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Purpose: Growing evidence shows the complex interaction between lung and kidney in critically ill patients. The renal resistive index (RRI) is a bedside measurement of the resistance of the renal blood flow and it is correlated with kidney injury. The positive end-expiratory pressure (PEEP) level could affect the resistance of renal blood flow, so we assumed that RRI could help to monitoring the changes in renal hemodynamics at different PEEP levels. Our hypothesis was that the RRI at ICU admission could predict the risk of acute kidney injury in mechanical ventilated critically ill patients. Methods: We performed a prospective study including 92 patients requiring mechanical ventilation for ≥ 48 h. A RRI ≥ 0.70, was deemed as pathological. RRI was measured within 24 h from ICU admission while applying 5,10 and 15 cmH2O of PEEP in random order (PEEP trial). Results: Overall, RRI increased from 0.62 ± 0.09 at PEEP 5 to 0.66 ± 0.09 at PEEP 15 (p < 0.001). The mean RRI value during the PEEP trial was able to predict the occurrence of AKI with AUROC = 0.834 [95%CI 0.742–0.927]. Patients exhibiting a RRI ≥ 0.70 were 17/92(18%) at PEEP 5, 28/92(30%) at PEEP 10, 38/92(41%) at PEEP 15, respectively. Thirty-eight patients (41%) exhibited RRI ≥ 0.70 at least once during the PEEP trial. In these patients, AKI occurred in 55% of the cases, versus 13% remaining patients, p < 0.001. Conclusions: RRI seems able to predict the risk of AKI in mechanical ventilated patients; further, RRI values are influenced by the PEEP level applied. Trial registration: Clinical gov NCT03969914 Registered 31 May 2019. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high‐resolution renal arterial (RA) impedance. This study examines the effects of ANG II and its type 1 receptor blocker telmisartan (TELM) on RA impedance. In baroreflex-deactivated rats, we measured RA pressure (Pr) and blood flow (Fr) during random ventricular pacing to induce pressure fluctuation at three different mean Pr (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from Fr to Pr. The RA impedance was found to align with a three‐element Windkessel model consisting of proximal (Rp) and distal (Rd) resistance and compliance (C). Our study showed Rd reflected the composite characteristics of afferent and efferent arterioles. Rd increased with increasing Pr under the baseline condition with a slope of 1.03 ± 0.21 (× 10−1) min·mL−1. ANG II significantly increased the slope by 0.72 ± 0.29 (× 10−1) min·mL−1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10−1) mmHg·min·mL−1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10−1) mmHg·min·mL−1, whereas it did not affect the slope. In contrast, Rp was less sensitive than Rd to ANG II or TELM, suggesting Rp may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANG II on the dynamics of the renal vasculature. NEW & NOTEWORTHY: This present method of quantifying high-resolution renal arterial impedance could contribute to elucidating the characteristics of renal vasculature influenced by physiological mechanisms, renal diseases, or pharmacological effects. The present findings help construct a lumped-parameter renal hemodynamic model that reflects the influence of angiotensin II. [ABSTRACT FROM AUTHOR]

Introduction: Kidney perfusion on CT is an encouraging surrogate for renal scintigraphy in assessing renal function. However, data on dynamic volumetric CT in patients with kidney obstruction is lacking. Thus, the aim of this study is to determine the feasibility of CT-based renal perfusion using a dynamic volume to assess renal hemodynamics at different degrees and durations of obstruction. Materials and methods: We included patients with unilateral kidney obstruction in our single-center, prospective study. The patients were divided into three groups. Patients without dilatation of the pelvicalyceal system (PCS) and normal parenchyma thickness were included into Group 1; patients with PCS dilatation and parenchyma thickness 1.8–2.4 cm—into Group 2; and patients with ureteropyelocalicoectasia and parenchyma thickness less than 1.8 cm—into Group 3. Results: Total of 56 patients were enrolled. In Group 1 mean values of cortical and medullar arterial blood flow, blood volume, and extraction fraction were within the normal range. Changes in contralateral kidney were not determined. Patients from Group 2 showed significant differences in blood flow parameters in the cortical and medulla of the obstructed kidney. No changes in perfusion values in the contralateral kidney was observed. In patients from Group 3 there was a marked decrease in perfusion on the side of obstruction compared to Group 2, indicating that the degree of expansion of the PCS directly correlates with the change in blood flow. However, in the contralateral kidney, these indicators exceeded the normal values of perfusion. Conclusion: CT perfusion allows to objectively assess changes in blood flow in the setting of renal obstruction. The degree of obstruction directly affects the measured rate of blood flow. [ABSTRACT FROM AUTHOR]

Purpose: Assessing renal perfusion in‐vivo is challenging and quantitative information regarding renal hemodynamics is hardly incorporated in medical decision‐making while abnormal renal hemodynamics might play a crucial role in the onset and progression of renal disease. Combining physiological stimuli with rubidium‐82 positron emission tomography/computed tomography (82Rb PET/CT) offers opportunities to test the kidney perfusion under various conditions. The aim of this study is: (1) to investigate the application of a one‐tissue compartment model for measuring renal hemodynamics with dynamic 82Rb PET/CT imaging, and (2) to evaluate whether dynamic PET/CT is sensitive to detect differences in renal hemodynamics in stress conditions compared to resting state. Methods: A one‐tissue compartment model for the kidney was applied to cardiac 82Rb PET/CT scans that were obtained for ischemia detection as part of clinical care. Retrospective data, collected from 17 patients undergoing dynamic myocardial 82Rb PET/CT imaging in rest, were used to evaluate various CT‐based volumes of interest (VOIs) of the kidney. Subsequently, retrospective data, collected from 10 patients (five impaired kidney functions and five controls) undergoing dynamic myocardial 82Rb PET/CT imaging, were used to evaluate image‐derived input functions (IDIFs), PET‐based VOIs of the kidney, extraction fractions, and whether dynamic 82Rb PET/CT can measure renal hemodynamics differences using the renal blood flow (RBF) values in rest and after exposure to adenosine pharmacological stress. Results: The delivery rate (K1) values showed no significant (p = 0.14) difference between the mean standard deviation (SD) K1 values using one CT‐based VOI and the use of two, three, and four CT‐based VOIs, respectively 2.01(0.32), 1.90(0.40), 1.93(0.39), and 1.94(0.40) mL/min/mL. The ratio between RBF in rest and RBF in pharmacological stress for the controls were overall significantly lower compared to the impaired kidney function group for both PET‐based delineation methods (region growing and iso‐contouring), with the smallest median interquartile range (IQR) of 0.40(0.28–0.66) and 0.96(0.62–1.15), respectively (p < 0.05). The K1 of the impaired kidney function group were close to 1.0 mL/min/mL. Conclusions: This study demonstrated that obtaining renal K1 and RBF values using 82Rb PET/CT was feasible using a one‐tissue compartment model. Applying iso‐contouring as the PET‐based VOI of the kidney and using AA as an IDIF is suggested for consideration in further studies. Dynamic 82Rb PET/CT imaging showed significant differences in renal hemodynamics in rest compared to when exposed to adenosine. This indicates that dynamic 82Rb PET/CT has potential to detect differences in renal hemodynamics in stress conditions compared to the resting state, and might be useful as a novel diagnostic tool for assessing renal perfusion. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is associated with adverse outcomes in chronic kidney disease (CKD) patients. Our study suggests mildly elevated pulmonary vascular resistance (> 2 to ≤ 3) is independently associated with major adverse cardiovascular events at 1‐year follow‐up. Early diagnosis of precapillary PH in CKD patients can potentially improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract Pulmonary hypertension (PH) is associated with adverse outcomes in chronic kidney disease (CKD) patients. Our study suggests mildly elevated pulmonary vascular resistance ( > 2 to ≤ 3) is independently associated with major adverse cardiovascular events at 1‐year follow‐up. Early diagnosis of precapillary PH in CKD patients can potentially improve clinical outcomes.

Introduction: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Methods: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Results: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049–0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15–0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10–101 ± 11 mm Hg, p < 0.001), PP (76 ± 11–68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044–0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20–84 ± 24 mL/min/1.73 m2, p = 0.003). Discussion/Conclusion: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function.

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. Methods Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. Discussion The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. Trial registration jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020.

Background: Renal blood flow (RBF) decreases with exercise, but this change is only temporary, and habitual exercise may be an effective method to improve renal function. The kidney shows structural and functional changes with aging, but it is unclear how aging affects the hemodynamic response of the kidneys to exercise. Therefore, we evaluated the differences in the hemodynamic response of the kidneys to high-intensity exercise between younger and older men. Methods: Sixteen men (8 young and 8 older) underwent an incremental exercise test using a cycle ergometer with a 1-min warm up followed by exercise at 10–20 W/min until the discontinuation criteria were met. Renal hemodynamics were assessed before exercise, immediately after exercise, and at 60-min after exercise using ultrasound echo. Results: High-intensity exercise significantly reduced RBF in both groups (younger: ∆ – 53 ± 16%, p = 0.0005; older: ∆ – 53 ± 19%, p = 0.0004). In the younger group, RBF returned to the pre-exercise level 60-min after exercise (∆ – 0.4 ± 5.7%, p > 0.9999). In contrast, RBF 60-min after exercise was significantly lower than that before exercise in the older group (∆ – 24 ± 19%, p = 0.0006). The older group had significantly lower RBF than younger adults 60-min after exercise (423 ± 32 vs. 301 ± 98 mL/min, p = 0.0283). Conclusions: Our findings demonstrate that RBF following high-intensity exercise recovered 60-min after exercise in younger group, whereas RBF recovery was delayed in the older group. [ABSTRACT FROM AUTHOR]

In this study we re-examined the postulate that in the rat age-related body metabolism and kidney function changes progress only slowly. Thus we checked whether a moderate between-animal age distance may cause any marked difference, which could affect interpretation of experimental results. Food and water consumption, renal sodium and potassium excretion and haemodynamics were lower in rats aged 15 versus 9 weeks. In turn, hematocrit, mean arterial pressure, and renal vascular resistance were significantly higher in older animals, whereas renal excretion of NO3-/NO2- and vascular endothelial growth factor A and in situ renal tissue NO signal did not differ. Evidently, an age older by 6 weeks was associated with decreased hydration, tone of systemic and renal blood vessels, and renal excretion. In conclusion, since the actual age is an important determinant of the animal's functional status, accurate age-matching of experimental groups is a necessary pre-condition for correct data interpretation. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. Methods: Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. Discussion: The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. Trial registration: jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti‐inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age‐matched males. As females are known to have greater NO bioavailability than age‐matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition‐induced increases in BP compared to male WKY. Twelve‐week‐old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl‐L‐NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L‐NAME or VNIO infusion. L‐NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L‐NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L‐NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L‐NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non‐isoform‐specific NOS inhibition in WKY, with females being more responsive to L‐NAME‐induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition. [ABSTRACT FROM AUTHOR]

Background Septic shock may lead to renal perfusion abnormalities, and even acute kidney injury (AKI) , seriously threatening the life of patients. Color Doppler ultrasound (CDU) can be used as a tool to evaluate changes of renal blood flow. However, there are few studies on its evaluation value for AKI in patients with septic shock. Objective To examine the value of CDU in assessing AKI and hemodynamic changes in patients with septic shock. Methods Participants were recruited from Xuzhou Central Hospital between June 2019 and July 2021, including 105 patients with septic shock, and 58 physical examinees. The general demographics and renal hemodynamic indices measured by CDU 〔the luminal diameter of renal artery (D) , peak systolic velocity (Vs) , end-diastolic velocity (Vd) , resistance index (RI) , pulsatility index (PI) 〕 were collected and compared with the groups. The renal hemodynamic indices were further compared between septic shock patients with and without AKI within 72 h after admission. The predictive value of renal hemodynamic indices for AKI in septic shock was analyzed by receiver operating characteristic (ROC) curve. The influencing factors of AKI in septic shock were explored by univariate and multivariate Logistic regression analyses. Then associations of the severity of AKI (stage 1, 2, 3 AKI) with renal hemodynamic indices were analyzed by Spearman rank analysis. Results Thirty-nine septic shock patients had AKI within 72 h after admission, including 19 cases with stage 1 AKI, 15 with stage 2 AKI, and 5 with stage 3 AKI. Septic shock patients had lower D, Vs and Vd, and higher RI and PI than physical examinees (P0.05) . Conclusion CDU could detect the changes of renal hemodynamics in patients with septic shock. Renal hemodynamic indices are related to the development and severity of AKI, which could be used as diagnostic markers or predictors of AKI in septic shock. So it may be possible to diagnose and predict AKI in septic shock by detecting renal hemodynamic indices.

Purpose The mean perfusion pressure (MPP) was recently proposed to personalized management tissue perfusion pressure in critically ill patients. Increased MPP variability (MPPV) may be associated with organ injuries. Our objective was to determine if increased MPPV was associated with subsequent deterioration of renal function in critically ill patients.Methods We analyzed data stored in the eICU-CRD and MIMIC-IV databases. The exposure was MPPV, measured as the coefficient of variation (CV) using the MPP data of the first 24 h after first ICU admission. The primary endpoint was deterioration of renal function, defined as new-onset or progress of acute kidney injury between 24 and 72 h after ICU admission.Results The study population consisted of 8,590 patients from eICU-CRD and 6,723 patients from MIMIC-IV database. A total of 28.4% and 30.2% of the study population experienced deteriorated renal function, respectively. Patients with deteriorated renal function had significantly higher median MPP-CV compared with those without (12.2% vs 11.5% and 12.8% vs 12.5%, p

Age-related decline in functional elastin is associated with increased arterial stiffness, a known risk factor for developing cardiovascular disease. While the contribution of elastin insufficiency to the stiffening of conduit arteries is well described, little is known about the impact on the structure and function of the resistance vasculature, which contributes to total peripheral resistance and the regulation of organ perfusion. In this study, we determined how elastin insufficiency impinges on age-related changes in the structure and biomechanical properties of the renal microvasculature, altering renal hemodynamics and the response of the renal vascular bed to changes in renal perfusion pressure (RPP) in female mice. Using Doppler ultrasonography, we found that resistive index and pulsatility index were elevated in young Eln+/- and aged mice. Histological examination showed thinner internal and external elastic laminae, accompanied by increased elastin fragmentation in the medial layer without any calcium deposits in the small intrarenal arteries of kidneys from young Eln+/- and aged mice. Pressure myography of interlobar arteries showed that vessels from young Eln+/- and aged mice had a slight decrease in distensibility during pressure loading but a substantial decline in vascular recoil efficiency upon pressure unloading. To examine whether structural changes in the renal microvasculature influenced renal hemodynamics, we clamped neurohumoral input and increased renal perfusion pressure by simultaneously occluding the superior mesenteric and celiac arteries. Increased renal perfusion pressure caused robust changes in blood pressure in all groups; however, changes in renal vascular resistance and renal blood flow (RBF) were blunted in young Eln+/- and aged mice, accompanied by decreased autoregulatory index, indicating greater impairment of renal autoregulation. Finally, increased pulse pressure in aged Eln+/- mice positively correlated with high renal blood flow. Together, our data show that the loss of elastin negatively affects the structural and functional integrity of the renal microvasculature, ultimately worsening age-related decline in kidney function. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure–response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure–response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0–tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0–tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables. [ABSTRACT FROM AUTHOR]

Abstract Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti‐inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age‐matched males. As females are known to have greater NO bioavailability than age‐matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition‐induced increases in BP compared to male WKY. Twelve‐week‐old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl‐L‐NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L‐NAME or VNIO infusion. L‐NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L‐NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L‐NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L‐NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non‐isoform‐specific NOS inhibition in WKY, with females being more responsive to L‐NAME‐induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

Age-related decline in functional elastin is associated with increased arterial stiffness, a known risk factor for developing cardiovascular disease. While the contribution of elastin insufficiency to the stiffening of conduit arteries is well described, little is known about the impact on the structure and function of the resistance vasculature, which contributes to total peripheral resistance and the regulation of organ perfusion. In this study, we determined how elastin insufficiency impinges on age-related changes in the structure and biomechanical properties of the renal microvasculature, altering renal hemodynamics and the response of the renal vascular bed to changes in renal perfusion pressure (RPP) in female mice. Using Doppler ultrasonography, we found that resistive index and pulsatility index were elevated in young Eln+/− and aged mice. Histological examination showed thinner internal and external elastic laminae, accompanied by increased elastin fragmentation in the medial layer without any calcium deposits in the small intrarenal arteries of kidneys from young Eln+/− and aged mice. Pressure myography of interlobar arteries showed that vessels from young Eln+/− and aged mice had a slight decrease in distensibility during pressure loading but a substantial decline in vascular recoil efficiency upon pressure unloading. To examine whether structural changes in the renal microvasculature influenced renal hemodynamics, we clamped neurohumoral input and increased renal perfusion pressure by simultaneously occluding the superior mesenteric and celiac arteries. Increased renal perfusion pressure caused robust changes in blood pressure in all groups; however, changes in renal vascular resistance and renal blood flow (RBF) were blunted in young Eln+/− and aged mice, accompanied by decreased autoregulatory index, indicating greater impairment of renal autoregulation. Finally, increased pulse pressure in aged Eln+/− mice positively correlated with high renal blood flow. Together, our data show that the loss of elastin negatively affects the structural and functional integrity of the renal microvasculature, ultimately worsening age-related decline in kidney function.

The present study was to examine sex and strain differences in glomerular filtration rate (GFR) and renal blood flow (RBF) in C57BL6, 129/Sv, and C57BLKS/J mice, three commonly used mouse strains in renal research. GFR was measured by transdermal measurement of FITC‐sinitrin clearance in conscious mice. RBF was measured by a flow probe placed in the renal artery under an anesthetic state. In C57BL6 mice, there were no sex differences in both GFR and RBF. In 129/Sv mice, females had significantly greater GFR than males at age of 24 weeks, but not at 8 weeks. However, males had higher RBF and lower renal vascular resistance (RVR). Similar to 129/Sv, female C57BLKS/J had significantly greater GFR at both 8 and 24 weeks, lower RBF, and higher RVR than males. Across strains, male 129/Sv had lower GFR and higher RBF than male C57BL6, but no significant difference in GFR and greater RBF than male C57BLKS/J. No significant difference in GFR or RBF was observed between C57BL6 and C57BLKS/J mice. Deletion of eNOS in C57BLKS/J mice reduced GFR in both sexes, but decreased RBF in males. Furthermore, there were no sex differences in the severity of renal injury in eNOS−/−dbdb mice. Taken together, our study suggests that sex differences in renal hemodynamics in mice are strain and age dependent. eNOS was not involved in the sex differences in GFR, but in RBF. Furthermore, the sexual dimorphism did not impact the severity of renal injury in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O2 transport. The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent the risk of organ failure, especially acute kidney injury. However, different vasopressors exert variable effects on the kidney, depending on the nature and dose of the substance chosen as follows: Norepinephrine increases mean arterial pressure both via its α-1-mediated vasoconstriction leading to increased systemic vascular resistance and its β1-related increase in cardiac output. Vasopressin, through activation of V1-a receptors, induces vasoconstriction, thus increasing mean arterial pressure. In addition, these vasopressors have the following different effects on renal hemodynamics: Norepinephrine constricts both the afferent and efferent arterioles, whereas vasopressin exerts its vasoconstrictor properties mainly on the efferent arteriole. Therefore, this narrative review discusses the current knowledge of the renal hemodynamic effects of norepinephrine and vasopressin during hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Introduction: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Methods: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Results: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049–0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15–0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10–101 ± 11 mm Hg, p < 0.001), PP (76 ± 11–68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044–0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20–84 ± 24 mL/min/1.73 m2, p = 0.003). Discussion/Conclusion: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function. [ABSTRACT FROM AUTHOR]

Perirenal 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. 91 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 (P GLO), afferent (R A) and efferent (R E) 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. All 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 R A were significantly increased. PRFT was negatively correlated with GFR, ERPF and P GLO , and positively correlated with RVR and R A 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 R A mediated the effect of PRF on GFR, with a mediated proportion of 29.1 % and 41.4 % respectively. In T2DM patients, PRF was negatively correlated with GFR, and positively correlated with R A. R A mediated the relationship between PRF and CKD. [ABSTRACT FROM AUTHOR]

Abstract The present study was to examine sex and strain differences in glomerular filtration rate (GFR) and renal blood flow (RBF) in C57BL6, 129/Sv, and C57BLKS/J mice, three commonly used mouse strains in renal research. GFR was measured by transdermal measurement of FITC‐sinitrin clearance in conscious mice. RBF was measured by a flow probe placed in the renal artery under an anesthetic state. In C57BL6 mice, there were no sex differences in both GFR and RBF. In 129/Sv mice, females had significantly greater GFR than males at age of 24 weeks, but not at 8 weeks. However, males had higher RBF and lower renal vascular resistance (RVR). Similar to 129/Sv, female C57BLKS/J had significantly greater GFR at both 8 and 24 weeks, lower RBF, and higher RVR than males. Across strains, male 129/Sv had lower GFR and higher RBF than male C57BL6, but no significant difference in GFR and greater RBF than male C57BLKS/J. No significant difference in GFR or RBF was observed between C57BL6 and C57BLKS/J mice. Deletion of eNOS in C57BLKS/J mice reduced GFR in both sexes, but decreased RBF in males. Furthermore, there were no sex differences in the severity of renal injury in eNOS−/− dbdb mice. Taken together, our study suggests that sex differences in renal hemodynamics in mice are strain and age dependent. eNOS was not involved in the sex differences in GFR, but in RBF. Furthermore, the sexual dimorphism did not impact the severity of renal injury in diabetic nephropathy.

The mean perfusion pressure (MPP) was recently proposed to personalized management tissue perfusion pressure in critically ill patients. Increased MPP variability (MPPV) may be associated with organ injuries. Our objective was to determine if increased MPPV was associated with subsequent deterioration of renal function in critically ill patients. We analyzed data stored in the eICU-CRD and MIMIC-IV databases. The exposure was MPPV, measured as the coefficient of variation (CV) using the MPP data of the first 24 h after first ICU admission. The primary endpoint was deterioration of renal function, defined as new-onset or progress of acute kidney injury between 24 and 72 h after ICU admission. The study population consisted of 8,590 patients from eICU-CRD and 6,723 patients from MIMIC-IV database. A total of 28.4% and 30.2% of the study population experienced deteriorated renal function, respectively. Patients with deteriorated renal function had significantly higher median MPP-CV compared with those without (12.2% vs 11.5% and 12.8% vs 12.5%, p <.001). In fully adjusted multivariate logistic models, higher MPP-CV (adjusted OR per 1-SD, 1.08; 95% CI, 1.02–1.13 and adjusted OR per 1-SD, 1.06; 95% CI, 1.00–1.12, respectively) was significantly associated with greater risk of primary endpoint. The pooled analyses showed heterogeneity in patients with cardiac surgery, medical sepsis and others. Increased MPPV was associated with an increased risk of subsequent deterioration of renal function in critically ill patients with central venous pressure monitoring. Maintaining stable MPP may reduce the risk of renal function deterioration. [ABSTRACT FROM AUTHOR]

Hypertension is prevalent in patients with systemic lupus erythematosus (SLE). The goal of the current study is to track the pathogenesis of hypertension and renal injury in SLE, identify contributory mechanisms, and highlight differences in disease development among sexes. Mean arterial pressure was measured in conscious male and female SLE (NZBWF1) and control (NZW) mice at 34–35 wk of age using indwelling arterial catheters. Measures of renal injury, renal inflammation, and renal hemodynamics were used to monitor the potential contributors to latent sex differences. Both male and female SLE mice were hypertensive at 35 wk of age, and the hypertension was linked to renal injury in females, but not in males. A known contributor of renal pathology in SLE, Toll-like receptor (TLR)-7, and its downstream effector, the proinflammatory cytokine tumor necrosis factor (TNF)-α, were lower in male SLE mice than in females. Male SLE mice also had higher glomerular filtration rate (GFR) and lower renal vascular resistance (RVR) than females. Our data suggest that although hypertension in female SLE mice is associated with renal mechanisms, hypertension in male SLE mice may develop independent of renal changes. Future studies will continue to dissect sex-specific factors that should be considered when treating patients with hypertension with underlying chronic inflammation and/or autoimmunity. NEW & NOTEWORTHY There is a high prevalence of hypertension in male and female SLE; however, male SLE mice are hypertensive without renal involvement. The development of hypertension in female SLE mice is renocentric and strongly associated with injurious renal mechanisms like the TLR-7→TNF-α pathway. This clear difference in the pathogenesis among the sexes could have a significant impact on how we treat patients with hypertension with underlying chronic autoimmune/inflammatory diseases. [ABSTRACT FROM AUTHOR]

Diabetes, hypertension, and aging are major contributors to cardiovascular and chronic kidney disease (CKD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors have become a preferred treatment for type II diabetic patients since they have cardiorenal protective effects. However, most elderly diabetic patients also have hypertension, and the effects of SGLT2 inhibitors have not been studied in hypertensive diabetic patients or animal models. The present study examined if controlling hyperglycemia with empagliflozin, or given in combination with lisinopril, slows the progression of renal injury in hypertensive diabetic rats. Studies were performed using hypertensive streptozotocin-induced type 1 diabetic Dahl salt-sensitive (STZ-SS) rats and in deoxycorticosterone-salt hypertensive type 2 diabetic nephropathy (T2DN) rats. Administration of empagliflozin alone or in combination with lisinopril reduced blood glucose, proteinuria, glomerular injury, and renal fibrosis in STZ-SS rats without altering renal blood flow (RBF) or glomerular filtration rate (GFR). Blood pressure and renal hypertrophy were also reduced in rats treated with empagliflozin and lisinopril. Administration of empagliflozin alone or in combination with lisinopril lowered blood glucose, glomerulosclerosis, and renal fibrosis but had no effect on blood pressure, kidney weight, or proteinuria in hypertensive T2DN rats. RBF was not altered in any of the treatment groups, and GFR was elevated in empagliflozin-treated hypertensive T2DN rats. These results indicate that empagliflozin is highly effective in controlling blood glucose levels and slows the progression of renal injury in both hypertensive type 1 and type 2 diabetic rats, especially when given in combination with lisinopril to lower blood pressure. [ABSTRACT FROM AUTHOR]

ObjectiveTo assess the effect of renal denervation (RDN) on renal vascular resistance and renal function in patients with drug-resistant hypertension (HTN) and type 2 diabetes mellitus (T2DM).Materials and methodsFifty-nine patients (mean age 60.3 ± 7.9 years, 25 men) with resistant HTN [mean 24-h ambulatory blood pressure (BP) 158.0 ± 16.3/82.5 ± 12.7 mmHg, systolic/diastolic] and T2DM (mean HbA1c 7.5 ± 1.5%) were included in the single-arm prospective study and underwent RDN. Renal resistive index (RRI) derived from ultrasound Doppler; estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration formula), office and 24-h ambulatory BP were measured at baseline, 6, and 12 months after RDN to evaluate the respective changes in renal vascular resistance, renal function, and BP during treatment.ResultsForty-three patients completed 12 months follow-up. The RRI changed depending on the baseline value. Specifically, the RRI decreased significantly in patients with elevated baseline RRI values ≥ 0.7 {n = 23; −0.024 [95% confidence interval (CI): −0.046, −0.002], p = 0.035} and did not change in those with baseline RRI < 0.7 [n = 36; 0.024 (95% CI: −0.002, 0.050), p = 0.069]. No significant change was observed in eGFR whereas BP was significantly reduced at 12 months after RDN by −10.9 (95% CI: −16.7, −5.0)/−5.5 (95% CI: −8.7, −2.4) mmHg, systolic/diastolic. No relationship was found between the changes in RRI and BP.ConclusionOur study shows that RDN can decrease elevated renal vascular resistance (RRI > 0.7) and stabilize kidney function in patients with RHTN and T2DM independently of its BP-lowering effect.

Exercise is restricted for individuals with reduced renal function because exercising reduces blood flow to the kidneys. Safe and effective exercise programs for individuals with reduced renal function have not yet been developed. We previously examined the relationship between exercise intensity and renal blood flow (RBF), revealing that moderate‐intensity exercise did not reduce RBF. Determining the effects of exercise duration on RBF may have valuable clinical applications. The current study examined the effects of a single bout of continuous exercise at lactate threshold (LT) intensity on renal hemodynamics. Eight adult males participated in this study. Participants underwent 30 min of aerobic exercise at LT intensity using a cycle ergometer. Evaluation of renal hemodynamics was performed before and after exercise, in the recovery phase using ultrasound echo. Furthermore, blood and urine samplings were conducted before and after exercise, in the recovery phase. Compared with resting, RBF was not significantly changed immediately after continuous exercise (319 ± 102 vs. 308 ± 79 ml/min; p = 0.976) and exhibited no significant changes in the recovery phase. Moreover, urinary kidney injury molecule‐1 (uKIM‐1) level exhibited no significant change immediately after continuous exercise (0.52 ± 0.20 vs. 0.46 ± 0.27 μg/g creatinine; p = 0.447). In addition, the results revealed no significant change in urinary uKIM‐1 in 60‐min after exercise. Other renal injury biomarkers exhibited a similar pattern. These findings indicate that a single bout of moderate‐intensity continuous exercise maintains RBF and does not induce renal injury. [ABSTRACT FROM AUTHOR]

Abstract Exercise is restricted for individuals with reduced renal function because exercising reduces blood flow to the kidneys. Safe and effective exercise programs for individuals with reduced renal function have not yet been developed. We previously examined the relationship between exercise intensity and renal blood flow (RBF), revealing that moderate‐intensity exercise did not reduce RBF. Determining the effects of exercise duration on RBF may have valuable clinical applications. The current study examined the effects of a single bout of continuous exercise at lactate threshold (LT) intensity on renal hemodynamics. Eight adult males participated in this study. Participants underwent 30 min of aerobic exercise at LT intensity using a cycle ergometer. Evaluation of renal hemodynamics was performed before and after exercise, in the recovery phase using ultrasound echo. Furthermore, blood and urine samplings were conducted before and after exercise, in the recovery phase. Compared with resting, RBF was not significantly changed immediately after continuous exercise (319 ± 102 vs. 308 ± 79 ml/min; p = 0.976) and exhibited no significant changes in the recovery phase. Moreover, urinary kidney injury molecule‐1 (uKIM‐1) level exhibited no significant change immediately after continuous exercise (0.52 ± 0.20 vs. 0.46 ± 0.27 μg/g creatinine; p = 0.447). In addition, the results revealed no significant change in urinary uKIM‐1 in 60‐min after exercise. Other renal injury biomarkers exhibited a similar pattern. These findings indicate that a single bout of moderate‐intensity continuous exercise maintains RBF and does not induce renal injury.

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s−1 cm−5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s−1 cm−5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium–glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin–angiotensin–aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population. [ABSTRACT FROM AUTHOR]

Intravital multiphoton microscopy has empowered investigators to study dynamic cell and subcellular processes in vivo within normal and disease organs. Advances in hardware, software, optics, transgenics and fluorescent probe design and development have enabled new quantitative approaches to create a disruptive technology pioneering advances in understanding of normal biology, disease pathophysiology and therapies. Offering superior spatial and temporal resolution with high sensitivity, investigators can follow multiple processes simultaneously and observe complex interactions between different cell types, intracellular organelles, proteins and track molecules for cellular uptake, intracellular trafficking, and metabolism in a cell specific fashion. The technique has been utilized in the kidney to quantify multiple dynamic processes including capillary flow, permeability, glomerular function, proximal tubule processes and determine the effects of diseases and therapeutic mechanisms. Limitations include the depth of tissue penetration with loss of sensitivity and resolution due to scattered emitted light. Tissue clearing technology has virtually eliminated penetration issues for fixed tissue studies. Use of multiphoton microscopy in preclinical animal models offers distinct advantages resulting in new insights into physiologic processes and the pathophysiology and treatment of diseases. [ABSTRACT FROM AUTHOR]

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory and antioxidant actions, particularly in conditions of elevated HO-1 expression or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function in comparison with males. Diabetes was induced in pregnant rats by a single dose of streptozotocin (STZ, 50 mg/kg ip) in late gestation. Three-month-old male offspring from diabetic mothers (MODs) exhibited higher blood pressure (BP), higher renal vascular resistance (RVR), worse endothelium-dependent response to acetylcholine (ACH), and an increased constrictor response to phenylephrine (PHE) compared with those in age-matched female offspring of diabetic mothers (FODs), which were abolished by chronic tempol (1 mM) treatment. In anesthetized animals, stannous mesoporphyrin (SnMP; 40 µmol/kg iv) administration, to inhibit HO activity, increased RVR in FODs and reduced glomerular filtration rate (GFR) in MODs, without altering these parameters in control animals. When compared with MODs, FODs showed lower nitrotirosyne levels and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with tempol in MODs prevented elevations in nitrotyrosine levels and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex-specific hypertension and renal alterations associated with oxidative stress mainly in adult male offspring, which are reduced in the female offspring by elevation in HO-1 expression and lower oxidative stress levels. [ABSTRACT FROM AUTHOR]

Objective: Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF.Methods: In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5).Results: The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only.Conclusions: A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile. [ABSTRACT FROM AUTHOR]

Intravital multiphoton microscopy has empowered investigators to study dynamic cell and subcellular processes in vivo within normal and disease organs. Advances in hardware, software, optics, transgenics and fluorescent probe design and development have enabled new quantitative approaches to create a disruptive technology pioneering advances in understanding of normal biology, disease pathophysiology and therapies. Offering superior spatial and temporal resolution with high sensitivity, investigators can follow multiple processes simultaneously and observe complex interactions between different cell types, intracellular organelles, proteins and track molecules for cellular uptake, intracellular trafficking, and metabolism in a cell specific fashion. The technique has been utilized in the kidney to quantify multiple dynamic processes including capillary flow, permeability, glomerular function, proximal tubule processes and determine the effects of diseases and therapeutic mechanisms. Limitations include the depth of tissue penetration with loss of sensitivity and resolution due to scattered emitted light. Tissue clearing technology has virtually eliminated penetration issues for fixed tissue studies. Use of multiphoton microscopy in preclinical animal models offers distinct advantages resulting in new insights into physiologic processes and the pathophysiology and treatment of diseases.

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min, p <0.05) and GFR (−0.77±0.18ml/min, p <0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (−22.4±4.1 vs. −9.9±2.3mmHg, p <0.05), whereas the decrease in heart rate (HR) was less (−5±6bpm vs. −23±4bpm, p <0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (−0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction. [ABSTRACT FROM AUTHOR]

Objective: Chronic glomerular hypertension is associated with glomerular injury and sclerosis; however, the mechanism by which increases in pressure damage glomerular podocytes remains unclear. We tested the hypothesis that increases in glomerular pressure may deleteriously affect podocyte structural integrity by increasing the strain of the glomerular capillary walls, and that glomerular capillary wall strain may play a significant role in the perpetuation of glomerular injury in disease states that are associated with glomerular hypertension. Methods: We developed an anatomically accurate mathematical model of a compliant, filtering rat glomerulus to quantify the strain of the glomerular capillary walls in a remnant glomerulus of the 5/6‐nephrectomized rat model of chronic kidney disease. In terms of estimating the mechanical stresses and strains in the glomerular capillaries, this mathematical model is a substantial improvement over previous models which do not consider pressure‐induced alterations in glomerular capillary diameters in distributing plasma and erythrocytes throughout the network. Results: Using previously reported data from experiments measuring the change of glomerular volume as a function of perfusion pressure, we estimated the Young's modulus of the glomerular capillary walls in both control and 5/6‐nephrectomized conditions. We found that in 5/6‐nephrectomized conditions, the Young's modulus increased to 8.6 MPa from 7.8 MPa in control conditions, but the compliance of the capillaries increased in 5/6‐nephrectomized conditions due to a 23.3% increase in the baseline glomerular capillary diameters. We found that glomerular capillary wall strain was increased approximately threefold in 5/6‐nephrectomized conditions over control, which may deleteriously affect both mesangial cells and podocytes. The magnitudes of strain in model simulations of 5/6‐nephrectomized conditions were consistent with magnitudes of strain that elicit podocyte hypertrophy and actin cytoskeleton reorganization in vitro. Conclusions: Our findings indicate that glomerular capillary wall strain may deleteriously affect podocytes directly, as well as act in concert with other mechanical changes and environmental factors inherent to the in vivo setting to potentiate glomerular injury in severe renoprival conditions. [ABSTRACT FROM AUTHOR]

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (−1.9±0.4ml/min, p

Background: Fenoldopam, a vasodilating agent, may represent a potential therapeutic opportunity to increase renal perfusion in those conditions where renal hemodynamics are severely impaired by vascular sub-occlusion, as, indeed, is the case in thrombotic microangiopathies. Methods: The renal resistance index (RRI) was measured, on and off fenoldopam, in 27 children with STEC-HUS. Results: A 12% decrease in RRI was observed on fenoldopam compared to off treatment without changes in the systemic hemodynamics and with no side effects. Conclusions: If confirmed in larger series, fenoldopam may become an important addition to supportive care to reduce ischemic damage in STEC-HUS and improve long-term outcomes. [ABSTRACT FROM AUTHOR]

Objective: Diabetic kidney disease is a microvascular complication of diabetes. Here, we assessed the association between skin microvascular function and renal hemodynamic function in a cohort of well‐phenotyped adults with type 2 diabetes (T2D). Methods: We included 81 overweight/obese adults (age: 62 ± 8 years; BMI: 32 ± 4 kg/m2) with well‐controlled T2D and no renal impairment. Skin microvascular function was assessed by nailfold capillary density in rest and after arterial occlusion (ie, peak capillary density). Renal hemodynamic functions (ie, measured glomerular filtration rate [mGFR], effective renal blood flow [ERBF], filtration fraction [FF], and effective renal vascular resistance [ERVR]) were assessed by combined inulin and para‐aminohippurate clearances and blood pressure measurements. Results: Skin capillary density was 45 ± 10 capillaries/mm2 at baseline and 57 ± 11 capillaries/mm2 during post‐occlusive peak; mGFR averaged 108 ± 20 ml/min. In multivariable regression analyses, positive associations between capillary density during post‐occlusive peak and mGFR (β = 0.224; p = 0.022) and ERBF (β = 0.203; p = 0.020) and a positive trend for hyperemia and mGFR (β = 0.391; p = 0.053) were observed, while a negative association for post‐occlusive capillary density with ERVR (β = −0.196; p = 0.027) was found. Conclusion: These findings indicate that microvascular dysfunction in overweight adults with T2D is associated with lower mGFR and ERPF and higher ERVR. We hypothesize that increased renal vascular resistance may contribute to glomerular dysfunction due to impaired renal perfusion. [ABSTRACT FROM AUTHOR]

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s−1 cm−5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s−1 cm−5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated. [ABSTRACT FROM AUTHOR]

Abstract A novel anatomically accurate model of rat glomerular filtration is used to quantify shear stresses on the glomerular capillary endothelium and hoop stresses on the glomerular capillary walls. Plasma, erythrocyte volume, and plasma protein mass are distributed at network nodes using pressure differentials calculated taking into account volume loss to filtration, improving on previous models which only took into account blood apparent viscosity in calculating pressures throughout the network. Filtration is found to be heterogeneously distributed throughout the glomerular capillary network and is determined by concentration of plasma proteins and surface area of the filtering capillary segments. Hoop stress is primarily concentrated near the afferent arteriole, whereas shear stress is concentrated near the efferent arteriole. Using parameters from glomerular micropuncture studies, conditions of diabetes mellitus (DM), 5/6‐Nephrectomy (5/6‐Nx), and Angiotensin II‐induced hypertension (HTN) are simulated and compared to their own internal controls to assess the changes in mechanical stresses. Hoop stress is increased in all three conditions, while shear stress is increased in 5/6‐Nx, decreased in HTN, and maintained at control levels in DM by the hypertrophic response of the glomerular capillaries. The results indicate that these alterations in mechanical stresses and the consequent release of cytokines by or injury of the glomerular cells may play a significant role in the progression of glomerulopathy in these disease conditions.

Abstract Measurement of the concentration of hippurate in the inferior vena cava and renal blood samples performed in 13 subjects with normal or near‐normal serum creatinine concentrations confirmed the prediction that endogenous hippurate was cleared on a single pass through the kidney with the same avidity as that reported for infused para‐amino hippurate. This suggests that a timed urine collection without infusion would provide a measure of effective renal plasma flow. Comparison of the arteriovenous concentration differences for a panel of protein‐bound solutes identified solutes that were secreted by the renal tubule and solutes that were subjected to tubular reabsorption.

Background. Timely correction of hemodynamic disorders in children with chronic pyelonephritis is a component of nephroprotection. Аngiotensin-converting enzyme inhibitors (ACEI) are the basis of renoprotective therapy. The purpose of the study was to evaluate the efficiency of nephroprotective therapy in children with chronic pyelonephritis during follow-up observation. Materials and methods. Ninety three children aged 4 to 17 years with chronic pyelonephritis (disease duration from 3 to 7 years) were examined. The control group consisted of 30 healthy children of the same age. Daily blood pressure monitoring and Doppler sonography of the renal blood vessels were performed. Furthermore, ACEI enalapril was administered in the maximum allowed and tolerated doses, for 2–3 years. Results. During the follow-up examination, there was a significant reduction in the incidence and severity of hypertension syndrome according to the data of daily blood pressure monitoring on the background of ACEI administration (vs baseline from 28.5 to 7 % in general; p < 0.05). Moreover, there were reliable changes of renal hemodynamic parameters at the level of segmental and stem arteries in the form of reduced peripheral resistance parameters and rate indices that indicated the processes of vessel remodeling in the kidneys. In the prospective analysis, there has been determined an improvement of intrarenal hemodynamics on the background of ACEI administration. Conclusions. Chronic pyelonephritis in children is associated with gradual disorders of the central and peripheral blood flow, ischemic and hemodynamic changes in parenchyma that require proper correction. ACEI enalapril is a drug of choice. Moreover, enalapril inclusion in the treatment leads to positive dynamics in majority of patients (75.2 %).

Background. Prompt detection of changes in the cardiovascular system in children with chronic pyelonephritis is important for slowing down the development of arterial hypertension and the progression of chronic kidney disease. Nowadays, daily monitoring of blood pressure and ultrasound Doppler of the renal vessels are the up-to-date non-invasive me­thods for early diagnosis of cardiovascular disorders. The purpose of the study was to determine the prognostic value of ultrasound symptoms of renal hemodynamic disorders and daily blood pressure monitoring in children with chronic pyelonephritis. Materials and methods. The correlation analysis of indicators of daily blood pressure monitoring and ultrasound Doppler examination have been performed in 107 children aged 3–17 years with chronic pyelonephritis. Results. There was statistically significant correlation between such indicators as pulsation index, resistance index, systolic-diastolic ratio at the level of stem, segmental renal arteries and daily indexes (blood pressure, systolic pressure and diastolic pressure), variation coefficient at night, mean diastolic pressure and diastolic pressure at night. However, correlation between ultrasound indicators of renal hemodynamics and daily blood pressure monitoring at the level of interlobular renal arteries was statistically unreliable. Furthermore, children with chronic pyelonephritis on the background of urinary tract abnormalities had the strongest associations between the indicators of the peripheral resistance at the level of the stem renal arteries and the indexes of daily blood pressure monitoring. Conclusions. Indicators of renal hemodynamics — pulsation index, index of resistance, systolic-diastolic ratio at the level of the stem and segmental arteries of the kidney can distinguish the features of renal hemodynamics in order to predict the development of renal hypertension in children with chronic pyelonephritis. The intensity of deviations of these parameters from the normal rates of renal hemodynamics determines the severity of arterial hypertension in 57 % of cases.

A novel anatomically accurate model of rat glomerular filtration is used to quantify shear stresses on the glomerular capillary endothelium and hoop stresses on the glomerular capillary walls. Plasma, erythrocyte volume, and plasma protein mass are distributed at network nodes using pressure differentials calculated taking into account volume loss to filtration, improving on previous models which only took into account blood apparent viscosity in calculating pressures throughout the network. Filtration is found to be heterogeneously distributed throughout the glomerular capillary network and is determined by concentration of plasma proteins and surface area of the filtering capillary segments. Hoop stress is primarily concentrated near the afferent arteriole, whereas shear stress is concentrated near the efferent arteriole. Using parameters from glomerular micropuncture studies, conditions of diabetes mellitus (DM), 5/6‐Nephrectomy (5/6‐Nx), and Angiotensin II‐induced hypertension (HTN) are simulated and compared to their own internal controls to assess the changes in mechanical stresses. Hoop stress is increased in all three conditions, while shear stress is increased in 5/6‐Nx, decreased in HTN, and maintained at control levels in DM by the hypertrophic response of the glomerular capillaries. The results indicate that these alterations in mechanical stresses and the consequent release of cytokines by or injury of the glomerular cells may play a significant role in the progression of glomerulopathy in these disease conditions. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by circulating autoantibodies, prevalent hypertension, renal injury, and cardiovascular disease. Onset of the disease often occurs in young women of childbearing age. Although kidney involvement is common to patients with SLE, little is known about temporal changes in renal hemodynamic function and its relationship to the pathogenesis of hypertension during autoimmune diseases. We hypothesized that the loss of immunological tolerance and subsequent production of autoantibodies in SLE leads to impaired renal hemodynamic function that precedes the development hypertension. Female NZBWF1 (SLE) mice and female NZW/LacJ (control) mice were instrumented with carotid artery and jugular vein catheters to determine mean arterial pressure (MAP) and glomerular filtration rate, respectively, at ages of 15, 20, 24, 28, 31, and 34 wk. In addition, urinary albumin excretion, blood urea nitrogen, circulating autoantibodies, and glomerulosclerosis were assessed at each age. Levels of circulating autoantibodies are increased between 24 and 28 wk of age in NZBWF1 mice and were significantly greater than in control mice. Glomerular filtration rate was significantly increased at 28 wk of age in NZBWF1 mice followed by a sharp decline at 34 wk of age. NZBWF1 mice had an increase in MAP that occurred by 34 wk of age. These data show that changes in circulating autoantibodies, renal hemodynamic function, and glomerular injury occur in NZBWF1 mice before changes in MAP, suggesting an important mechanistic role for autoimmunity to directly impair renal hemodynamic function and promote the development of hypertension. [ABSTRACT FROM AUTHOR]

We found previously that intravenous kynurenic acid (KYNA), a native broad spectrum glutamate antagonist, increases renal blood flow and induces natriuresis in anesthetized spontaneously hypertensive rats (SHR). Since such changes may affect systemic circulation and can potentially find therapeutic application, in this study we examined long term influence of orally administered KYNA on systemic and renal hemodynamics and renal excretion in conscious SHR. KYNA was administered in drinking water at a dose of 25 mg/kg/day for 3 weeks. Heart rate (HR), systolic (SBP), and mean arterial pressure (MAP) were measured through telemetry. The records were taken at the beginning of the study (control, day 0), and then on day 7, 14, and 21 of treatment. Diuresis (V), total solute excretion (UosmV), and sodium excretion (UNaV) were determined on days 0, 7, and 14. KYNA consistently decreased HR, from 319 ± 8 to 291 ± 5, 299 ± 9 and 284 ± 6 beats/min on day 7, 14, and 21, respectively, (− 9, − 6, and − 11%; p < 0.01–0.0001); HR was stable in the solvent group. SBP, MAP, V, and UNaV were not affected by KYNA, whereas UosmV increased modestly. Chronic oral administration of KYNA to conscious SHR decreased HR without affecting MAP. Since tachycardia is an independent risk factor for cardiovascular disorders, and most drugs used to decrease HR have strong inotropic negative or hypotensive effect, such selective action seems of therapeutic potential. Moreover, food supplementation with KYNA can be considered in the prevention of heart diseases. [ABSTRACT FROM AUTHOR]