 treatment may have both beneficial and harmful effects on kidney health. How to interpret and balance these conflicting risks requires further research, which could also inform more individualized management on the basis of the context of patient characteristics or (intercurrent) comorbidities. Another important difference between our study and the data from real-world databases or long-term follow-up trials is the moment of treatment initiation. 8 , 27 Chronic GLP-1 RA use results in effective plasma concentrations before an index event, potentially leading to AKI (such as critical illness or surgery). In this study, GLP-1 was administered after 24 hours of established sepsis when 14/16 sheep had already met the KDIGO criteria for Stage 1 AKI. While in line with the clinical practice of the ICU, this illustrates a critical difference between preventive effects from chronic treatment and the attempt to treat after the moment of recognition of AKI. The effects of GLP-1 treatment on renal oxygenation and perfusion have been studied previously in animals and healthy human volunteers. 9 Studies in rodents demonstrated the presence of GLP-1 receptors in the renal vasculature, which were found to induce preglomerular vasodilation, reduce renal vascular resistance, and increase renal blood flow. 29 , 30 In our study, we observed a similar effect on renal blood flow, although not on renal vascular resistance. In humans, magnetic resonance imaging demonstrated that GLP-1 infusion improved renal cortical and medullary perfusion, although renal blood flow was unaffected. 9 This study also demonstrated that GLP-1 infusion improved oxygenation of the renal cortex, although not of the medulla. 9 Notably, our study included an ovine model and the context of sepsis induction, resulting in increased renal blood flow with reduced renal medullary perfusion and oxygenation. In our model, GLP-1 increased renal blood flow, renal cortical oxygenation, and medullary perfusion. While oxygenation of the renal medulla did not improve, augmenting renal medullary perfusion in a state of compromised perfusion could have contributed to kidney protection. 31 Regardless, in our study, the difference in medullary perfusion did not translate into improved oxygenation or renal function. A modest increase in the resting heart rate during GLP-1 treatment has been extensively described in animal and human studies. 32 , 33 This seems to be mediated through direct action on the sinus node. 33 However, these effects were demonstrated during periods of dominant parasympathetic activity. 32 The lack of increase in heart rate following GLP-1 treatment in our study might be explained by the context of sepsis-induced sympathetic activation, which elevated heart rate and cardiac output. Strengths and limitations We studied the renal effects of GLP-1 in an established, reproducible, clinically relevant large animal model of sepsis-associated AKI. 12 , 13 , 16 , 18 , 19 The model closely resembles cardiovascular and renal physiology during the early stage of sepsis. 12 , 13 , 16 , 18 , 19 The study methodology was designed with clinical practice in mind. Sepsis was induced over 24 hours without other interventions; then, at a time analogous to hospital presentation, treatment was initiated, following per-protocol fluid resuscitation. Group allocation was based on randomization, and histopathological analyses were performed by an experienced pathologist blinded to treatment group allocation. However, our treatment period was limited to 6 hours (from 24–30 h of sepsis). Therefore, we cannot comment on the effects and outcomes of longer continuous treatment. Assessing the state and severity of sepsis in an animal model can be difficult, especially compared with clinical experience. However, the degree of organ dysfunction reflected by increases in cardiac output and lactate levels or decreases in arterial oxygenation and urine output is comparable to that reported in previous studies and reflects a state of early sepsis and the development of organ dysfunction. Comparison to clinical practice is likewise limited by, the experimental induction of sepsis through the intravenous administration of E. coli , in contrast to the primary organ focus of sepsis. Unlike in clinical practice, we studied young female sheep without known comorbidities. Conclusion In a large animal model of live gram-negative sepsis-associated AKI, we found no significant improvement in kidney function or renal medullary oxygenation following GLP-1 infusion. However, GLP-1 infusion increased renal blood flow, renal oxygen delivery, renal cortical oxygenation, and renal medullary perfusion. Declarations Acknowledgments We sincerely thank Mr. Tom Vale and Mr. Tony Dornom for their excellent technical assistance in surgical procedures and Ms. Jennifer Horvath and Ms. Violetta Kirac in Austin Health Pathology, Australia, for their technical expertise in the assessment of the concentrations of plasma and urinary creatinine and sodium. We also thank Dr Ian Birchall from the Neuropathology Laboratory at the Florey Institute for his expert assistance with performing renal histopathology. Authors' contributions Abraham Hulst: Conceptualization, Methodology, Investigation, Formal Analysis, Validation, Writing - Original Draft, Funding Acquisition. Connie Ow: Investigation, Formal analysis, Validation, Writing - Review & Editing. Clive May: Investigation, Resources, Writing - Review & Editing, Supervision. Sally Hood: Investigation, Writing - Review & Editing. Mark Plummer: Conceptualization, Methodology, Writing - Review & Editing. Jeroen Hermanides: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Funding Acquisition. Daniël van Raalte: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Funding Acquisition. Adam Deane: Conceptualization, Methodology, Writing - Review & Editing, Funding Acquisition. Rinaldo Bellomo: Conceptualization, Methodology, Resources, Writing - Review & Editing, Supervision, Funding Acquisition. Yugeesh Lankadeva: Conceptualization, Methodology, Validation, Resources, Writing - Review & Editing, Supervision, Funding Acquisition. Competing interests All the authors declare that they have no competing interests. Availability of data and material Data are available upon request to the corresponding author. Ethics approval The Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health (Ethics identification number: 21-030-FINMH) approved these experiments under the guidelines of the National Health and Medical Research Council of Australia. Funding This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101024833. This publication is part of the project NEPHRITIC (project number 452020104) of the research programme Rubicon, financed by the Dutch Research Council (NWO). Dr Hulst is also supported by the Netherlands Organization for Health Research and Development (Veni‐ 09150162410006). Professor Lankadeva was supported by a Future Leader Fellowship from the National Heart Foundation of Australia (FLF105666) and an Emerging Leader Investigator Grant from the National Health and Medical Research Council of Australia (GNT2025266). References Hoste, E. A. J. et al. 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Clin Kidney J 17 , (2024). Farah, L. X. S. et al. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am J Physiol Renal Physiol 310 , 123–127 (2016). Jensen, E. P. et al. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. Am J Physiol Renal Physiol 308 , 867–877 (2015). Chen, R., Liu, D., Zhao, H. & Wang, X. Renal medullary perfusion differs from that in renal cortex in patients with sepsis associated acute kidney injury and correlates with renal function prognosis: A prospective cohort study. Clin Hemorheol Microcirc 1–18 (2024) doi:10.3233/ch-242296. Lorenz, M. et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovascular Diabetology vol. 16 Preprint at https://doi.org/10.1186/s12933-016-0490-6 (2017). Lubberding, A. F. et al. Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. Cardiovasc Res 120 , 1427–1441 (2024). Supplementary Figure S1 Supplementary Figure S1 is not available with this version. Additional Declarations No competing interests reported. Supplementary Files TableS1.docx Cite Share Download PDF Status: Published Journal Publication published 24 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 25 Sep, 2025 Reviews received at journal 20 Sep, 2025 Reviews received at journal 19 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers invited by journal 13 Sep, 2025 Editor assigned by journal 13 Sep, 2025 Editor invited by journal 09 Sep, 2025 Submission checks completed at journal 08 Sep, 2025 First submitted to journal 08 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7445170","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":517283521,"identity":"5388e7d7-4fce-4141-b2bc-56a3657b637d","order_by":0,"name":"Abraham H. 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06:21:13","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":124141,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/44cb313400e626d493a707f4.html"},{"id":92054088,"identity":"01880f2e-d3c3-434d-a7f5-8b14d4f810ed","added_by":"auto","created_at":"2025-09-24 06:29:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":148433,"visible":true,"origin":"","legend":"\u003cp\u003eStudy overview and experimental timeline.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/50c2749265b36f97f3f792b9.png"},{"id":92052369,"identity":"9142fe40-2f6d-4f84-8da5-517ae9ab34cc","added_by":"auto","created_at":"2025-09-24 06:13:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":274879,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute change in heart rate (A), stroke volume (B), cardiac output (C), mean arterial pressure (D), systemic vascular resistance (E) and dose of noradrenaline required (F) during the intervention period. 0 h is the start of the intervention period, corresponding to 24 h of sepsis. Sheep randomized to intravenous infusion of 3.6 pmol/kg/min GLP-1 (n=8) are presented as closed gold circles and those to vehicle solution (n=8) as open gray squares. Values are mean ± sd. P values resulted from repeated-measures ANOVA.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/228fe3baa505f1993b25f5f3.png"},{"id":92053113,"identity":"9e42046c-e7dd-41d2-a457-dce9a352b2b2","added_by":"auto","created_at":"2025-09-24 06:21:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":130880,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute change in Plasma creatinine (A), creatinine clearance (B), and fractional excretion of sodium (C) during the intervention period. 0 h is the start of the intervention period, corresponding to 24 h of sepsis. Sheep randomized to intravenous infusion of 3.6 pmol/kg/min GLP-1 (n=8) are presented as closed gold circles and those to vehicle solution (n=8) as open gray squares. Values are mean ± sd. P values resulted from repeated-measures ANOVA.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/ce77d02a65f0a298e5af5d9f.png"},{"id":92052371,"identity":"9c4a0c2f-a13d-4ff0-afb9-0c6cc5519d3b","added_by":"auto","created_at":"2025-09-24 06:13:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":273193,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute change in renal blood flow (A), renal vascular conductance (B), renal oxygen delivery (C), renal oxygen consumption (E), urine output (E), and, urine oxygenation (F) during the intervention period. 0 h is the start of the intervention period, corresponding to 24 h of sepsis. Sheep randomized to intravenous infusion of 3.6 pmol/kg/min GLP-1 (n=8) are presented as closed gold circles and those to vehicle solution (n=8) as open gray squares. Values are mean ± sd. P values resulted from repeated-measures ANOVA.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/76cffdf1e77b977166f4ad71.png"},{"id":92054378,"identity":"b24adb6d-b669-4bb5-8163-1777e0438a1b","added_by":"auto","created_at":"2025-09-24 06:37:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":216973,"visible":true,"origin":"","legend":"\u003cp\u003eAbsolute change in renal cortical perfusion (A) and oxygenation (B), and renal medullary perfusion (C) and oxygenation (D) during the intervention period. 0 h is the start of the intervention period, corresponding to 24 h of sepsis. Sheep randomized to intravenous infusion of 3.6 pmol/kg/min GLP-1 (n=8) are presented as closed gold circles and those to vehicle solution (n=8) as open gray squares. Values are mean ± sd. P values resulted from repeated-measures ANOVA.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/ce1e4e402f3411c6360f60ba.png"},{"id":99172402,"identity":"822d7070-d1c8-40d1-91f0-b943ba779bc1","added_by":"auto","created_at":"2025-12-29 16:08:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2122746,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/c480a6cb-2958-44fd-a1ec-599a165dbf36.pdf"},{"id":92052366,"identity":"e08792f8-e8e9-45d8-95e7-b2f338a86de3","added_by":"auto","created_at":"2025-09-24 06:13:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17959,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7445170/v1/1e35e6d8afb9718ca5da797f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of glucagon-like peptide-1 on systemic hemodynamics, kidney function, and intrarenal oxygenation in sheep with sepsis-associated acute kidney injury","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis is the leading cause of acute kidney injury (AKI) in intensive care units (ICUs).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Compared with either disease alone, sepsis-associated AKI (SA-AKI) has a worse prognosis.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e SA-AKI is associated with a prolonged length of stay in the ICU, increased mortality, increased likelihood of developing chronic kidney disease, and reduced quality of life.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The consensus among intensivists for managing patients at risk of AKI due to sepsis is as follows: preservation of tissue oxygenation, correction of hypovolemia and hypotension, and avoidance of nephrotoxins. However, apart from these generalized interventions, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eno specific targeted protective therapies exist to treat or prevent AKI in patients with sepsis.\u003c/span\u003e\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eTreatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is an established therapy for patients with type 2 diabetes that improves glucose control, induces weight loss, and reduces major adverse cardiovascular events. In these studies, GLP-1 RAs also reduced the incidence of important kidney events and kidney failure.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In addition, a mechanistic imaging study revealed that GLP-1 increases the perfusion and oxygenation of healthy human kidneys.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The effects of GLP-1 have been evaluated clinically in patients admitted to the ICU for their effects on blood glucose and gastric emptying.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e To date, the effects of GLP-1 on renal macro- and microcirculation, kidney function and renal histopathology have not been studied in the context of sepsis-associated AKI.\u003c/p\u003e\u003cp\u003eWe aimed to investigate whether GLP-1 infusion could alleviate renal tissue hypoperfusion and hypoxia in an ovine model of live gram-negative SA-AKI. We hypothesized that GLP-1 would improve renal cortical and medullary tissue perfusion, oxygenation and kidney function in sheep with established septic AKI.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAnimals\u003c/h2\u003e\u003cp\u003eSixteen healthy female merino ewes (35\u0026ndash;45 kg body weight) were housed in individual metabolic cages with free access to water and 800 g/day oaten chaff. The animals were procured from a farm in Central Victoria, Australia, and delivered into our facility at the Florey Institute for acclimatization before any experimentation. The Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health (Ethics identification number: 21-030-FINMH) approved these experiments under the guidelines of the National Health and Medical Research Council of Australia. All methods and procedures were performed according to these guidelines and regulations. This report was written in accordance with the ARRIVE 2.0 guidelines.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe ewes underwent two aseptic surgical procedures under general anesthesia, described in detail previously\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e and summarized below. Anesthesia was induced with intravenous sodium thiopentone (15 mg/kg, Jurox Pty Ltd, Rutherford, NSW, Australia) and maintained with isoflurane (2.0\u0026ndash;2.5% v/v oxygen/air/isoflurane) following intubation. Prior to incision, the sheep was given 900 mg of the antibiotic procaine penicillin (Ilium Propercillin, Troy Laboratories, Glendenning, NSW, Australia) and 1 mg/kg of the analgesic flunixin meglumine (Ilium Flunixil, Troy Laboratories). First, the left carotid artery was exteriorized into a skin fold to form a carotid arterial loop for subsequent access to arterial cannulation.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e A 20-mm transit-time flow probe (Transonic Systems, Ithaca, NY) for cardiac output (CO) measurement was placed around the pulmonary artery.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Three weeks later, the carotid artery was cannulated and connected to a pressure transducer for measurement of systolic, diastolic, and mean arterial pressure (SBP, DBP, and MAP), heart rate and blood sampling.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Three catheters were inserted into the right jugular vein: one for delivery of treatment, one for administering \u003cem\u003eE. coli\u003c/em\u003e, and one for fluid resuscitation and vasopressors, as needed. The arterial and venous catheters were continuously infused with heparinized saline (10 U heparin/mL at 3 mL/hr) to maintain patency. During the second surgical procedure, a 4-mm transit-time flow probe (Transonic Systems) was placed around the left renal artery to measure renal blood flow (RBF),\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and the left renal vein was cannulated for blood sampling. Two fiber-optic probes (Oxford Optronix, Abingdon, United Kingdom) were inserted into the renal cortex and medulla to measure renal cortical and medullary oxygenation (PrcO\u003csub\u003e2\u003c/sub\u003e, RrmO\u003csub\u003e2\u003c/sub\u003e) and perfusion (RCP, RMP).\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e A Foley catheter was inserted into the bladder with a fiber-optic probe inserted into the tip to measure partial urinary oxygen pressure (PuO\u003csub\u003e2\u003c/sub\u003e).\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e For both surgical procedures, the animals were injected with intramuscular antibiotics (900 mg procaine penicillin, Ilium Propen, Troy Laboratories, Smithfield, NSW, Australia) and analgesics (Flunixin meglumine, 1 mg/kg; Troy Laboratories or Mavlab) at the start of surgery and 24 and 48 hours after surgery.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The animals were allowed at least five days after the second surgical procedure to recover prior to experimental intervention.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eExperimental Protocol\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eExperimental Protocol\u003c/div\u003e\u003cp\u003eA schematic representation of the experimental protocol and data collection time points is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Following a 24-hour baseline period, sepsis was induced in nonanesthetized sheep with an intravenous dose of live \u003cem\u003eE. coli\u003c/em\u003e (2.8\u0026times;10\u003csup\u003e9\u003c/sup\u003e colony-forming units [CFUs] over 30 min) as a bolus, followed by a continuous infusion (1.26 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e CFU/hr for the rest of the experiment). At 23.5 hours of sepsis, fluid bolus therapy with Hartmann\u0026rsquo;s solution (Baxter Australia, 30 mL/kg over 30 min) was administered.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e At 24 h after sepsis, the animals were randomized via online software built into electronic data capture software (Castor EDC, Castor B.V., Amsterdam, Netherlands). The animals in the intervention group received an IV GLP-1 infusion of 3.6 pmol/kg/min for six hours (Bachem AG., Bubendorf, Switzerland) dissolved in 20% Albumin (CSL Behring, Broadmeadows, VIC, Australia). This is a clinically effective dose, as indicated by previous studies in critically ill patients in which no major adverse events were reported.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The animals in the comparator group received an equal volume of vehicle solution with 20% Albumin. At the end of the protocol, the animals were euthanized with a lethal dose of sodium pentobarbitone (100 mg/kg, IV). The positions of the renal fiber-optic probes were confirmed at autopsy, and kidney biopsies were taken for histopathological assessment.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eA computer with a CED 1401 interface running a data acquisition system (Spike 2 Software, Cambridge Electronic Design, Cambridge, United Kingdom) continuously recorded analog signals (MAP, heart rate, CO, renal blood flow, RCP, RMP, PrcO\u003csub\u003e2,\u003c/sub\u003e and RrmO\u003csub\u003e2\u003c/sub\u003e, temperature, and PuO\u003csub\u003e2\u003c/sub\u003e) at 100 Hz. Renal vascular conductance (RVC) was calculated as RBF/MAP. Stroke volume (SV) was calculated as CO/heart rate. We calculated the body surface area (BSA) as 0.09*weight \u003csup\u003e(0.67)\u003c/sup\u003e, and the cardiac index (CI) and stroke volume index (SVI) were calculated as the CO/BSA and SV/BSA, respectively. We recorded the hourly urine flow and collected 1-hourly urine samples at baseline and at 24, 26, 28, and 30 h after the induction of sepsis, corresponding to before the start of the intervention and 2, 4, and 6 h after the intervention, respectively. Urine samples were collected for measurement of creatinine and sodium concentrations and subsequent analysis of renal excretory function. Arterial and renal venous blood samples were collected at baseline, just prior to the infusion of \u003cem\u003eE. coli\u003c/em\u003e, and subsequently at 24, 26, 28, and 30 hours of sepsis for the measurement of blood oximetry (ABL System 625, Radiometer Medical, Copenhagen, Denmark), creatinine, and glucose. The occurrence of AKI was based on the \u0026ldquo;Kidney Disease: Improving Global Outcomes (KDIGO)\u0026rdquo; clinical criteria; stage 1 AKI is characterized by a\u0026thinsp;\u0026gt;\u0026thinsp;1.5-fold increase in plasma creatinine or oliguria of 0.5 ml/kg/h for \u0026gt;\u0026thinsp;6 hours.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData are reported as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and between-group differences are reported as the difference with a 95% confidence interval (95% CI). All outcome measurements are reported as the absolute changes from the start of the intervention period.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e The data were analyzed via repeated-measures analysis of variance (ANOVA) with the factors intervention (P\u003csub\u003eIntervention\u003c/sub\u003e: vehicle or GLP-1) and time (P\u003csub\u003eTime\u003c/sub\u003e). The treatment effect was evaluated on the basis of the interaction term P\u003csub\u003eIntervention*Time\u003c/sub\u003e. Given its critical role in the development of AKI, we defined renal medullary tissue oxygenation as the primary outcome.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e On the basis of previous studies, detecting a 50% improvement in medullary tissue oxygenation (mean pO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;10\u0026thinsp;\u0026plusmn;\u0026thinsp;9) with 90% power and α\u0026thinsp;=\u0026thinsp;.05 required a sample size of eight sheep per group.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The histological assessment of kidney tissues was performed according to the semiquantitative histological scoring system\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e by a pathologist blinded to group allocation and analyzed with Fisher\u0026rsquo;s exact test. Statistical analysis was performed via GraphPad PRISM 6.0 (GraphPad Software, La Jolla, CA). All variables were assessed for normality and log-transformed where appropriate. A two-sided \u003cem\u003eP\u003c/em\u003e value less than or equal to 0.05 was considered statistically significant without correction for multiple comparisons.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe body weights of sheep treated with GLP-1 (38.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 kg; n\u0026thinsp;=\u0026thinsp;8) were similar to those of sheep treated with vehicle (39.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 kg; n\u0026thinsp;=\u0026thinsp;8). During the 24-hour period of sepsis induction, the sheep in both groups developed changes in hemodynamics and organ dysfunction consistent with sepsis, including hyperdynamic circulation with reductions in blood pressure, arterial oxygenation, and renal medullary oxygenation. Creatinine clearance and urine output decreased as plasma creatinine increased, which is consistent with the development of acute kidney injury (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No animals died during the 30-hour period after the infusion of \u003cem\u003eE. coli\u003c/em\u003e commenced. No animals were excluded from the analysis.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eChanges in systemic hemodynamics, global and regional kidney perfusion, oxygenation, and renal function from baseline (premorbid) to 24 hours of gram-negative sepsis in nonanesthetized sheep in both treatment groups.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGLP-1 group (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eVehicle group (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystemic and renal variables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBefore sepsis (0 h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEnd sepsis\u003c/p\u003e\u003cp\u003e(23.5 h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBefore sepsis\u003c/p\u003e\u003cp\u003e(0 h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEnd sepsis\u003c/p\u003e\u003cp\u003e(23.5 h)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean arterial pressure\u003c/p\u003e\u003cp\u003e(MAP, mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e83\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeart rate\u003c/p\u003e\u003cp\u003e(HR, bpm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e106\u0026thinsp;\u0026plusmn;\u0026thinsp;21 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e138\u0026thinsp;\u0026plusmn;\u0026thinsp;28 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac output\u003c/p\u003e\u003cp\u003e(CO, l/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystemic vascular resistance\u003c/p\u003e\u003cp\u003e(SVR, mmHg/ml/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;11 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine Output\u003c/p\u003e\u003cp\u003e(UO, ml/kg/h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary Oxygenation\u003c/p\u003e\u003cp\u003e(PuO\u003csub\u003e2\u003c/sub\u003e, mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23\u0026thinsp;\u0026plusmn;\u0026thinsp;14 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;16 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAKI grade 1\u003c/p\u003e\u003cp\u003e(UO\u0026thinsp;\u0026lt;\u0026thinsp;0.5 ml/kg/h for \u0026gt;\u0026thinsp;6 h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7/8 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7/8 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine clearance\u003c/p\u003e\u003cp\u003e(ml/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86\u0026thinsp;\u0026plusmn;\u0026thinsp;31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;14 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e58\u0026thinsp;\u0026plusmn;\u0026thinsp;26 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlasma creatinine\u003c/p\u003e\u003cp\u003e(\u0026micro;mol/l)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e65.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e109.3\u0026thinsp;\u0026plusmn;\u0026thinsp;34.1 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e63.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e101.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlasma lactate\u003c/p\u003e\u003cp\u003e(mmol/l)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArterial oxygen tension\u003c/p\u003e\u003cp\u003e(PaO\u003csub\u003e2,\u003c/sub\u003e mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e91\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal blood flow\u003c/p\u003e\u003cp\u003e(RBF, ml/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e278\u0026thinsp;\u0026plusmn;\u0026thinsp;73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e283\u0026thinsp;\u0026plusmn;\u0026thinsp;130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e335\u0026thinsp;\u0026plusmn;\u0026thinsp;75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e397\u0026thinsp;\u0026plusmn;\u0026thinsp;64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal oxygen delivery\u003c/p\u003e\u003cp\u003e(RDO\u003csub\u003e2\u003c/sub\u003e, ml O\u003csub\u003e2\u003c/sub\u003e/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31\u0026thinsp;\u0026plusmn;\u0026thinsp;16 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;10 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal oxygen consumption\u003c/p\u003e\u003cp\u003e(RVO\u003csub\u003e2\u003c/sub\u003e, ml O\u003csub\u003e2\u003c/sub\u003e/min)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal cortical tissue perfusion\u003c/p\u003e\u003cp\u003e(RCP, BPU)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2067\u0026thinsp;\u0026plusmn;\u0026thinsp;773\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1367\u0026thinsp;\u0026plusmn;\u0026thinsp;1231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1861\u0026thinsp;\u0026plusmn;\u0026thinsp;902\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2406\u0026thinsp;\u0026plusmn;\u0026thinsp;1105\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal medullary tissue perfusion\u003c/p\u003e\u003cp\u003e(RMP, BPU)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1211\u0026thinsp;\u0026plusmn;\u0026thinsp;858\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e512\u0026thinsp;\u0026plusmn;\u0026thinsp;371 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e817\u0026thinsp;\u0026plusmn;\u0026thinsp;358\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e563\u0026thinsp;\u0026plusmn;\u0026thinsp;279 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal cortical oxygen tension\u003c/p\u003e\u003cp\u003e(PrcO\u003csub\u003e2\u003c/sub\u003e, mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;19 *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e45\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 *\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal medullary oxygen tension\u003c/p\u003e\u003cp\u003e(PrmO\u003csub\u003e2\u003c/sub\u003e, mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e26\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 comparison of measurements before with end of sepsis.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSystemic hemodynamic function\u003c/h2\u003e\u003cp\u003eAfter 24 hours of \u003cem\u003eE. coli\u003c/em\u003e infusion, the sheep developed a hypotensive hyperdynamic circulatory state, with an increased heart rate and a reduced stroke volume and systemic vascular resistance (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During sepsis induction, arterial lactate increased from 0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10 to 1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63 mmol/L. Following fluid resuscitation, the intervention period did not result in significant between-group differences in systemic hemodynamics, and the interaction effect of intervention*time did not reach statistical significance for any of these systemic hemodynamic parameters when GLP-1 infusion was compared with vehicle. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-F).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eKidney function\u003c/h3\u003e\n\u003cp\u003eAt 24 hours after the commencement of \u003cem\u003eE. coli\u003c/em\u003e infusion, 7 out of 8 sheep in each group had developed stage 1 AKI. During the induction of sepsis, plasma creatinine increased, and creatinine clearance decreased (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the intervention period, plasma creatinine decreased, and creatinine clearance increased without any differences between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA\u0026thinsp;+\u0026thinsp;B). While the fractional excretion of sodium was stable in the vehicle group, it decreased during the intervention period in the GLP-1-treated group, with P\u003csub\u003eintervention*time\u003c/sub\u003e = 0.032 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eGlycemia\u003c/h3\u003e\n\u003cp\u003eBlood glucose levels remained stable and within normal ranges during the study period (0 h\u0026thinsp;=\u0026thinsp;3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45, 24 h\u0026thinsp;=\u0026thinsp;2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5, 30 h\u0026thinsp;=\u0026thinsp;3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 mmol/l). Normal ovine glycemia ranges from 1.4 to 3.6 mmol/l.\u003csup\u003e25,26\u003c/sup\u003e Glucose measurements are summarized per group in supplementary figure S1, without any between-group differences.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGlobal kidney perfusion and oxygen handling\u003c/h2\u003e\u003cp\u003eDuring the induction of sepsis, renal blood flow and renal vascular conductance increased, whereas urine output and urinary oxygenation decreased (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the intervention period, renal blood flow increased in the GLP-1 group compared with a further decrease in the placebo group (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). This was also reflected in a significant between-group difference in renal oxygen delivery (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC), which was maintained in the GLP-1 group but decreased in the placebo group during the intervention period. In contrast, renal oxygen consumption was stable during the intervention period, without between-group differences (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). Urine output (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE) decreased between baseline and the end of sepsis induction (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the intervention period, urine output remained relatively stable, without significant differences between the groups. Similarly, urinary oxygenation did not differ significantly between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eIntrarenal perfusion and oxygenation\u003c/h2\u003e\u003cp\u003eDuring sepsis, renal cortical perfusion and oxygenation increased, whereas medullary perfusion and oxygenation decreased (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the intervention period, renal cortical perfusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA) did not differ between the groups, whereas renal cortical oxygenation increased in the GLP-1 group compared with a decrease in the placebo group (P\u003csub\u003eIntervention*Time\u003c/sub\u003e \u0026lt; 0.001). The GLP-1 group maintained renal medullary perfusion throughout the intervention period, whereas this decreased in the placebo group (P\u003csub\u003eIntervention*Time\u003c/sub\u003e = 0.029). We observed a similar profile in renal medullary oxygenation, although the between-group difference was not statistically significant (P\u003csub\u003eIntervention*Time\u003c/sub\u003e = 0.101).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eRenal histopathology\u003c/h2\u003e\u003cp\u003eHistopathological examination of renal biopsies revealed diffuse tubular injury in three sheep in the GLP-1 group and one in the vehicle group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, focal tubular injury was present in one sheep in each group. The incidence of tubular injury was not significantly different between the groups (4/8 vs. 2/8, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6). Inflammatory changes were present in three of the sheep in each treatment group. Tubular casts were observed in 4/8 of the GLP-1-treated group and in 5/8 of the vehicle-treated group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.32). Between-group comparisons of inflammatory changes and the presence of tubular casts revealed no significant differences between the GLP-1 and vehicle groups (Table S1).\u003c/p\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eRenal pathological changes in GLP-1 and vehicle-treated groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eGLP-1 (n = 8)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eVehicle (n = 8)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTubular injury\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterstitial inflammation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTubular casts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"17\"\u003e\n \u003cp\u003e\u003cem\u003eZero (0), no histological renal tubular injury, inflammation, or tubular casts; (+) = mild or focal histological renal tubular injury, inflammation, or tubular casts; (++) = significant histological renal tubular injury, inflammation, or tubular casts.\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eIn an ovine model of gram-negative SA-AKI, we studied the acute effects of GLP-1 on systemic hemodynamics, renal function, and intrarenal perfusion and oxygenation. GLP-1 infusion did not result in a significant difference between groups in the primary endpoint of renal medullary oxygenation or kidney function. However, GLP-1 increasedincreases renal blood flow, renal oxygen delivery, cortical oxygenation, and medullary perfusion.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eRelationship to previous studies\u003c/h2\u003e\u003cp\u003eClinical research on GLP-1 in critically ill patients has focused mainly on its effects on glycemia, glucose-regulating hormones, and gastric emptying.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e These studies revealed that GLP-1 significantly attenuated hyperglycemia in the ICU but also delayed gastric emptying.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Currently, the literature concerning GLP-1 treatment is conflicting regarding the associated risk of AKI. A meta-analysis including 11 large (\u0026gt;\u0026thinsp;500 participants) randomized trials studying the effects of GLP-1 receptor agonists on kidney outcomes reported 16% lower rates of kidney failure (HR\u0026thinsp;=\u0026thinsp;0.84, 95% CI\u0026thinsp;=\u0026thinsp;0.72\u0026ndash;0.99).\u003csup\u003e8\u003c/sup\u003e In addition, real-world data analysis of the outcomes of GLP-1 RA users revealed significantly lower incidences of major adverse kidney events (HR\u0026thinsp;=\u0026thinsp;0.66, 95% CI\u0026thinsp;=\u0026thinsp;0.60\u0026ndash;0.73).\u003csup\u003e27\u003c/sup\u003e In contrast, concerns have been raised that GLP-1 RAs could be associated with kidney injury on the basis of case reports of acute interstitial nephritis following GLP-1 RA treatment, likely in the context of reduced intake during illness.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e While our study revealed improvements in renal blood flow, cortical oxygenation, and medullary perfusion, histopathology revealed tubular injury in four of the eight sheep in the GLP-1 group compared with two in the vehicle group. Therefore, GLP-1 treatment may have both beneficial and harmful effects on kidney health. How to interpret and balance these conflicting risks requires further research, which could also inform more individualized management on the basis of the context of patient characteristics or (intercurrent) comorbidities.\u003c/p\u003e\u003cp\u003eAnother important difference between our study and the data from real-world databases or long-term follow-up trials is the moment of treatment initiation.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Chronic GLP-1 RA use results in effective plasma concentrations before an index event, potentially leading to AKI (such as critical illness or surgery). In this study, GLP-1 was administered after 24 hours of established sepsis when 14/16 sheep had already met the KDIGO criteria for Stage 1 AKI. While in line with the clinical practice of the ICU, this illustrates a critical difference between preventive effects from chronic treatment and the attempt to treat after the moment of recognition of AKI.\u003c/p\u003e\u003cp\u003eThe effects of GLP-1 treatment on renal oxygenation and perfusion have been studied previously in animals and healthy human volunteers.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Studies in rodents demonstrated the presence of GLP-1 receptors in the renal vasculature, which were found to induce preglomerular vasodilation, reduce renal vascular resistance, and increase renal blood flow.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e In our study, we observed a similar effect on renal blood flow, although not on renal vascular resistance. In humans, magnetic resonance imaging demonstrated that GLP-1 infusion improved renal cortical and medullary perfusion, although renal blood flow was unaffected.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e This study also demonstrated that GLP-1 infusion improved oxygenation of the renal cortex, although not of the medulla.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Notably, our study included an ovine model and the context of sepsis induction, resulting in increased renal blood flow with reduced renal medullary perfusion and oxygenation. In our model, GLP-1 increased renal blood flow, renal cortical oxygenation, and medullary perfusion. While oxygenation of the renal medulla did not improve, augmenting renal medullary perfusion in a state of compromised perfusion could have contributed to kidney protection.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Regardless, in our study, the difference in medullary perfusion did not translate into improved oxygenation or renal function.\u003c/p\u003e\u003cp\u003eA modest increase in the resting heart rate during GLP-1 treatment has been extensively described in animal and human studies.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e This seems to be mediated through direct action on the sinus node.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e However, these effects were demonstrated during periods of dominant parasympathetic activity.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e The lack of increase in heart rate following GLP-1 treatment in our study might be explained by the context of sepsis-induced sympathetic activation, which elevated heart rate and cardiac output.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eWe studied the renal effects of GLP-1 in an established, reproducible, clinically relevant large animal model of sepsis-associated AKI.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The model closely resembles cardiovascular and renal physiology during the early stage of sepsis. \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The study methodology was designed with clinical practice in mind. Sepsis was induced over 24 hours without other interventions; then, at a time analogous to hospital presentation, treatment was initiated, following per-protocol fluid resuscitation. Group allocation was based on randomization, and histopathological analyses were performed by an experienced pathologist blinded to treatment group allocation. However, our treatment period was limited to 6 hours (from 24\u0026ndash;30 h of sepsis). Therefore, we cannot comment on the effects and outcomes of longer continuous treatment. Assessing the state and severity of sepsis in an animal model can be difficult, especially compared with clinical experience. However, the degree of organ dysfunction reflected by increases in cardiac output and lactate levels or decreases in arterial oxygenation and urine output is comparable to that reported in previous studies and reflects a state of early sepsis and the development of organ dysfunction. Comparison to clinical practice is likewise limited by, the experimental induction of sepsis through the intravenous administration of \u003cem\u003eE. coli\u003c/em\u003e, in contrast to the primary organ focus of sepsis. Unlike in clinical practice, we studied young female sheep without known comorbidities.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn a large animal model of live gram-negative sepsis-associated AKI, we found no significant improvement in kidney function or renal medullary oxygenation following GLP-1 infusion. However, GLP-1 infusion increased renal blood flow, renal oxygen delivery, renal cortical oxygenation, and renal medullary perfusion.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eWe sincerely thank Mr. Tom Vale and Mr. Tony Dornom for their excellent technical assistance in surgical procedures and Ms. Jennifer Horvath and Ms. Violetta Kirac in Austin Health Pathology, Australia, for their technical expertise in the assessment of the concentrations of plasma and urinary creatinine and sodium. We also thank Dr Ian Birchall from the Neuropathology Laboratory at the Florey Institute for his expert assistance with performing renal histopathology.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions\u003c/h2\u003e\n\u003cp\u003eAbraham Hulst: Conceptualization, Methodology, Investigation, Formal Analysis, Validation, Writing - Original Draft, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003eConnie Ow: Investigation, Formal analysis, Validation, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eClive May: Investigation, Resources, Writing - Review \u0026amp; Editing, Supervision.\u003c/p\u003e\n\u003cp\u003eSally Hood: Investigation, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eMark Plummer: Conceptualization, Methodology, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eJeroen Hermanides: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Supervision, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003eDani\u0026euml;l van Raalte: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Supervision, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003eAdam Deane: Conceptualization, Methodology, Writing - Review \u0026amp; Editing, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003eRinaldo Bellomo: Conceptualization, Methodology, Resources, Writing - Review \u0026amp; Editing, Supervision, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003eYugeesh Lankadeva: Conceptualization, Methodology, Validation, Resources, Writing - Review \u0026amp; Editing, Supervision, Funding Acquisition.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eAll the authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and material\u003c/h2\u003e\n\u003cp\u003eData are available upon request to the corresponding author.\u003c/p\u003e\n\u003ch2\u003eEthics approval\u003c/h2\u003e\n\u003cp\u003eThe Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health (Ethics identification number: 21-030-FINMH) approved these experiments under the guidelines of the National Health and Medical Research Council of Australia.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis project has received funding from the European Union\u0026rsquo;s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101024833.\u003c/p\u003e\n\u003cp\u003eThis publication is part of the project NEPHRITIC (project number 452020104) of the research programme Rubicon, financed by the Dutch Research Council (NWO). Dr Hulst is also supported by the Netherlands Organization for Health Research and Development (Veni‐ 09150162410006). Professor Lankadeva was supported by a Future Leader Fellowship from the National Heart Foundation of Australia (FLF105666) and an Emerging Leader Investigator Grant from the National Health and Medical Research Council of Australia (GNT2025266).\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoste, E. A. J. \u003cem\u003eet al.\u003c/em\u003e Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. \u003cem\u003eIntensive Care Med\u003c/em\u003e \u003cstrong\u003e41\u003c/strong\u003e, 1411\u0026ndash;1423 (2015).\u003c/li\u003e\n\u003cli\u003ePeerapornratana, S., Manrique-Caballero, C. L., G\u0026oacute;mez, H. \u0026amp; Kellum, J. A. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. \u003cem\u003eKidney Int\u003c/em\u003e \u003cstrong\u003e96\u003c/strong\u003e, 1083\u0026ndash;1099 (2019).\u003c/li\u003e\n\u003cli\u003eBellomo, R. \u003cem\u003eet al.\u003c/em\u003e Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference. \u003cem\u003eAnn Intensive Care\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 1\u0026ndash;40 (2017).\u003c/li\u003e\n\u003cli\u003eZarbock, A., Gomez, H. \u0026amp; Kellum, J. A. 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R. \u003cem\u003eet al.\u003c/em\u003e Effects of Fluid Bolus Therapy on Renal Perfusion, Oxygenation, and Function in Early Experimental Septic Kidney Injury. \u003cem\u003eCrit Care Med\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e, E36\u0026ndash;E43 (2019).\u003c/li\u003e\n\u003cli\u003eLankadeva, Y. R. \u003cem\u003eet al.\u003c/em\u003e Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury. \u003cem\u003eKidney Int\u003c/em\u003e \u003cstrong\u003e96\u003c/strong\u003e, 1150\u0026ndash;1161 (2019).\u003c/li\u003e\n\u003cli\u003eOkazaki, N. \u003cem\u003eet al.\u003c/em\u003e Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury. \u003cem\u003eCrit Care Med\u003c/em\u003e \u003cstrong\u003e48\u003c/strong\u003e, E951\u0026ndash;E958 (2020).\u003c/li\u003e\n\u003cli\u003eLankadeva, Y. R. \u003cem\u003eet al.\u003c/em\u003e Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis. \u003cem\u003eCrit Care Med\u003c/em\u003e \u003cstrong\u003e43\u003c/strong\u003e, e221\u0026ndash;e229 (2015).\u003c/li\u003e\n\u003cli\u003eCalzavacca, P. \u003cem\u003eet al.\u003c/em\u003e Long-term measurement of renal cortical and medullary tissue oxygenation and perfusion in unanesthetized sheep. \u003cem\u003eAm J Physiol Regul Integr Comp Physiol\u003c/em\u003e \u003cstrong\u003e308\u003c/strong\u003e, R832\u0026ndash;R839 (2015).\u003c/li\u003e\n\u003cli\u003eLankadeva, Y. R. \u003cem\u003eet al.\u003c/em\u003e Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C. \u003cem\u003eCrit Care Med\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, e179\u0026ndash;e190 (2021).\u003c/li\u003e\n\u003cli\u003ePlummer, M. P. \u003cem\u003eet al.\u003c/em\u003e The insulinotropic effect of pulsatile compared with continuous intravenous delivery of GLP-1. \u003cem\u003eDiabetologia\u003c/em\u003e \u003cstrong\u003e59\u003c/strong\u003e, 966\u0026ndash;969 (2016).\u003c/li\u003e\n\u003cli\u003eVan Breukelen, G. J. P. ANCOVA versus change from baseline had more power in randomized studies and more bias in nonrandomized studies. \u003cem\u003eJ Clin Epidemiol\u003c/em\u003e \u003cstrong\u003e59\u003c/strong\u003e, 920\u0026ndash;925 (2006).\u003c/li\u003e\n\u003cli\u003eVenkatachalam, M. A., Weinberg, J. M., Kriz, W. \u0026amp; Bidani, A. K. Failed tubule recovery, AKI-CKD transition, and kidney disease progression. \u003cem\u003eJournal of the American Society of Nephrology\u003c/em\u003e vol. 26 1765\u0026ndash;1776 Preprint at https://doi.org/10.1681/ASN.2015010006 (2015).\u003c/li\u003e\n\u003cli\u003eUlbrich, M., Nienke, U. \u0026amp; Hakim, N. F. Glucose content of lambs\u0026rsquo; blood. 1. 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S. \u003cem\u003eet al.\u003c/em\u003e The physiological role of glucagon-like peptide-1 in the regulation of renal function. \u003cem\u003eAm J Physiol Renal Physiol\u003c/em\u003e \u003cstrong\u003e310\u003c/strong\u003e, 123\u0026ndash;127 (2016).\u003c/li\u003e\n\u003cli\u003eJensen, E. P. \u003cem\u003eet al.\u003c/em\u003e Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. \u003cem\u003eAm J Physiol Renal Physiol\u003c/em\u003e \u003cstrong\u003e308\u003c/strong\u003e, 867\u0026ndash;877 (2015).\u003c/li\u003e\n\u003cli\u003eChen, R., Liu, D., Zhao, H. \u0026amp; Wang, X. Renal medullary perfusion differs from that in renal cortex in patients with sepsis associated acute kidney injury and correlates with renal function prognosis: A prospective cohort study. \u003cem\u003eClin Hemorheol Microcirc\u003c/em\u003e 1\u0026ndash;18 (2024) doi:10.3233/ch-242296.\u003c/li\u003e\n\u003cli\u003eLorenz, M. \u003cem\u003eet al.\u003c/em\u003e Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. \u003cem\u003eCardiovascular Diabetology\u003c/em\u003e vol. 16 Preprint at https://doi.org/10.1186/s12933-016-0490-6 (2017).\u003c/li\u003e\n\u003cli\u003eLubberding, A. F. \u003cem\u003eet al.\u003c/em\u003e Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node. \u003cem\u003eCardiovasc Res\u003c/em\u003e \u003cstrong\u003e120\u003c/strong\u003e, 1427\u0026ndash;1441 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplementary Figure S1","content":"\u003cp\u003eSupplementary Figure S1 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"glucagon-like peptide-1, Sepsis, Acute kidney injury, Medullary oxygenation, Sheep","lastPublishedDoi":"10.21203/rs.3.rs-7445170/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7445170/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce chronic kidney disease progression in people with type 2 diabetes mellitus. Sepsis is the leading cause of acute kidney injury (AKI). This study investigated whether GLP-1 is renoprotective in an ovine model of gram-negative septic AKI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eSixteen healthy merino ewes were surgically instrumented to measure mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion and oxygenation, and renal function. After a 5-day recovery period, sepsis was induced via continuous intravenous infusion of live \u003cem\u003eEscherichia coli\u003c/em\u003e for 30 hours. After 24 hours, the sheep were randomized to receive an intravenous infusion of 3.6 pmol/kg/min GLP-1 (n\u0026thinsp;=\u0026thinsp;8) or a fluid-matched vehicle (n\u0026thinsp;=\u0026thinsp;8) for 6 hours.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAfter 24 hours of sepsis, 7/8 sheep in each group developed oliguria, which was consistent with the criteria for AKI. Compared with vehicle, GLP-1 significantly increased renal blood flow (p\u0026thinsp;=\u0026thinsp;0.0054), renal oxygen delivery (p\u0026thinsp;=\u0026thinsp;0.0032), and renal cortical oxygenation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and improved renal medullary perfusion (p\u0026thinsp;=\u0026thinsp;0.029) during the intervention period. However, GLP-1 did not significantly improve the primary endpoint of renal medullary oxygenation (p\u0026thinsp;=\u0026thinsp;0.115).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn an ovine model of gram-negative sepsis-associated AKI, GLP-1 infusion improved global renal perfusion, renal oxygen delivery, and cortical oxygenation but failed to improve renal medullary oxygenation and kidney function.\u003c/p\u003e","manuscriptTitle":"Effects of glucagon-like peptide-1 on systemic hemodynamics, kidney function, and intrarenal oxygenation in sheep with sepsis-associated acute kidney injury","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-24 06:13:08","doi":"10.21203/rs.3.rs-7445170/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-25T19:44:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-20T16:36:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-19T10:14:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62090831694105641226106672278943768060","date":"2025-09-16T10:29:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56028820714146234538835136267261495254","date":"2025-09-16T05:55:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-13T19:56:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-13T19:05:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-09T12:34:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-08T18:45:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-08T10:54:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ebfd702c-970e-44ec-8d9b-bf66ac5f956b","owner":[],"postedDate":"September 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54970416,"name":"Health sciences/Diseases"},{"id":54970417,"name":"Health sciences/Medical research"},{"id":54970418,"name":"Health sciences/Nephrology"},{"id":54970419,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2025-12-29T16:03:33+00:00","versionOfRecord":{"articleIdentity":"rs-7445170","link":"https://doi.org/10.1038/s41598-025-33109-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-12-24 15:58:30","publishedOnDateReadable":"December 24th, 2025"},"versionCreatedAt":"2025-09-24 06:13:08","video":"","vorDoi":"10.1038/s41598-025-33109-0","vorDoiUrl":"https://doi.org/10.1038/s41598-025-33109-0","workflowStages":[]},"version":"v1","identity":"rs-7445170","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7445170","identity":"rs-7445170","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}