Kidney Hemodynamics Research Articles

406Phenotyping acute decompensated heart failure by intrarenal venous flow and right ventricle-pulmonary circulation uncoupling

Abstract Background Intrarenal venous blood flow (IRVF) has recently been used to assess renal haemodynamics in heart failure (HF).Different IRVF patterns have been described, with discontinuous IRVF related to a worse outcome compared to the continuous one. Purpose We aimed at studying the interaction between IRVF and the right heart dynamics thorough the study of right ventricular (RV) to pulmonary circulation (PC) coupling in acute decompensated (AD) HF patients. Methods 92 ADHF patients underwent a transthoracic echocardiography followed by renal ultrasonography and laboratory tests. The IRVF was evaluated by Venous Impedance Index (VII) Results Dividing the population according to the different IRVF patterns allowed to phenotype the HF population. Patients with the worst IRVF pattern (monophasic) showed significantly higher prevalence of pulmonary hypertension and RV dysfunction with a lower TAPSE/PASP ratio. Patients with continuous IRVF pattern showed normal pulmonary pressures and RV function with a higher TAPSE/PASP ratio. A strong logarithmic correlation between VII and TAPSE/PASP ratio was observed (R2=0,5406). At multivariate linear regression analysis, RV to PC uncoupling was identified as independent determinant of VII. TAPSE/PASP was inversely associated with VII (−0.55±0.16, p=0.0011). LVEF was not associated with VII (p=0.08). No difference in renal function laboratory test was found while NT-proBNP was significantly higher in the IRVF monophasic group. Patients characteristics Total (92) Continuous (32) Pulsatile (19) Biphasic (15) Monophasic (26) P value VII 0.49±0.36 0.11±0.06 0.38±0.12 0.74±0.05 0.95±0.02 <0.0001 LVEF (%) 43.9±16.1 51.4±13.4 41.6±15 43±15.3 34±16.3 0.002 TAPSE (mm) 16.7±5.5 20.1±5.1 13.9±2.7 17±6.5 13.7±4.3 <0.0001 PASP (mmHg) 41.6±14.5 30.9±6.9 42.9±9.3 52.6±12.6 50.3±16.3 <0.0001 TAPSE/PASP 0.46±0.26 0.69±0.24 0.33±0.08 0.34±0.14 0.29±0.11 <0.0001 Creatinine (mg/dL) 1.25±0.52 1.25±0.59 1.17±0.49 1.26±0.52 1.31±0.48 0.6 GFR (ml/min/1.73sqm) 58.9±2.2 59.6±22.9 60.2±17.8 61.6±23.5 55.4±16.9 0.7 NT-proBNP (ng/L) 5511±7764 2231±2463 6365±10318 7257±8173 7509±8380 0.004 VII = Venous impedance index; LVEF = left ventricle ejection fraction; TAPSE = Tricuspid annular plane systolic excursion; PASP = Pulmonary artery systolic pressure; IVC = Inferior vena cava; GFR = Glomerular filtration rate. Conclusions The identified correlation between RV to PC uncoupling and the IRVF pattern provides new evidence regarding the pathophysiological mechanisms of cardio-renal syndrome paving the way to interventions with proven effectiveness on the RV to reverse the unfavorable kidney hemodynamics and failure.

Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: results from the OptimaCC trial.

Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of cardiovascular mediators. Its administration has been shown to be associated with impaired cardiac contraction and kidney haemodynamics while its inhibition restored cardiac contraction in a pre-clinical model of severe heart failure in mice. Circulating DPP3 (cDPP3) was found to be elevated in shock. The present study aims to assess the association between cDPP3 and worsening haemodynamics, namely refractory shock, in a cohort of cardiogenic shock (CS). This is an ancillary study of OptimaCC, a prospective, double-blind, multicentre, randomized study assessing efficacy and safety of catecholamines in 57 patients with CS after acute myocardial infarction. cDPP3 was measured in plasma at inclusion, 24 h, 48 h, and 72 h, and haemodynamic and biological parameters were recorded at inclusion. cDPP3 values were higher in refractory CS than non-refractory CS at inclusion (median [interquartile range]; 76.1 [37.9-238.7] ng/mL vs. 32.8 [23.9-47.6] ng/mL, P= 0.014), at 24 h (P< 0.001) and up to 48 h (P= 0.027). Furthermore, cDPP3 at inclusion discriminated CS patients who did develop refractory shock vs. non-refractory with an area under the curve of 0.73 (95% confidence interval [CI] 0.55-0.92). The high cDPP3 group (cDPP3 ≥59.1ng/mL) at inclusion had a higher Simplified Acute Physiology Score II (SAPS II), lower cardiac index and lower estimated glomerular filtration rate. More importantly, in CS patients with high cDPP3 at inclusion, those who rapidly decreased cDPP3 at 24 h exhibited a striking reduction in the occurrence of refractory shock and death. In CS patients, cDPP3 gives an early prediction of outcome, including development of refractory status and/or survival. clinicaltrials.gov Identifier NCT01367743.

Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics

Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short-term mortality risk (standardized hazard ratio: 1.4 (1.1-1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (-10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.

Role of carbonic anhydrase in acute recovery following renal ischemia reperfusion injury.

Ischemia reperfusion (IR) injury can cause acute kidney injury. It has previously been reported that kidney oxygen consumption (QO2) in relation to glomerular filtration rate (GFR), and thus tubular sodium load, is markedly increased following IR injury, indicating reduced electrolyte transport efficiency. Since proximal tubular sodium reabsorption (TNa) is a major contributor to overall kidney QO2, we investigated whether inhibition of proximal tubular sodium transport through carbonic anhydrase (CA) inhibition would improve renal oxygenation following ischemia reperfusion. Anesthetized adult male Sprague Dawley rats were administered the CA inhibitor acetazolamide (50 mg/kg bolus iv), or volume-matched vehicle, and kidney function, hemodynamics and QO2 were estimated before and after 45 minutes of unilateral complete warm renal ischemia. CA inhibition per se reduced GFR (-20%) and TNa (-22%), while it increased urine flow and urinary sodium excretion (36-fold). Renal blood flow was reduced (-31%) due to increased renal vascular resistance (+37%) without affecting QO2. IR per se resulted in similar decrease in GFR and TNa, independently of CA activity. However, the QO2/TNa ratio following ischemia-reperfusion was profoundly increased in the group receiving CA inhibition, indicating a significant contribution of basal oxygen metabolism to the total kidney QO2 following inhibition of proximal tubular function after IR injury. Ischemia increased urinary excretion of kidney injury molecule-1, an effect that was unaffected by CA. In conclusion, this study demonstrates that CA inhibition further impairs renal oxygenation and does not protect tubular function in the acute phase following IR injury. Furthermore, these results indicate a major role of the proximal tubule in the acute recovery from an ischemic insult.

A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback.

In this review, we summarized the current knowledge of connecting tubule-glomerular feedback (CTGF), a novel mechanism of renal microcirculation regulation that integrates sodium handling in the connecting tubule (CNT) with kidney hemodynamics. Connecting tubule-glomerular feedback is a crosstalk communication between the CNT and the afferent arteriole (Af-Art), initiated by sodium chloride through the epithelial sodium channel (ENaC). High sodium in the CNT induces Af-Art vasodilation, increasing glomerular pressure and the glomerular filtration rate and favoring sodium excretion. CTGF antagonized and reset tubuloglomerular feedback and thus increased sodium excretion. CTGF is absent in spontaneous hypertensive rats and is overactivated in Dahl salt-sensitive rats. CTGF is also modulated by angiotensin II and aldosterone. CTGF is a feedback mechanism that integrates sodium handling in the CNT with glomerular hemodynamics. Lack of CTGF could promote hypertension, and CTGF overactivation may favor glomerular damage and proteinuria. More studies are needed to explore the alterations in renal microcirculation and the role of these alterations in the genesis of hypertension and glomerular damage in animals and humans. • CTGF is a vasodilator mechanism that regulates afferent arteriole resistance. • CTGF is absent in spontaneous hypertensive rats and overactivated in Dahl salt-sensitive rats. • CTGF in excess may promote glomerular damage and proteinuria, while the absence may participate in sodium retention and hypertension.

Hepatorenal arterial resistive and pulsatility indexes in dogs with ascites

Ascites is one of the complications in cirrhosis. Prognosis depends on systemic hemodynamics. This study was designed for determination of the liver and kidney hemodynamics in dogs with ascites via Doppler Ultrasonography (USG). 20 dogs with ascites and 10 healthy dogs were included. CBC, biochemical profile, USG and Doppler measurement were taken. Increased hepatic and renal RI and PI were statistically significant (p Less than 0,01-0,001). There were positive correlations between ALP and hepatic PI, between urea and renal RI, negative correlations between ALP and renal RI, between creatinine and hepatic and renal PI values (p less than 0,05-0,01). In conclusion, liver and kidney Doppler findings will help determination of the prognosis and implementation of effective treatment.

Need for a Judicious Use of Nonsteroidal Anti-inflammatory Drugs to Avoid Community-Acquired Acute Kidney Injury.

Millions of Americans use over-the-counter analgesics on a daily basis, and nearly 100 million nonsteroidal anti-inflammatory drug (NSAID) prescriptions are filled per year. In high-risk patients, these medications can disrupt kidney hemodynamics and precipitate community-acquired acute kidney injury (CA-AKI). The risk of NSAID-associated CA-AKI increases 3- to 5-fold in patients taking renin-angiotensin system inhibitors and diuretics concurrently. CA-AKI increases the risk of developing chronic kidney disease (CKD) or accelerating progression of pre-existing CKD. Importantly, many cases of NSAID-induced CA-AKI may be avoided by identifying high-risk patients and providing patient and provider education on when to avoid these medications and minimize risk.

The Role of Mas Receptor on Renal Hemodynamic Responses to Angiotensin 1-7 in Both Irreversible and Reversible Unilateral Ureteral Obstruction Rats.

Background:Unilateral ureteral obstruction (UUO) alters the expression of renin-angiotensin system (RAS) components and angiotensin 1-7 (Ang 1-7) as a main arm of RAS is affected by UUO. The role of Mas receptor antagonist (A779) was examined in renal hemodynamic responses to Ang 1-7 in 3-day UUO and UUO removal (RUUO) in rats.Materials and Methods:Forty-five male Wistar rats were randomly divided into three groups of sham operated, UUO, and RUUO, while each group was divided into two subgroups treated with vehicle or A779. Renal blood flow (RBF) and renal vascular resistance (RVR) responses to graded Ang 1-7 infusion were measured at controlled renal perfusion pressure.Results:Mean arterial pressure response to Ang 1-7 was increased in vehicle-treated subgroup significantly (P < 0.05) when compared with A779-treated subgroup. However, such observation was not seen in UUO and RUUO rats. The graded Ang 1-7 infusion increased RBF and decreased RVR significantly in vehicle-treated rats (P < 0.005). Furthermore, a significant difference was found between vehicle and A779-treated subgroups in sham, UUO, and RUUO groups (P < 0.005).Conclusion:Ang 1-7 could alter the kidney hemodynamics responses in ureteral obstruction models.

Are SGLT2 Inhibitors Ready for Prime Time for CKD?

Sodium-glucose cotransporter-2 (SGLT2) is a sodium-dependent glucose transport protein, and its inhibitors (SGLT2i - gliflozins) are indicated as an adjunct therapy to diet and exercise for improving glycemic control in type 2 diabetes mellitus (DM2). In fact, SGLT2i usage has been associated with a

Acoustic Radiation Force Impulse Imaging of the Transplant Kidney: Correlation Between Cortical Stiffness and Arterial Resistance in Early Post-transplant Period

BackgroundAcoustic radiation force impulse (ARFI) imaging is a noninvasive imaging modality for quantitative assessment of tissue stiffness. This study utilized ARFI imaging to assess the stiffness of a transplant renal cortex within the first month after renal transplantation and to explore the correlation between the cortical stiffness and arterial resistance of the transplant kidney. MethodsForty renal transplant recipients (male/female = 26/14; mean age: 45.3 years; deceased donor/living related donor = 27/13) were included in this study. ARFI imaging with virtual touch tissue imaging quantification was applied to assess the stiffness of the transplant renal cortex by using a linear ultrasound transducer. Arterial resistance was acquired by spectral Doppler examination of the main artery and intrarenal arteries of the transplant kidney using a curvilinear ultrasound transducer. ResultsThe stiffness of transplant renal cortex was expressed as shear wave velocity (m/s). The mean value of cortical stiffness was 3.19 ± 1.01 m/s (range: 1.55–5.54). The stiffness of transplant renal cortex was positively correlated with the resistance index of the main renal artery (r = 0.55, P = .001), segmental artery (r = 0.43, P = .005), and interlobar artery (r = 0.42, P = .006). ConclusionThe stiffness of a transplant renal cortex is positively correlated with the arterial resistance of the renal transplant in the early post-transplant period. This result indicates that, in addition to renal fibrosis, the stiffness of the transplant renal cortex is also influenced by the hemodynamics of the transplant kidney.

Thyroid dysfunction and kidney disease: An update.

Thyroid hormones influence renal development, kidney hemodynamics, glomerular filtration rate and sodium and water homeostasis. Hypothyroidism and hyperthyroidism affect renal function by direct renal effects as well as systemic hemodynamic, metabolic and cardiovascular effects. Hypothyroidism has been associated with increased serum creatinine and decreased glomerular filtration rate. The reverse effects have been reported in thyrotoxicosis. Most of renal manifestations of thyroid dysfunction are reversible with treatment. Kidney disease may also cause thyroid dysfunction by several mechanisms. Nephrotic syndrome has been associated to changes in serum thyroid hormone concentrations. Different forms of glomerulonephritis and tubulointerstitial disease may be linked to thyroid derangements. A high prevalence of thyroid hormone alteration has been reported in acute kidney injury. Thyroid dysfunction is highly prevalent in chronic kidney disease patients. Subclinical hypothyroidism and low triiodothyronine syndrome are common features in patients with chronic kidney disease. Patients treated by both hemodialysis and peritoneal dialysis, and renal transplantation recipients, exhibit thyroid hormone alterations and thyroid disease with higher frequency than that found in the general population. Drugs used in the therapy of thyroid disease may lead to renal complications and, similarly, drugs used in kidney disorders may be associated to thyroid alterations. Lastly, low thyroid hormones, especially low triiodothyronine levels, in patients with chronic kidney disease have been related to a higher risk of cardiovascular disease and all-cause mortality. Interpretation of the interactions between thyroid and renal function is a challenge for clinicians involved in the treatment of patients with thyroid and kidney disease.

Modeling of Kidney Hemodynamics: Probability-Based Topology of an Arterial Network.

Through regulation of the extracellular fluid volume, the kidneys provide important long-term regulation of blood pressure. At the level of the individual functional unit (the nephron), pressure and flow control involves two different mechanisms that both produce oscillations. The nephrons are arranged in a complex branching structure that delivers blood to each nephron and, at the same time, provides a basis for an interaction between adjacent nephrons. The functional consequences of this interaction are not understood, and at present it is not possible to address this question experimentally. We provide experimental data and a new modeling approach to clarify this problem. To resolve details of microvascular structure, we collected 3D data from more than 150 afferent arterioles in an optically cleared rat kidney. Using these results together with published micro-computed tomography (μCT) data we develop an algorithm for generating the renal arterial network. We then introduce a mathematical model describing blood flow dynamics and nephron to nephron interaction in the network. The model includes an implementation of electrical signal propagation along a vascular wall. Simulation results show that the renal arterial architecture plays an important role in maintaining adequate pressure levels and the self-sustained dynamics of nephrons.

Role of Mas receptor antagonist (A779) in renal hemodynamics in condition of blocked angiotensin II receptors in rats.

The vasodilatory effect of angiotensin 1-7 (Ang 1-7) is exerted in the vascular bed via Mas receptor (MasR) gender dependently. However, the crosstalk between MasR and angiotensin II (Ang II) types 1 and 2 receptors (AT1R and AT2R) may change some actions of Ang 1-7 in renal circulation. In this study by blocking AT1R and AT2R, the role of MasR in kidney hemodynamics was described. In anaesthetized male and female Wistar rats, the effects of saline as vehicle and MasR blockade (A779) were tested on mean arterial pressure (MAP), renal perfusion pressure (RPP), renal blood flow (RBF), and renal vascular resistance (RVR) when both AT1R and AT2R were blocked by losartan and PD123319, respectively. In male rats, when AT1R and AT2R were blocked, there was a tendency for the increase in RBF/wet kidney tissue weight (RBF/KW) to be elevated by A779 as compared with the vehicle (P=0.08), and this was not the case in female rats. The impact of MasR on renal hemodynamics appears not to be sexual dimorphism either when Ang II receptors were blocked. It seems that co-blockade of all AT1R, AT2R, and MasR may alter RBF/ KW in male more than in female rats. These findings support a crosstalk between MasR and Ang II receptors in renal circulation.

Differences in GFR and Tissue Oxygenation, and Interactions between Stenotic and Contralateral Kidneys in Unilateral Atherosclerotic Renovascular Disease.

Atherosclerotic renal artery stenosis (ARAS) can reduce renal blood flow, tissue oxygenation, and GFR. In this study, we sought to examine associations between renal hemodynamics and tissue oxygenation with single-kidney function, pressor hormones, and inflammatory biomarkers in patients with unilateral ARAS undergoing medical therapy alone or stent revascularization. Nonrandomized inpatient studies were performed in patients with unilateral ARAS (>60% occlusion) before and 3 months after revascularization (n=10) or medical therapy (n=20) or patients with essential hypertension (n=32) under identical conditions. The primary study outcome was change in single-kidney GFR. Individual kidney hemodynamics and volume were measured using multidetector computed tomography. Tissue oxygenation (using R(2)* as a measure of deoxyhemoglobin) was determined by blood oxygen level-dependent magnetic resonance imaging at 3 T. Renal vein neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), and plasma renin activity were measured. Total GFR did not change over 3 months in either group, but the stenotic kidney (STK) GFR rose over time in the stent compared with the medical group (+2.2[-1.8 to 10.5] versus -5.3[-7.3 to -0.3] ml/min; P=0.03). Contralateral kidney (CLK) GFR declined in the stent group (43.6±19.7 to 36.6±19.5 ml/min; P=0.03). Fractional tissue hypoxia fell in the STK (fraction R(2)* >30/s: 22.1%±20% versus 14.9%±18.3%; P<0.01) after stenting. Renal vein biomarkers correlated with the degree of hypoxia in the STK: NGAL(r=0.3; P=0.01) and MCP-1(r=0.3; P=0.02; more so after stenting). Renal vein NGAL was inversely related to renal blood flow in the STK (r=-0.65; P<0.001). Biomarkers were highly correlated between STK and CLK, NGAL (r=0.94; P<0.001), and MCP-1 (r=0.96; P<0.001). These results showed changes over time in single-kidney GFR that were not evident in parameters of total GFR. Furthermore, they delineate the relationship of measurable tissue hypoxia within the STK and markers of inflammation in human ARAS. Renal vein NGAL and MCP-1 indicated persistent interactions between the ischemic kidney and both CLK and systemic levels of inflammatory cytokines.

Influence of Shenkang Injection on Hemodynamics of Kidney in Patients with Early Diabetic Nephropathy

Influence of Shenkang Injection on Hemodynamics of Kidney in Patients with Early Diabetic Nephropathy

1D.03

OBJECTIVE Renal resistive index (RRI) varies directly with renal vascular stiffness and pulse pressure. RRI correlates positively with arteriolosclerosis in damaged kidneys and predicts progressive renal dysfunction. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular (CV) markers, CV outcomes and mortality. In this study we hypothesize that increased RRI is associated with high levels of dp-ucMGP. DESIGN AND METHOD We recruited participants via a multi-center family-based cross-sectional study in Switzerland exploring the role of genes and kidney hemodynamics in blood pressure regulation. Dp-ucMGP was quantified in plasma samples by sandwich ELISA. Renal doppler sonography was performed using a standardized protocol to measure RRIs on 3 segmental arteries in each kidney. The mean of the 6 measures was reported. Multiple regression analysis was performed to estimate associations between RRI and dp-ucMGP adjusting for sex, age, pulse pressure, mean pressure, renal function and other CV risk factors. RESULTS We included 1035 participants in our analyses. Mean values were 0.64 ± 0.06 for RRI and 0.44 ± 0.21 (nmol/L) for dp-ucMGP. RRI was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, pulse pressure, mean pressure, heart rate, renal function, low and high density lipoprotein, smoking status, diabetes, blood pressure and cholesterol lowering drugs, and history of CV disease (P < 0.001). CONCLUSIONS RRI is independently and positively associated with high levels of dp-ucMGP after adjustment for pulse pressure and common CV risk factors. Further studies are needed to determine if vitamin K supplementation can have a positive effect on renal vascular stiffness and kidney function.

P1237 : The modified iron avidity index: A promising phenotypical predictor in HFE-haemochromatosis

Background and Aims: Hemorrhage from gastroesophageal varices in children with prehepatic portal hypertension is best controlled by various types of portosystemic shunt, but long-term follow up of children who have had splenorenal shunt surgery due to portal hypertension gave evidence for assuming the risk of renal venous hypertension (RVH). The purpose of this study was to investigate the impact of portosystemic shunt surgery on renal blood Methods: The results of 170 portosystemic shunt operations were followed from 2005 to 2014. 12 patients applied side to side splenorenal shunt, 12 children assessed the distal splenorenal shunt (DSRSh), 82 had central splenorenal shunt (CSRSh) with splenectomy. 44 iliacomesenterial anastomosis (IMA) and in 20 cases performed mesocaval anastomosis (MCA). Patients had a standard pre and postoperative work up including gastrointestinal endoscopy, Doppler ultrasonography (US), angiography, multislice computed tomography and MR imaging. Results: On Doppler US at early and late postoperative periods PI and RI of left renal artery remained at high numbers (PI = 1.48±0.17 and RI = 0.72±0.19, p ≤ 0.05 respectively) after the CSRSh with splenectomy. After DSRSh, these signs haven’t been detected. 11 (13.4%) patients after CSRSh on Doppler US revealed signs of impeded venous outflow on the left renal vein (LRV). 8 patients after IMA on US Doppler and CT and MRI angiography revealed dilated left testicular and ovarian veins (Figure 1), with retrograde blood flow in them, which clinically manifested as left flank pain, macroand microhematuria, varicocele and ovaricocele Conclusions: Portosystemic shunt surgery is highly effective treatment for children with prehepatic portal hypertension. But study shows that total shunts such as central splenorenal shunt with splenectomy and iliacomesenterial anastomosis more negatively effect on hemodynamics of left kidney. Shunting the large amounts of blood from a system of high pressure to a low manifests as clinical signs of renal venous hypertension.

P1236 : Impact of high portal pressure on renal hemodynamics in children with portal hypertension

Background and Aims: Hemorrhage from gastroesophageal varices in children with prehepatic portal hypertension is best controlled by various types of portosystemic shunt, but long-term follow up of children who have had splenorenal shunt surgery due to portal hypertension gave evidence for assuming the risk of renal venous hypertension (RVH). The purpose of this study was to investigate the impact of portosystemic shunt surgery on renal blood Methods: The results of 170 portosystemic shunt operations were followed from 2005 to 2014. 12 patients applied side to side splenorenal shunt, 12 children assessed the distal splenorenal shunt (DSRSh), 82 had central splenorenal shunt (CSRSh) with splenectomy. 44 iliacomesenterial anastomosis (IMA) and in 20 cases performed mesocaval anastomosis (MCA). Patients had a standard pre and postoperative work up including gastrointestinal endoscopy, Doppler ultrasonography (US), angiography, multislice computed tomography and MR imaging. Results: On Doppler US at early and late postoperative periods PI and RI of left renal artery remained at high numbers (PI = 1.48±0.17 and RI = 0.72±0.19, p ≤ 0.05 respectively) after the CSRSh with splenectomy. After DSRSh, these signs haven’t been detected. 11 (13.4%) patients after CSRSh on Doppler US revealed signs of impeded venous outflow on the left renal vein (LRV). 8 patients after IMA on US Doppler and CT and MRI angiography revealed dilated left testicular and ovarian veins (Figure 1), with retrograde blood flow in them, which clinically manifested as left flank pain, macroand microhematuria, varicocele and ovaricocele Conclusions: Portosystemic shunt surgery is highly effective treatment for children with prehepatic portal hypertension. But study shows that total shunts such as central splenorenal shunt with splenectomy and iliacomesenterial anastomosis more negatively effect on hemodynamics of left kidney. Shunting the large amounts of blood from a system of high pressure to a low manifests as clinical signs of renal venous hypertension.

Potential Mechanisms of Renoprotection in the Stenotic Kidney After Endothelin‐type A Receptor Antagonism: Podocytes, VEGF and sFlt‐1

Podocytes are major components of the filtration barrier and a source of vascular endothelial growth factor (VEGF). Renal artery stenosis (RAS) deteriorates stenotic kidney function and the renal microvascular architecture, accompanied by a progressive reduction in renal VEGF and podocyte damage. The endothelin (ET) pathway plays a pivotal pathophysiological role in this process. We showed that renoprotection in RAS results from ET-A but not ET-B receptor antagonism. We hypothesize that these effects are due to a distinct protection on podocytes. To mimic the chronic hypoxic millieu of RAS on podocytes, human podocytes were incubated under hypoxic conditions for 96 hours and divided in untreated or treated with specific ET-A (ABT 627) or ET-B (A-192621) receptor antagonist (0.01 mg/mL). Cell viability was quantified after 96 hours. Cell homogenates and media were obtained after 1, 12, 24, 72, and 96 hours to quantify production of VEGF and sFlt-1 and expression of apoptotic mediators Bax and AIF. Hypoxia decreased podocyte counts, which was exacerbated by ET-B blockade but improved by ET-A antagonism. Production of VEGF was similar in all groups but sFlt-1 was only significantly increased in hypoxic cells after ET-B antagonism, accompanied by a greater increase in podocyte expression of pro-apoptotic mediators Our results suggest that, under chronic hypoxia, ET-A antagonism preserves podocyte viability and angiogenic function whereas ET-B antagonism exacerbates podocyte dysfunction and death. Our study offers a potential mechanistic explanation for the distinct protective effect of ET-A antagonism recovering the stenotic kidney hemodynamics and function in RAS.

Systemic Administration of a Biopolymer‐delivered VEGF Improved Renal Hemodynamics and Microvascular Rarefaction in Renal Artery Stenosis

Elastin-like polypeptides (ELP) are drug delivery vectors that can be fused to therapeutic compounds to increase their efficacy. ELPs have high affinity for kidney tissue. We showed that the stenotic kidney in renal artery stenosis (RAS) develops progressive loss of function and renal microvascular (MV) damage associated to loss of vascular endothelial growth factor (VEGF). We designed a novel ELP-VEGF121 fusion and tested its therapeutic potential for the kidney after systemic (IV) administration. We hypothesized that IV ELP-VEGF therapy will preserve the stenotic kidney function and microcirculation. Unilateral RAS was induced in 10 pigs. After 6 weeks, stenotic kidney blood flow (RBF) and filtration (GFR) was quantified in vivo using multi-detector computed tomography. Then, pigs were randomized in placebo (RAS) or treated with a single IV infusion of ELP-VEGF121 (RAS+ELP-VEGF, 1 mg/kg, n=5 each). Pigs were observed for 4 weeks, in vivo studies repeated and then euthanized for ex vivo studies. Hypertension and degree of stenosis was similar in RVD and RVD+ELP-VEGF treated pigs. Stenotic kidney RBF and GFR were similarly reduced in all RVD animals after 6 weeks, remained attenuated in RVD at 10 weeks but were significantly improved (albeit not normalized) after IV ELP-VEGF, accompanied by ameliorated cortical and medullary vascular rarefaction A single IV administration of an ELP-VEGF121 construct improved stenotic kidney hemodynamics, filtration, and reduced cortical microvascular damage in RAS. Our study supports the therapeutic feasibility of systemic administration of a novel compound never tested before for renoprotection.