Electrolyte Excretion Research Articles

Evaluation of nocturnal blood pressure changes and urinary electrolyte excretion in children with enuresis.

Monosymptomatic nocturnal enuresis (MNE) is defined as involuntary nighttime urination of children over five years of age without any congenital or acquired defect in the central nervous system. Many factors, mainly nocturnal polyuria, sleep disorders, decreased bladder capacity, and bladder dysfunctions play a role in the etiology of MNE. Eighty-three children diagnosed with MNE were included in the study. Complete blood cell count, blood biochemistry, renin, and aldosterone levels of all children were obtained. Twenty-four-hour urine samples were collected separately daytime and nighttime and urinary electrolytes were evaluated. Also, 24-hour ambulatory blood pressure monitoring (ABPM) was performed for each patient. The results were evaluated by comparing both enuretic children vs. control group and enuretic children with polyuria vs. without polyuria. When we compared the enuretic children and the control group in terms of urinary electrolytes, the fractional excretion of sodium (FENa) and fractional excretion of potassium (FEK) values of the enuretic group were higher than the control. The evaluation of the 24-hour ABPM findings revealed no significant difference in terms of the mean arterial pressure (MAP) and diastolic blood pressure (DBP) during the daytime and nighttime measurements. The daytime systolic blood pressure (SBP), however, was significantly lower in the enuretic group. When enuretic children with and without polyuria and the control group were compared, the nighttime, FENa, FEK, as well as nighttime urinary excretion of calcium and protein were significantly higher in enuretic children with polyuria. No difference was detected on the MAP, SBP, or DBP values. In conclusion, the nighttime urinary solute excretion of enuretic children was found to be higher and this condition may especially be associated with pathogenesis of nighttime polyuria. In enuretic children, nighttime blood pressure changes were not influential in the etiopathogenesis in all patient groups and multiple mechanisms may play a role in the pathogenesis of enuresis.

Evaluation of Diuretic activity of Fractional Extracts of Ajuga remota Benth (Lamiaceae) in Albino mice

The present study was evaluated the in vivo diuretic activity of fractional extracts of A. remota in albino mice. The dried aqueous crude extracts were subjected to soxhlet extraction by n-butanol, methanol and water solvents. The mice were randomly divided into eleven groups with 8 mice in each. All fractions were administered orally at doses of 250, 500 and 1000 mg/kg to adult male mice, and the positive and negative controls were treated with furosemide (10 mg/kg, p.o) and the vehicle distilled water (2 ml/100 gm of body weight) respectively. The diuretic effect of the extracts was evaluated by measuring urine volume, urinary electrolytes and urinary pH. The result indicates that aqueous and methanolic fractions at 1000 mg/kg dose produced significant (p<0.001) increase in urine output and electrolyte excretion (p<0.001) when compared to control. Additionally, potassium sparing activity (27%, p<0.05) and high natriuretic index (2.7-3.03) were produced by the n-butanol fraction relatively even if it showed minimal effect on urine output. Therefore, from the present study it may be concluded that the compounds present in methanolic and aqueous fraction are responsible for diuretic activity. This finding together with previous results on the aqueous crude extracts provides a quantitative basis for developing a new diuretic medicine from A. remota plant.

Fractional electrolyte excretion and osmolality in the early diagnosis of acute kidney injury in cats with urethral obstruction

Acute Kidney Injury (AKI) can be defined as a spectrum of diseases associated with a sudden onset of a renal failure status, the feline patient has azotemia, the disorder in fractional electrolyte excretion (FE), and shedding of epithelial cells from renal tubular segments observed in the urinary sediment. Thus, the objective of the present study was to evaluate the FE, plasma and urinary osmolality, and urinary specific gravity (USG) in cats that spontaneously developed AKI due to urethral obstruction (UO) and healthy cats. Blood and urine samples were collected from a group of 20 cats diagnosed with AKI secondary to urethral obstruction (GAKI; n=20) and clinically healthy cats (GC; n=15). The serum creatinine (sCre) and urinary creatinine (uCre), were measured by spectrophotometry, serum and urinary analyzes of sodium, potassium and chloride by ion selective electrode device and serum and urinary osmolarity by osmometer. The GAKI results were statistically compared with those of the CG using Student's t tests to assess normal data, while the Maan-Whitney test was used for non-normal data. A significant increase in the sCr, sK, FENa, FECl and RFI parameters of the GAKI cats when compared to the GC (p < 0.05). The sCl, USG, uCr, uK and uOSM parameters decreased significantly when compared between the two groups. Thus, given the established methodology and the results found, it is possible to infer that an increase in EFNa, EFCl in addition to the RFI and a decrease in USG and uOSM were associated with cats with AKI and can serve as markers of kidney damage, as well as monitoring the prognosis.

Renal Magnesium Handling: A Comparison Between Dogs With Chronic Kidney Disease and Healthy Elderly Dogs

Chronic kidney disease (CKD) and aging are known to possibly cause a progressive reduction in glomerular filtration rate, which may be associated with an increase in fractional excretion of electrolytes due to an adaptive response of the remaining functioning nephrons. However, the behavior of magnesium excretion has not been studied in CKD and healthy elderly dogs. The objective was to evaluate the fractional excretion of magnesium (FEMg) in dogs with (CKD) compared to healthy elderly dogs. Sixteen healthy elderly dogs and 43 dogs with CKD were divided into 3 groups (CKD 2 [n = 14], CKD 3 [n = 17], CKD 4 [n = 12]), in accordance with the current International Renal Interest Society (IRIS) criteria that were used in this study. Blood samples were obtained by jugular venipuncture and urine samples were obtained by cystocentesis. The FEMg was evaluated at a single time point in both urine and blood samples. FEMg was significantly higher in dogs with CKD compared to healthy elderly dogs, especially in advanced stages. This preliminary study demonstrates that FEMg may be altered in dogs with CKD. Further research is warranted to elucidate magnesium's potential role in cardiovascular and arterial calcification in dogs with CKD as observed in humans with CKD.

COMPARATIVE STUDY ON DIURETIC ACTIVITY OF DIFFERENT PLANT SOURCES USED AS MORAT [CONTROVERSIALAYURVED PLANT

Morat is considered as a signicant medicinal plant in the Indian system of medicine [Ayurveda] as it is very effective in various Urinary disorders. Under the name of Morat, botanical identity such as Leea macrophylla Roxb., Saccharum officinarum L., Alangium lamarkii Thw. Marsdenia tenacissima Wight. & Arn., Maerua arenaria Hook, Chonemorpha macrophylla (Roxb) G. Don are considered as they exhibit same medicinal properties. The purpose of this work was to differentiate the plants which are known as Morat by determining and comparing their diuretic activity by Lipschitz method. Two positive control Furosemide (standard drug) & Cystone (herbal plant compound) were compared. The effect on electrolytes changes and urine output were measured. In the result, decoction of all plants has shown diuresis except M. tenacissima. In inter comparison C. macrophylla decoction produced most signicant diuresis & excretion of electrolytes. This suggest that use of C. macrophylla root as “Morat”; most effective diuretic plant.

Whey beverage improves hydrating capacity of the soccer players

The hydration process is critical in soccer players. The hydrating capacity, energy recovery, and electrolyte excretion in urine were determined by the use of a whey beverage as a hydration medium for high-performance athletes compared to the effects of purified water and a sport beverage. The study was carried out through an approved research protocol, which contemplates the determination of hydrating capacity by monitoring body weight during a period of exercise and a subsequent hydration period. Energy recovery was determined by monitoring blood glucose levels and electrolyte excretion was performed by quantifying the concentration of sodium (Na+ ), potassium (K+ ), calcium (Ca2+) and magnesium (Mg2+) in urine samples provided by the participants during the research protocol. It was concluded that the whey beverage has an appropriate capacity for hydration and energy recovery, while with regard to minerals it was observed that it effectively regulates the excretion of Na+ , Ca2+ and Mg2+ .

Pharmacokinetics and diuretic effect of furosemide after single intravenous, oral tablet, and newly developed oral disintegrating film administration in healthy beagle dogs

BackgroundFurosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal patients, which leads to noncompliance, especially during long-term administration. Oral disintegrating film (ODF) has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The objective of this study was to research the pharmacokinetic (PK) profiles and diuretic effect of furosemide after intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered a single dose (2 mg/kg) of furosemide via each route using a cross-over design.ResultsThe most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. In the blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h), whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF).ConclusionsThese results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (< 10 kg), for the management of congestive heart failure.

Stage 1-Biomarkers of Kidney Injury in Dogs Undergoing Constant Rate Infusion of Hydroxyethyl Starch 130/0.4.

Simple SummaryConcern about the use of hydroxyethyl starch (HES) and the development of kidney injury has emerged in human medicine. In veterinary medicine, some retrospective and prospective studies were conducted to investigate the presence of renal damage in dogs using different types and dosages of hydroxyethyl starch. The present study aimed to evaluate the effects of the constant rate infusion of HES 130/0.4 at a dose of 2 mL/kg/h for 24 h on the renal biomarkers of tubular damage and dysfunction. Ten adult dogs with hypoalbuminemia were enrolled, and serum creatinine, fractional excretion of electrolytes, urinary protein to creatinine ratio, urinary albumin to creatinine ratio, qualitative proteinuria, and urinary neutrophil gelatinase-associated lipocalin were measured at the baseline before HES infusion and after 24 and 48 h from the baseline. No significant change in the selected renal biomarkers was observed across time, ruling out the possibility of significant tubular damage after HES 130/0.4 infusion at the dose and rate applied. Further prospective studies are needed to assess the renal safety profile of low-molecular-weight HES administration in more severely affected dogs.In veterinary medicine, investigations relating the effects of hydroxyethyl starch (HES) on renal function report contrasting results. This study aimed to assess the changes in the selected biomarkers of kidney injury in dogs after the administration of HES 130/0.4 as a constant rate infusion (CRI) for 24 h. Ten adult client-owned dogs with hypoalbuminemia (albumin < 2 g/dL) and ongoing fluid losses were included. Enrolled dogs received intravenous fluid therapy with crystalloids and a CRI of HES 130/0.4 at a dose of 2 mL/kg/h for 24 h. Serum creatinine (sCr), fractional excretion (FE) of electrolytes, urinary protein to creatinine ratio (UPC), urinary albumin to creatinine ratio (UAC), SDS-page, and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were measured at the baseline before HES infusion, and after 24 h (T24) and 48 h (T48) from the baseline. No statistically significant difference was found between the baseline value vs. T24 and the baseline vs. T48 for sCr, UAC, UPC, FE of sodium, chloride and calcium, and uNGAL. A significant increase in FEK (p = 0.04) was noticed between the baseline and T48. In this study sample of hypoalbuminemic dogs, HES 130/0.4 at the dose and rate of infusion applied did not cause any significant changes in the investigated biomarkers of kidney injury.

Hemodynamic, renal and hormonal effects of lung protective ventilation during robot-assisted radical prostatectomy, analysis of secondary outcomes from a randomized controlled trial

BackgroundLung protective ventilation with low tidal volume (TV) and increased positive end-expiratory pressure (PEEP) can have unfavorable effects on the cardiovascular system. We aimed to investigate whether lung protective ventilation has adverse impact on hemodynamic, renal and hormonal variables.MethodsIn this randomized, single-blinded, placebo-controlled study, 24 patients scheduled for robot-assisted radical prostatectomy were included. Patients were equally randomized to receive either ventilation with a TV of 6 ml/IBW and PEEP of 10 cm H2O (LTV-h.PEEP) or ventilation with a TV of 10 ml/IBW and PEEP of 4 cm H2O (HTV-l.PEEP). Before, during and after surgery, hemodynamic variables were measured, and blood and urine samples were collected. Blood samples were analyzed for plasma concentrations of electrolytes and vasoactive hormones. Urine samples were analyzed for excretions of electrolytes and markers of nephrotoxicity.ResultsComparable variables were found among the two groups, except for significantly higher postoperative levels of plasma brain natriuretic peptide (p = 0.033), albumin excretion (p = 0.012) and excretion of epithelial sodium channel (p = 0.045) in the LTV-h.PEEP ventilation group compared to the HTV-l.PEEP ventilation group. In the combined cohort, we found a significant decrease in creatinine clearance (112.0 [83.4;126.7] ml/min at baseline vs. 45.1 [25.4;84.3] ml/min during surgery) and a significant increase in plasma concentrations of renin, angiotensin II, and aldosterone.ConclusionLung protective ventilation was associated with minor adverse hemodynamic and renal effects postoperatively. All patients showed a substantial but transient reduction in renal function accompanied by activation of the renin-angiotensin-aldosterone system.Trial registrationClinicalTrials, NCT02551341. Registered 13 September 2015.

Circadian Control of Sodium and Blood Pressure Regulation.

The attention for the control of dietary risk factors involved in the development of hypertension, includes a large effort on dietary salt restrictions. Ample studies show the beneficial role of limiting dietary sodium as a lifestyle modification in the prevention and management of essential hypertension. Not until the past decade or so have studies more specifically investigated diurnal variations in renal electrolyte excretion, which led us to the hypothesis that timing of salt intake may impact cardiovascular health and blood pressure regulation. Cell autonomous molecular clocks as the name implies, function independently to maintain optimum functional rhythmicity in the face of environmental stressors such that cellular homeostasis is maintained at all times. Our understanding of mechanisms influencing diurnal patterns of sodium excretion and blood pressure has expanded with the discovery of the circadian clock genes. In this review, we discuss what is known about circadian regulation of renal sodium handling machinery and its influence on blood pressure regulation, with timing of sodium intake as a potential modulator of the kidney clock.

Diurnal rhythms of urine volume and electrolyte excretion in healthy young men under differing intensities of daytime light exposure

In humans, most renal functions, including urine volume and electrolyte excretions, have a circadian rhythm. Light is a strong circadian entrainment factor and daytime-light exposure is known to affect the circadian rhythm of rectal temperature (RT). The effects of daytime-light exposure on the diurnal rhythm of urinary excretion have yet to be clarified. The aim of this study was to clarify whether and how daytime exposure to bright-light affects urinary excretions. Twenty-one healthy men (21–27 years old) participated in a 4-day study involving daytime (08:00–18:00 h) exposure to two light conditions, Dim (< 50 lx) and Bright (~ 2500 lx), in a random order. During the experiment, RT was measured continuously. Urine samples were collected every 3 ~ 4 h. Compared to the Dim condition, under the Bright condition, the RT nadir time was 45 min earlier (p = 0.017) and sodium (Na), chloride (Cl), and uric acid (UA) excretion and urine volumes were greater (all p < 0.001), from 11:00 h to 13:00 h without a difference in total daily urine volume. The present results suggest that daytime bright light exposure can induce a phase shift advance in urine volume and urinary Na, Cl, and UA excretion rhythms.

Measurement of Selected Renal Biochemical Parameters in Healthy Adult Donkeys Considering the Influence of Gender, Age and Blood Freezing.

Simple SummaryIn animal medicine, laboratory test profiles containing selected blood or urine parameters are used to diagnose diseases of a given organ. The normal values of the serum and urine biochemical parameters are well-known in horses, but they have not been studied well in donkeys. This means that their results are often compared with horses’ reference values. The interest in donkeys continues to grow, as well as increasing attention being paid to kidney damage in animals. The objective of the study was to determine the values of the selected serum and urine parameters to assess the renal function in healthy donkeys. The effects of age, sex and freezing of the material were then assessed. Sixty-five healthy adult donkeys participated in the study. The results showed different reference values for the kidney parameters such as urea, total protein, albumin, urine protein/creatinine ratio and fractional electrolyte excretion in donkeys compared to those reported for horses. The donkeys’ gender had an effect on the creatinine and urea, while age had an effect on the albumin, total protein and electrolytes. Freezing of the material also influenced most of the parameters. To the authors’ knowledge, this is the first study to analyze the selected renal biomarkers in donkeys.The reference values of the serum and urine biochemical parameters have not been well-studied in donkeys. This study aimed to assess the normal values of the selected renal biomarkers, such as: serum creatinine, blood urea nitrogen (BUN), albumin, total protein (TP), electrolytes and symmetric dimethylarginine (SDMA), urine protein concentration (UPC), urine protein/creatinine ratio (UPCR), the urine gamma-glutamyl transferase (GGTP)-to-creatinine ratio, serum creatinine-to-urine creatinine ratio (sCr/uCr), serum BUN-to-serum creatinine ratio (sBUN/sCr) and UPC-to-TP ratio, as well as the fractional electrolyte excretion of sodium (FENa) and potassium (FEK) in donkeys. The effects of age, gender and deep freezing of the serum material were investigated. Sixty-five healthy adult donkeys were involved in this study. The results showed higher BUN and TP values and lower albumin, UPCR, FENa and FEK levels in donkeys when compared to the reference values in horses. A significant gender relationship for creatinine and BUN was found. Age influenced the values of albumin, TP, potassium and chlorine. Potassium, sodium and SDMA did not show significant concentration changes after freezing. The study results demonstrated that horse reference range values for some parameters cannot be applied to donkey samples. Only a few of the serum parameters were not affected by freezing, and this should be taken into account when storing biological materials.

419-P: Correlation between 24-Hour Urinary Electrolyte and Urinary Albumin in Patients with Type 2 Diabetes

Objective: To explore the characteristics of 24-hour urinary electrolyte excretion in patients with type 2 diabetes mellitus (T2DM), and its correlation with urinary albumin and early renal injury. Methods: A total of 1475 T2DM and 265 nondiabetic patients (ND group) from 2018 to 2020 were enrolled. According to the urinary albumin excretion rate (UAER), T2DM patients were divided into normal albuminuria group (NA group): UAER &amp;lt; 30mg/24h; Microalbuminuria group (MA group): UAER 30~300 mg/24 h; massive albuminuria group (PR group): UAER &amp;gt; 300mg/24h. The characteristics of 24h urinary electrolyte excretion in different groups were observed and the correlation between 24h urinary electrolyte excretion and urinary albumin was analyzed. Results: We found that 24h urinary potassium, sodium, chlorine, phosphorus and magnesium in all subgroups of T2DM were higher than those in ND group (P &amp;lt; 0.001), 24h urinary calcium in ND group was higher than that in PR group (4.3±2.1 vs. 3.2±2.5, P &amp;lt; 0.001), but lower than that in NA group (4.3±2.1 vs. 4.7±2.8, P &amp;lt; 0.001). As urinary albumin increased, 24h urinary calcium of T2DM patients showed a decreasing trend while the other urinary electrolytes showed an increasing trend (P &amp;lt; 0.001). Urinary albumin was positively correlated with 24h urinary potassium, sodium, chlorine, phosphorus, magnesium (r=0.133~0.169, P &amp;lt; 0.001) and negatively correlated with 24h urinary calcium (r= -0.130, P &amp;lt; 0.001). Multiple linear regression showed that 24h urinary potassium was an independent influencing factor of urinary albumin (β = 0.178, P &amp;lt; 0.001). Conclusion: There is a difference in 24h urinary electrolyte excretion between T2DM and nondiabetic patients. The urinary electrolyte excretion of T2DM patients varies with urinary albumin. 24h urinary electrolyte excretion changes before the appearance of albuminuria, which may be an indicator of early renal injury. High urinary potassium may serve as a parameter to predict early diabetic nephropathy. Disclosure Y. Wang: None. M. Zhang: None. H. Li: None. S. Qu: None.

Diuretic activities of hydro-alcoholic extract and solvent fractions of the roots of Withania somnifera L. (Solanacaea) in rats

Background: Withania somnifera (Local name ‘Gsawa’) is used in folkloric medicine for the management of hypertension in different parts of the world including Ethiopia. This may be due to its diuretic activity. However, it has not been yet scientifically validated for its efficacy and safety. Objective: The aim of this study was to investigate the diuretic potential of both hydro-alcoholic (80% methanol) extract and solvent fractions of the hydro-alcoholic root extract of W. somnifera in rats. Results: The hydro-alcoholic extract increased diuresis significantly at the doses of 400 and 600mg/kg (p<0.05). Similarly, the solvent fractions of the hydro-alcoholic extract -the aqueous and n-butanol fractions- significantly increased urine volume at 400mg/kg (p<0.05). Regarding electrolyte excretion, the larger doses of both hydro-alcoholic extract and aqueous fraction increased natriuresis (p<0.05). Phytochemical analysis revealed the presence of secondary metabolites including tannins, terpenoids, flavonoids and saponins, which could be the responsible component (s) for the diuretic activity. Conclusion: The results of the present study indicated that the W. somnifera extract is endowed with significant diuretic activity providing evidence for its traditional claim. The increased diuresis effects of the crude extracts and fractions may be attributable for presence of polar phytoconstitutents. Background: Withania somnifera (Local name ‘Gsawa’) is used in folkloric medicine for the management of hypertension in different parts of the world including Ethiopia. This may be due to its diuretic activity. However, it has not been yet scientifically validated for its efficacy and safety. Objective: The aim of this study was to investigate the diuretic potential of both hydro-alcoholic (80% methanol) extract and solvent fractions of the hydro-alcoholic root extract of W. somnifera in rats. Results: The hydro-alcoholic extract increased diuresis significantly at the doses of 400 and 600mg/kg (p<0.05). Similarly, the solvent fractions of the hydro-alcoholic extract -the aqueous and n-butanol fractions- significantly increased urine volume at 400mg/kg (p<0.05). Regarding electrolyte excretion, the larger doses of both hydro-alcoholic extract and aqueous fraction increased natriuresis (p<0.05). Phytochemical analysis revealed the presence of secondary metabolites including tannins, terpenoids, flavonoids and saponins, which could be the responsible component (s) for the diuretic activity. Conclusion: The results of the present study indicated that the W. somnifera extract is endowed with significant diuretic activity providing evidence for its traditional claim. The increased diuresis effects of the crude extracts and fractions may be attributable for presence of polar phytoconstitutents. Background: Withania somnifera (Local name ‘Gsawa’) is used in folkloric medicine for the management of hypertension in different parts of the world including Ethiopia. This may be due to its diuretic activity. However, it has not been yet scientifically validated for its efficacy and safety. Objective: The aim of this study was to investigate the diuretic potential of both hydro-alcoholic (80% methanol) extract and solvent fractions of the hydro-alcoholic root extract of W. somnifera in rats. Results: The hydro-alcoholic extract increased diuresis significantly at the doses of 400 and 600mg/kg (p<0.05). Similarly, the solvent fractions of the hydro-alcoholic extract -the aqueous and n-butanol fractions- significantly increased urine volume at 400mg/kg (p<0.05). Regarding electrolyte excretion, the larger doses of both hydro-alcoholic extract and aqueous fraction increased natriuresis (p<0.05). Phytochemical analysis revealed the presence of secondary metabolites including tannins, terpenoids, flavonoids and saponins, which could be the responsible component (s) for the diuretic activity. Conclusion: The results of the present study indicated that the W. somnifera extract is endowed with significant diuretic activity providing evidence for its traditional claim. The increased diuresis effects of the crude extracts and fractions may be attributable for presence of polar phytoconstitutents.

Plasma Renin Activity after Diuretic Treatment in Patients with Stable Heart Failure: With Special Reference to its Association with Electrolyte Chloride

A recent study reported an intimate association between urinary chloride (Cl) and plasma renin activity (PRA) in acute heart failure (HF) status, reflecting normal functioning of the ‘tubulo-glomerular feedback’ mechanism. Whether the ‘tubuloglomerular feedback’ mechanism functions normally in stable HF status, however, is unclear. This study examined whether the ‘tubulo-glomerular feedback’ mechanism functions normally under resolution of worsening HF after decongestive therapy. Data from 26 patients with acute HF and its recovery after decongestive therapy were analyzed. Clinical tests included measurement of peripheral blood tests, serum and spot urinary electrolytes, plasma neurohormones, and fractional urinary excretions of electrolytes. In a total of 26 patients, PRA increased after acute HF treatment (from 1.64±2.0 to 5.48±6.1 ng/ mL/h, p=0.002). Changes in the serum logPRA and urinary Cl concentration from worsening to its recovery tended to be inversely correlated (R2 =0.12, p=0.085) and logPRA and the serum Cl concentration at recovery were inversely correlated (R2 =0.23, p=0.01). When divided into 2 groups (n=13 in each) according to the median PRA, the group with greater PRA changes showed a larger decrease in the urinary Cl concentration (from 110±44 to 72.8±38, p=0.03). The group with higher PRA at recovery showed a lower serum Cl concentration than the group with lower PRA at recovery (102±6.5 vs 107±4.2 mEq/L, p=0.04). In conclusion, the association between PRA and the serum/urinary Cl concentration is blunted in stable HF under-decongestive therapy, possibly due to the physiologic status under full cardiovascular medication compared with that in acute HF status.

Empagliflozin ameliorates symptoms of diabetes and renal tubular dysfunction in a rat model of diabetes with enlarged kidney (DEK).

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to reduce hyperglycemia. The present study investigated the effects of a SGLT2 inhibitor, empagliflozin, on hyperglycemia in a novel rat model of non-obesity type 2 diabetes with enlarged kidney (DEK).MethodsMale DEK rats with non-fasting blood glucose concentrations ≤300 mg/dl and >300 mg/dl were classified as nondiabetic and diabetic, respectively. Groups of nondiabetic (control) and diabetic (DM-cont) rats were fed standard chow for 12 weeks, whereas another group of diabetic (DM-empa) rats was fed standard chow containing empagliflozin (300 mg/kg/day) for 12 weeks. Blood glucose, body weight, glucose tolerance, food and water intake, urinary volume, plasma and urinary biochemical parameters, and bone mineral density were measured, and their kidneys and pancreas histologically analyzed.ResultsTreatment with empagliflozin reduced blood glucose concentration and food intake in diabetic rats, but inhibited loss of adeps renis and led to body weight gain. Empagliflozin attenuated polyuria and polydipsia but increased plasma concentrations of total cholesterol, sodium and total protein toward normal level. Empagliflozin also significantly reduced urinary excretion of proteins and electrolytes and restored bone mineral density and plasma concentrations of valine and isoleucine to normal levels. Moreover, dilation of renal tubules and kidney enlargement were not attenuated in the DM-empa group.ConclusionThe response of DEK rats to empagliflozin differed from that of other diabetic animal models, suggesting that DEK rats have unique characters for studying and evaluating the multiple biological effects of SGLT2 inhibitors. These findings also indicted that empagliflozin could ameliorate systemic metabolism and improve renal tubule function in diabetic condition.

Physiological effects of histamine on renal function in salt‐sensitive hypertension

Introduction . Histamine is a regulatory agent involved in the immune response, neurotransmission, and gastric acid secretion, and is produced and released from the mast cells and basophils. Elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in kidney diseases. The goal of this study is to provide insight into the physiological importance of the histamine-related pathways in salt-sensitive hypertension (SSH), a disease accompanied with inflammation-driven kidney damage. Methods . SSH was induced in Dahl Salt-Sensitive (DSS) rats by a 3-week long high salt diet challenge (HS, 4% NaCl); age-matched normal salt diet (NS, 0.4% NaCl) fed rats were used as a control group. To characterize the expression of histamine receptors, mast cells markers, and histamine metabolism-related enzymes, Western blot or IHC were performed on renal tissues collected from DSS rats maintained on HS or NS diets for 3 weeks. In order to test the effects of histamine receptor 2 (HR2) inhibition, he DSS rats were injected with a single daily i.p. dose of an HR2 blocker, ranitidine (RAN, 25mg/kg in saline) or saline (VEH), for 3 consecutive days before the switch to a HS diet, and at the end of the 21-day long HS challenge. Urine and water consumption were assessed in metabolic cages during hours 0-8 (acute), and 8-24 post-injections. At the end of the protocol, GFR was measured, and tissues were harvested. Results . Western blots revealed similar expression of the mast cell markers’ (FCER1A and tryptase) in NS and HS diet fed rats, however, we observed significantly lower histamine decarboxylase (HDC, p=0.002), and higher histamine N-methyltransferase (HNMT, p=0.035) levels in HS diet fed rats. Renal IHC revealed that expression of HR2 was downregulated, while HR3 and HR4 were upregulated in the collecting ducts of HS diet fed rats. In vivo experiments showed that RAN-administered rats on NS diet exhibited an acute (8-24 hr period) decrease in urine output and 24 h water intake on day 1 of injections (p=0.01). We observed trends for an increase in urinary electrolytes, and an overall increase in the excretion of osmolesin RAN vs VEH animals 24 hours post day 1 injection on the NS diet. Post HS challenge, electrolyte excretion, urine flow and water intake were similar between RAN and VEH animals. At the endpoint on HS, GFR between the groups was similar on day 3 post-injection. Conclusions . Differential expression of HRs, as well as changes in the enzymes responsible for histamine synthesis and metabolism between HS and NS fed rats, indicate a shift in the renal histaminergic tone during SSH development. Similar mast cell levels suggest an alternate, perhaps intrarenal, source of histamine. Our in vivo data show that inhibition of HR2 has effects on urine output and water consumption in SSH. Further research is required to discern the molecular pathways downstream of specific HRs, as well as the consequences of chronic administration of HR-specific pharmacology, in renal pathophysiology.

The Role of Superoxide in Sex Differences in Angiotensin II‐induced Hypertensive and Natriuretic Responses in Mice with Proximal Tubule‐Specific Deletion of Mitochondrial Protein Sirtuin 3 in The Kidney

Sirtuin 3 (SIRT3), aNAD-dependent deacetylase, is a major mitochondrial protein in the matrix that is encoded by the SIRT3 gene. The key functions of SIRT3 in the mitochondria include anti-oxidative, anti-aging, anti-inflammation, and blood pressure-regulating effects by decreasing reactive oxygen species/superoxide production. However, the role of SIRT3 via superoxide in the proximal tubules (PT) of the kidney in angiotensin II-induced hypertensive or natriuretic responses remains poorly understood. To test our hypothesis, five groups of adult male and female wild-type (WT) and PT-SIRT3-/- mice were treated without (Control) or with Ang II (~0.65 mg/kg/day, i.p.) treated with 2% NaCl diet or tempol, a membrane-permeable radical scavenger and superoxide dismutase-mimetic (50 mg/kg/day, p.o.) for 2 weeks. Under basal conditions, systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) were significantly lower in adult male and female PT-SIRT3-/- mice than male and female wild-type mice (~13 ± 3 mmHg, P<0.01). Although there were no sex differences in male and female WT mice, SBP and MAP were significantly lower in female than male PT-SIRT3-/- mice (P<0.01). Urinary excretion of electrolytes including sodium (Na+), potassium (K+), chloride (Cl-), and lithium (Li+) were also significantly lower in female PT-SIRT3-/- mice (P<0.01). In response to Ang II infusion and 2% high salt treatment, SBP was increased similarly to 136 ± 7 mmHg in male and 135 ± 7 mmHg in female PT-SIRT3-/- mice (P<0.01). Urinary Na+, K+, Cl-, and Li+ excretion were all significantly increased in male and female PT-SIRT3-/- mice without significant sex differences in these responses to Ang II-induced hypertension. There were also no sex differences found in response to Ang II infusion alone. Tempol treatment alone had no significant effects on blood pressure and urinary electrolyte excretory responses compared with their basal levels. Interestingly, however, tempol treatment of Ang II-infused and 2% NaCl-fed male and female PT-SIRT3-/- mice revealed significant sex differences in these responses (P<0.01). SBP and MAP increased further in male (P<0.01), but not in female PT-SIRT3-/- mice (n.s.), whereas the natriuretic response was significantly greater in female PT-SIRT3-/- mice (P<0.01). Taken together, we concluded that SIRT3 in the mitochondria of the proximal tubules plays an important role in the development of ANG II-dependent hypertension, and that superoxide may be implicated in sex differences in Ang II-induced hypertensive and natriuretic responses in PT-SIRT3-/- mice.

Acute decrease of urine calcium by amiloride in healthy volunteers under high-sodium diet.

Amiloride is a competitive blocker of the epithelial sodium (Na) channel in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association with its potassium (K)-sparing profile. Whether amiloride has a hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium (Ca) reabsorption in the distal nephron, but human studies are scarce. We performed a post hoc analysis of a study with 48 healthy males (mean ± standard deviation age, 23.2 ± 3.9 years) who were assigned to a high-Na/low-K diet for 7 days before receiving 20 mg of amiloride orally. Urinary excretions of electrolytes were measured at 3 and 6 h afterwards; we calculated the relative changes in urinary excretion rates after amiloride administration. The high-Na/low-K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary Ca excretion dropped substantially (by 80%) 3 h after amiloride administration and remained low at the sixth hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption. During a high-Na/low-K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal Ca reabsorption, even though a distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.

Clinical Significance of Spot Urinary Chloride Concentration Measurements in Patients with Acute Heart Failure: Investigation on the Basis of the ‘TubuloGlomerular Feedback’ Mechanism

Urinary chloride (Cl) is the key electrolyte for regulating renin secretion at the macula densa under the ‘tubulo-glomerular feedback’. Whether or not Cl filtrated into the urinary tubules actually associates with plasma renin activity (PRA) in clinical heart failure (HF) remains unclear. Data from 29 patients with acute worsening HF (48% men; 80.3±12 years) were analyzed. Blood and urine samples were immediately obtained before decongestive therapy after the patients rested in a supine position for 20-min. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), plasma neurohormones, and fractional urinary electrolyte excretion. In the 29 patients, urinary Cl concentrations inversely correlated with logarithmically transformed PRA (R2 =0.41, p=0.0002). The correlation was weaker in worsening chronic HF patients (R2 =0.32, p=0.01) compared with de novo HF patients (R2 =0.70, p=0.0026). Patients were divided into 2 groups according to the median urinary Cl concentration, a low group and a high group. Compared with the high group (100~184 mEq/L; n=14), the low group (4~95 mEq/L; n=15) exhibited more renal (serum creatinine; 1.45±0.63 vs 1.00±0.38 mg/d, p=0.029) and cardiac (log BNP; 2.99±0.3 vs 2.66±0.32 pg/mL, p=0.008 p=0.008) impairment, and higher PRA (3.42±4.7 vs 0.73±0.46 ng/mL/h, p=0.049), and lower fractional excretion of urinary Cl (1.34±1.3 vs 5.33±4.1%, p&lt;0.0001). The present study provides clinical data on the possible functioning of urinary Cl involved in the mechanism of ‘tubulo-glomerular feedback’, and thus advances our understanding of the clinical meanings of the significance of urinary Cl concentration measurement.