Kidney Perfusion Research Articles

Intrarenal Vein Congestion Score but Not Venous Excess Ultrasonography Is Associated with Kidney Perfusion and Etiology of AKI

Intrarenal Vein Congestion Score but Not Venous Excess Ultrasonography Is Associated with Kidney Perfusion and Etiology of AKI

Ex Vivo Kidney Perfusion as a Model for Recurrent Focal Segmental Glomerulosclerosis

Ex Vivo Kidney Perfusion as a Model for Recurrent Focal Segmental Glomerulosclerosis

Radiosynthesis and Preclinical Evaluation of [99mTc]Tc-Tigecycline Radiopharmaceutical to Diagnose Bacterial Infections.

As a primary source of mortality and disability, bacterial infections continue to develop a severe threat to humanity. Nuclear medicine imaging (NMI) is known for its promising potential to diagnose deep-seated bacterial infections. This work aims to develop a new technetium-99m (99mTc) labeled tigecycline radiopharmaceutical as an infection imaging agent. Reduced 99mTc was used to make a coordinate complex with tigecycline at pH 7.7-7.9 at room temperature. Instantaneous thin-layer chromatography impregnated with silica gel (ITLC-SG) and ray detector equipped high-performance liquid chromatography (ray-HPLC) was performed to access the radiolabeling yield and radiochemical purity (RCP). More than 91% labeling efficiency was achieved after 25 min of mild shaking of the reaction mixture. The radiolabeled complex was found intact up to 4 h in saline. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infection-induced rats were used to record the biodistribution of the radiopharmaceutical and its target specificity; 2 h' post-injection biodistribution revealed a 2.39 ± 0.29 target/non-target (T/NT) ratio in the E. coli infection-induced animal model, while a 2.9 ± 0.31 T/NT value was recorded in the S. aureus bacterial infection-induced animal model. [99mTc]Tc-tigecycline scintigraphy was performed in healthy rabbits using a single photon emission computed tomography (SPECT) camera. Scintigrams showed normal kidney perfusion and excretion into the bladder. In conclusion, the newly developed [99mTc]Tc-tigecycline radiopharmaceutical could be considered to diagnose broad-spectrum bacterial infections.

Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39

We previously reported that normothermic ex vivo kidney perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation.

Renal dysfunction in surgical patients.

To provide an overview of the current diagnostic criteria for acute kidney injury (AKI) including their limitations and to discuss prevention and treatment approaches in the perioperative setting. AKI is common in the perioperative period and is associated with worse short- and long-term outcomes. Current definitions of AKI have several limitations and lead to delayed recognition of kidney dysfunction which is why novel diagnostic approaches by using renal biomarkers may be helpful. In general, prevention of the development and progression of AKI is vital as a causal treatment for AKI is currently not available. Optimization of kidney perfusion and avoidance of nephrotoxic drugs reduce the occurrence of AKI in surgical patients. Angiotensin II as a new vasopressor, the use of remote ischemic preconditioning, and amino acids may be approaches with a positive effect on the kidneys. Evidence suggests that the implementation of supportive measures in patients at high risk for AKI might reduce the occurrence of AKI. Novel biomarkers can help allocating resources by detecting patients at high risk for AKI.

448.4: Development of an automated multi-sensor normothermic kidney perfusion device for ex-vivo preservation and assessment.

448.4: Development of an automated multi-sensor normothermic kidney perfusion device for ex-vivo preservation and assessment.

Impact of device variability and protocol differences on kidney function during normothermic machine perfusion: A comparative study using porcine and human kidneys.

A growing interest in renal normothermic machine perfusion (NMP) has resulted in more clinically available perfusion devices. While all perfusion systems have the same aim, there are significant differences in their circuits, pumps, sensors, and software. Therefore, our objective was to assess the impact of different perfusion protocols and devices on kidney function and perfusion parameters during NMP. Porcine kidneys were subjected to 30 min of warm ischemia, 24 h of static cold storage, and subsequently perfused for 6 h using (1) the Kidney Assist (KA) machine with a pressure of 75 mm Hg, (2) the KA device incorporating several adjustments and a pressure of 85 mm Hg (modified KA), or (3) the Perlife (PL) perfusion device (n = 4). Consecutively, discarded human kidneys were perfused using the KA or modified KA (n = 3) protocol. The PL group quickly reached the device's upper flow limit and consequently received a significantly lower pressure compared to the KA groups. The arterial pO2 was significantly lower in the PL group. Yet, hemoglobin concentration increased over time, and oxygen consumption was significantly higher compared to the KA groups. Fractional sodium excretion was significantly lower in the PL group. Tissue ATP levels, urine production, and creatinine clearance rates did not differ between groups. In human kidneys, the modified KA group showed significantly lower vascular resistance, higher oxygen delivery, and lower levels of lactate in the perfusate compared to the KA group. This study shows that perfusion characteristics and kidney function are significantly influenced by the perfusion protocol and the device and its settings during normothermic machine perfusion and therefore should be interpreted with caution.

Contrast-enhanced computed tomography for exvivo assessment of human kidneys: A proof-of-concept study.

Ex vivo perfusion of transplant-declined human organs has emerged as a promising platform to study the response of an organ to novel therapeutic strategies. However, to fully realize the capability of this platform for performing translational research in human organ pathophysiology, there is a need for robust assays to assess organ function and disease. State-of-the-art research methods rely on analyses of biopsies taken during perfusion, which both damages the organ and only provides localized information. Developing non-invasive, whole organ methods of assessment is critical to the further development of this research platform. We use ex vivo cold infusion scanning (EXCIS) with contrast-enhanced computed tomography (CT) to quantify perfusion in kidneys preserved ex vivo. EXCIS-CT computes three complementary metrics for whole organ assessment: a dynamic assessment of contrast filling, a measure of vascular network anatomical structure, and a static assessment of perfusion heterogeneity. These metrics were applied to a series of six transplant-declined human kidneys, which demonstrated a range of anatomies and perfusion. Lastly, two transplant-declined human kidneys were imaged before and after a 1-h period of ex vivo normothermic perfusion (NMP). We found variable responses to NMP, with one kidney maintaining the vascular network and hemodynamics and the other showing significant changes in vessel size and spatial perfusion profile. EXCIS-CT provides metrics that can be used to characterize whole organ perfusion and vascular function.

Absolute Stenosis Measures of Renal Artery Independently Influence Kidney Perfusion in Contrast-Enhanced Multidetector Computed Tomography.

Background: A renal artery lumen reduction of ≥60% indicates hemodynamically significant stenosis and is one of the main criteria for invasive revascularization. We hypothesize that direct parameters describing renal artery stenosis (RAS) could better correlate with renal blood flow and improve the criterion for revascularization. This study aimed to investigate RAS parameters independently associated with renal blood flow estimated in contrast-enhanced multidetector computed tomography (CE-MDCT). Methods: Ultrasound Doppler dynamic renal cortical perfusion (dRCP), CE-MDCT with cortical blood flow (CBF), and RAS assessment in the form of cross-sectional area reduction (CSAR), maximal diameter reduction (MaxDR), mean diameter (MeD), and minimal diameter (MinD) were investigated. Results: CBF correlated with CSAR (r = -0.422, p = 0.003), MeD (r = 0.344, p = 0.005) and MinD (r = 0.348, p= 0.005), whereas RCP correlated only with MeD (r = 0.357, p = 0.005) and MinD (r = 0.427, p< 0.001). In multivariable regression, only MeD was independently associated with CBF (R2 = 0.179; p < 0.001), and MeD < 3.5 mm substantially indicated CBF < 175 mL/100 g/min in ROC analysis. Conclusions: The directly measured mean diameter of RAS is independently associated with renal cortex blood flow and is probably a more appropriate parameter for the invasive RAS treatment criterion.

Case Report: A right-sided testicular artery of renal origin, in coexistence with a renal artery duplication: Dissection findings with clinical significance

Purpose The current cadaveric report describes the abnormal origin and course of testicular arteries (TAs) in two donated cadavers, along with a renal artery (RA) duplication. Methods Dissection of the inferior vena cava (IVC) and the abdominal aorta (AA) branching patterns were performed in 90-year-old- and 76-year-old formalin-embalmed donated male cadavers. Results Variants of the TA origin and course were identified, as coexisting with RA variants. Case 1: A right-sided RA (RRA) duplication (recorded as superior and inferior renal artery-SRA and IRA) with origin from the AA, coexisted with a right TA (RTA) that originated from the IRA and descended anteriorly to the ureter. The left TA (LTA) originated from the AA proximal to the origin of the left RA (LRA). The LTA coursed in front of the common drainage of the left testicular and renal vein into the IVC. Case 2: A bilateral RA duplication was identified and recorded as SRA and IRA. The right-sided SRA originated from the AA upper level and played the role of the accessory RA (ARA). The main perfusion of the right kidney was performed by the IRA which was further trifurcated into a superior polar, an inferior polar (IPA), and a TA. The RTA had a high origin from the IPA. Conclusion The current study reported two cases of TAs with abnormal origin and course accompanied by an RA duplication. A thorough knowledge of the origin and course of the TAs has clinical implications for the kidneys and testicle’ surgery.

Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12- hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.

Renovascular Disease and Mitochondrial Dysfunction in Human Mesenchymal Stem Cells.

Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue-derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. MSCs were harvested from subcutaneous abdominal fat of renovascular disease patients and healthy volunteers (n=3 each), characterized and subsequently injected (5x10^5/200μL) into mice 2 weeks after renal artery stenosis or sham surgery (n=6/group). Two weeks later, mice underwent imaging and tissue studies. Healthy volunteer- and renovascular disease-MSCs were also characterized by mRNA/microRNA (miRNA)-sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in-vitro before and after miRNA modulation, and in-vivo in additional renal artery stenosis mice administered with renovascular disease-MSCs pre-treated with miR-378h mimic (n=5) or inhibitor (n=4). MSCs engrafted in stenotic mouse kidneys. Healthy volunteer-MSCs (but not renovascular disease-MSCs) decreased blood pressure, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease-MSCs versus healthy volunteer-MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes.

The role of urine chloride in acute heart failure

In our retrospective study, we aimed to investigate the relationship between urinary chloride (uCl−) and selected clinical and laboratory biomarkers, renal function, and patient outcomes in the acute heart failure (AHF) population. We divided 248 adult patients (≥ 18 years) with AHF into two groups: low uCl− (< 115 mmol/L) and high uCl−. The mean age of the patient group was 70.2 ± 12.6, and 182 patients were male (73.4%). Clinical endpoints included in-hospital mortality, one-year mortality, and a composite endpoint of one-year mortality and rehospitalization for heart failure. Patients were followed up for at least one year. Relevant clinical and baseline biomarker data were collected, including markers concerning inflammation, liver and kidney function, perfusion and congestion, iron status, cardiac remodeling, gasometry, renin and aldosterone. Low uCl− was associated with worse in-hospital outcomes, including higher in-hospital mortality (7.7% vs. 1.4%, p = 0.014), the need for inotropic support (20.19% vs. 2.08%, p ≤ 0.001), worsening of HF during therapy (17.31% vs. 4.86%, p ≤ 0.001), and the need for treatment in an intensive cardiac care unit (33.65% vs. 15.28%, p ≤ 0.001). Low uCl− was a significant predictor of one-year mortality (40.4% vs. 16.7%, p < 0.05) and the composite outcome (HR 2.42, 95% CI 1.43–4.08, p < 0.001). In the multivariable analysis, uCl− was independently associated with the risk of one-year mortality (HR 0.92, 95% CI 0.87–0.98, p < 0.05) and the composite outcome (HR 0.95, 95% CI 0.92–0.99, p < 0.05). Our findings suggest that low uCl− is a marker of more advanced heart failure, activation of the renin–angiotensin–aldosterone system and is related to worse one-year outcomes.

Changes in Microwave Ablation Zone Dimensions after Transarterial Embolization in an Ex Vivo Human Kidney Perfusion Model

PurposeTo utilize a novel ex vivo perfused human renal model and quantify microwave ablation (MWA) size differences in renal tissue when combining MWA with transarterial embolization (TAE). Materials and MethodsHuman kidneys (n = 5) declined for transplantation were obtained and connected to a fluoroscopy-compatible ex vivo perfusion system. Two ablations—1 standard MWA and 1 TAE-MWA—were performed in each kidney for 2 minutes at 100 W using a MWA system (Solero Angiodynamics). MWA alone was performed in the upper pole. In the lower pole, MWA was performed after TAE with 40–90 μm radiopaque microspheres to achieve angiographic stasis. Ablation zones of coagulative necrosis were sectioned along the long axis and segmented for maximal short-axis diameter (SAD) and long-axis diameter (LAD) measurements. ResultsA total of 10 ablations (5 MWAs and 5 TAE-MWAs) were performed in 5 human kidneys. TAE-MWA resulted in significantly increased SAD, LAD, volume, and sphericity compared with standard MWA ± SD, with mean measurements as follows (5 standard MWAs ± SD vs 5 TAE-MWAs ± SD, 2-tailed t-test): (a) SAD, 1.8 cm (SD ± 0.1) versus 2.5 cm (SD ± 0.1) (P < .001); (b) LAD, 2.9 cm (SD ± 0.3) versus 3.2 cm (SD ± 0.1) (P = .039); (c) volume, 5.0 mL (SD ± 0.5) versus 11.0 mL (SD ± 0.7) (P < .001); and (d) sphericity, 0.4 (SD ± 0.2) versus 0.6 (SD ± 0.1) (P = .049). Histology demonstrated no differences in TAE-MWA other than concentrated microspheres. ConclusionsThis ex vivo human kidney perfusion model confirmed that combined MWA-TAE significantly increased ablation size and spherical shape compared with MWA alone.

A Randomized Trial of Intravenous Amino Acids for Kidney Protection.

Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).

Effects of Cardiopulmonary Bypass on Kidney and Brain Tissue Microcirculatory Perfusion and Oxygenation

Effects of Cardiopulmonary Bypass on Kidney and Brain Tissue Microcirculatory Perfusion and Oxygenation

Influence of Aortic Arch Morphology on Renal Perfusion in Patients with Coarctation of the Aorta: An Exploratory Study.

Objectives: The configuration of the aortic arch, particularly a Gothic arch shape, in individuals with corrected coarctation of the aorta (CoA) has been associated with a decreased systolic wave amplitude across the arch, which could potentially impair renal perfusion and elevate the risk of arterial hypertension. This study aims to explore the relationship between the morphological characteristics of the aortic arch and their impact on renal perfusion in patients with CoA. Methods: Seventy-one subjects with corrected CoA underwent continuous 24 h ambulatory blood pressure monitoring, computed tomography to assess the aortic arch, and renal perfusion scanning. Subjects were stratified into three groups based on the height-to-width (H/W) ratio of their aortic arch: Group 1 with a H/W ratio of <0.65, Group 2 with a H/W ratio between 0.65 and 0.85, and Group 3 with a H/W ratio of >0.85. Results: Groups 1 and 2 (53,78% and 62.63%) presented with a higher hypertension prevalence of elevated blood pressure than Group 3 (38.89%). Notable variations were observed among the subjects in the time to peak perfusion (Tmax) in the left kidney across the groups. Group 1 showed a median Tmax at 0.27, Group 2 at 0.13, and Group 3 at -0.38 (p-value = 0.079). The differences in Tmax for the right kidney followed a similar trend but were not statistically significant (Group 1 at 0.61, Group 2 at 0.22, and Group 3 at 0.11; p-value = 0.229). Conclusions: This study suggests that variations in the aortic arch morphology might not significantly influence renal perfusion in CoA patients. This indicates the potential adaptability of the renal blood flow, which appears to compensate for reduced perfusion, thus minimizing adverse effects on the kidney function. This adaptability suggests an inherent physiological resilience, emphasizing the need for further targeted research to understand the specific interactions and impacts on treatment strategies for CoA.

Subnormothermic Oxygenated Machine Perfusion (24 h) in DCD Kidney Transplantation.

Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation. SNMP at 22-25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys. In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs. These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS.

#573 Development of a model for simultaneous normothermic perfusion in porcine kidney grafts

Abstract Background and Aims In recent years, DCD or ECD deceased donors have been increasingly used in kidney transplantation as a partial response to the deceased donor shortage, leading to a suboptimal quality of kidney grafts. There is a need for developing better kidney graft preservation methods, such as hypo- or normo- thermic machine perfusion. Machine perfusion might provide the unique opportunity to directly treat the perfused kidney grafts to improve their quality and to decrease ischemia/reperfusion injury during transplantation. Our aim was to develop a pig model of simultaneous normothermic perfusion of both kidneys procured from the same donor and to compare the assessment of renal function through the injection of creatinine and iohexol. Method Under general anaesthesia, the donor pigs (n = 5) were euthanized by exsanguination and the blood was recovered using a cell-saving system. Both kidneys (n = 10) were submitted to 30 min of warm and a 2-hour cold ischemia period, before being perfused for 6 hrs at 37°C. Kidney perfusion started and run in parallel using 2 independents, modified extracorporeal machines. Urine production, arterial blood gas exchange, and perfusion parameters (flow, pressure, resistance) were monitored and compared. Creatinine and iohexol were added to the perfusate of both machines to assess renal function. Results A parallel evolution of blood parameters in both perfusions was observed. By maintaining a constant perfusion pressure of 70 mmHg, flow rates increased to 100 mL/min. Despite variations in urinary excretion, creatinine and iohexol clearances remained comparable, demonstrating a parallel kidney function. Conclusion In conclusion, we established a model of parallel and simultaneous normothermic perfusion of pig kidneys, and for the first time, we demonstrated the utility of iohexol measurements for improved functional assessment in an isolated perfusion model. After randomization of the grafts, this model will be used for testing innovative therapies as MSC during perfusion, both in swine kidneys and human discarded grafts, using the contralateral kidney as a paired control.

Volenrelaxin (LY3540378) increases Renal Plasma Flow: A Randomized Phase 1 Trial.

Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n=56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n=77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p<0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and+4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.