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

Abstract

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

Multiparametric magnetic resonance imaging: A robust tool to test pathogenesis and pathophysiology behind nephropathy in humans

“…In healthy subjects, GLP‐1 increases mainly renal medullary perfusion, but also cortical perfusion and renal oxygenation during sodium loading (Haddock et al, 2023) (Figure 2). By preserving tissue oxygenation, improved perfusion may contribute to the beneficial long‐term renal and cardiovascular effects of GLP‐1 RAs.…”

“…Perfusion and R 2 * maps for one participant immediately before (baseline) and 15 min after commencement of GLP‐1 (glucagon‐like‐peptide‐1) infusion (Haddock et al, 2023). Significant increases in both medullary and cortical perfusion were observed as was either stable or slightly improved oxygenation (similar or reduced R 2 * values).…”

Magnetic Resonance Imaging in Clinical Trials of Diabetic Kidney Disease

“…Of note, changes in ASL cortical perfusion with no significant decrease in RBF have been reported after infusions designed to expand blood volume, where the decrease in ASL cortical perfusion measured in mL/100 g per min was due to an increase in kidney volume [96]. It has also been speculated that an increase in ASL cortical perfusion with no change in RBF after treatment with a GLP-1 agonist may be due to changes in kidney volume [97]. The intra-subject CV has been reported to be 9% and 31% in healthy volunteers [46,89], 23% in CKD patients [81], and 33% in DKD patients and matched healthy controls [48].…”

“…A major advantage of using BOLD to indirectly assess renal tissue oxygenation lies in its non-invasive nature compared to direct oxygen pressure measurement using microelectrodes as the only existing alternative and not acceptable for use in volunteers or patients. BOLD has been used to explore the potential renoprotective role of drug interventions, such as GLP-1 agonists [97], lipo-prostaglandin E1 (Lipo-PGE1) [124], or SGLT2i [125,126] (see also Table 1). A single 50 mg dose of dapagliflozin, a medication that inhibits the uptake of sodium and glucose from the filtrate, decreased cortical R 2 * with no change in renal perfusion and RBF, potentially due to reduced workload because of the reduced sodium re-uptake [73] (see Table 1).…”

The GLP-1-mediated gut-kidney cross talk in humans: mechanistic insight

“…The natriuretic action of GLP-1, high renal GLP-1 extraction, and ANGII suppression can be blocked by a GLP-1R antagonist. ( 13 , 15 , 22 ). Differences between species may obviously contribute to explaining these discrepancies; however, in animal experiments ( 23 ), GLP-1 levels are typically increased 100-fold above physiological levels compared with a 10-fold increase (slightly supraphysiological levels) investigated in mechanistic human studies.…”