bluuebunny/crossref_metadata_2025_split huggingface dataset:
VIEWS AND PERSPECTIVES OF HYPERTENSION EXPERTS IN GREECE REGARDING THE EFFICACY AND SAFETY OR RENAL SYMPATHETIC DENERVATION
Authors: Doumas Michael , Andreadis Emmanouil , Davlouros Periklis , Dimitriadis Kyriakos , Gkaliagkousi Eugene , Grassos Harris , Hatzitolios Apostolos , Imprialos Konstantinos , Kalaitzidis Rigas , Kallistratos Emmanouil , Konstantinidis Dimitrios , Kotsis Vasilios , Makris Thomas , Manolis Athanasios , Marketou Maria , Papadakis Ioannis , Papadopoulos Dimitrios , Poulimenos Leonidas , Sanidas Ilias , Savopoulos Christos , Stavropoulos Konstantinos , Stergiou George S. , Thomopoulos Konstantinos , Triantafyllidi Helen , Triantafyllou Areti , Vlachakos Dimitrios , Zebekakis Pantelis , Ziakas Antonios , Tsioufis Costas 
Published: April 2021

Objective:
The role of renal sympathetic denervation (RSD) in the management of arterial hypertension remains controversial, given the initial enthusiasm by the first studies, the great disappointment by the first sham-controlled randomized study and the current promising finding in recent randomized trials. Therefore, an uncertainty exists about the beliefs of hypertension specialists regarding RSD. This analysis presents the opinions of hypertension experts in Greece regarding the efficacy and safety of RSD.

Design and method:
Chairpersons of ESH Hypertension Excellence Centers in Greece and their senior clinical research fellows, were invited to participate in a meeting aiming to discuss the current evidence on the clinical utility of RSD. Individual responses were recorded and qualitatively analyzed, in order to reach consensus about the safety and efficacy of RSD.

Results:
Twenty-five experts participated in the meeting (cardiologists 52%, internists 40%, nephrologists 8%). Participants agreed upon the favorable results of three recent clinical trials and supported the view that RSD is an effective method. 44% believe that further technological development of the denervation catheter is expected to improve the results of the technique. Importantly, 22% of the experts highlighted the additional benefits of the method in regressing target organ damage and in patients with increased activity of the sympathetic nervous system. However, 44% of the experts underlined the lack of reliable predictive markers for the efficacy of RSD, while 32% highlighted the lack of long-term efficacy studies. Experts universally agreed on the safety of the method. However, 64% stated that the duration of the RSD trials was short, and thus there is lack of data on the long-term safety of RDS. Of note, 76% considered the method as easy to perform and minimally invasive.

Conclusions:
The majority of the hypertension experts in Greece agree upon the efficacy of RSD and all had minimal concerns of the safety of method. More data are needed to reveal the degree of confidence among hypertension experts regarding the efficacy and the safety of the whole procedure and its specific aspects.
EFFECT OF RENAL DENERVATION ON AMBULATORY BLOOD PRESSURE IN PATIENTS WITH UNCONTROLLED HYPERTENSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED, SHAM-CONTROLLED TRIALS
Authors: Stavropoulos Konstantinos , Patoulias Dimitrios , Katsimardou Alexandra , Imprialos Konstantinos , Koutsampasopoulos Konstantinos , Toumpourleka Maria , Sachinidis Alexandros , Dimitriadis Kyriakos , Papademetriou Vassilios , Tsioufis Konstantinos , Doumas Michael 
Published: April 2021

Objective:
Untreated and uncontrolled hypertension remains among the most important cardiovascular risk factors worldwide, while hypertension treatment and control rates remain low in many countries. The aim of this study was to meta-analyze the effects of renal denervation (RDN) on ambulatory blood pressure levels in patients with untreated or uncontrolled hypertension.

Design and method:
PubMed and CENTRAL, along with grey literature sources, were searched from their inception to May 2019 for randomized, sham-controlled trials evaluating the efficacy and safety of RDN on the management of hypertension, irrespective of study blinding, setting and sample size.

Results:
Six randomized, sham-controlled trials were identified and included in the meta-analysis. In total, 981 patients with hypertension were randomized in all 6 trials to undergo either RDN (n = 585) or sham-procedure (n = 396). Compared to sham, RDN resulted in a decrease in 24-h systolic ambulatory blood pressure (ABP) by 3.62 mmHg (95% CI: -5.28 to -1.96; I^2 = 0%) and in 24-h diastolic ABP by 1.92 mmHg (95% CI: -3.65 to -0.20; I^2 = 46%). Grade of evidence was rated as low for both outcomes. Further analysis documented that RDN decreased daytime systolic ABP by 5.51 mmHg (95% CI: -7.79 to -3.23; I2 = 0%), nighttime systolic ABP by 3.06 mm Hg (95% CI: -8.69 to 2.56; I^2 = 73%), daytime diastolic ABP by 1.90 mmHg (95% CI: -3.48 to -0.32; I^2 = 4%) and nighttime diastolic ABP by 0.80 mmHg (95% CI: -3.61 to 2.02; I2 = 57%), compared to sham procedure. No major safety issues were identified.

Conclusions:
RDN is associated with a significant reduction in both 24-h systolic and diastolic ABP levels. Importantly, RDN decreases significantly daytime ABP levels, while it does not consistently induce a substantial reduction in nighttime ABP levels.
DIRECT REDUCTIONS IN BLOOD PRESSURE AND NOREPINEPHRINE LEVELS AFTER RENAL DENERVATION OF THE COLLECTING SYSTEM
Authors: Hering Dagmara , Hubbard Brad , Heuser Richard 
Published: April 2021

Objective:
Variability in both renal arterial anatomy and distribution of peri-arterial renal efferent and afferent nerves affect the magnitude of blood pressure (BP) response to arterial renal denervation (RDN). No useful markers of procedural success for RDN have yet been identified. This study was performed to examine the effectiveness of RDN of the renal pelvis nerves on BP, norepinephrine (NE) and histopathology of the treated zone in a porcine model.

Design and method:
A total of 74 porcine kidneys obtained from female swine (3.5–5 months old) weighting 60–65 kg underwent bilateral RDN via ureteral access with the catheter-based 4-electode VERVE Medical PhoenixTM system positioned in the renal pelvis. Renal cortical tissue was harvested and NE levels were measured using HPLC directly post procedure and 7, 14, 30 and 90 days after RDN. Intraarterial BP was measured directly throughout RDN and at 14 days follow-up. Pyelograms, direct visual evidence of RDN with ureteroscopy, gross examination and histopathology of the kidneys, and ureters were also performed.

Results:
Using a baseline of 600 ng/g (controls), the porcine kidneys had a mean NE concentration reduction of 76% directly post procedure, 60% at 7 days, 60% at 14 days, 57% at 30 days and 65% at 90 days follow-up. There was an immediate fall in BP for systolic of -20.6 ± 20.5 and diastolic of -6.0 ± 9.3 mmHg during ablation of the renal pelvis which was maintained at follow-up. Histopathological results confirmed nerve ablation of the treated zone with unremarkable kidney, ureter, and peripelvic nerves peripheral to the immediate treatment sites. Pyelograms of renal pelvis showed no remodeling in the renal pelvis related to the device.

Conclusions:
The immediate reduction in BP and NE accompanied by nerve damage of the treated zone suggest a successful ablation of abundance of efferent and afferent nerves residing in the collecting system, providing an encouraging target for RDN. If VERVE clinical studies confirm efficacy and safety, this approach can be widely used for the treatment of hypertension, and alternative therapy for patients with renal artery abnormalities and anatomical ineligibility for arterial approach.
CHANGES IN RENAL HEMODYNAMICS DURING A COLD PRESSURE TEST ARE DETECTABLE BY DOPPLER AND CONTRAST-ENHANCED ULTRASOUND
Authors: Hendriks-Balk M. , Polychronopoulou E. , Brito W. , Pruijm M. , Wuerzner G. 
Published: April 2021

Objective:
The cold pressure test (CPT) is a classic cardiovascular stress test known to increase blood pressure and heart rate secondary to an increase in nervous sympathetic activity. Its effect on renal hemodynamics using both Doppler ultrasound (DU) and contrast-enhanced ultrasound (CEUS) has not been reported previously. We hypothesized that a CPT would induce changes in renal hemodynamics detectable by DU and CEUS. The objective was to measure the renal responses during a CPT using DU and CEUS.

Design and method:
This was a single center prospective study in healthy participants. Renal resistive index (RRI) and mean acceleration time (MAT) were measured 4 times during 2 minutes baseline conditions (water at body temperature) and 4 times during 2 minutes CPT conditions (water at 4°C). The same protocol was then repeated after 5 minutes washout period for the measurement of the perfusion index (PI), relative blood volume and mean transit time using CEUS. Renal hemodynamic responses during baseline and CPT were compared using a t-test or a Wilcoxon matched-pair signed-rank test if variables were not normally distributed.

Results:
24 healthy participants (15 women, 9 men) were included. Mean age and body mass index were respectively (mean ± standard deviation) 33.9 ± 11.8 years and 24.3 ± 3.4 kg/m2. The CPT increased mean blood pressure by 19.8 ± 4.4 mmHg, heart rate by 14.0 ± 3.8 beats per min. The CPT decrease RRI from 0.60 ± 0.04 to 0.58 ± 0.04 (p = 0.018). This decrease was associated with the systolic blood pressure (rho: -0.43, p = 0.038) and heart rate response (rho = -0.52, p = 0.009). Mean acceleration time did not change. Perfusion index (median and interquartile range) increased from 2578 UI (1789; 4901) to 4148UI (2499; 6739) (p < 0.001). Relative blood volume increased, but mean transit time did not change.

Conclusions:
This is the first demonstration that the CTP induces detectable changes in renal hemodynamics using both DU and CEUS. The CPT combined to DU and CEUS may be a valuable tool to assess the renal response to increased sympathetic drive in hypertensive or chronic kidney disease patients.
N-METHYL-D-ASPARTATE (NMDA) RECEPTORS IN THE CONNECTING TUBULE INDUCE RENAL VASODILATION AND REGULATES BLOOD PRESSURE
Authors: Romero Cesar , Wang Hong , Ren Yiling , Wynne Brandi , Wall Susan 
Published: April 2021

Objective:
N-methyl-D-aspartate (NMDA) receptors are expressed throughout the nephron, including distal nephron principal cells (PC), and induce renal vasodilation through an unknown mechanism. Connecting tubule-glomerular feedback (CNTGF) is a vasodilator feedback mechanism producing afferent arteriole (AfA) vasodilatation and promote sodium excretion. We hypothesized that NMDA receptors activation stimulate CNTGF and that the inhibition of NMDA receptors decrease CNTGF inducing hypertension.

Design and method:
To determine the effect of NMDA receptor on CNTGF-mediated AfA dilation, we measured CNTGF-mediated AfA dilation in the presence or absence of NMDA receptor antagonists with and without NMDA antagonist (MK801), using a double-perfusion method of the AfA and CNT ex vivo in rabbits and stop-flow pressure (SFP) technique in vivo in rats. To evaluate the effect of the NMDA receptor in blood pressure regulation, we use the NMDA inhibitor MK801 infused by osmotic minipumps for 7 days in liddle syndrome mouse (βENaC mutated allele on129/Sv background) on normal salt diet. Under normal salt diet, blood pressure (BP) is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. BP was measure using tail cuff methods.

Results:
In pre-constricted AfA, in vitro NMDA agonist application to the connecting tubule lumen increased AfA dilation (p < 0.001). This amino-acid-induced dilation was blocked with the CNTGF inhibitor benzamil and blunted with the NMDA receptor blocker MK-801. In vivo, NMDA agonist increase CNTGF (P < 0.01). Basal BP was similar in both mice group (p = 0.4). The infusion of NMDA inhibitor (Mk-801) during 7 days induces hypertension (SBP 146 ± 8 mmHg) while the vehicle infused mice remained normotensives (110.7 ± 7.7 mmHg; p < 0.01).

Conclusions:
NMDA receptor activation induced renal vasodilation by increasing CNTGF responses. NMDA inhibition decrease CNTGF induced-vasodilation and promote hypertension. These results provide evidence on the role of NMDA receptors on renal hemodynamic and blood pressure regulation.
ACID-BASE BALANCE IN HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASE: INFLUENCE OF DIABETES
Authors: Mule’ Giuseppe , Carollo Caterina , Sorce Alessandra , Giambrone Marta , Ferrara Alida , Giarratana Carmen , Sinatra Nicola , Vaccaro Francesco , Guarneri Marco , Cottone Santina 
Published: April 2021

Objective:
Metabolic acidosis is a common complication of advanced CKD and it has been associated with an increased risk of death and faster renal function decline. Diabetes mellitus is one of the most crucial cause of CKD. The dysregulation of glucose homeostasis may lead to many acid–base balance disorders.
Our study was aimed to compare the acid-base status in diabetic patients with severe CKD with non diabetic CKD subjects.

Design and method:
Study population included 143 consecutive CKD hypertensive subjects attending our Nephrology unit with advanced renal failure. To be included on the study, patients were required to have an estimated eGFR of less than 30 mL/min, no intake of alkali within the previous 30 days, and the absence of pulmonary diseases and other clinical conditions at the time of the study that could explain an acute imbalance of the acid-base status, such as heart failure, hemorrhage, or sepsis. Patients were divided into two groups on the basis of the presence (n = 73) or the absence of Type 2 diabetes mellitus (n = 70) Arterial blood samples were drawn in all the subjects.

Results:
Age, sex distribution, serum creatinine, eGFR and proteinuria were not different in the two groups. Blood pH [7.406 (7.35–7.43) vs 7.384 (7.32–7.41), p = 0.02], bicarbonate levels [22 (19.1–23.7) vs 20.5 (17.4–23.1); p = 0.05] were higher and the prevalence of metabolic alkalosis (16.8 vs 8.4 %) was greater in diabetic patients as compared to non diabetic ones. The positive associations between diabetes and pH values (beta: 0.186; p = 0.02) and between diabetes and metabolic alkalosis (odds ratio 2.68; p < 0.05), were confirmed respectively in linear multiple regression analyses and in logistic multivariate models even after adjustment for potential confounders.

Conclusions:
Our results, in agreement with those obtained in a previous study (Caracava F et al, Am J Kidney Dis 1999), seem to suggest that metabolic alkalosis is more common than metabolic acidosis in diabetic patients with severe CKD. Further studies are needed in order to provide the pathophysiological explanations of these findings.
AORTIC STIFFNESS AND AORTIC TO ARTERIAL MISMATCH AS MARKERS OF KIDNEY INJURY IN HYPERTENSION
Authors: Lundwall Kristina , Jekell Andreas , Jacobson Stefan , Kahan Thomas , Desta Liyew , Spaak Jonas 
Published: April 2021

Objective:
Vascular stiffening is an important feature of the cardiorenal syndrome. Which hemodynamic and vascular parameters that are of most importance, and thereby best might serve as predictive markers for kidney failure in a hypertensive population, remains unclear. We therefore investigated a broad spectrum of hemodynamic parameters in a hypertensive population with kidney function ranging from normal to severe dysfunction, and then studied their independent relation to eGFR.

Methods:
Individuals with hypertension and varying degree of kidney dysfunction from two RCTs (DoRa and SOLID) were studied. Carotid to femoral (CF) pulse wav velocity (PWV), carotid to radial PWV, aortic (CF) to arterial (CR) mismatch (CF/CRPWV ratio), flow mediated vasodilation (FMD), subendocardial viability ratio (SEVR), central pulse pressure, central blood pressure, and echocardiographic measures of stiffness (left atrial volume index, E/é, left ventricular mass index) were measured. Hemodynamic parameters were correlated to kidney function, and for significant correlations, independence was investigated with multivariate regression.

Design and method:
107 participants were investigated, with eGFR ranging from 130 to 21 ml/min, mean eGFR of 73.8 ml/min. Mean age was 58 years, 9.3% had experienced a cardiovascular event, and 30.8% were on antihypertensive treatment. Mean BP was 150/87mmHg. CFPWV, a measure of aortic stiffness, and CF/CRPWV, a measure of the mismatch between aortic and arterial stiffness, showed independent correlations with eGFR (−coeff −0,159, p = 0.01 and −coeff −0.123, p = 0.04 respectively), whereas neither measures of endothelial dysfunction nor measures of ventricular stiffness showed significant correlations.

Conclusion:
Our results imply a profound importance of aortic stiffness in chronic kidney disease related vascular dysfunction, and suggest that measures of aortic PWV and the mismatch to arterial PWV might serve as risk markers of kidney injury in the hypertensive population.
URINARY PLASMIN PLAYS PATHOGENIC ROLES FOR THE DEVELOPMENT OF HYPERTENSION IN SALT-SENSITIVE HYPERTENSION WITH PROTEINURIA
Authors: Kakizoe Yutaka , Deng Qinyuan , Iwata Yasunobu , Adachi Masataka , Nakagawa Terumasa , Izumi Yuichiro , Kuwabara Takashige , Mukoyama Masashi 
Published: April 2021

Objective:
The epithelial sodium channel (ENaC) in the renal collecting duct plays pivotal roles in the regulation of sodium homeostasis and blood pressure. The proteolytic cleavage of γENaC by extracellular serine proteases is an important process for the full activation of this channel and is physiologically regulated by aldosterone. In the setting of proteinuria, plasminogen/plasmin filtered through damaged glomeruli could activate ENaC leading to hypertension, independently of aldosterone. We reported that Dahl salt-sensitive (DS) rats with high-salt (HS) diet developed severe hypertension together with aberrant activation of γENaC by serine proteases. However, the role of plasmin in the hypertension of DS rats remain to be elucidated. In this study, we evaluated the relationship of proteinuria, urinary plasmin activity and hypertension, and the antihypertensive effect of a serine protease inhibitor camostat mesilate (CM) in DS rats.

Design and method:
Five-week-old DS rats were divided into normal-salt (NS) diet, HS and HS+CM (0.1% diet) groups. After systolic BP (SBP) measurement and 24h urine collection were performed for 5 weeks, rats were sacrificed for biochemical examination. Urinary plasmin activities were evaluated by zymography and Western blotting (WB). The proteolytic cleavage of γENaC in urinary exosome was evaluated by WB.

Results:
HS diet induced severe hypertension, marked proteinuria and urinary plasmin activation, as well as the cleavage of urinary exosomal γENaC. The treatment with CM suppressed these changes, together with significantly reduced BP and proteinuria [SBP (mmHg): NS, 141.1 ± 5.8; HS, 222.3 ± 15.4; HS + CM, 199.5 ± 5.0. urinary protein (mg/day): NS, 23.8 ± 12.1; HS 272.3 ± 79.9; HS ± CM, 135.1 ± 27.4].

Conclusions:
In conclusion, plasmin is associated with the pathogenesis of hypertension in DS rats, and serine protease inhibition could be a potential therapeutic strategy against salt-sensitive hypertension with proteinuria.
UP-REGULATION OF SGLT-5 AS A CAUSE OF FRUCTOSE-INDUCED VOLUME-DEPENDENT HYPERTENSION
Authors: Hara Hiroaki , Takayanagi Kaori , Terao Masaaki , Kurosawa Akira , Iwasita Takatugu , Simizu Taisuke , Ogawa Tonari , Kanozawa Kouichi , Hasegawa Hajime 
Published: April 2021

Objective:
Excessive intake of fructose causes a variety of adverse conditions including obesity, hepatic steatosis, insulin resistance, uric acid overproduction and hypertension which is the most common and significant pathological setting. Cause of the hypertension is not known at present. This study aimed to elucidate the underlying mechanism of fructose-induced hypertension by rat model.

Design and method:
Male SD rats (7 weeks old) were fed by food containing 60% glucose (GLU) and 60% fructose (FRU) for 3, 6 and 12 weeks. Histological, immunohistological and molecular biological analysis, and gene chip study were applied. No difference of calorie and salt intake of individual animal was daily checked by the measured weight of remaining food.

Results:
Mean blood pressure and fractional sodium excretion (FENa) of FRU were both significantly higher (BP 12w-GLU: 94.8 ± 3.4 vs 12w-FRU: 103.7 ± 1.2 mmHg; FENa 12w-GLU: 0.084 ± 0.011 vs 12w-FRU: 0.059 ± 0.08%), suggesting that fructose caused ECF volume-dependent hypertension. Glomerular expansion in FRU (glomerular surface area in 12w-GLU: 7495 ± 181 vs 12w-FRU: 9831 ± 164 square micrometer) was agreed with the increase in the ECF volume. The expression of GLUT-5, fructose entry pathway, and ketohexokinase, phosphatase of fructose, in the proximal tubule were both up-regulated by fructose. As a candidate of fructose-induced salt reabsorption pathway, NHE3 was focused first because it is principal salt reabsorption pathway of proximal tubule. However, gene expression analysis, immunohistochemistry and immunoblotting of whole and phosphorylated NHE3 indicated negative results. To explore salt transporting molecules responding to fructose, gene chip analysis was conducted, and Slc5a10, corresponding to SGLT-5, showed significant up-regulation. The result was confirmed by RT-PCR (12w-GLU: 75.0 ± 5.8% vs 12w-FLU: 230.1 ± 16.0%) and in-situ hybrydization.

Conclusions:
Excess intake of fructose caused volume-dependent hypertension due to increased salt reabsorption through fructose-induced up-regulation of SGLT-5.
DIVERSIFIED RENAL TUBULAR EPITHELIAL REMODELING AND WATER BALANCE IN GITELMAN'S SYNDROME AND THIAZIDE-TREATED HYPERTENSIVE PATIENTS
Authors: Verzicco Ignazio , Tedeschi Stefano , Perlini Stefano , Graiani Gallia , Coghi Pietro , Merla Simona , Montanari Alberto , Musiari Luisa , Brusasco Irene , Gerra Luigi , Savona Ambra , Figus Giuliano , Cannone Valentina , Negro Aurelio , Vignali Alessandro , Volpi Riccardo , Cabassi Aderville 
Published: April 2021

Objective:
Mutations leading to loss of function of NaCl cotransporter (NCC) in the distal convoluted tubule is the basis defect of Gitelman's Syndrome (GS), which is clinically characterized by hypokaliemic metabolic alkalosis, hypomagnesemia, hypocalciuria and normal or low blood pressure with increased renin activity and high aldosterone levels. NCC is the target of thiazide diuretics (TZ) and clinical and laboratory findings of GS patients resemble those on chronic thiazide diuretics treatment. From a physiopathological perspective, this similarity in term of site of defect or site of action (NCC in distal convoluted tubule) for GS or TZ-treated patients respectively, should not alter their urine-concentrating or diluting ability. We aimed to study water balance pathways in these 2 clinical settings.

Design and method:
We investigated two groups of patients: 1) GS (n = 5, age range 21–43, 2 females and 3 males, mean concentration of blood potassium 2.9 mmol/L, bicarbonate 34 mmol/L and magnesium 1.2 mg/dl, normotensive) and 2) TZ hypertensive patients (n = 11, age range 26–48, 4 female and 7 males, blood pressure normalized with chronic thiazide type or like diuretics including hydrochlorothiazide, chlortalidone and indapamide maintained for at least 2 months) to evaluate their water balance pathway by determining plasma and urine osmolarity and to assess through urine aquaporin 2 (AQP2)/creatinine ratio their sensitivity to antidiuretic hormone. These measurements were repeated three times in the same patients.

Results:
Four out of five GS patients showed a urinary AQP2/creatinine ratio lower than TZ-treated patients (mean value of AQP2/creatinine of GS vs TZ-treated p < .05), associated with lower urine osmolarity (p = 0.03).

Conclusions:
Our study shows that water balance in these two groups may be differently handled: A diversified renal tubular epithelial remodeling of medullary collecting duct cells related to TZ treatment could be suggested, leading to an increased prevalence of principal cells on intercalated cells, thus increasing free water reabsorption.