Increased Urine Flow Rate Research Articles

SGLT-2 Inhibitors and Their Correlation With Kidney Stones. A Systematic Review

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have emerged as a valuable class of medications for managing Type 2 Diabetes Mellitus (T2DM) due to their efficacy in glycemic control and cardiovascular and renal benefits. However, concerns have been raised regarding their potential association with an increased risk of kidney stone formation. Objective: This systematic review aimed to comprehensively evaluate the existing literature to determine the association between SGLT-2 inhibitors and kidney stone formation, elucidate potential underlying mechanisms, and discuss implications for clinical practice. Methods: A systematic search of databases including PubMed, Google Scholar, Web of Sciences, Medline, and Scopus was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant research articles investigating the utilization of SGLT-2 inhibitors in humans and their potential correlation with kidney stones were included. Data extraction and quality assessment were performed, and a mixed-methods synthesis approach was used for data analysis. Results: The systematic review identified several studies examining the association between SGLT-2 inhibitors and kidney stones. Overall, SGLT-2 inhibitors were found to be associated with a potential protective effect against kidney stone formation. Mechanistically, SGLT-2 inhibitors promote glycosuria and natriuresis, leading to increased urine flow rate and enhanced urinary volume, which may help dilute and flush out stone-forming substances. However, certain limitations and considerations, including potential adverse events and variations in study designs, were also highlighted. Conclusion: This systematic review provides valuable insights into the potential correlation between SGLT-2 inhibitors and kidney stones. While the observed protective effect against kidney stone formation is promising, further research with longer follow-up durations and larger sample sizes is warranted to establish a more conclusive understanding of this relationship. Nonetheless, clinicians should remain vigilant in monitoring patients using SGLT-2 inhibitors and carefully assess individual risk factors when prescribing these medications.

Subchronic exposure to PM2.5 induced renal function damage and intestinal microflora changes in rats

BackgroundExposure to inhalable environmental particulate matter with a diameter of 2.5 µm or smaller (PM2.5) is associated with decreased or impaired kidney function, but the underlying biological mechanisms are not fully understood. Gut microbiota is an emerging key player in the homeostasis regulation of the gut-kidney axis. Few studies have investigated its role in PM2.5 exposure-induced gut-kidney axis homeostasis abnormalities. MethodsIn this study, a versatile aerosol concentration enrichment system for medium- to long-term whole-body exposure was used to expose Sprague-Dawley rats to filtered air (FA) or concentrated ambient PM2.5 for 12 weeks. A correlation analysis of renal impairment and the intestinal microbiome was performed. ResultsThe urine flow rate calculation and renal function analysis showed that PM2.5 exposure significantly impaired renal function and increased the urine flow rate. The fecal microbiota analysis showed that renal impairment and increased urine flow rates were consistent with the reduced estimates of the fecal bacteria Chao1, observed-species, Shannon, and Simpson (richness and diversity indices). Pearson’s correlation analysis showed that the estimated bacterial richness and diversity were correlated with the urine flow rate and renal function. The linear discriminant analysis effect size (LEfSe) analysis revealed differences between animals exposed to PM2.5 and FA in 25 bacterial groups. Further correlation of a single bacterial taxon with the urine flow rate and renal function showed that the relative abundances of 30, 29, 21, and 50 distinct bacterial groups were significantly correlated with the urine flow rate, estimated glomerular filtration rate (eGFR), serum cystatin C (CysC), and beta-2 microglobulin (β2-MG), respectively. ConclusionSubchronic exposure to PM2.5 can cause intestinal ecological disorders, which may, in turn, lead to decreased kidney function or the development of impaired kidney function.

The SGLT2 inhibitor, empagliflozin reduces early progressive proteinuria in obese SS rats

Childhood/prepubertal obesity (PPO) is a world-wide epidemic and is considered a risk factor for renal injury. Therefore, there is a need to control this trend to decrease the future risk of chronic kidney disease. Recently, we reported that the SS LepR mutant rat is a novel model to study the mechanisms of renal injury associated with PPO. The SS LepR mutant rat develops progressive renal injury in the absence of hyperglycemia before puberty. SGLT2 inhibitors have been demonstrated to exert renoprotective effects independent of lowering blood glucose. Therefore, the objective of this study was to determine the effects of SGLT2 blockade with empagliflozin on the early progression of proteinuria in SS LepR mutant rats, during PPO. Four-week-old SS and SS LepR mutant rats (n = 5/group) were either treated with vehicle (diet) or empagliflozin (30 mg/kg/day, orally) for four weeks. While the SS LepR mutant rats had significantly higher body weights vs SS rats, there were no detectable differences in body weight or blood glucose levels in response to empagliflozin treatment in SS LepR mutant rats. We observed a significant increase in plasma insulin in control SS LepR mutant rats vs SS rats (7±1 vs 1±0.3 ng/mL, respectively, p<0.05), and treatment with empagliflozin did not have any effect on plasma insulin in SS LepR mutant rats (8±2 ng/mL). At baseline, we did not observe any significant difference in urine flow rate between control SS LepR mutant vs SS rats. After two weeks of treatment, while there was no observed difference in urine flow rate between SS LepR mutant and SS rats (17±3 ml/day vs 18±2 ml/day, respectively), empagliflozin significantly increased urine flow rate in SS LepR mutant rats (29±4 ml/day, p<0.05), but not in SS rats (17±3 ml/day). At baseline, we observed a difference in proteinuria between control SS LepR mutant vs SS rats (68±11 vs 6±3 mg/day, respectively, p<0.05), which remained elevated over the course of the study (471±75 vs 32±5 mg/day, respectively, p<0.05). Treatment with empagliflozin significantly decreased proteinuria in SS LepR mutant rats (223±52 mg/day, p<0.05) without affecting SS rats (27±8 mg/day). At the end of the study, we observed a significant increase in GFR in control SS LepR mutant rats vs SS rats (2.4±0.6 vs 0.5 mL/min/gkwt, respectively, p<0.05). Treatment with empagliflozin only significantly reduced GFR in SS LepR mutant rats (0.9±0.2 mL/min/gkwt, p<0.05). In conclusion, these data suggest that empagliflozin attenuates renal hyperfiltration and confers renoprotective effects during the early progression of renal disease associated with PPO. DK109133 and HL151407 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.

The effect of exogenous peroxiredoxin 6 on morphofunctional state of isolated rat kidney

Objective: to investigate the role of peroxiredoxin 6 (PRX6) in preserving the morphofunctional state of ischemic isolated kidney during perfusion.Materials and methods. The model of an isolated perfused rat kidney was used. Ischemia time was 5 and 20 minutes, perfusion was 50 minutes. To evaluate the effectiveness of PRX6 at different ischemia times, we used the conventional criteria of kidney function and histological methods.Results. During short warm ischemia times, exogenous PRX6 improves the morphofunctional state of an isolated kidney during perfusion. During this period, the main criteria for functioning of the isolated ischemic kidney reach acceptable values, renal parenchyma is without severe damage. By the end of perfusion, there was an increase in urine flow rate, glomerular filtration rate, fractional glucose reabsorption, urine urea concentration and proportion of primary urine from 1.5 to 2 times compared with the control lesion. At 20-minute ischemia, the isolated kidney can be recognized as non-viable according to the functioning criteria; the positive effect of PRX6 is leveled.Conclusion. The use of recombinant peroxiredoxin 6 for preserving the morphofunctional state of isolated kidneys can be an effective approach in preventing ischemia–reperfusion injury.

Diuretic, Kaliuretic and Anti-Natriuretic Properties of Aqueous Extract of Celosia trigyna L. (Amaranthaceae) on Wistar Rats

Aims: The purpose of this study was to determine the diuretic and electrolyte excretion properties of the aqueous extract of Celosia trigyna L. (Amaranthaceae) on female Wistar rats.
 Methodology: The extraction of active principles was done by macerating aerial parts of the plant. The administration of the extract and other products was done by single-dose gavage. Measurements of urinary flow rate (UFR), natriuria, kaliuria and chloruria were taken on urine collected for twenty-four hours after each product was administered. Diuretic activity (DA) and diuretic index (DI), natriuretic and saluretic effects, and carbonic anhydrase inhibition were calculated. A NaCl solution (0.9%) was used as a negative control; furosemide and aldactone were respectively used as hypokalemic and hyperkalemic positive controls.
 Results: We observed a significant increase in UFR, confirmed by the values of DA and DI, obtained after the administration of extract. For electrolyte excretion, we observed an increase of the kaliuria (p ˂ 0.001) and a decrease of natriuria (p ˂ 0.001) after the extract was administered; chloruria did not significantly changed. We also found a drastic anti-natriuretic dose-dependent effect while saluretic activity and carbonic anhydrase inhibition were not clearly observable.
 Conclusion: These results confirm the ethnobotanical data about diuretic effect of Celosia trigyna L. extract. This diuretic effect would be supported by a specific increase in K+ excretion suggesting that the extract is possibly hypokalemic. The anti-natriuretic effect suggests that extract possess an aldosterone-like properties.

Possibilities of phytotherapy in patients with lower urinary tract symptoms due to benign prostate enlargement

The results of the use of the phytopreparation Tadimax in the treatment of 60 men with mild and moderate lower urinary tract symptoms (LUTS) developed as a result of benign enlargement of the prostate gland are presented. The average age of the patients was 66.5 3.8 years. Tadimax was prescribed 2 tablets 3 times a day, in courses of 7 days with 7 day breaks for 3 months (a total of 6 courses). The data obtained indicate high efficacy and good tolerability of treatment. A decrease in the severity of LUTS was noted in 59 (96.6%) patients, which was accompanied by significant changes in objective clinical indicators: a decrease in residual urine volume and an increase in urine flow rate. Tadimax is a combined preparation, which includes extracts of several medicinal plants, and the main component is Crinum latifolium. The therapeutic effect of Tadimax is based on anti-inflammatory, antiproliferative and immunotropic action.

Baroreflex Control of Renal Sympathetic Nerve Activity and Renal Responses to Volume Expansion Following Intermittent Hypoxia in Rats

The baroreceptor reflex provides negative‐feedback control to reduce blood pressure fluctuations. Dysfunction of the baroreflex was reported in hypertension disease models that involve kidney injury. This study investigated the high‐ and low‐pressure baroreflex control of renal sympathetic nerve activity (RSNA), in addition to renal diuretic and natriuretic responses to volume expansion (VE) in rats exposed to intermittent hypoxia (IH). Wistar rats were exposed to IH (210 sec at 21% O2 and 90 sec at 6% O2, 12 cycles/hr, n=9) or to normoxia (sham, 21% O2, n=8) for 14 days. On day 15, rats were anaesthetized (induction: urethane, α‐chloralose and sodium pentobarbitone mixture i.p. (416, 27 and 33mg/kg), maintenance: urethane and α‐chloralose mixture i.v.) and prepared to record cardiovascular parameters and RSNA, and measure renal sodium and water excretory function. High‐pressure baroreflex was assessed using i.v. injections of phenylephrine and sodium nitroprusside (50μg/kg/min) to induce blood pressure changes. RSNA was calculated as a percentage of baseline values and plotted against mean arterial blood pressure. Low‐pressure baroreflex was studied using two successive VE challenges (0.25ml saline/100g body weight/min for 30min i.v.) during which saline or capsaizepine (CPZ, 5μg/ml/hr), a TRPV1 blocker were infused intra‐renally and the RSNA sympatho‐inhibitory response was recorded. Urine samples were collected to measure urine flow rate (UFR) and absolute Na + excretion (UNa+). Data are expressed as mean±SD and analyzed using t‐test or ANOVA where relevant. IH rats had higher blood pressure (97±11 vs. 84±9 mmHg) and RSNA to maximum RSNA ratio (0.36±0.15 vs. 0.17±0.07, all p<0.05), compared with sham. The slope (sensitivity) of the baroreflex gain curve of RSNA was smaller (0.09±0.05 vs. 0.29±0.27 a.u./mmHg, p=0.016) while the operating pressure was greater (129±14 vs. 109±6 mmHg, p=0.005) in IH rats compared with sham. VE decreased RSNA during the 30 min period from baseline to an equivalent extent (−35%) in sham and IH groups. However, VE‐induced increase in UFR (p=0.015) and UNa+ (p=0.02) was blunted after 30 min of VE challenge in IH rats compared with sham. This was revealed by a decrease in the area under UFR (5875±1574 vs. 9785±2714 ml/kg, p=0.002) and UNa+ (467±120 vs. 655±249 μmol, p=0.062) curves of IH rats compared with sham. Intra‐renal CPZ increased UFR (AUC; IH, 9868±4098 vs. sham, 10157±4081 ml/kg) and UNa+ (AUC, IH, 612±217 vs. sham, 721±223 μmol) in the IH group to comparable levels of sham. This was associated with potentiation of RSNA sympatho‐inhibition response to VE by 54% (p<0.05) in both groups. There was no evidence of oxidative stress or inflammation in IH kidneys. These findings suggest that moderate IH exposure blunts baroreflex regulation of RSNA. Renal diuretic and natriuretic responses to VE were perturbed by IH exposure although low‐pressure baroreflex control of RSNA was preserved. TRPV1 blockade restored the blunted excretory response to VE in IH rats.

Modulation of Renal Excretory Function by the Conformationally Restricted Enantiomeric κ‐Opioid Receptor Agonists: (+) U‐50,488 and (−) U‐50,488

Currently, more than half of the drugs in clinical use are chiral compounds. In many instances the enantiomers of chiral drugs demonstrate pronounced differences in biological activity, toxicology, pharmacokinetics, and metabolism. Administration of racemic U‐50,488, a highly selective chiral κ‐opioid receptor agonist, produces a marked sodium and potassium sparing diuresis (i.e. aquaresis), dysphoria, and analgesia in conscious rats. Though U‐50,488 enantiomers have been the subject of various behavioral and analgesic studies, there is a distinct lack of data pertaining to isomers and kappa induced aquaresis. Therefore, the aim of the present study was to pharmacologically characterize the renal excretory effects produced by the isolated (−)‐(1S,2S)‐U‐50,488 versus (+)‐(1R,2R)‐U50,488 enantiomers. Methods Male Sprague‐Dawley rats with an indwelling intracerebroventricular (ICV) cannula were surgically implanted with an arterial, venous, and bladder catheter and continuously infused intravenously (i.v.) with iso‐saline. After stabilization, mean arterial pressure (MAP), heart rate (HR), and urine flow rate (V) were measured in conscious rats for 20‐min before (control) and 90‐min after (experimental) ICV bolus injection (1 ug) of (−)‐(1S,2S)‐U‐50,488, (+)‐(1R,2R)‐U50,488, racemic (+/−)‐U‐50,488, or vehicle (n=6/group). Urine samples were analyzed for urinary sodium excretion (UNaV) and urinary potassium excretion (UKV). Results ICV injection of racemic U‐50,488 (1 ug) produced a significant diuretic (control (C), 56±6, 30‐min, 152±7 ul/min), antinatriuretic (C, 8.7±2.2, 30 min, 3.7±2 ueq/min), and antikaluretic (C, 1.1±0.5; 0.4±0.4 ueq/min) response. At the same dose, both the (−)‐(1S,2S)‐U‐50,488 and (+)‐(1R,2R)‐U50,488 isomers produced a significant sodium and potassium sparing diuresis without changing MAP or HR. At 1 ug, (−)‐(1S,2S)‐U‐50,488 significantly increased peak urine flow rate (C, 58±6 ul/min; 20 min 196±29 ul/min) and decreased urinary sodium (C, 8.9±2.3 μeq/min; 30 min 3.9±0.8 μeq/min) and potassium (C, 0.8±0.2 μeq/min, 30 min, 0.2±0.1 μeq/min) excretion. In contrast, 1 ug of (+)‐(1R,2R)‐U50,488 increased urine flow rate to a lessor magnitude (C, 57±6 ul/min; 10 min 119±26 ul/min) while decreasing urinary sodium excretion (C, 8.0±0.7 μeq/min, 30 min 4.3±1.5 μeq/min) but not urinary potassium excretion. ICV pretreatment (1ug, 10 min) with the kappa antagonist nor‐BNI abolished the kappa‐mediated diuresis by both enantiomers and racemic U‐50,488.ConclusionsThese results indicate (−)‐(1S,2S)‐U‐50,488 is the predominant isomer responsible for producing the centrally mediated aquaresis observed with racemic U‐50,488. Blockade of the aquaresis by ICV nor‐BNI indicates that both enantiomers mediate their renal excretory effects through activation of central kappa receptors. Further renal excretory studies are needed to fully elucidate the pharmacological variances between these two compounds and determine whether a selective entaniomer of U‐50,488 may be used therapeutically as a water diuretic.Support or Funding InformationNIH P30GM106392 (DRK)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute SGLT2 Inhibition and the Pressure Natriuresis Response in Rats with Type 1 Diabetes

Increasing blood pressure (BP) induces natriuresis due to downregulation of sodium transport in the proximal tubule. This pressure natriuresis (PN) response influences long‐term BP. Type‐1 diabetic (T1DM) patients show enhanced tubular sodium reabsorption and high BP. We have found that tubular sodium reabsorption is not modulated by BP in T1DM rats. The molecular mechanism of impaired PN is unknown but the sodium‐glucose cotransporter SGLT2 is a plausible candidate and inhibitors acutely induce diuresis in T1DM rats. This study tested the hypothesis that SGLT2 inhibition with dapagliflozin would improve the acute PN response in T1DM rats.T1DM was induced in male Sprague‐Dawley rats by streptozotocin (30–45mg/kg IP; plasma glucose 13.3–>35mmol). After 3 weeks rats were anaesthetised with Inactin (120mg/kg, IP). The jugular vein was cannulated and isotonic saline (containing FITC‐inulin and p‐amino hippurate for measurement of glomerular filtration rate (GFR) and renal plasma flow (RPF)) was infused. Rats were randomly allocated to receive either dapagliflozin (50mg/kg; n=7) or saline vehicle (n=7) and after an equilibration period and baseline urine collection, BP was increased by sequential arterial ligation of first the coeliac and mesenteric arteries and then the distal aorta and the natriuretic response was measured. Experiments were performed under a single blind and rats were euthanised by an overdose of anaesthetic. Data are mean +SD and comparisons were made by 2‐way ANOVA. GFR and RPF were not different between treatment groups and were unaffected by the experimentally‐induced rise in BP, consistent with autoregulation. In vehicle‐treated rats, incremental rises in BP increased urine flow rate from a baseline of 6 ± 3 to a peak of 51 ± 28μl/min/gkw (P<0.01), sodium excretion from 1.7 ± 0.5 to 16.7 ± 1.4 μmol/min/gkw (P<0.01) and fractional sodium excretion from 0.2 ± 7.6 to 5.4 ± 4.5% (P<0.01). The dapaglifozin‐treated rats responded to increasing pressure with a diuresis and natriuresis but the peak absolute (3.8 ± 4.1μmol/min/gkw; P=0.010) and fractional (15.2 ± 8.0%; P=0.018) sodium excretion were significantly lower than in the vehicle‐ group. Dapagliflozin increased urinary glucose excretion from 0.1 ± 0.2 to 0.4 ± 0.2μmol/min/gkw: glucose excretion was not modified by increasing BP in either group. Although dapagliflozin increased urine flow and glucose excretion at steady‐state BP, it did not enhance the acute PN response in T1DM rats. Thus, impaired PN in T1DM does not reflect increased SGLT2 activity.Support or Funding InformationBritish Heart Foundation studentship FS/16/54/32730 & Kidney Research UK Project Grant RP2/2014This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Treatment with Mesenchymal Stem Cells Improves Renovascular Hypertension and Preserves the Ability of the Contralateral Kidney to Excrete Sodium

Background: Mesenchymal stem cells (MSC) improve renal function and renovascular hypertension in the 2-kidney 1-clip model (2K-1C). While MSC play an immunomodulatory role, induce neoangiogenesis, and reduce fibrosis, they do not correct sodium loss by the contra­lateral kidney. Objectives: We investigated the tubular function of both stenotic and contralateral kidneys and the effect of MSC treatment by evaluating diuresis, natriuresis, and the expression of the main water and sodium transporters. Method: Adult Wistar rats were allocated into four groups: control (CT), CT+MSC, 2K-1C, and 2K-1C+MSC. MSC (2 × 10⁵) were infused through the tail vein 3 and 5 weeks after clipping. Systolic blood pressure (SBP) was monitored weekly by plethysmography. Six weeks after clipping, 24-hour urine and blood samples were collected for biochemical analysis. Gene expression of the Na/H exchanger-3, epithelial sodium channel, Na/K-ATPase, Na/K/2Cl cotransporter, and aquaporins 1 and 2 (AQP1 and AQP2) were analyzed by RT-PCR. Intrarenal distribution of AQP1 and AQP2 was analyzed by immunohistochemistry. Results: In hypertensive 2K-1C animals, MSC prevented additional increases in BP. AQP1, but not AQP2, was suppressed in the contralateral kidney, resulting in significant increase in urinary flow rate and sodium excretion. Gene expressions of sodium transporters were similar in both kidneys, suggesting that the high perfusing pressure in the contralateral kidney was responsible for increased natriuresis. Contralateral hypertensive kidney showed signs of renal deterioration with lower GFR in spite of normal RPF levels. Conclusions: MSC treatment improved renal function and enhanced the ability of the contralateral kidney to excrete sodium through a tubular independent mechanism contributing to reduce SBP.

The effects of chronic acetaminophen exposure on the kidney, gill and liver in rainbow trout (Oncorhynchus mykiss)

In this study, we examined if rainbow trout chronically exposed to acetaminophen (10 and 30 μgL−1) showed histological changes that coincided with functional changes in the kidney, gill and liver. Histological changes in the kidney included movement and loss of nuclei, non-uniform nuclei size, non-uniform cytoplasmic staining, and loss of tubule integrity. Histological effects were more severe at the higher concentration and coincided with concentration dependent increases in urine flow rate and increased urinary concentrations of sodium, chloride, potassium, calcium, urea, ammonia, glucose, and protein. Yet, glomerular filtration rate was not altered with acetaminophen exposure. In the gill, filament end swelling, whole filament swelling, and swelling of the lamellae were observed in exposed fish. Lamellar spacing decreased in both exposure groups, but lamellar area decreased only with 30 μgL−1 exposure. At faster swimming speeds, oxygen consumption was limited in acetaminophen exposed fish, and critical swimming speed was also decreased in both exposure groups. The liver showed decreased perisinusoidal spaces at 10 and 30 μgL−1 acetaminophen, and decreased cytoplasmic vacuolation with 30 μgL−1 acetaminophen. A decrease in liver glycogen was also observed at 30 μgL−1. There was no change in plasma concentrations of sodium, chloride, potassium, calcium, magnesium, and glucose with exposure, suggesting compensation for urinary loss. Indeed, an increase in Na+-K+-ATPase activity in the gills was found with 30 μgL−1 acetaminophen exposure. Chronic exposure of rainbow trout to the environmentally relevant pharmaceutical acetaminophen, alters both histology and function of organs responsible for ion and nutrient homeostasis.

Rectus abdominis detrusor myoplasty (RADM) for acontractile/hypocontractile bladder in spinal cord injury patients: Preliminary report

Urinary bladder dysfunction in the form of acontractile/hypocontractile bladder is very common after spinal cord injury and it may lead to recurrent urinary tract infection (UTI), stones formation, and deteriorating renal function. Conventionally, these patients evacuate their bladders by life-long clean intermittent catheterization (CIC) or an indwelling catheter (IC). For these patients, another option is to use innervated skeletal muscle wrap around the bladder to augment detrusor function and voluntary evacuation of bladder. We selected 5 patients with acontractile/hypocontractile bladder following spinal cord trauma. These patients were assessed by urodynamic study for post void residual volume (PVRV), detrusor pressure (Pdet), urine flow rate (Vmax), and bladder contractility index (BCI). All five patients underwent Rectus Abdominis Detrusor Myoplasty (RADM). Complete spontaneous voiding was achieved in all patients. Rectus abdominis detrusor myoplasty (RADM) elicits a statistically significant reduction in PVRV and statistically significant increase in urine flow rate, bladder contractility and detrusor pressure after 6 months. Recurrent UTIs ceased in all patients. There were no immediate or late complications. RADM appears to be a promising option in a patient with acontractile/hypocontractile bladder to restore the bladder function. It avoids CIC in all patients leading to improvement in quality of life in select group of patients.

Diuretic and Hypotensive Effect of Morelloflavone from Garcinia dulcis in Two-Kidneys-One-Clip (2K1C) Hypertensive Rat

Morelloflavone, a biflavonoid from Southeast Asian folk medical plant Garcinia dulcis, possesses powerful antioxidant activity both in vivo and in vitro. We aimed to evaluate the hypotensive and diuretic effect of morelloflavone in two-kidneys-one-clip (2K1C) renovascular hypertensive rats together with its vasorelaxant mechanism. Male Wistar rats (175±4 g) were undergone 2K1C and sham operation (SO) (n=6, each group). Four weeks after the rats were anesthetized and clearance markers (0.5% para-aminohippuric acid and 1% inulin) were given via a jugular vein (1.6 mL/h/100 g BW) to estimate renal blood flow (RBF) and glomerular filtration rate. The arterial blood pressure (AP) was monitored via a carotid artery and urine samples were collected. After equilibration, either morelloflavone or vehicle (DMSO) was given (0.1 mg/kg BW+5 μg/min/kg BW). Baroreflex sensitivity (BRS) (ΔHR/ΔMAP) was performed by an intravenous injection of 1, 2, 4, 8, 16 and 32 μg/kg BW phenylephrine (PE) or sodium nitroprusside. The PE-preconstricted isolated thoracic aortic rings (intact and denuded) relaxation were experimented using organ bath technique by cumulative additions of morelloflavaone (10-13-10-5 M) in the presence of specific vasorelaxant inhibitors and expressed as %relaxation from pre-contraction tension. In 2K1C rats, morelloflavone significantly lowered mean AP, increased RBF and increased urine flow rate when compared to vehicle control (138±6 vs. 152±1 mmHg, 3.44±0.49 vs. 2.29±0.25 mL/min/g KW and 42.0±9.4 vs. 18.2±3.9 μL/min/g KW, p<0.05), respectively and also restored the blunt BRS. Nitric oxide signaling pathway triggered by morelloflavone might be responsible for its diuretic and hypotensive effect.

EFFECTIVENESS AND SAFETY OF THE «DE ALEX» BIO COMPLEX AS MONOTHERAPY AND IN COMBINATION WITH TAMSULOSIN IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

Introduction . Lower urinary tract symptoms (LUTS) are a common complaint in patients with benign prostatic hyperplasia (BPH), and they significantly affect patients’ quality of life. According to the guidelines of the European Association of Urology on management of LUTS (2016), herbal drug preparations can be used as monotherapy and as a part of combination therapy. Plant extracts with anti-inflammatory, spasmolytic, anti-oedemic, anti-androgenic, estrogenic effect can inhibit prostatic growth, stimulation, proliferation factors, α-adrenoreceptors, 5α-reductase, muscarine acetylcholine receptors. The article describes experience of using the «De Alex» bio complex as monotherapy and in combination with tamsulosin in patients with BPH. The study objective is to evaluate effectiveness and safety of the "De Alex" bio complex as monotherapy and in combination with tamsulosin in patients with BPH. Materials and methods . Clinical and laboratory examinations of 30 patients with BPH were performed. The patients were selected at the stage of primary clinical screening in Moscow city polyclinics (branch No. 1 of the City Polyclinic No. 62 of the Moscow Healthcare Department) and Moscow Region polyclinics (City Polyclinic No. 3 of the Orekhovo-Zuyevo Central City Hospital of the Moscow Region). The study duration was 12 weeks. Results . Based on the obtained data, the "De Alex" bio complex has significant anti-inflammatory, spasmolytic effect, can affect prostate volume, increase urine flow rate and control (which was confirmed by the results of the follow-up examination) and therefore increase patients’ quality of life. Conclusion . The "De Alex" bio complex has shown a high level of safety: during the study, the dietary supplement didn’t cause any side effects. Furthermore, the bio complex didn’t significantly affect the total and free levels of prostate-specific antigen and testosterone. The patients demonstrated high compliancy since "De Alex" has proved to be an effective and safe supplement with fast effect. Considering the above, we can recommend the "De Alex" bio complex at dose 1 tablet 2 times a day for 3 months (1–2 courses a year) as an effective and safe preparation that can be used as monotherapy or in combination with alpha-blockers to manage LUTS.

Hydrochlorothiazide Does Not Acutely Acidify Urine

Urine acidification is fine‐tuned in the collecting duct. The α‐intercalated cells in this segment express the apical H+‐ATPase, which activity is assumed to be dependent on the transepithelial voltage (Vte). The lumen‐negative Vte generated by Na+ influx via the epithelial Na+ channel (ENaC) is believed to promote H+‐ATPase‐dependent H+ secretion. An increased Na+ delivery to the collecting duct would result in additional Na+ uptake through ENaC, increased lumen‐negative Vte, and thus, favor acid secretion via the H+‐ATPase. This mechanism has been the main explanation for the marked urine acidification by loop diuretics. However, we recently showed that urine acidification by furosemide occurs independent of ENaC activity. We demonstrated that furosemide directly stimulates H+ secretion in the thick ascending limb via the Na+/H+ exchanger NHE3. Here, we investigate whether hydrochlorothiazide, an inhibitor of Na+, Cl− cotransporter (NCC) in the distal convoluted tubule causes acute alterations of urine pH. NCC inhibition should similar to the loop diuretics lead to increased Na+ delivery to the collecting duct and, thus, cause urine acidification.Mice were anesthetizes and infused (0.5 ml/h) via a jugular vein catheter with control or hydrochlorothiazide (HCT) (30 mg/kg/h) and bladder was catheterized. Urine pH was measured directly in the outflow of bladder catheter and urine Na+ and K+ were measured using flame photometry.HCT increased urine flow rate from 8.1±1.8 to 15.8±2.6 μl/h/g BW (n=11). Na+ excretion was increased from 20.81±4.15 to 51.8±7.73 μmol/h, whereas no change in K+ excretion was observed. These results clearly demonstrate the diuretic properties of HCT. Interestingly, urine pH was unchanged during the entire infusion period of HCT (1h) compared to control (pH 6.13±0.23 vs 6.15±0.16).Hence, despite the natriuresis induced by HCT, an acute increased H+ secretion was not observed. These results therefore challenge the current understanding of loop‐diuretic‐induced urine acidification, because other means for increasing Na+ delivery to the collecting duct do not acidify urine. Thus, this study supports our previous finding that H+ secretion by furosemide takes place already in the thick ascending limb and will contribute to a better understanding of how the kidneys secrete acid.

Hemodynamic responses to acute angiotensin II infusion are exacerbated in male versus female spontaneously hypertensive rats

We previously reported that male spontaneously hypertensive rats (SHRs) are more sensitive to chronic angiotensin (Ang) II-induced hypertension compared with female rats. This study was designed to test the hypothesis that anesthetized male SHRs are also more responsive to acute Ang II-induced increases in blood pressure and renal hemodynamic changes when compared with female SHRs. Baseline mean arterial pressure (MAP) was higher in male SHRs than in female SHRs (135±2 vs. 124±4mmHg, P<0.05). Acute intravenous infusion of Ang II (5ng/kg/min) for 60minutes significantly increased MAP to 148±2mmHg in male SHRs (P<0.05) without a significant change in MAP in female SHRs. Baseline glomerular filtration rate (GFR) was also higher in male SHRs than in female SHRs (2.6±0.3 vs. 1.3±0.1mL/min, P<0.05). Ang II infusion for 60min significantly decreased GFR in male SHRs (2.0±0.2mL/min; P<0.05) without significant changes in urine flow rate, sodium, or chloride excretion. In contrast, Ang II infusion increased GFR in female SHRs (1.9±0.2mL/min; P<0.05). The increase in GFR upon Ang II infusion in female SHRs was associated with increases in urine flow rate (4.3±0.3 to 7.1±0.9μL/min), sodium excretion (0.16±0.04 to 0.4±0.1μmol/min), and chloride excretion (0.7±0.08 to 1.1±0.1μmol/min; for all P<0.05). These findings support the hypothesis that there is sex difference in response to acute Ang II infusion in SHRs with females being less responsive to Ang II-induced elevations in blood pressure and decreases in GFR relative to male SHRs.

Invasive urodynamic studies for the management of lower urinary tract symptoms (LUTS) in men with voiding dysfunction

Invasive urodynamic tests are used to investigate men with lower urinary tract symptoms (LUTS) and voiding dysfunction to determine a definitive objective diagnosis. The aim is to help clinicians select the treatment that is most likely to be successful. These investigations are invasive and time-consuming. To determine whether performing invasive urodynamic investigation, as opposed to other methods of diagnosis such as non-invasive urodynamics or clinical history and examination alone, reduces the number of men with continuing symptoms of voiding dysfunction. This goal will be achieved by critically appraising and summarising current evidence from randomised controlled trials related to clinical outcomes and cost-effectiveness. This review is not intended to consider whether urodynamic tests are reliable for making clinical diagnoses, nor whether one type of urodynamic test is better than another for this purpose.The following comparisons were made.• Urodynamics versus clinical management.• One type of urodynamics versus another. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, issue 10), MEDLINE (1 January 1946 to Week 4 October 2014), MEDLINE In-Process and other non-indexed citations (covering 27 November 2014; all searched on 28 November 2014), EMBASE Classic and EMBASE (1 January 2010 to Week 47 2014, searched on 28 November 2014), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (searched on 1 December 2014 and 3 December 2014, respectively), as well as the reference lists of relevant articles. Randomised and quasi-randomised trials comparing clinical outcomes in men who were and were not investigated with the use of invasive urodynamics, or comparing one type of urodynamics against another, were included. Trials were excluded if they did not report clinical outcomes. Three review authors independently assessed trial quality and extracted data. We included two trials, but data were available for only 339 men in one trial, of whom 188 underwent invasive urodynamic studies. We found evidence of risk of bias, such as lack of outcome information for 24 men in one arm of the trial.Statistically significant evidence suggests that the tests did change clinical decision making. Men in the invasive urodynamics arm were more likely to have their management changed than men in the control arm (proportion with change in management 24/188 (13%) vs 0/151 (0%), risk ratio (RR) 39.41, 95% confidence interval (CI) 2.42 to 642.74). However, the quality of the evidence was low.Low-quality evidence indicates that men in the invasive urodynamics group were less likely to undergo surgery as treatment for voiding LUTS (164/188 (87%) vs 151/151 (100%), RR 0.87, 95% CI 0.83 to 0.92).Investigators observed no difference in urine flow rates before and after surgery for LUTS (mean percentage increase in urine flow rate, 140% in invasive urodynamic group vs 149% in immediate surgery group, P value = 0.13). Similarly, they found no differences between groups with regards to International Prostate Symptom Score (IPSS) (mean percentage decrease in IPSS score, 58% in invasive urodynamics group vs 59% in immediate surgery group, P value = 0.22).No evidence was available to demonstrate whether differences in management equated to improved health outcomes, such as relief of symptoms of voiding dysfunction or improved quality of life.No evidence from randomised trials revealed the adverse effects associated with invasive urodynamic studies. Although invasive urodynamic testing did change clinical decision making, we found no evidence to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment. Larger definitive trials of better quality are needed, in which men are randomly allocated to management based on invasive urodynamic findings or to management based on findings obtained by other diagnostic means. This research will show whether performance of invasive urodynamics results in reduced symptoms of voiding dysfunction after treatment.

The Cardiovascular Effects Produced by Intracerebroventricular Microinjection of N/OFQ in Angiotensin II/High Salt Diet Rats.

Intracerebroventricular (ICV) administration of the opioid‐like peptide, nociceptin/Orphanin (N/OFQ), produces a free water diuresis, in addition to marked effects on cardiovascular function and renal sympathetic nerve activity (RSNA). The present study utilized an angiotensin II high salt diet (ANGII) hypertension model to determine the central‐mediated cardiovascular effects of N/OFQ in anesthetized rats. Rats were chronically instrumented with cannulas in the femoral artery, femoral vein and urinary bladder and implanted with a renal nerve electrode. Cardiovascular and renal parameters were measured during control (C, two 10‐minutes) and for 60 minutes after ICV injection of saline vehicle or N/OFQ (10 mg/5 ml) in normotensive or ANGII rats. ICV N/OFQ produced a marked decrease in heart rate (HR), mean arterial pressure (MAP) and RSNA in both normotensive and ANGII rats. However, N/OFQ produced greater percentage decreases in HR, MAP and RSNA in ANGII rats than normotensive rats. N/OFQ also produced a significant increase in urine flow rate (V) in both groups, but ANGII blunted this diuretic effect. ICV saline did not produce any significant changes in any of the measured parameters. These findings suggest that, in urethane‐alpha‐chloralose anesthetized rats, N/OFQ appears to have greater effect on the cardiovascular system than on the renal. As such, drugs targeting the central N/OFQ receptors could facilitate the lowering of blood pressure in diseases, such as salt‐sensitive hypertension. Supported by NIH 5SC2 HL104639

Contrast-induced acute kidney injury: potential new strategies.

Contrast-induced acute kidney injury (CI-AKI) is an impairment of renal function following contrast media administration in the absence of an alternative cause. It represents a powerful predictor of poor early and late outcomes. Here, we review the major strategies to prevent CI-AKI. Hydration represents the gold standard as a prophylactic measure to prevent CI-AKI, acting by increasing urine flow rate and, thereby, by limiting the time of contact between the contrast media and the tubular epithelial cells. An optimal hydration regimen should be defined according to predefined clinical markers, such as urine flow rate, or left ventricular end-diastolic pressure. Recently, high-dose statins pretreatment has been included in the guidelines of CI-AKI prevention. However, uncertainty still exists on the efficacy of several compounds tested in both observational trials and randomized studies to prevent CI-AKI. Compounds evaluated include diuretics (furosemide), antioxidants (i.e. N-acetylcysteine and statins) and vasodilators (i.e. calcium antagonists, dopamine and fenoldopam). Hydration still represents the most reliable strategy to prevent CI-AKI. New prophylactic strategies for acute kidney injury are still under investigation.

Acute pretreatment with chloroquine attenuates renal I/R injury in rats.

BackgroundAcute kidney injury (AKI) still remains an unresolved problem in pharmacotherapy and renal inflammation is a major factor in its development. Chloroquine, a well-known antimalarial drug, posses pleitropic effects as well: antiinflammatory, anticoagulant and vascular actions. The effects of chloroquine on renal function may involve significant increase in urine flow rate, glomerular filtration rate and sodium excretion, as well as stimulation of nitric oxide synthase. However, its role in experimental models of renal I/R injury is unknown. We aimed to analyze the acute effects of a single-dose intravenous chloroquine administered at three different times in the experimental model of I/R injury in rat.MethodsRats were subjected to bilateral renal ischemia (45 min) followed by reperfusion with saline lasting 4 hours. Chloroquine was administered in doses of 0.3 mg/kg i.v. and 3 mg/kg i.v. 30 min before ischemia, 30 min before reperfusion and 5 min before reperfusion. Selected a hemodynamic, biochemical and morphological parameters were followed in the Sham-operated animals and rats subjected to I/R injury and pretreated with saline or chloroquine.ResultsChloroquine (0.3 and 3 mg/kg, i.v.) protected the I/R injured kidney in an U-shaped manner. Both doses were protective regarding biochemical and histological markers of the I/R injury (serum urea, creatinine and fractional excretion of sodium, as well as total histological score, tubular necrosis score and KIM-1 staining score) (P<0.05 vs. corresponding controls, i.e. rats subjected to I/R injury and treated with saline only). The protective effects of the lower dose of chloroquine were more profound. Time-related differences between pretreatments were not observed (P>0.05, all).ConclusionOur study shows for the first time that a single dose of chloroquine (0.3 mg/kg i.v.) could afford significant protection of the injured rat kidney.