Decrease In Renal Blood Flow Research Articles

Randomized, placebo-controlled trial on the renal and systemic hemodynamic effects of empagliflozin

IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcomes in type 2 diabetes (DM2) and chronic kidney disease (CKD). A decrease in renal blood flow (RBF) with attenuation of glomerular hyperfiltration may contribute. We examined renal and systemic hemodynamic effects of SGLT2i in relevant patient categories. MethodsUsing a double-blind placebo controlled cross-over design we randomized patients with DM2 and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m2 (n=16), patients with DM2 and eGFR 20-60 ml/min/1.73m2 (n=17) and patients with non-diabetic CKD and eGFR 20-60 ml/min/1.73m2 (n=16) to empagliflozin 10 mg daily or placebo for four weeks and crossed over to the opposite treatment after two-week washout. RBF was measured with 82Rubidium-positron emission-tomography/computed-tomography, GFR with 99mTechnetium-diethylene-triamine-pentaacetate-clearance. 24-hour blood pressure (BP) and total vascular resistance (TVR) were recorded using a Mobil-O-graph. ResultsCompared to placebo empagliflozin reduced RBF by 6% in the DM2-CKD group (p<0.001) with non-significant decreases of 4% in the DM2 group and 1% in the CKD group (p=0.29 and 0.72). Empagliflozin reduced GFR, BP and TVR in all groups, while renal vascular resistance (RVR) remained unchanged ConclusionEmpagliflozin reduced RBF in patients with DM2 and CKD, whereas GFR, BP and TVR were reduced in all groups. This pattern, together with a lack of reduction in RVR, suggests SGLT2i protect the glomerulus through combined pre-glomerular and post-glomerular effects.

Abstract P399: High Salt Induced Mitochondrial Uncoupling And Enhanced Respiratory Activity In Isolated Proximal Tubules From Dahl Salt-sensitive Rats

The nephron actively reabsorbs ~99% of the Na + from the glomerular filtrate to maintain fluid and solute homeostasis, ~70% of which occurs in the proximal tubules (PT), where mitochondria consume a great amount of O 2 for ATP production to meet the energy demand. However, the effect of a high salt diet upon the PT energy metabolism and respiratory activity is not well-known. To determine this, the PT of Dahl salt-sensitive (SS) rats were isolated with the rats fed either 0.4% NaCl (LS) or 7, 14 and 21 days after feeding a 4.0% NaCl (HS) diet. Changes in O 2 consumption rate (OCR) of the PT were determined using a high-throughput Agilent Seahorse XF96 Extracellular Flux Analyzer and Mitochondrial Stress Test Protocol. Basal OCRs were assessed with only amino acids used as fuel for oxidative phosphorylation (OxPhos). Under these conditions, by day 7 of the HS diet, OCR increased from 9.2±0.5 to 17.2±0.8 pmol/min/μg, (p&lt;0.05), which rose to 20.2±1.0 and 18.9±0.7 pmol/min/μg (p&lt;0.05 vs LS), respectively, at HS day 14 and HS day 21. The Seahorse protocol was also modified to determine the OCR responses to representative circulating substrates. The OCR responses from baseline to glucose or pyruvate were unchanged by the HS diet compared to the PT of LS fed rats. However, a sustained increase in the proton leak OCR was observed for glucose (LS: 2.5±0.5 vs HS day 7: 7.3±1.1; p&lt;0.05) and for pyruvate (LS: 2.3±0.3 vs HS day 7: 7.9±0.2; p&lt;0.05). These high levels of proton leak were maintained throughout the 21 days of the HS diet. Since it is known that uncoupling proteins (UCP) and ADP/ATP translocase (ANT) enhance proton leak, gene expression was quantified from the isolated PT segments. Increased Ucp2 expression was found (p&lt;0.05) in response to the HS diet (days 7, 14, and 21) compared to LS fed rats but no changes were observed in the expression of Slc25A4 (ANT1) or Slc25A5 (ANT2). In summary, the HS diet resulted in increased PT O 2 consumption and proton leak in SS rats which was associated with an increase of Ucp2 gene expression. Given recent evidence that this is associated with a decrease in renal blood flow (RBF/kidney wt), we propose that increases in the PT O 2 consumption contribute to the onset of regional chronic ischemia and exacerbates renal damage and hypertension.

The role of Mas receptor on renal hemodynamic responses to angiotensin II administration in chronic renal sympathectomized male and female rats.

Renal hemodynamics is influenced by renal sympathetic nerves and the renin-angiotensin system. On the other hand, renal sympathetic denervation impacts kidney weight by affecting renal hemodynamics. The current study evaluated the role of the Mas receptor on renal hemodynamic responses under basal conditions and in response to angiotensin II (Ang II) in chronic renal sympathectomy in female and male rats. Forty-eight nephrectomized female and male rats were anesthetized and cannulated. Afterward, the effect of chronic renal sympathectomy was investigated on hemodynamic parameters such as renal vascular resistance (RVR), mean arterial pressure (MAP), and renal blood flow (RBF). In addition, the effect of chronic sympathectomy on kidney weight was examined. Chronic renal sympathectomy increased RVR and subsequently decreased RBF in both sexes. Renal perfusion pressure also increased after sympathectomy in male and female rats, while MAP did not change, significantly. In response to the Ang II injection, renal sympathectomy caused a greater decrease in RBF in all experimental groups, while it did not affect the MAP response. In addition, chronic sympathectomy increased left kidney weight in right nephrectomized rats. Chronic renal sympathectomy changed systemic/renal hemodynamics in baseline conditions and only renal hemodynamics in response to Ang II administration. Moreover, chronic sympathectomy increased compensatory hypertrophy in nephrectomized rats. These changes are unaffected by gender difference and Mas receptor blocker.

#3462 A STUDY OF ETIOLOGY OF ACUTE KIDNEY INJURY AND ACUTE ON CHRONIC KIDNEY DISEASE AMONGST IN-HOSPITAL PATIENTS IN A TERTIARY CARE CENTRE IN INDIA

Abstract Background and Aims Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include sepsis, ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with a decrease in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. Recent data suggest that AKI represents a potential link to chronic kidney disease (CKD) in surviving patients. Patients with CKD may be at risk for the development of a transient decrease in renal function consistent with AKI. Such rapidly declining renal function causing an acute deterioration of CKD is termed acute-on-chronic kidney disease (ACKD). The mechanisms by which these occur include failure of auto-regulation, abnormal vasodilatation, susceptibility to antihypertensive agents &amp; side effects of medication. The successful recovery from AKI depends on the degree to which these repair processes ensue &amp; these may be compromised in elderly or CKD patients. Aim To determine the burden of AKI among the in-hospital patients &amp; their progression to CKD if at all along with the number &amp; cause of the cases of CKD who develop ACKD due to an acute insult. Method The first 100 consecutive patients admitted with Acute Kidney Injury and Acute on Chronic Kidney Disease in the Department of General Medicine, Nephrology, Intensive care unit in KPC Medical College &amp; Hospital, Kolkata, were selected for the study. Inclusion criteria: • Patients admitted with AKI, ACKD or developing them during the course of stay. • CKD stages I to V with acute exacerbation (reduced GFR, reduced urine output). Exclusion criteria: • Patients &amp;lt;14 years • ESRD patients already on hemodialysis. • Patients with acute Glomerulonephritis (due to the unavailability of biopsy in our institution) • Patients not giving consent to participate in the study. For statistical analysis, data were entered into a Microsoft excel spreadsheet and then analyzed by SPSS and GraphPad Prism version 5. Data had been summarized as mean and standard deviation for numerical variables and count and percentages for categorical variables. Unpaired proportions were compared by Chi-square test or Fischer's exact test, as appropriate. p-value ≤ 0.05 was considered statistically significant. Results ● Out of the first 100 consecutive patients fulfilling the study criteria, 33 patients had AKI &amp; 15 patients had ACKD. ● The male population was higher than the female population. ● T2DM and HTN were more common in ACKD patients than the AKI patients. ● Patients with AKI were clinically dehydrated compared to patients with ACKD. ● Metabolic acidosis was less in AKI patients. ● Most of the ACKD patients had sepsis than the AKI patients. Conclusion The most common etiology of AKI amongst in-hospital patients is dehydration whereas that of ACKD is sepsis associated with more incidence of metabolic acidosis &amp; comorbidities. Earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.

Insuficiencia renal aguda secundaria a obstrucción esofágica en un pony: Reporte de caso

Esophageal obstruction is the most common esophageal pathology in horses, and the time of diagnosis and treatment can significantly affect the prognosis of this condition, since it is always associated with failure of water intake and dehydration, which leads to hemodynamic imbalance and, with the worsening of the condition, to acute renal failure due to the decrease in renal blood flow. This paper aims to report the case of a pony, treated at the Veterinary Hospital of the University of Franca, presenting primary esophageal obstruction for a prolonged period of time and consecutive severe dehydration that resulted in acute renal failure, evidenced by the decrease of the urine production, signs of encephalopathy caused by accentuated azotemia, and necroscopic findings including nephritis, tubular necrosis, and diffuse corticomedullary inflammatory infiltrate. This work also aims to underline the severity of both pathologies, the need for quick intervention in cases of esophageal obstruction and the complexity of renal failure in horses.

Decreased renal apparent diffusion coefficient after COVID-19 associated acute kidney injury

Study objective: To investigate if there are any differences in total renal blood flow, regional renal perfusion, renal oxygenation or renal tissue properties, studied by non-invasive MRI, in patients having recovered from severe COVID-19 with different grades of acute kidney injury (AKI). Hypothesis: We hypothesize that the decrease in renal blood flow and perfusion that our research group have previously found in severe COVID-19 patients with AKI 1 may persist together with possible renal edema and development of fibrosis. Material and methods: We identified patients with AKI grade 3 from a cohort of patients previously treated in the intensive care unit for severe COVID-19 with respiratory failure. These patients were matched to possible extent regarding age, sex, height, weight, body mass index (BMI) and body surface area (BSA) with patients from the same cohort that had AKI grade 1 and patients that did not have AKI. A total of 22 patients were included. Because of common occurrence of oliguria without a reduction of glomerular filtration, AKI grade was determined using the Kidney Disease Improving Global Outcome (KDIGO) creatinine criteria only. All patients had a record of a plasma creatinine inside normal range within two years prior to ICU care, and had no history of renal disease. Comorbidities were common in the study population. Follow up examination was performed approximately five months after the patients were admitted the ICU. Results: Significant differences in cortical and medullary ADC were demonstrated between the study groups. Both cortical and medullary ADC was significantly reduced in the ‘AKI grade 3’ group compared to the ‘no AKI’ group and the ‘AKI grade 1’ group. Total renal blood flow was significantly lower in the ‘AKI grade 3’ group compared to the ‘no AKI’ group and global renal perfusion was significantly lower in the ‘AKI grade 3’ group compared to the ‘no AKI’ and ‘AKI grade 1’ groups. No significant differences in either cortical or medullary perfusion were seen between the groups. Cortical and medullary oxygenation and renal vein oxygen saturation did not differ significantly between the groups. Conclusion: In this study we demonstrates that, approximately five months after intensive care for severe COVID-19, patients that had high grades of AKI during hospitalization have reduced cortical and medullary ADC together with reduced total renal blood flow and global renal perfusion compared to similar patients that did not have AKI. These findings might indicate development of renal fibrosis. No differences regarding renal oxygenation were observed between the studied groups. 1. Luther T, Eckerbom P, Cox E, Lipcsey M, Bulow S, Hultstrom M, et al. Decreased renal perfusion during acute kidney injury in critical COVID-19 assessed by magnetic resonance imaging: a prospective case control study. Crit Care. 2022;26(1):262. Public and private funding sources. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

How should we treat acute kidney injury caused by renal congestion?

Decreased kidney function is associated with increased risk of cardiovascular events and mortality, and heart failure (HF) is a well-known risk factor for renal dysfunction. Acute kidney injury (AKI) in patients with HF often is attributed to prerenal factors, such as renal hypoperfusion and ischemia as a result of decreased cardiac output. Another such factor is reduction of absolute or relative circulating blood volume, with the decrease in renal blood flow leading to renal hypoxia followed by a decrease in the glomerular filtration rate. However, renal congestion is increasingly being recognized as a potential cause of AKI in patients with HF. Increased central venous pressure and renal venous pressure lead to increased renal interstitial hydrostatic pressure and a reduction of the glomerular filtration rate. Both decreased kidney function and renal congestion have been shown to be important prognostic factors of HF, and adequate control of congestion is important for improving kidney function. Loop and thiazide diuretics are recommended as standard therapies to reduce volume overload. However, these agents are associated with worsening renal function even though they are effective for improving congestive symptoms. There is growing interest in tolvaptan, which can improve renal congestion by increasing excretion of free water and decreasing the required dose of loop diuretic, thereby improving kidney function. This review summarizes renal hemodynamics, the pathogenesis of AKI due to renal ischemia and renal congestion, and diagnosis and treatment options for renal congestion.

S-18-6: SALT AND AGE-RELATED HYPERTENSION

Hypertension is the greatest risk factor for cardiovascular disease and stroke, and its incidence increases with age. Clinical studies have shown that salt intake is involved in the development of age-related hypertension and that salt sensitivity of blood pressure (BP) increases with age, but the mechanism was unknown. On the other hand, it was reported that circulating Klotho level, an anti-aging factor protein, decreased with age, and there was an inverse relationship between circulating Klotho and mean BP changes after saline infusion. We hypothesized that the decrease in circulating Klotho levels might be involved in the increase in salt sensitivity of BP with aging. We found that circulating Klotho significantly decreased in aged mice and Klotho heterozygous knockout (KO) mice than in young wild-type mice. They showed salt-sensitive hypertension unlike young wild-type mice, suggesting that a decrease in circulating Klotho was involved in the pathogenesis of salt-sensitive hypertension in aged mice. In both aged mice and Klotho heterozygous KO mice, it was revealed that vascular Wnt5a-RhoA pathway was activated and vasoconstriction was enhanced during high salt intake, resulting in hypertension. We also demonstrated that Klotho supplementation and Wnt and Rho kinase inhibitors significantly suppressed the BP elevation during high salt intake in these mice. Furthermore, we found that Wnt5a was essential for the activation of RhoA by Angiotensin II, an important agent in the formation of hypertension. Since increased vascular resistance of the renal arteries and decreased renal blood flow are involved in the pathogenesis of salt-sensitive hypertension. We analyzed the effects of Angiotensin II and RhoA stimulators to the renal arteries of high-salt fed aged mice and Klotho heterozygous KO mice. Marked vasoconstriction of the renal arteries and decrease in renal blood flow with BP elevation were observed, while responses were less in young mice. Augmented responses observed in aged mice and Klotho heterozygous KO mice were normalized by Klotho supplementation. These findings suggest that in aged mice with low circulating Klotho, salt intake causes activation of the vascular Wnt5a-RhoA pathway, resulting in increased contraction of the renal arteries as well as peripheral blood vessels, which reduces renal blood flow and eventually caused hypertension. We suggest that reducing salt consumption is highly important and lifestyle habits preserving adequate levels of Klotho are useful in the prevention of age-related hypertension. Wnt and Rho inhibitors may be new treatment options. Therapeutic development focusing on the unique background of aging may be applied to other age-related diseases.

S-12-5: IMPAIRMENT OF RENAL BLOOD FLOW AUTOREGULATION AND PRESSURE-NATRIURESIS: ROLE IN THE DEVELOPMENT OF HEART FAILURE IN REN-2 TRANSGENIC HYPERTENSIVE RATS

Objective: The prognosis of patients with heart failure (HF), particularly those who were hypertensive before the onset of HF, remains poor and new therapeutic strategies are needed, based on understanding the pathophysiology of the progression of HF. We hypothesized that the kidney is here not simply a victim but also a culprit of the progression. Specifically, we hypothesized that the impairment of renal blood flow (RBF) autoregulation and pressure-natriuresis relationship is present in the very early HF phase, and precedes HF decompensation. Design and method: In Ren-2 transgenic rats (TGR), a model of hypertension with increased endogenous activity of the renin-angiotensin system (RAS), HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). One week after ACF creation or sham-operation animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and pressure-natriuresis relationship after stepwise changes in renal arterial pressure (RAP) that were induced by aortic clamps. Sham-operated TGR were evaluated at physiological level of RAP, then at RAP reduced to 125, 100, 90 and 80 mmHg. In ACF TGR RAP was reduced to 100, 90 and 80 mmHg, followed by period of RAP increased to 125 mmHg. Results: In sham-operated TGR as compared with ACF TGR the basal mean arterial pressure (156 ± 3 vs. 98 ± 3 mmHg), RBF (11.45 ± 0.6 vs. 8.13 ± 0.3 ml.min-1.g-1), urine flow (UF) (38.3 ± 3.1 vs. 8.7 ± 1.0 μl.min-1.g-1) and absolute sodium excretion (UNaV) (4.77 ± 0.54 vs. 0.46 ± 0.11 μmol.min-1.g-1) were all significantly lower. In sham-operated TGR reductions in RAP resulted in significant decreases in RBF whereas in ACF TGR it did not change in response to RAP alterations. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Conclusions: Our data show that at the physiological RAP level ACF TGR displayed marked reduction in RBF, UF and UNaV as compared with sham-operated TGR. However, in contrast to sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and better slope of pressure-natriuresis relationship. Thus, even in the very early HF stage the renal dysfunction is demonstrable but such dysfunction and the subsequent onset of HF decompensation cannot be simply ascribed to impaired RBF autoregulation and pressure-natriuresis relationship, at least not in the high-output HF model of originally RAS-dependent hypertensive rat.

Abstract 10366: Ep3 Receptor Contributes to Renal Ischemia and Inflammation During Development of Renal Pathologies and Hypertension in Pgis Deficient Mice

Introduction: Abnormalities in prostacyclin synthase (PGIS) cause hypertension and/or renal pathologies in humans and mice due to increased thromboxane A2 (TxA 2 ) produced by platelets and/or kidneys. However, the kidney, which is the key organ in blood pressure regulation, mainly produces prostaglandin E2 (PGE 2 ), which could evoke renal vasoconstriction via activating the E prostanoid receptor-3 (EP3) and the Tx prostanoid receptor (TP; the receptor of TxA 2 ). We hypothesized that increased PGE 2 in the kidney contributes to hypertension and renal pathologies in the above-mentioned disorders via activating the EP3 receptor. Methods: To unravel the effect of PGE 2 , we first generated mice deficient for both PGIS and EP3 ( Pgis -/- Ep3 -/- ) or both PGIS and cyclooxygenase-1 ( Pgis -/- Cox-1 -/- ). To further exclude the effect of TxA 2 produced by the platelet COX-1, chimeric mice with Cox-1 -/- in hematopoietic cells were created by bone marrow transplantations of Pgis -/- and Cox-1 -/- mice. Results: Significant increases in blood pressure and heart-to-body-weight ratio were observed in Pgis -/- mice compared with WT mice, which were secondary to renal inflammation and fibrosis. In contrast, Pgis -/- Ep3 -/- had less renal damage resulting in fewer cardiovascular disorders. Furthermore, compared with WT kidneys, Pgis -/- kidneys showed increased levels of PGE 2 without PGI 2 and TxA 2 production as measured with high performance liquid chromatography-mass spectrometry. EP3 deficiency drastically diminished the decrease in renal blood flow evoked by ACh in Pgis -/- perfused kidneys. Interestingly, Pgis -/- Cox-1 -/- mice, but not Pgis -/- mice engrafted with bone marrow cells from Cox-1 -/- mice, displayed a much smaller extent of renal fibrosis than Pgis -/- mice. Conclusions: Increased levels of PGE 2 in the kidney contribute to hypertension and renal pathologies in PGIS abnormalities via activating the EP3 receptor. Our findings suggest a novel mechanism for intrarenal PGE 2 regulation of blood pressure and renal hemodynamics.

Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.

Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

Systemic immune inflammation index: is it a new marker for contrast-induced nephropathy?

Introduction: Worldwide, &amp;gt;200 million patients are affected by peripheral arterial disease (PAD) and endovascular interventional treatments are increasingly being applied. Contrast-induced nephropathy (CIN) is the third most common cause of renal failure in hospitals. However, factors such as renal vasoconstriction, decrease in renal blood flow, endothelial dysfunction, and oxidative stress have been suggested in the etiology of CIN. Studies are showing that inflammatory markers increase in CIN. Systemic immune inflammation index (SII), a newly defined parameter, is calculated by multiplying the platelet and lymphocyte counts and dividing by the neutrophil count. Studies are showing that this parameter influences prognosis in various cancer types. Considering that inflammation may play a role in CIN, we planned this study to investigate the role of SII in patients undergoing percutaneous peripheral vascular interventions. Material and Method: 300 patients who underwent percutaneous peripheral vascular interventions between August 2018-December 2021 due to peripheral arterial disease were included in the study. The data of the patients were scanned retrospectively from the patient files. The neutrophil-lymphocyte ratio (NLR) was calculated by dividing the neutrophil count by the lymphocyte count. SII was found by multiplying NLR with platelet count Results: Contrast-induced nephropathy developed in 41 (12.3%) patients. CIN(+) patients also, had higher CRP levels (5.1±0.7vs 2.4±0.4,P&amp;lt;0.05), NLR (4.07±1.07vs 2.65±0.84, P&amp;lt;.005), SII score (1778±627.57vs 867.14±491.88, P&amp;lt;.005.) the contrast media used was also higher in CIN(+) patients (176.19±48.44 vs 128.72±48.44;P&amp;lt;0.05) Multivariate logistic regression analysis demonstrated that a high SII score was an independent predictor of development of CIN (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.001-1.002, P&amp;lt;.0005) together with high NLR (OR: 3.56, 95% CI: 1.905-6.675, P&amp;lt;.005) and CRP (OR: 1.002, 95% CI: 1.001-1.002, P&amp;lt;.005 Receiver operating characteristic curve analysis demonstrated that the best cutoff value of 1224 for SII to predict the development of CIN with 85% sensitivity and 72% specificity (area under ROC curve 0.904 [95% CI: 0.866-0.942], P&amp;lt;.005). Conclusion: Imbalance in inflammatory cells, the increase in neutrophils, and the decrease in lymphocytes play a role in developing kidney damage. Impaired immune functions due to lymphocytopenia contribute to the development of acute kidney injury. Oxidative stress exacerbates the inflammatory state by increasing inflammatory cell infiltration. AS a result, SII may be a powerful predictor of inflammation and can be used to determine the risk before interventional procedures.

Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia.

Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischaemia, typically following cardiac surgery, renal transplant or severe haemorrhage. We examined the cause of the sustained reduction in renal blood flow ('no-reflow'), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. Adult male Sprague-Dawley rats, or NG2-dsRed male mice were used in this study. After 60 min kidney ischaemia and 30-60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischaemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischaemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury.

Study of Association of Serum Uric Acid Level with Severity of Essential Hypertension

Hypertension is one of the leading causes of the global burden of disease. Hyperuricemia is present in 25-50% of individuals with untreated primary hypertension, about 5 times the frequency found in normotensive persons. Raised serum uric acid concentrations in the blood are commonly encountered in essential hypertension. The hyperuricemia observed in untreated hypertension may reflect the decrease in renal blood flow and early hypertensive nephrosclerosis. Hence it is important to associate the serum uric acid level and the severity of hypertension and to find whether serum uric acid can be used as a useful tool to assess the severity of hypertension. Keywords: Hypertension, Serum Uric Acid.

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

BACKGROUND: Reactive oxygen species and cytokines are the main players in the development of renal ischemia-reperfusion (I/R) injury. AIM: The current study aimed to evaluate the effects of carvedilol and/or glibenclamide and the interaction between autophagy and oxidative stress. METHODS: 50 male rats were divided into five groups: Control, IR injury (IRI), carvedilol pretreated, glibenclamide pretreated, and combined carvedilol and glibenclamide pretreated. Measurements of renal blood flow (RBF), creatinine clearance, serum blood urea nitrogen (BUN), histopathological, and immunohistochemical evaluation of autophagy marker Becl-1 in the rat kidney were performed. Beclin-1and light chain 3 (LC3) Mrna expression was detected by real time polymerase chain reaction. RESULTS: IRI was associated with significant increases in BUN, tumor necrosis factor-alpha, nuclear factor κB, and histo (H) score value of Becl-1. However, there was a significant decrease in RBF, creatinine clearance, and glutathione peroxidase compared to the control group. There was significant increase in Beclin-1 and LC3 mRNA gene expression in carvedilol, glibenclamide, and combined treatment groups as compared to IRI and control groups. Combination of carvedilol and glibenclamide significantly restored IRI changes when compared with the other pretreated groups. CONCLUSION: This study suggests that carvedilol and glibenclamide are promising reno-protective drugs to reduce renal injury induced by I/R through their antioxidant and autophagy stimulation.

Effects of Renal Denervation on the Enhanced Renal Vascular Responsiveness to Angiotensin II in High-Output Heart Failure: Angiotensin II Receptor Binding Assessment and Functional Studies in Ren-2 Transgenic Hypertensive Rats.

Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin II (ANG II) and to characterize ANG II type 1 (AT1) and type 2 (AT2) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT1 subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT1 alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT1 receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).

Angiotensin II-induced natriuresis is attenuated in knockout mice lacking the receptors for tumor necrosis factor-α.

Intravenous infusion of relatively higher doses of angiotensin II (AngII) elicits natriuresis as opposed to its usual anti‐natruretic response. As AngII can induce tumor necrosis factor‐α (TNFα) production which elicits natriuresis via its action on TNFα receptor type 1 (TNFR1), we hypothesize that the concomitant release of TNFα contributes to the natriuretic response to AngII. Responses to AngII infusion (1 ng min−1 g−1 for 75 min, iv) were evaluated in anesthetized knockout (KO) mice lacking TNFR1 (n = 6) and TNFR2 (TNFα receptor type 2; n = 6) and compared these responses with those in wild type (WT; n = 6) mice. Arterial pressure (AP) was recorded from a cannula placed in the carotid artery. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by PAH and inulin clearances, respectively. Urine was collected from a catheter placed in the bladder. AngII caused similar increases (p < 0.05 vs basal values) in AP (WT, 37 ± 5%; TNFR1KO, 35 ± 4%; TNFR2KO, 30 ± 4%) and decreases (p < 0.05) in RBF (WT, −39 ± 5%; TNFR1KO, −28 ± 6%; TNFR2KO, −31 ± 4%) without significant changes in GFR (WT, −17 ± 7%; TNFR1KO, −18 ± 7%; TNFR2KO, −12 ± 7%). However, despite similar changes in AP and renal hemodynamics, AngII induced increases (p < 0.05) in urinary sodium excretion in WT (3916 ± 942%) were less in the KO strains, more or less in TNFR1KO (473 ± 170%) than in TNFR2KO (1176 ± 168%). These data indicate that TNF‐α receptors, particularly TNFR1 are involved in the natriuretic response that occur during acute infusion of AngII and thus, plays a protective role in preventing excessive salt retention at clinical conditions associated with elevated AngII level.

Is There a Place for Elastography in the Assessment of Chronic Kidney Disease?

Renal elastography is a real-time ultrasound-based imaging method that can potentially be used in order to assess diffuse diseases of native kidneys. In order to find a place in the clinical practice for renal elastography, what is influencing the obtained results should be known. The kidney shear wave speed is influenced by different factors such as age, gender, measurement depth or urinary pressure. The relationship with renal function and also with renal fibrosis is different across different studies, with not all studies showing an increase in renal stiffness in more advanced renal diseases. However, the changes in renal blood flow seem to influence renal elastography, and a decrease in renal blood flow could be the cause of the decrease in the shear wave speed and could have a bigger influence on elastography compared to renal fibrosis. This paper provides a summary about the factors that seem to influence renal elastography and also regarding the limitations of this method according to the published studies thus far.

Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man.

The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.

Acetic acid treatment causes renal inflammation and chronic kidney disease in mice

We established a novel mouse model of chronic kidney disease (CKD) using acetic acid and compared it with the 5/6-nephrectomized mouse model. In our novel model, significant increases were observed in blood biochemical values and urinary parameters. Moreover, a decrease in creatinine clearance (Ccr) was observed. This model also demonstrated a higher survival rate than the 5/6-nephrectomized model. Observed histological changes in our model included cell infiltration in the renal interstitium, tubular dilation, regenerated tubules, and glomerulosclerosis. Inflammation of the renal interstitium was particularly remarkable. TNF-α, IL-1β, and ICAM-1 mRNA expression were up-regulated prior to elevation of mean blood pressure and prior to changes in blood biochemical values and urinary parameters. Up-regulation of TGF-β mRNA and down-regulation of nephrin mRNA were also observed at 12 weeks after acetic acid treatment. However, no correlation between the progression of CKD and the decrease in renal blood flow was observed. Finally, repeated losartan administration attenuated the effects of acetic acid-induced renal injury. Our findings suggest that chronic kidney conditions associated with this model may be triggered by interstitial inflammation. Moreover, we suggest that this model is useful for understanding the pathophysiological mechanisms of CKD, and for evaluating the effects of therapeutic agents.