Changes in renal blood flow after surgically induced weight loss: can bariatric surgery halt the progression of chronic kidney disease?

BACKGROUND: We previously demonstrated how kidney injury in patients with morbid obesity can be reversed by bariatric surgery (BaS). OBJECTIVE(S): Based on previous experience, we hypothesize patients' potentially reversible kidney injury might be secondary to reduction in renal blood flow (RBF), which improves following BaS. SETTING: Academic Hospital. METHODS: We conducted a retrospective analysis of patients who underwent BaS at our institution from 2002 to 2019. We identified patients with chronic kidney disease (CKD) using the estimated glomerular filtration rate (eGFR) from the CKD Epidemiology Collaboration Study (CKD-EPI) classification system. We used the BUN/Creatinine (Cr) ratio pre- and postoperatively to determine a prerenal (decreased RBF) versus intrinsic component as the responsible cause of CKD in this patient population. Decreased RBF was defined as BUN/Cr > 20 preoperatively. RESULTS: Our analysis included n = 2924 patients, of which 11% (n = 325) presented decreased RBF. From our original sample, only n = 228 patients had the complete data necessary to assess both eGFR and RBF (BUN/Cr). Patients with baseline CKD stage 2 demonstrated preoperative BUN/Cr 20.85 ± 10.23 decreasing to 14.99 ± 9.10 at 12-month follow-up (P < .01). Patients with baseline CKD stage 3 presented with preoperative BUN/Cr 23.88 ± 8.75; after 12-month follow-up, BUN/Cr ratio decreased to 16.38 ± 9.27 (P < .01). Patients with CKD stage 4 and ESRD (eGFR < 30) did not demonstrate a difference for pre- and postoperative BUN/Cr 21.71 ± 9.28 and 19.21 ± 14.58, respectively. CONCLUSION(S): According to our findings, patients with CKD stages 1-3 present improvement of their kidney function after BaS. This amelioration could be secondary to improvement of the RBF, an unstudied reversible mechanism of kidney injury in the bariatric population.

Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis.

AIM: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti-inflammatory drug, tempol, may modify these responses. METHODS: Following unilateral nephrectomy, we inserted renal arterial catheters and laser-Doppler/oxygen-sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT; 30 mg kg-1 h-1 ), renal arterial tempol (RAT; 3 mg kg-1 h-1 ), or vehicle. RESULTS: Septic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min-1 ). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3-nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative/nitrosative stress markers, cortical and medullary nuclear factor-erythroid-related factor-2 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis-induced overexpression of cortical tissue tumor necrosis factor alpha (TNF-α; 51 ± 16% decrease; p = 0.003) and medullary Thr-495 phosphorylation of endothelial nitric oxide synthase (eNOS; 63 ± 18% decrease; p = 0.015). CONCLUSIONS: In ovine Gram-negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF-α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram-negative sepsis.

The differences in renal hemodynamic response following high-intensity exercise between younger and older males.

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.

Arterial spin labeling and diffusion-weighted MR imaging: quantitative assessment of renal pathological injury in chronic kidney disease.

PURPOSE: The aim of the study was to investigate the performance of arterial spin labeling (ASL), diffusion-weighted imaging (DWI), and clinical biomarkers in assessing renal pathological injury in CKD. MATERIALS AND METHODS: Forty-five biopsy-proven CKD patients and 17 healthy volunteers underwent DWI and ASL examinations. Renal cortical blood flow (RBF) and apparent diffusion coefficient (ADC) values were acquired. Correlations between RBF, ADC, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), and pathological scores were assessed. The diagnostic efficacy of SCr, eGFR, RBF, and ADC in assessing renal pathological injury was assessed by ROC curve analysis. RESULTS: The cortical RBF, ADC, SCr, and eGFR were significantly correlated with the renal histology score (all p < 0.01). The AUC values of SCr, eGFR, RBF, and ADC were 0.705 (95% confidence interval (CI): 0.536-0.827), 0.718 (0.552-0.839), 0.823 (0.658-0.916), and 0.624 (0.451-0.786), respectively, in discriminating the minimal-mild renal pathological injury group (N = 30) from the control group (N = 17). The diagnostic ability of ASL was significantly higher than that of DWI (p = 0.049) and slightly but not significantly higher than that of eGFR and SCr (p = 0.151 and p = 0.129, respectively). When compared with that of eGFR, the sensitivity of ASL in detecting early renal injury increased from 50 to 70% (p = 0.014). However, in differentiating between the minimal-mild and moderate-severe renal injury groups (N = 15), there was no significant difference in diagnostic ability among the four parameters (all p > 0.05). CONCLUSION: ASL is practicable for noninvasive evaluation of renal pathology, especially for predicting early renal pathological injury in CKD patients.

Microvascular remodeling and altered angiogenic signaling in human kidneys distal to occlusive atherosclerotic renal artery stenosis.

BACKGROUND: Renal artery stenosis (RAS) is an important cause of chronic kidney disease and secondary hypertension. In animal models, renal ischemia leads to downregulation of growth factor expression and loss of intrarenal microcirculation. However, little is known about the sequelae of large-vessel occlusive disease on the microcirculation within human kidneys. METHOD: This study included five patients who underwent nephrectomy due to renovascular occlusion and seven nonstenotic discarded donor kidneys (four deceased donors). Micro-computed tomography was performed to assess microvascular spatial densities and tortuosity, an index of microvascular immaturity. Renal protein expression, gene expression and histology were studied in vitro using immunoblotting, polymerase chain reaction and staining. RESULTS: RAS demonstrated a loss of medium-sized vessels (0.2-0.3 mm) compared with donor kidneys (P = 0.037) and increased microvascular tortuosity. RAS kidneys had greater protein expression of angiopoietin-1, hypoxia-inducible factor-1α and thrombospondin-1 but lower protein expression of vascular endothelial growth factor (VEGF) than donor kidneys. Renal fibrosis, loss of peritubular capillaries (PTCs) and pericyte detachment were greater in RAS, yet they had more newly formed PTCs than donor kidneys. Therefore, our study quantified significant microvascular remodeling in the poststenotic human kidney. RAS induced renal microvascular loss, vascular remodeling and fibrosis. Despite downregulated VEGF, stenotic kidneys upregulated compensatory angiogenic pathways related to angiopoietin-1. CONCLUSIONS: These observations underscore the nature of human RAS as a microvascular disease distal to main vessel stenosis and support therapeutic strategies directly targeting the poststenotic kidney microcirculation in patients with RAS.

Detection of impaired renal allograft function in paediatric and young adult patients using arterial spin labelling MRI (ASL-MRI).

The study aimed to discriminate renal allografts with impaired function by measuring cortical renal blood flow (cRBF) using magnetic resonance imaging arterial spin labelling (ASL-MRI) in paediatric and young adult patients. We included 18 subjects and performed ASL-MRI on 1.5 T MRI to calculate cRBF on parameter maps. cRBF was correlated to calculated glomerular filtration rate (GFR) and compared between patient groups with good (GFR ≥ 60 mL/min/1.73 m2) and impaired allograft function (GFR < 60 mL/min/1.73 m2). Mean cRBF in patients with good allograft function was significantly higher than in patients with impaired allograft function (219.89 ± 57.24 mL/min/100 g vs. 146.22 ± 41.84 mL/min/100 g, p < 0.008), showing a highly significant correlation with GFR in all subjects (r = 0.75, p < 0.0001). Also, the diffusion-weighted imaging (DWI-MRI) apparent diffusion coefficient (ADC) and Doppler measurements of peak-systolic and end-diastolic velocities and the resistive index (PS, ED, RI) were performed and both methods showed no significant difference between groups. ADC implied no correlation with GFR (r = 0.198, p = 0.464), while PS indicated moderate correlation to GFR (r = 0.48, p < 0.05), and PS and ED moderate correlation to cRBF (r = 0.58, p < 0.05, r = 0.56, p < 0.05, respectively). Cortical perfusion as non-invasively measured by ASL-MRI differs between patients with good and impaired allograft function and correlates significantly with its function.

Associations of Serum Uric Acid Levels With Macrovascular and Renal Microvascular Dysfunction Among Individuals From Sub-Saharan Africa.

Importance: Serum uric acid (SUA) level is associated with vascular dysfunction in Eurasian populations, but little is known about this association in individuals from sub-Saharan Africa, who have a high prevalence of both relatively high SUA levels and vascular dysfunction. Objectives: To assess the associations of SUA levels with macrovascular and kidney microvascular dysfunction in individuals of sub-Saharan African ancestry and evaluate potential factors that could mediate these associations. Design, Setting, and Participants: Cross-sectional analyses of baseline data from the multicenter Research on Obesity and Diabetes Among African Migrants study, conducted from 2012 to 2015, were performed from January to March 2021. The population included Ghanaian individuals living in Ghana and Europe. Exposure: Abnormal SUA levels. Main Outcomes and Measures: Logistic regression was used to examine the associations of SUA level quartiles with microvascular (albuminuria) and macrovascular (peripheral artery disease and coronary artery disease) dysfunction, with adjustments for age, sex, estimated glomerular filtration rate, site of residence, socioeconomic status, alcohol, smoking, diabetes, hypertension, waist-hip ratio, and total cholesterol level. Mediation analysis was performed to assess whether the association was via elevated blood pressure, hemoglobin A1c, and high-sensitivity C-reactive protein levels or via weight-hip ratio. The research questions were formulated after data collection. Results: A total of 4919 Ghanaian individuals (3047 [61.9%] women) aged 25-75 years (mean [SD], 46.26 [11.08] years) were included. There was a significant positive association between SUA quartiles and albuminuria, but not coronary artery disease or peripheral artery disease, after adjustment for covariates. After full adjustment, individuals in the fourth SUA quartile had higher odds of albuminuria (adjusted odds ratio [aOR], 1.54; 95% CI, 1.07-2.21), but not peripheral artery disease (aOR, 1.35; 95% CI, 0.87-2.08) or coronary artery disease (aOR, 1.09; 95% CI, 0.77-1.55), compared with individuals in the first quartile. After full adjustment, systolic and diastolic blood pressure significantly mediated the association between SUA concentrations and albuminuria, accounting for 19.4% of the total association for systolic and 17.2% for diastolic blood pressure; hemoglobin A1c, high-sensitivity C-reactive protein, and waist-hip ratio did not mediate this association. Conclusions and Relevance: In this cross-sectional study among a sub-Saharan African population, elevated SUA levels were significantly associated with kidney microvascular dysfunction and mediated partly through elevated blood pressure. These findings suggest that individuals from sub-Saharan Africa with elevated SUA levels may benefit from periodic screening for kidney microvascular dysfunction to aid early detection or treatment.

Application of dynamic contrast enhanced ultrasound in the assessment of kidney diseases.

PURPOSE OF REVIEW: Many forms of acute and chronic disease are linked to changes in renal blood flow, perfusion, vascular density and hypoxia, but there are no readily available methods to assess these parameters in clinical practice. Dynamic contrast enhanced ultrasound (DCE-US) is a method that provides quantitative assessments of organ perfusion without ionising radiation or risk of nephrotoxicity. It can be performed at the bedside and is suitable for repeated measurements. The purpose of this review is to provide updates from recent publications on the utility of DCE-US in the diagnosis or assessment of renal disease, excluding the evaluation of benign or malignant renal masses. RECENT FINDINGS: DCE-US has been applied in clinical studies of acute kidney injury (AKI), renal transplantation, chronic kidney disease (CKD), diabetic kidney disease and to determine acute effects of pharmacological agents on renal haemodynamics. DCE-US can detect changes in renal perfusion across these clinical scenarios and can differentiate healthy controls from those with CKD. In sepsis, reduced DCE-US measures of perfusion may indicate those at increased risk of developing AKI, but this requires confirmation in larger studies as there can be wide individual variation in perfusion measures in acutely unwell patients. Recent studies in transplantation have not provided robust evidence to show that DCE-US can differentiate between different causes of graft dysfunction, although it may show more promise as a prognostic indicator of graft function 1 year after transplant. DCE-US can detect acute haemodynamic changes in response to medication that correlate with changes in renal plasma flow as measured by para-aminohippurate clearance. SUMMARY: DCE-US shows promise and has a number of advantages that make it suitable for the assessment of patients with various forms of kidney disease. However, further research is required to evidence its reproducibility and utility before clinical use can be advocated.

Evaluation of renal oxygenization in laparoscopic pediatric surgery by near infrared spectroscopy.

PURPOSE: Increased intraabdominal pressure IAP may reduce renal blood flow (RBF). The study aims to evaluate the pneumoperitoneum effect on RBF by comparing renal regional oxygen saturation index (rSrO2) measured by near-infrared spectroscopy (NIRS) in pediatric patients having laparotomy and laparoscopy. METHODS: Of 58 patients having laparoscopy and laparotomy, 18 were excluded due to renal pathologies, combined open surgical procedures, and administration of inotropic drugs. Hemodynamic parameters and rSrO2 were recorded in laparoscopy (n = 20) and laparotomy (n = 20) groups before induction and with 5 min intervals up to 60 min and at post-extubation. RESULTS: Decrease in right renal rSrO2 at 45th and 60th min and 30th, 45th and 60th min in left were significant in the laparoscopy group compared to laparotomy group. In the laparoscopy group, reductions at T25, T30, T45, and T60 were significant in both renal rSrO2. Renal rSO2 increased to normal with desufflation. CONCLUSION: IAP with pneumoperitoneum may lead to renal hypoxia in children. Renal rSO2 returns to normal with desufflation. Renal NIRS monitorization might be needed in patients with renal parenchymal and vascular pathologies, solitary kidney, and multiorgan pathologies that may affect renal oxygenation.

Peristenotic Collateral Circulation in Atherosclerotic Renovascular Disease: Association With Kidney Function and Response to Treatment.

The significance of peristenotic collateral circulation (PCC) development around a stenotic renal artery is unknown. We tested the hypothesis that PCC is linked to loss of kidney function and recovery potential in patients with atherosclerotic renovascular disease (ARVD). Thirty-four patients with ARVD were assigned to medical-therapy with or without revascularization based on clinical indications. The PCC was visualized using multidetector computed tomography and defined relative to segmental arteries in patients with essential hypertension. PCC number before and 3 months after treatment was correlated with various renal parameters. Thirty-four stenotic kidneys from 30 patients were analyzed. PCC number correlated inversely with kidney volume. ARVD-stenotic kidneys with baseline PCC (collateral ARVD [C-ARVD], n=13) associated with elevated 24-hour urine protein and stenotic kidney vein level of tumor necrosis factor-α, lower single-kidney volume and blood flow, and greater hypoxia than in stenotic kidneys with no PCC (no collateral ARVD [NC-ARVD], n=17). Revascularization (but not medical-therapy alone) improved stenotic kidney function and reduced inflammation in both NC-ARVD and C-ARVD. In C-ARVD, revascularization also increased stenotic kidney volume, blood flow, and oxygenation to levels comparable to NC-ARVD, and induced PCC regression. However, revascularization improved systolic blood pressure, plasma renin activity, and filtration fraction only in NC-ARVD. Therefore, patients with C-ARVD have greater kidney dysfunction, atrophy, hypoxia, and inflammation compared with patients with NC-ARVD, suggesting that PCC does not effectively protect the stenotic kidney in ARVD. Renal artery revascularization improved in C-ARVD stenotic kidney function, but not hypertension or renin-angiotensin system activation. These observations may help direct management of patients with ARVD.

The Correlation of Intraabdominal Pressure With Renal Resistive Index.

BACKGROUND: To evaluate the correlation between intraabdominal pressure (IAP) measured via the bladder and renal resistive index (RRI) measured by Doppler ultrasonography (USG). METHODS: Eighty consecutive surgical patients were included into this study. Before Doppler USG evaluation, IAP was measured by a Foley catheter via the bladder. The left and right RRI, the diameters of the inferior vena cava and portal vein were measured by colored Doppler USG. Spearman correlation analysis was used to evaluate the correlation between different measurements. Intraabdominal hypertension (IAH) was defined as of IAP ≥ 12 mmHg. Significantly different variables from the univariate analysis between patients with and without IAH were entered into backward stepwise binary logistic regression analysis of IAH as the dependent variable. P values < 0.05 were accepted as statistically significant. RESULTS: In total, 80 patients were included into study. In 27 patients (34%) IAP was normal and in 53 patients (66%) IAH was diagnosed. The Spearman correlation analysis of IAP and the ultrasonographic measurements revealed a strong correlation between RRI and IAP (P < 0.001). Patients with IAH were more likely to be diabetic and had abdominal incisional hernia compared with patients with normal IAP (P < 0.05). The results of the multivariate logistic regression analysis revealed right RRI as the only independent predictor of IAH (B: 57.04, S. E.: 13.7, P < 0.001). CONCLUSIONS: There is a strong correlation between IAP and RRI. RRI can be an alternative, noninvasive technique for the diagnosis and follow-up of IAH after further evaluations in different patient groups.

Purinoceptors, renal microvascular function and hypertension.

Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation.

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in Gpr81-/- mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81-/- mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

Aerobic Endurance Exercise Ameliorates Renal Vascular Sclerosis in Aged Mice by Regulating PI3K/AKT/mTOR Signaling Pathway.

Renal vascular sclerosis caused by aging plays an important role in the occurrence and development of chronic kidney disease. Clinical studies have confirmed that endurance exercise is able to delay the aging of skeletal muscle and brain tissue. However, to date, few studies have assessed whether endurance exercise is able to improve the occurrence of renal vascular sclerosis caused by natural aging and its related mechanisms. In this study, we investigated the protective effect of aerobic endurance exercise on renal vascular sclerosis in aged mice and its effect on the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. The results suggested that aerobic endurance exercise preserved kidney morphology and renal function. Glomerular basement membrane thickness was evidently increased, podocyte foot processes were effaced in aged mice, and aerobic endurance exercise significantly ameliorated the overall lesion range. The protein expression of vascular endothelial growth factor (VEGF) and JG12 was lower in the senile control group (OC group). The protein expression of VEGF and JG12 was significantly increased after aerobic endurance exercise. Furthermore, aerobic endurance exercise resulted in downregulation of Bax, Caspase 3, IL-6, and senescent cells and upregulation of Bcl-2. The upregulation of PI3K and its downstream signal molecules AKT and mTOR after aerobic endurance exercise was further observed. Our observations indicated that aerobic endurance exercise may inhibit renal vascular sclerosis in aged mice by regulating the PI3K/AKT/mTOR signaling pathway.

Nicotine Improves Survivability, Hypotension, and Impaired Adenosinergic Renal Vasodilations in Endotoxic Rats: Role of α7-nAChRs/HO-1 Pathway.

The nicotinic/cholinergic antiinflammatory pathway protects against acute kidney injury and other end-organ damages induced by endotoxemia. In this study, we tested the hypothesis that functional α7-nAChRs/heme oxygenase-1 (HO-1) pathway is imperative for the nicotine counteraction of hemodynamic and renovascular dysfunction caused by acute endotoxemia in rats. Renal vasodilations were induced by cumulative bolus injections of acetylcholine (ACh, 0.01 nmol-7.29 nmol) or ethylcarboxamidoadenosine (NECA, adenosine receptor agonist, 1.6 nmol-100 nmol) in isolated phenylephrine-preconstricted perfused kidneys. The data showed that 6-h treatment with lipopolysaccharide (LPS, 5 mg/kg i.p.) decreased systolic blood pressure and renal vasodilations caused by NECA but not Ach. The endotoxic insult also increased the mortality rate and elevated serum urea and creatinine. These LPS effects were sex-unrelated, except hypotension, and enhanced mortality which were more evident in male rodents, and abrogated after co-administration of nicotine (0.5, 1 mg/kg and 2 mg/kg) in a dose-dependent fashion. The advantageous effects of nicotine on NECA vasodilations, survivability, and kidney biomarkers in endotoxic male rats disappeared upon concurrent exposure to methyllycaconitine citrate (α7-nAChR blocker) or zinc protoporphyrin (HO-1 inhibitor) and were reproduced after treatment with bilirubin, but not hemin (HO-1 inducer) or tricarbonyldichlororuthenium (II) dimer (carbon monoxide-releasing molecule). Together, current biochemical and pharmacological evidence suggests key roles for α7-nAChRs and the bilirubin byproduct of the HO-1 signaling in the nicotine counteraction of renal dysfunction and reduced adenosinergic renal vasodilator capacity in endotoxic rats.

Sympathetic activation by lower body negative pressure decreases kidney perfusion without inducing hypoxia in healthy humans.

PURPOSE: There is ample evidence that systemic sympathetic neural activity contributes to the progression of chronic kidney disease, possibly by limiting renal blood flow and thereby inducing renal hypoxia. Up to now there have been no direct observations of this mechanism in humans. We studied the effects of systemic sympathetic activation elicited by a lower body negative pressure (LBNP) on renal blood flow (RBF) and renal oxygenation in healthy humans. METHODS: Eight healthy volunteers (age 19-31 years) were subjected to progressive LBNP at - 15 and - 30 mmHg, 15 min per level. Brachial artery blood pressure was monitored intermittently. RBF was measured by phase-contrast MRI in the proximal renal artery. Renal vascular resistance was calculated as the MAP divided by the RBF. Renal oxygenation (R2*) was measured for the cortex and medulla by blood oxygen level dependent (BOLD) MRI, using a monoexponential fit. RESULTS: With a LBNP of - 30 mmHg, pulse pressure decreased from 50 ± 10 to 43 ± 7 mmHg; MAP did not change. RBF decreased from 1152 ± 80 to 1038 ± 83 mL/min to 950 ± 67 mL/min at - 30 mmHg LBNP (p = 0.013). Heart rate and renal vascular resistance increased by 38 ± 15% and 23 ± 8% (p = 0.04) at - 30 mmHg LBNP, respectively. There was no change in cortical or medullary R2* (20.3 ± 1.2 s-1 vs 19.8 ± 0.43 s-1; 28.6 ± 1.1 s-1 vs 28.0 ± 1.3 s-1). CONCLUSION: The results suggest that an increase in sympathetic vasoconstrictor drive decreases kidney perfusion without a parallel reduction in oxygenation in healthy humans. This in turn indicates that sympathetic activation suppresses renal oxygen demand and supply equally, thus allowing adequate tissue oxygenation to be maintained.

Aging Impairs Renal Autoregulation in Mice.

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

Hypoxia and Endothelial Dysfunction in Autosomal-Dominant Polycystic Kidney Disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disease, characterized by growth of bilateral renal cysts, hypertension, and multiple extrarenal complications that eventually can lead to renal failure. It is caused by mutations in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Over the past few years, studies investigating the role of primary cilia and polycystins, present not only on the surface of renal tubular cells but also on vascular endothelial cells, have advanced our understanding of the pathogenesis of ADPKD and have shown that mechanisms other than cyst formation also contribute to renal functional decline in this disease. Among them, increased oxidative stress, endothelial dysfunction, and hypoxia may play central roles because they occur early in the disease process and precede the onset of hypertension and renal functional decline. Endothelial dysfunction is linked to higher asymmetric dimethylarginine levels and reduced nitric oxide bioavailability, which would cause regional vasoconstriction and impaired renal blood flow. The resulting hypoxia would increase the levels of hypoxia-inducible-transcription factor 1α and other angiogenetic factors, which, in turn, may drive cyst growth. In this review, we summarize the existing evidence for roles of endothelial dysfunction, oxidative stress, and hypoxia in the pathogenesis of ADPKD.

Real-time kidney graft perfusion monitoring using infrared imaging during pediatric kidney transplantation.

INTRODUCTION: Ischemia times in kidney transplantation have shown to be predictive for future graft function. Preservation solutions and anticoagulation protocols have improved the management of pediatric kidney transplantation. Nonetheless, there is no current tool for intra-operative graft monitoring. The aim of this project is to present a novel technique for intra-operative real-time assessment of graft perfusion using a non-invasive infrared camera. METHODS: Prospectively, the authors included 10 pediatric patients. Surgical procedure followed their institutional protocol. Infrared imaging was captured at graft preparation, vascular anastomosis, unclamping, and at 30 s, 1, 5, and 10 min after unclamping. Analyzed variables included type of transplant, ischemia and procedure times, type of anastomosis, and results of doppler/ultrasound. Postoperative variables included creatinine levels during first 72 h. Any complications were also recorded. Delta analysis was calculated to establish the variation of temperature after unclamping. RESULTS: Average age at transplant was 9.9 years. Five cases were living donor transplants. Mean overall ischemia time was 395.6 (SD 64.4 min). Two patients had poor graft perfusion after unclamping. Of those, one had torsion of the arterial anastomosis and the other was a graft from a donor that required cardiopulmonary resuscitation for 45 min. Thermal imaging showed a correlation of 0.318 between graft temperature change and creatinine decrease. Cut-off delta for temperature for good reperfusion was above 0.2 at 1 min CONCLUSION: Real-time infrared imaging shows to be a promising option for non-invasive graft perfusion monitoring. Initial results show good correlation between intra-operative temperature changes, graft perfusion, and postoperative graft function.