Renal Blood Flow Research Articles

The Influence of Anthropometric Factors on Renal mpMRI: Insights From Regional Analysis.

Multiparametric MRI (mpMRI) provides detailed insights into renal function, but the impact of anthropometric factors on renal imaging is not fully understood. To investigate regional correlations between mpMRI parameters and age, body mass index (BMI), and body surface area (BSA). Prospective, cross-sectional observational study. Twenty-nine healthy volunteers (44.5 ± 18.3 years, 18 females) without a history of renal disease. 3-T, pseudo-continuous arterial spin labeling, multi-echo gradient-recalled echo, diffusion-weighted imaging, T1 and T2 mapping. Bilateral kidneys were segmented into nine concentric layers (outer cortex to inner regions) and nine equiangular sections (lower to upper pole). Key parameters (renal blood flow [RBF], , apparent diffusion coefficient [ADC], T1 and T2 maps) were correlated with age, BMI, and BSA. Differences in parameters between age and BMI groups were also evaluated. Spearman correlation, Mann-Whitney U test, and rank-biserial correlation coefficient for effect size. A P-value <0.05 was considered statistically significant. RBF correlated negatively with age in all regions and BMI in inner layers and lower pole. ADC negatively correlated with BMI (significance was not reached in layers 2, 7, 8; P-value = 0.06-0.12) and BSA in layers 1-7. T1 negatively correlated with age in inner regions and lower medial pole. Significant positive correlations were found between age and (outermost layer, upper pole), age and T2 (inner and cranial-caudal regions), as well as BMI and T2 (except upper pole; P-value = 0.06). Significant differences between age groups were observed for RBF (all regions), (outermost and second innermost layers, central lateral region), T1 (innermost layer), and T2 (upper medial pole). Between BMI groups, ADC (middle layers, upper medial pole) and T2 (outermost and inner layers, lower pole to lateral region) differed significantly. Intrarenal variance of mpMRI parameters correlated with age, BMI, and BSA. 4 TECHNICAL EFFICACY: Stage 1.

Effect of intrarenal pelvic pressure on pyelo-tubular backflow and renal cortical blood perfusion during mini-percutaneous nephrolithotomy.

To investigate the effects of intrarenal pelvic pressure (IPP) on pyelo-tubular backflow and renal cortical blood perfusion during mini-percutaneous nephrolithotomy (MPCNL). Dynamic changes in pyelo-tubular backflow and renal cortical blood perfusion were studied in six patients undergoing MPCNL using dynamic contrast-enhanced ultrasonography (CEUS) and IPP monitoring. CEUS of intrarenal pelvic perfusion revealed that renal tubules began to exhibit contrast agent reflux when IPP exceeded 34 mmHg during the MPCNL procedure. There was a positive correlation between renal tubule contrast agent reflux and IPP (P < 0.05). Intravenous CEUS of renal cortical blood flow demonstrated that both intrarenal pelvic perfusion time and IPP during MPCNL significantly affected renal cortical blood perfusion. Intrarenal pelvic perfusion time and pressure were negatively correlated with contrast agent peak intensity (PI) and area under the curve (AUC) (P < 0.05). Longer intrarenal pelvic perfusion times and higher pressures resulted in decreased renal cortical blood perfusion. This study directly confirmed through dynamic CEUS and real-time IPP monitoring that an increase in IPP above the threshold of approximately 34 mmHg during MPCNL in patients leads to reflux through the renal tubules and a significant decrease in renal cortical blood perfusion. The safe upper limit for intrarenal pelvic perfusion pressure during MPCNL is approximately 34 mmHg.

The Paradise Renal Denervation System: An FDA-approved catheter-based treatment option for resistant hypertension

Resistant hypertension is defined as office blood pressure &gt;140/90 mm Hg with a mean 24-hour ambulatory blood pressure of &gt;130/80 mm Hg in patients who are compliant with 3 or more antihypertensive medications. Those who persistently fail pharmaceutical therapy may benefit from interventional treatment, such as renal denervation. Sympathetic nervous activity in the kidney is a known contributor to increased blood pressure because it results in efferent and afferent arteriole vasoconstriction, reduced renal blood flow, increased sodium and water reabsorption, and the release of renin. The Recor Paradise Renal Denervation System is designed to target renal sympathetic nerves via ultrasound ablation. The RADIANCE trials have demonstrated that patients who underwent renal denervation had a significant decrease in systolic blood pressure as compared with those who underwent a sham procedure. Furthermore, the device was found to have a favorable safety profile, with minimal major adverse events. The Food and Drug Administration granted approval to Recor, and the Paradise system is expected to serve as an adjunctive therapy for patients with true-resistant hypertension.

Concentric-object and equiangular-object methods to perform standardized regional analysis in renal mpMRI.

Renal multiparametric magnetic resonance imaging (mpMRI) sequences, including T1-T2 mapping, Blood oxygenation level-dependent (BOLD), Renal blood flow (RBF), and Apparent Diffusion Coefficient (ADC) from diffusion-weighted imaging (DWI), provide insights into kidney function. However, consensus on selecting regions of interest (ROIs) is lacking. This study aims to describe and compare the Concentric Objects (CO) and Equiangular Objects (EO) methods for standardized ROI selection and assess their efficacy in capturing regional variations in renal MRI parameters. Twelve healthy volunteers underwent mpMRI renal scans. ROIs were selected manually and by applying the CO and EO algorithms to each mpMRI sequence. The methods were tested across various subregion configurations. Regional differences in renal MRI parameters were evaluated. CO and EO methods demonstrated statistically significant differences in mpMRI parameters across renal regions. ASL-RBF, BOLD-MRI, and T2-map results indicated substantial variations from the lower to upper kidney areas. This study implemented CO and EO algorithms in renal mpMRI, showing their potential for evaluating cortico-medullary and cranio-caudal profiles. The findings validate the CO method for BOLD and ADC measurements and presented ASL-RBF and T1-T2 map profiles. The EO method's utility needs further validation with renal patients.

Cardiovascular and renal effects of apelin in chronic kidney disease: a randomised, double-blind, placebo-controlled, crossover study

Chronic kidney disease (CKD) affects ~10% of the population and cardiovascular disease is its commonest complication. Despite treatment, patient outcomes remain poor and newer therapies are urgently needed. Here, we investigated the systemic and renal effects of apelin in CKD. In a randomized, double-blind, placebo-controlled, crossover study, 24 subjects (12 patients with CKD and 12 matched healthy subjects) received pyroglutamated apelin-13 ([Pyr1]apelin-13, 1 nmol/min and 30 nmol/min) or matched placebo on two separate visits. Systemic and renal hemodynamics were monitored throughout. The co-primary endpoints were change in systemic vascular resistance index and renal blood flow. Secondary endpoints were change in blood pressure, cardiac output, pulse wave velocity, glomerular filtration rate, natriuresis, free water clearance and urinary protein excretion. In both health and CKD, 30 nmol/min [Pyr1]apelin-13 reduced mean arterial pressure by ~4%, systemic vascular resistance by ~12%, and increased cardiac index by ~10%, compared to placebo (p < 0.05 for all). Both doses of [Pyr1]apelin-13 increased renal blood flow by ~15%, natriuresis by ~20% and free water clearance by ~10%, compared to placebo (p < 0.05 for all). In patients with chronic kidney disease only, glomerular filtration rate fell by ~10%, effective filtration fraction by ~5% and proteinuria by ~25% (p < 0.01 for all). Apelin has short-term cardiovascular and renal benefits in CKD. If maintained longer-term, these should improve patient outcomes. Clinical trials of long-acting oral apelin agonists are justified in CKD and other conditions with impaired salt and water balance. Registration number at www.clinicalTrials.gov: NCT03956576. Funded by Kidney Research UK.

Angiotensin Receptor-Neprilysin Inhibitor for Chronic Kidney Disease: Strategies for Renal Protection.

Chronic kidney disease (CKD) and hypertension are significant global health challenges that often coexist and aggravate each other. Renin-angiotensin system (RAS) inhibitors are important to the management of these conditions; however, their efficacy for advanced CKD remains uncertain. Angiotensin receptor-neprilysin inhibitor (ARNI) have superior efficacy for heart failure (HF) management, as evidenced by landmark trials such as the PARADIGM-HF and PARAGON-HF, thus leading to its endorsement by various guidelines. Although direct evidence supporting the renal-protective effects of ARNI is lacking, post hoc analyses have suggested its potential to mitigate the decline of the estimated glomerular filtration rate and renal events, particularly in patients with HF with a relatively preserved ejection fraction. Mechanistically, ARNI augments the glomerular filtration rate by dilating glomerular arterioles, relaxing mesangial cells, and improving renal medullary blood flow, thereby mitigating interstitial fibrosis progression. ARNI also effectively addresses non-dipper hypertension, particularly in salt-sensitive individuals, thereby reducing the cardiovascular risk. Uncertainties regarding the efficacy and safety of ARNI for advanced renal failure (estimated glomerular filtration rate &lt;30 mL/min) exist. Excessive hypotension associated with ARNI use may exacerbate the renal function decline, especially in older patients with comorbid HF with a reduced ejection fraction. Hence, vigilant blood pressure monitoring is essential to optimizing the renal benefits of ARNI and minimizing adverse effects. Evidence supporting the renal benefits of ARNI continues to evolve; therefore, ARNI could mitigate renal dysfunction in select patient populations. Further research should be performed to clarify the efficacy of ARNI for advanced renal failure and refine its therapeutic application for patients with concurrent HF and renal dysfunction.

12518 Development Of A Four-compartment, Dynamic (In Vivo) Model For Insulin Disposition In Healthy Humans: Use Of Fick’s Law To Model Plasma-interstitial Insulin Flux

Abstract Disclosure: R.I. Dorin: None. C.R. Qualls: None. Introduction: Metabolic elimination of insulin (I) in vivo includes pathways mediated by high-affinity and potentially saturable insulin receptor binding; endogenous insulin secreted into the portal vein is subject to first pass elimination. The rate of insulin flux between vascular (Vp) and interstitial (Vi) compartments is often modeled by first order rate constants; here we analyzed an alternative approach using Fick’s law. Methods: The four-compartment, insulin (I) model is expressed by four differential equations that represent I flow (mass/time) in 4 volumes (V) (or compartments) having 3 corresponding elimination rate functions (α): (i) vascular plasma (Vp), (ii) interstitial (Vi, αi), (iii) hepatic (Vh, αh), and (iv) kidney (Vk, αk). Fick’s law was used to model diffusion of insulin between Vp and Vi; Michaelis-Menten like functions were used for saturable elimination functions (αh and αi); rates of hepatic (HPF) and renal (KPF) plasma flow were from literature. Realistic bounds for solved parameters (insulin permeability constant [k, L/min] and αi [min-[1]]) were developed by test bed analysis of published plasma (Ip) and interstitial (Ii) insulin concentration data. The inverse problem (estimating parameters) used Ip data from insulin-modified, frequently sampled iv glucose tolerance (IM-FSIVGT) studies performed in 40 healthy, non-diabetic women (1). Parameter solutions for individual subjects were obtained by iterative least squares method minimizing differences between model-predicted and measured Ip. Results: For infusion of exogenous I (ZI) at a constant rate (e.g., insulin clamp), reported steady state Ii/Ip data suggest that interstitial insulin elimination (αi) is conditionally saturable. Together with non-steady state data for Ip and Ii, initial estimates of k and αi were obtained. Steady state solutions give rise to four algebraic equations: (1) Ii/Ip = a, where a &amp;lt; 1 is consistent with experimental data, (2) Ih is a reduced version of a linear combination of Ip and endogenous insulin secretion (Zβ), where the factor of reduction (b) is &amp;lt;1, (3) Ik/Ip = d, where d&amp;lt;1, and (4) Ip is a linear combination of (i) ZI and (ii) the reduced (by factor b) Zβ. For Ip, this linear combination of ZI and reduced Zβ is also normalized by factor c (weighted sum of k, HPF, and KPF). Conclusions: (i) The proposed insulin flow model using Fick’s law was advantageous in providing realistic parameters and solutions that are tractable to physiologic interpretation, (ii) a simplified version of this model is generalizable to C-peptide, and (iii) since measurement of Ii is impractical in the clinical setting, the proposed prediction model may provide useful modeling adjunct to personalize pharmacokinetic and pharmacodynamic strategies for insulin administered by subcutaneous, iv, and hybrid closed-loop insulin pump routes. 1. Gower et al. Nutrition &amp; Metabolism (2016) 13:2 Presentation: 6/1/2024

8483 Changes in kidney hemodynamics during gender-affirming hormone therapy in transgender individuals - findings from the KNIGHT pilot study

Abstract Disclosure: S.A. van Eeghen: None. C. Wiepjes: None. L.L. Pyle: None. M. den Heijer: Research Investigator; Self; Kyowa Kirin. Other; Self; Novartis Pharmaceuticals. P. Bjornstad: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Novo Nordisk, XORTX. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly &amp; Company, LG Chemistry, Horizon Pharma, Novo Nordisk, Sanofi. Research Investigator; Self; AstraZeneca, Merck, Horizon Pharma. Other; Self; Bayer, Inc. D. van Raalte: Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly &amp; Company, Merck, Sanofi, MSD. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly &amp; Company, Merck, Sanofi, MSD. N.J. Nokoff: Consulting Fee; Self; Neurocrine Biosciences, Inc, Ionis Pharmaceuticals Inc.. Research Investigator; Self; Neurocrine Biosciences, Inc. Other; Self; World Athletics. Background: Studies in transgender individuals have shown that gender-affirming hormone therapy (GAHT) impacts estimated glomerular filtration rate (eGFR). Masculinizing hormone therapy decreases, while feminizing hormone therapy increases eGFR, based on changes in serum creatinine and cystatin C. These substantial changes suggest an effect of sex hormones on kidney hemodynamics. To investigate this, we studied kidney hemodynamic changes before and after 3 months of gender-affirming hormone therapy (GAHT) in transgender individuals. Methods: This prospective observational pilot study assessed kidney hemodynamics in 23 transgender individuals assigned male at birth receiving feminizing hormone therapy and 21 transgender individuals assigned female at birth receiving masculinizing hormone therapy. Feminizing therapy included transdermal (n=16), sublingual (n=5), or oral estradiol (n=2), in combination with an anti-androgen (n=22); intramuscular triptorelin (n=16), spironolactone (n=5) or finasteride (n=1). Masculinizing therapy involved transdermal (n=17) or injected testosterone (n=4). Measures included glomerular filtration rate (GFR; Iohexol clearance), effective renal plasma flow (ERPF; p-aminohippurate clearance), and renal vascular resistance (RVR; mean arterial pressure/renal blood flow). Glomerular hydraulic pressure (PGLO), and afferent/efferent vascular resistance (RA/RE) were estimated by Gomez equations. Linear mixed models compared baseline and three-month measurements. Results: Individuals undergoing feminizing hormone therapy [median age 21 (IQR 19-29) years, BMI median 22.9 (IQR 18.9-30.7) kg/m²] had increased GFR by 2.8 mL/min per 1.73m² (95% CI, 0.01 to 5.6) and a nonsignificant increase in ERPF (+42 mL/min per 1.73m²; 95% CI, -5 to 90). RVR and RA significantly decreased [RVR: -0.007 mmHg/L/min (95% CI, -0.015 to -0.0003), RA: -294 dyn/s per cm5 (5% CI, -568 to -21)], indicating afferent vasodilation. In contrast, individuals receiving masculinizing therapy (median age median 20 (IQR 18-23) years, BMI median 24.2 (IQR 21.1-27.3) kg/m²) showed a slight, nonsignificant decrease in GFR (-2.1 mL/min per 1.73m²; 95% CI, -4.9 to 0.8), with no changes in other kidney hemodynamic parameters. Conclusions: In this cohort of transgender individuals, GFR increased during feminizing hormone therapy, likely due to afferent vasodilatation, while during masculinizing hormone therapy GFR tended to decrease. These findings suggest an influence of sex hormones on kidney hemodynamics, especially during feminizing hormone therapy. Presentation: 6/3/2024

Evaluation of Early Renal Changes in Type 2 Diabetes Mellitus Using Multiparametric MR Imaging.

To evaluate the clinical value of early renal changes in type 2 diabetes mellitus (T2DM) using multiparameter MRI. The study included 41 diabetics (normoalbuminuria: n = 23; microalbuminuria: n = 18) and 30 healthy controls. All subjects underwent intravoxel incoherent motion diffusion-weighted imaging (IVIM), blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) examinations. One-way analysis of variance was used to compare MRI parameters among the three groups. Pearson correlation analysis was used to evaluate the relationship between MRI parameters and estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). Receiver operating characteristic analysis was performed to assess the diagnostic performance. There were statistical differences in cortical D, D*, f, renal blood flow (RBF) and medulla D, D*, f, R2* among the three groups (P < 0.05). The cortical or medullary D, cortical f, and RBF were significantly positively correlated with eGFR (all P < 0.01). The cortical or medullary D, D*, f, cortical RBF were negatively correlated with ACR (all P < 0.05).To evaluate early kidney changes and degree of diabetes, cortical combined D and RBF (AUC [area under the curve] = 0.796 and 0.947, respectively) was better than single D or RBF (all P > 0.05); medullary combined D and R2* (AUC = 0.899 and 0.923, respectively) was better than single D or R2* (all P > 0.05), except single D (P = 0.005) in differentiating normoalbuminuria group from control group. The early changes of renal diffusion and perfusion, oxygenation level, and blood flow in T2DM could be evaluated noninvasively and quantitatively using IVIM, BOLD and ASL. Renal medullary combined IVIM-derived D and BOLD-derived R2* and cortical combined IVIM-derived D and ASL-derived RBF were better for evaluating early renal changes in T2DM.

Renal Artery Blood Flow and Surface Parenchymal Perfusion During Renal Artery Endoshunting in a Porcine Model

ObjectiveIschaemia and reperfusion can result in permanent tissue damage. During complex open abdominal aortic surgery, transient clamping of renovisceral arteries may be required to successfully complete the vascular repair. Endovascular shunting (endoshunting) presents an alternative technique for managing such temporary renovisceral ischaemia. This study aimed to investigate the performance of endoshunting to the renal circulation in a porcine model. MethodsThis study of five domestic pigs investigated arterial volume flow rates during endoshunting of a single renal artery and the associated impact on renal perfusion parameters (laser Doppler renal parenchymal perfusion, renal oxygen extraction, and selective urinary output). The study was performed in three steps: baseline registrations (30 minutes), endoshunting (120 minutes), and restitution (60 minutes). The right kidney was used as the experimental side and the left kidney as control. ResultsThe median arterial flow rate in the left control kidney remained constant throughout the experiment. On the right (endoshunted) side, the baseline median arterial flow rate was 267 (range, 160 – 404) mL/min. Following activation of the endoshunt, the median arterial volume flow dropped by 59% to 110 (range, 45 – 150) mL/min (p = .018). During endoshunting, the median kidney surface perfusion decreased to 42% of the baseline value. On the control side, a rise in the median parenchymal perfusion was observed after endoshunt activation, which was again normalised following restitution of native right renal artery flow. During endoshunting, the median regional urine production was 0.32 (range, 0.12 – 0.50) mL/hour but resumed after renal artery flow restitution. ConclusionOn average, the endoshunted kidneys showed a rapid restoration of blood flow, parenchymal perfusion, and urine production after 120 minutes of endoshunting. This suggests that endoshunting to the kidney using an endoshunt system might be a promising strategy to preserve renal function when a temporary interruption of native renal artery blood flow is needed during complex vascular surgical repairs involving the renal arteries.

Pegloticase-Induced Rapid Uric Acid Lowering and Kidney and Cardiac Health Markers in Youth-Onset Type 2 Diabetes: A Pilot Clinical Trial

Rationale & ObjectiveElevated serum uric acid (SUA) is a risk factor for incident hypertension and diabetic kidney disease in young persons with type 2 diabetes (T2D), particularly men. The acute benefit of aggressively lowering SUA on kidney and cardiovascular function in this population remains underexplored. This study was conducted to investigate the impact of a single pegloticase infusion on kidney and cardiovascular function. Study DesignAn open-label pilot trial. Setting & ParticipantsThe study involved 10 young adult males with youth-onset T2D and SUA levels ≥5 mg/dL. Intervention(s)Participants received a single infusion of pegloticase (8 mg). Evaluations were conducted using iohexol-based measured glomerular filtration rate (mGFR) and cardiac/kidney MRI before and one week after infusion. OutcomesThe primary outcomes were changes in SUA and mGFR one week after pegloticase infusion. ResultsNine participants (mean [±SD] age 22±5 years, HbA1c 8.6±3.3%, BMI 40.1±11.0 kg/m2, SUA 6.7±1.1 mg/dL) completed the pegloticase infusion and were included in the analysis. One week after the infusion, median [p25,p75] SUA concentrations dropped from 6.4 [5.6,7.6] to 0.5 [0.5,4.6] mg/dL (p=0.01). Mean mGFR increased from 113±20 to 122±19 ml/min per 1.73 m2 (p=0.004). Among responders (SUA reduction ≥3 mg/dL), an increase in mGFR correlated with an increase in renal artery blood flow (r:0.60, p=0.24) and decrease in SUA (r:-0.79, p=0.05). Mean MRI peak longitudinal cardiac strain additionally decreased from 15.4±2.2 to 13.1±2.2 % (p=0.03) in these responders. LimitationsThe pilot nature of the study and the small sample size limit the generalizability of the findings. ConclusionsIn young adult males with T2D, a single pegloticase infusion decreased SUA levels, which increased mGFR and was strongly associated with increased renal blood flow and impaired cardiac global longitudinal strain. Further research is required to assess the long-term efficacy and safety of pegloticase in patients with T2D.

Renal Blood Flow during Adenosine-Stress by Magnetic Resonance Imaging in a Large Cohort of Patients with Type 2 Diabetes

Renal Blood Flow during Adenosine-Stress by Magnetic Resonance Imaging in a Large Cohort of Patients with Type 2 Diabetes

Perirenal fat and chronic kidney disease in type 2 diabetes: The mediation role of afferent arteriolar resistance

AimPerirenal fat (PRF) is an independent predictor for chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients. Previous studies speculated that PRF may promote renal dysfunction through affecting renal hemodynamics. To verify this hypothesis, we studied the relationship between PRF and renal hemodynamics in T2DM. Methods91 T2DM patients were included. PRF thickness (PRFT) was measured by magnetic resonance imaging. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by renal dynamic imaging. Renal vascular resistance (RVR), glomerular hydrostatic pressure (PGLO), afferent (RA) and efferent (RE) arteriolar resistance were calculated by Gomez equations. Multiple linear regression was used to determine the relationship between PRFT and renal hemodynamics. Mediation analysis was conducted to estimate the mediation effects of renal hemodynamics on the relationship between PRF and CKD. ResultsAll patients were divided into three groups according to the tertiles of PRFT. Compared with patients in tertile 1, GFR and ERPF were significantly decreased in patients in tertile 3, while RVR and RA were significantly increased. PRFT was negatively correlated with GFR, ERPF and PGLO, and positively correlated with RVR and RA after adjustment for sex, age, visceral adipose tissue and treatments with ACE inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter protein-2 inhibitors. Moreover, RVR and RA mediated the effect of PRF on GFR, with a mediated proportion of 29.1 % and 41.4 % respectively. ConclusionIn T2DM patients, PRF was negatively correlated with GFR, and positively correlated with RA. RA mediated the relationship between PRF and CKD.

Comparative Effects of Fedratinib and Upadacitinib on Renal Ischemia-Reperfusion Injury in Rat Models

Renal ischemia-reperfusion injury (RIRI) is a severe condition that frequently occurs following kidney transplantation or surgical procedures affecting renal blood flow. Inflammatory responses, oxidative stress, and apoptotic pathways significantly contribute to RIRI. This study aimed to compare the renoprotective effects of Fedratinib, a JAK2 inhibitor, and Upadacitinib, a JAK1 inhibitor, in rat models of RIRI. Both inhibitors were administered one hour prior to ischemia induction, and the effects on renal function, inflammation, and cell death pathways were assessed. The findings revealed that both Fedratinib and Upadacitinib significantly reduced serum creatinine and urea levels, inflammatory cytokines (TNF-α, IL-6), and markers of apoptosis (BCL2/BAX) by suppressing the JAK/STAT signaling pathways. Histopathological analysis showed substantial reduction in renal tissue damage in the treated groups compared to controls. The study concludes that JAK inhibition by either drug provides significant renoprotection in RIRI, though with some differences in the degree of pathway inhibition and clinical implications.

Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production

Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E2 (PGE2) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE2 and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE2 and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE2 signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE2 signaling, this effect is likely of clinical relevance.

Cardiovascular effects of Roflumilast during sepsis: Risks or benefits?

BackgroundPhosphodiesterase-4 (PDE4) is responsible for terminating cyclic adenosine monophosphate (cAMP) signalling. PDE4 inhibitors, such as roflumilast (RFM), have anti-inflammatory activity and have been studied in inflammation-induced tissue damage in sepsis. However, the role of RFM on cardiovascular derangements induced by sepsis is still unknown. Thus, we aimed to evaluate the potential effects of RFM on cardiovascular collapse and multiorgan damage caused by sepsis. MethodsSepsis was induced by cecal ligation and puncture (CLP) in male rats. Six hours after the CLP or sham procedure, animals were randomly assigned to receive either RFM (0.3 mg/kg) or vehicle subcutaneously, and cardiovascular parameters were assessed 24 h after the surgery and organ/plasma samples were collected for further analyses. ResultsSepsis induced hypotension, tachycardia, reduced renal blood flow (RBF) and hyporeactivity to vasoconstrictors both in vivo and ex vivo. RFM treatment increased systemic cAMP levels and RBF. RFM also attenuated hypoperfusion and liver damage induced by CLP. Furthermore, RFM reduced systemic nitric oxide (NO) levels in septic rats, while there were no changes in hepatic NOS-2 expression. Nevertheless, RFM exacerbated sepsis-induced hypotension and tachycardia without ameliorating vascular hyporeactivity. ConclusionOur data show that PDE-4 inhibition protects septic rats from hepatic injury and improves renal perfusion. However, RFM worsened hemodynamic parameters and showed no protection against sepsis-induced cardiovascular dysfunction and mortality. Thus, despite the anti-inflammatory benefits of RFM, its application in sepsis should be approached cautiously.

Protective effect of long-chain polyunsaturated fatty acids on hepatorenal syndrome in rats.

Hepatorenal syndrome (HRS) is the most prevalent form of acute kidney injury in cirrhotic patients. It is characterized by reduced renal blood flow and represents the most severe complication in cirrhotic patients with advanced disease. Previous research has indicated that antioxidants can delay the onset of a hyperdynamic circulatory state in cirrhosis and improve renal function in HRS patients. Regular omega-3 supplementation has significantly reduced the risk of liver disease. This supplementation could represent an additional therapy for individuals with HRS. To evaluated the antioxidant effect of omega-3 polyunsaturated fatty acid supplementation on the kidneys of cirrhotic rats. Secondary biliary cirrhosis was induced in rats by biliary duct ligation (BDL) for 28 d. We used 24 male Wistar rats divided into the following groups: I (control); II (treated with omega-3, 1 g/kg of body weight); III (BDL treated with omega-3, 1 g/kg of body weight); and IV (BDL without treatment). The animals were killed by overdose of anesthetic; the kidneys were dissected, removed, frozen in liquid nitrogen, and stored in a freezer at -80℃ for later analysis. We evaluated oxidative stress, nitric oxide (NO) metabolites, DNA damage by the comet assay, cell viability test, and apoptosis in the kidneys. Data were analyzed by one-way analysis of variance, and means were compared using the Tukey test, with P ≤ 0.05. Omega-3 significantly decreased the production of reactive oxygen species (P < 0.001) and lipoperoxidation in the kidneys of cirrhotic rats treated with omega-3 (P < 0.001). The activity of the antioxidant enzymes superoxide dismutase and catalase increased in the BDL+omega-3 group compared to the BDL group (P < 0.01). NO production, DNA damage, and caspase-9 cleavage decreased significantly in the omega-3-treated BDL group. There was an increase in mitochondrial electrochemical potential (P < 0.001) in BDL treated with omega-3 compared to BDL. No changes in the cell survival index in HRS with omega-3 compared to the control group (P > 0.05) were observed. The study demonstrates that omega-3 can protect cellular integrity and function by increasing antioxidant enzymes, inhibiting the formation of free radicals, and reducing apoptosis.

OXGR1-Dependent (Pro)Renin Receptor Upregulation in Collecting Ducts of the Clipped Kidney Contributes to Na+ Balance in Goldblatt Hypertensive Mice.

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.

Luminal Flow in the Connecting Tubule induces Afferent Arteriole Vasodilation.

Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF-whether NaCl concentration, independent luminal flow, or the combined total sodium delivery-is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2- generation and ENaC activation. Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfused ex-vivo with variable flow rates and sodium concentrations ranging from <1 mM to 80 mM and from 5 to 40 nL/min flow rates. Perfusion of the CNT with 5 mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow rate-dependent dilation of the Af-Art (p<0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with <1 mM NaCl did not result in flow-induced CNTGF vasodilation (p>0.05). Multiple linear regression modeling (R2=0.51;p<0.001) demonstrated that tubular flow (β=0.163 ± 0.04;p<0.001) and sodium concentration (β=0.14 ± 0.03;p<0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect. Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2- production and independent of nitric oxide synthase (NOS) activity.

Implications of Dysnatremia and Endocrine Disturbances in COVID-19 Patients.

Sodium imbalance is a common electrolyte disturbance in COVID-19, often linked to disruptions in hormonal regulation. This review explores the relationship between sodium dysregulation and endocrine disturbances, particularly focusing on primary and secondary hypothyroidism, hypocortisolism, and the renin-angiotensin-aldosterone system (RAAS). Hypocortisolism in COVID-19, due to adrenal insufficiency or secondary to pituitary dysfunction, can lead to hyponatremia through inadequate cortisol levels, which impair renal free water excretion and enhance antidiuretic hormone (ADH) secretion. Similarly, hypothyroidism is associated with decreased renal blood flow and the glomerular filtration rate (GFR), which also increases ADH activity, leading to water retention and dilutional hyponatremia. Furthermore, COVID-19 can disrupt RAAS (primarily through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor), diminishing aldosterone secretion and further contributing to sodium loss and hyponatremia. These hormonal disruptions suggest that sodium imbalance in COVID-19 is multifactorial and warrants further investigation into the complex interplay between COVID-19, endocrine function, and sodium homeostasis. Future research should focus on understanding these mechanisms to develop management algorithms that address both sodium imbalance and underlying hormonal disturbances in order to improve prognosis and outcomes in COVID-19 patients.