Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions - Part I: Loop Diuretics.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and the current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF amongst others, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

A comprehensive review of heart failure: Unraveling the etiology, decoding pathophysiological mechanisms, navigating diagnostic modalities, exploring pharmacological interventions, advocating lifestyle modifications, and charting the horizon of emerging therapies in the complex landscape of chronic cardiac dysfunction.

Heart failure (HF) poses a significant global health burden, necessitating a profound understanding of its multifaceted dimensions. This comprehensive review aims to unravel the etiology, decode pathophysiological mechanisms, navigate diagnostic modalities, explore pharmacological interventions, advocate lifestyle modifications, and chart the horizon of emerging therapies in the complex landscape of chronic cardiac dysfunction. The exploration of HF begins with an insightful journey into its diverse etiological factors, encompassing genetic predispositions, hypertension, and coronary artery disease. Delving into pathophysiological mechanisms, this review elucidates the intricate processes of cardiac remodeling, neurohormonal activation, and cellular dysfunction that underlie the progression of HF. Diagnostic modalities play a pivotal role in unraveling the mysteries of HF by examining advanced imaging techniques, biomarkers, and comprehensive clinical assessments. The pharmacological interventions section provides an in-depth analysis of traditional medications, such as diuretics and angiotensin-converting enzyme inhibitors, while highlighting the emergence of novel drug classes transforming HF management. Advocating lifestyle modifications emphasizes the crucial role of diet, exercise, smoking cessation, and alcohol moderation in enhancing patient outcomes. Lastly, the review delves into the promising horizon of emerging therapies, offering a glimpse into current research, innovative treatment approaches, and potential breakthroughs. As HF management faces challenges in patient compliance, healthcare access, and education, this comprehensive review aims to equip healthcare professionals and researchers with a holistic understanding of chronic cardiac dysfunction's intricacies. In conclusion, synthesizing key findings emphasizes the need for an integrated and multidimensional approach to effectively address the complex landscape of heart failure.

Adherence to Pharmacotherapies After Heart Transplantation in Relation to Multimorbidity and Socioeconomic Position: A Nationwide Register-Based Study.

No studies have examined the impact of multimorbidity and socioeconomic position (SEP) on adherence to the pharmacological therapies following heart transplantation (HTx). Using nationwide Danish registers, we tested the hypothesis that multimorbidity and SEP affect treatment patterns and adherence to pharmacological therapies in first-time HTx recipients. Pharmacological management included cost-free immunosuppressants and adjuvant medical treatment (preventive and hypertensive pharmacotherapies; loop diuretics). We enrolled 512 recipients. The median (IQR) age was 51 years (38-58 years) and 393 recipients (77%) were males. In recipients with at least two chronic diseases, prevalence of treatment with antihypertensive pharmacotherapies and loop diuretics was higher. The overall prevalence of adherence to treatment with tacrolimus or mycophenolate mofetil was at least 80%. Prevalence of adherence to preventive pharmacotherapies ranged between 65% and 95% and between 66% and 88% for antihypertensive pharmacotherapies and loop diuretics, respectively. In socioeconomically disadvantaged recipients, both the number of recipients treated with and adherence to cost-free everolimus, lipid modifying agents, angiotensin-converting enzyme/angiotensin II inhibitors, calcium channel blockers, and loop diuretics were lower. In recipients with multimorbidity, prevalence of treatment with antihypertensive pharmacotherapies and loop diuretics was higher. Among socioeconomically disadvantaged recipients, both number of patients treated with and adherence to cost-free everolimus and adjuvant pharmacotherapies were lower.

[Connotation of Shenqi Pills based on severe cases in cardiovascular care unit and modern pathophysiological mechanism and application of Shenqi Pills for heart failure, renal failure, cardiorenal syndrome, and diuretic resistance in critical care medicine].

Shenqi Pills, first recorded in Essentials from the Golden Cabinet(Jin Kui Yao Lue) from ZHANG Zhong-jing in Han dynasty, have the effect of warming and tonifying the kidney Qi and are mainly used for the treatment of insufficiency of kidney Qi and kidney Yang. According to modern medicine, kidney Qi involves heart function, kidney function, immune function, and so on. The clinical indications of Shenqi Pills include kidney deficiency, abnormal fluid, and abnormal urination, and the last one is classified into little urine, much urine, and dysuria. In clinical settings, Shenqi Pills can be applied for the treatment of heart failure, renal failure, cardiorenal syndrome, and diuretic resistance, as well as endocrine, urological, orthopedic, and other chronic degenerative diseases. Shenqi Pills are ideal prescriptions for the weak constitution and emergency treatment. It is of great value and significance to carry out in-depth research on the connotation of the classic articles by integrating TCM and western medicine based on "pathogenesis combined with pathology and drug properties combined with pharmacology".

Physical and psychological impact of yoga therapy in improving heart failure.

Effective therapy for patients with chronic cardiac failure (CCF) entails significant lifestyle modifications as well as often complex pharmaceutical regimes to alleviate symptoms, which, however, do not actually cure many patients. The gradual loss of cardiac function is impeded but not halted by such complicated pharmacological therapy, which primarily includes angiotensin-converting enzyme inhibitors, beta-blockers and diuretics, and sometimes digoxin, aspirin, warfarin, and anti-arrhythmic agents. Patients may be advised to track their weight and modify their diuretic prescription accordingly to avoid fluid overload or dehydration as part of the treatment plan. Non-pharmacologic treatment options are routinely integrated to improve the management of somatic complaints. Yoga and specialized breathing exercises seem to help CCF patients improve their cardiorespiratory and autonomic system function, and also their quality of life. We present the evidence.

Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

Connotation of Shenqi Pills based on severe cases in cardiovascular care unit and modern pathophysiological mechanism and application of Shenqi Pills for heart failure, renal failure, cardiorenal syndrome, and diuretic resistance in critical care medicine / 中国中药杂志

Shenqi Pills, first recorded in Essentials from the Golden Cabinet(Jin Kui Yao Lue) from ZHANG Zhong-jing in Han dynasty, have the effect of warming and tonifying the kidney Qi and are mainly used for the treatment of insufficiency of kidney Qi and kidney Yang. According to modern medicine, kidney Qi involves heart function, kidney function, immune function, and so on. The clinical indications of Shenqi Pills include kidney deficiency, abnormal fluid, and abnormal urination, and the last one is classified into little urine, much urine, and dysuria. In clinical settings, Shenqi Pills can be applied for the treatment of heart failure, renal failure, cardiorenal syndrome, and diuretic resistance, as well as endocrine, urological, orthopedic, and other chronic degenerative diseases. Shenqi Pills are ideal prescriptions for the weak constitution and emergency treatment. It is of great value and significance to carry out in-depth research on the connotation of the classic articles by integrating TCM and western medicine based on "pathogenesis combined with pathology and drug properties combined with pharmacology".

Treatment of Hypertension: A Review.

Importance: Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death. Observations: First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg. Conclusions and Relevance: Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

Effectiveness of Zhuling decoction on diuretic resistance in patients with heart failure: a randomized, controlled trial.

OBJECTIVE: To test the effects of Zhuling decoction on patients with diuretic resistance in heart failure compared with a group of patients undergoing conventional treatment alone. METHODS: This research was a prospective, randomized, controlled study. From July 2018 to August 2020, 96 diuretic resistance patients from the Cardiovascular Research Center of Taicang Hospital affiliated with Nanjing University of Traditional Chinese Medicine (Grade III Hospital of Traditional Chinese Medicine) were enrolled in the study. The subjects were randomly divided into an observation group (48 cases) and a control group (48 cases). Patients in both groups received conventional treatment. In addition, observation group patients received Traditional Chinese Medicine Zhuling decoction. The primary endpoint was the urine output mean difference between Day 1 and Day 7 after treatment. Secondary endpoints were the changes over time in the N-terminal pro-B type natriuretic peptide (NT-proBNP), New York Heart Association (NYHA) functional classification, and Minnesota Living with Heart Failure Questionnaire (MLHFQ). The safety and tolerability of the drug were comprehensively evaluated based on adverse drug reactions, as well as laboratory-assisted tests for liver and kidney function and electrolytes. RESULTS: Significant improvements were demonstrated for urine output in the two groups at Day 7, with a 1325 1045 mL difference in favor of the observation group ( = 0.018). The observation group also had greater improvements in NT-proBNP and NYHA functional classification changes than the control group. At the 30th day of follow-up, a significant reduction in negative findings on the MLHFQ from baseline was observed in both groups, but the observation group demonstrated a significantly greater reduction than the control group ( <0.001). CONCLUSIONS: Zhuling decoction could be used in combination therapy for patients with diuretic resistance in heart failure in addition to standard treatment.

Use of antihypertensive medications and the risk of glaucoma onset: Findings from the 45 and Up Study.

BACKGROUND: Abnormal blood pressure is a potential risk factor for glaucoma. However, the role of antihypertensive medications on glaucoma pathogenesis is controversial. This study aims to investigate the association between the use of antihypertensive medications and glaucoma onset. METHODS: This nested case-control study, based on a large-scale longitudinal cohort in Australia, retrieved participants' claims records on drugs and Medicare services from national health databases. Participants with three or more claim records of anti-glaucoma medications from 2009 to 2016 were classified as glaucoma patients; those with none were classified as controls. Claim records of antihypertensive medications were identified within the 5 years before glaucoma onset and contemporary periods in matched controls without glaucoma. The association between the use of antihypertensive medications and glaucoma onset was assessed by multivariable logistic regression models. RESULTS: A total of 6748 cases and 13 496 controls were analysed. Compared with controls, the proportion of users of antihypertensive medications was slightly higher in glaucoma patients (46.9% vs. 46.0%, p > 0.05). After adjustments for demographics, health-related factors and medical history, the association between the use of antihypertensive medications and glaucoma onset was nonsignificant (OR 0.95, 95% CI = 0.89-1.02). As for specific subtypes, only beta-blocking agents (BBA) (OR 0.82, 95% CI = 0.75-0.90) and diuretics (OR 0.85, 95% CI = 0.77-0.95) were significantly associated with reduced risks of glaucoma onset. CONCLUSIONS: This study indicated that the use of antihypertensive medications was not associated with glaucoma onset. Decreased risks of glaucoma onset in users of BBA and diuretics require further validation.

Biochemical and molecular effects of a commercial diuretic with herbal extract on experimentally induced urolithiasis in chickens.

This study evaluated the diuretic, antioxidant, anti-inflammatory, and immunological effects of a commercial diuretic (CD) (composed of ammonium chloride, potassium citrate, sodium chloride, ascorbic acid, biotin, halfa bar extract, and hexamine) on chickens with induced urolithiasis. A total of 100 one-day-old white Hy-Line chicks were fed a basal diet containing 20% crude protein (CP) and 1% Ca until they reached 48 days of age. Then, the birds were divided into five groups (G1-G5). G1 was fed a basal diet and kept as a negative control, G2 was fed a high protein (HP) diet containing 25% crude protein, G3 was fed high calcium (HC) diet containing 5% Ca, G4 was fed HP diet supplemented with CD, and G5 was fed HC diet supplemented with CD. The CD was supplemented with drinking water (at a dose of 0.5 ml/ liter) for 1 week. The experiment was held for 78 days. Clinical signs, postmortem lesions, and mortality rates were observed. Biochemical analytes, redox status biomarkers, and expression of interleukin-6 (IL-6) and interferon-gamma (IFN-γ) were measured. Tissue samples were taken for histopathological examination. No signs of CD toxicity were observed during the toxicity test prior to the experiment. Compared to all groups, birds in G2 and G3 showed impaired renal function and alterations in biochemical, redox status, lipid peroxidation, post-mortem, and histopathological lesions along with upregulation of IL-6 and IFN-γ in the kidney and spleen. In conclusion, commercial diuretic supplementation for one week improves renal function, redox status, immune and anti-inflammatory responses in chickens with induced urolithiasis.

Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.

BACKGROUND: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS: We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

[Safety and efficacy of ultrafiltration on heart failure patients with reduced ejection fraction and diuretic resistance: results from a single-center randomized controlled trial].

Objective: To investigate the safety and efficacy of ultrafiltration on diuretic sensitivity in heart failure patients with reduced ejection fraction and diuretic resistance. Methods: This was a single-center randomized controlled trial. A total of 148 heart failure patients with reduced ejection fraction admitted to the Hospital of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region from June 2010 to June 2020 were enrolled in this study, and these patients were randomly divided (ratio 1:1) into the ultrafiltration group (n=74) and the control group (n=74). All patients were treated with diuretics, cardiotonic, vasodilator and other comprehensive drugs according to relevant guidelines. After grouping, the patients in the control group were treated with standard treatment plan, while patients in the ultrafiltration group were treated with ultrafiltration on top of standard therapy. Diuretic drugs were discontinued during ultrafiltration, and intravenously furosemide (40 mg) was given immediately and 24 hours after the end of ultrafiltration. Clinical data including gender, age, complicated diseases, New York Heart Association (NYHA) function classification, etc. were collected. Effectiveness indicators include urine volume (the first 12-hour and 24-hour urine volume and the second 24-hour urine volume after using diuretic), body weight and dyspnea severity score. Safety indicators include systolic blood pressure, serum creatinine, serum Na+ concentration, blood K+ concentration and the number of deaths before and after intervention. Results: Two patients in the control group died due to worsening heart failure after randomization and were excluded in this study, 146 patients were finally analyzed (72 patients in the control group and 74 patients in the ultrafiltration group). There were 93 males, and the age was (68.3±11.2) years. There was no significant difference between patients in the ultrafiltration group and the control group in gender, age, body weight, course of disease, dyspnea severity score, NYHA function classification Ⅲ/Ⅳ, the proportion of patients with severe edema of both lower limbs, the proportion of patients with complicated diseases, and basic medication (all P>0.05). After using diuretics, the urine volume of the first 12-hour and 24-hour and the second 24-hour were significantly higher in the ultrafiltration group than in the control group (all P<0.05). Body weight decreased significantly after ultrafiltration treatment as compared with that before intervention in the ultrafiltration group (P<0.05). Compared with the control group, the dyspnea severity score was significantly improved in the ultrafiltration group (P<0.05). There was no significant difference in systolic blood pressure, serum creatinine, serum Na+ concentration, blood K+ concentration of patients between ultrafiltration group and control group before and after intervention (all P>0.05). During the clinical diagnosis and treatment, 2 male patients in the control group died, and the cause of death was aggravation of basic diseases complicated with acute heart failure and cardiogenic shock. There was no death in the ultrafiltration group, and there were no obvious clinical adverse events during and after ultrafiltration. Conclusion: Ultrafiltration therapy is safe and can improve diuretic sensitivity in heart failure patients with reduced ejection fraction and diuretic resistance.

Shenfu injection combined with furosemide in the treatment of chronic heart failure in patients with coronary heart disease: A protocol of randomized controlled trial.

BACKGROUND: Coronary heart disease (CHD) is an important cause of chronic heart failure, and chronic heart failure is also a serious complication in the end stage of coronary heart disease. At present, there is no specific treatment plan. Shenfu injection has advantages in the treatment of heart failure in patients with coronary heart disease, but there is a lack of standard clinical study to verify this. Therefore, the purpose of this randomized controlled trial is to evaluate the efficacy and safety of Shenfu injection combined with furosemide in the treatment of chronic heart failure in patients with coronary heart disease. METHODS: This is a prospective randomized controlled trial to study the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease and chronic heart failure. This study will be approved by the clinical research ethics committee of our hospital. The patients will be randomly divided into two groups according to 1:1:(a) Shenfu injection combined with furosemide group and (b) simple furosemide group. Standard treatment for 7 days followed up for 30 days at the same time, pay attention to its efficacy and safety indicators. The total effective rate of cardiac function improvement, left ventricular ejection fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-pro BNP), 6-minute walk test (6-MWTD), and adverse reactions will be observed. Data will be analyzed using the statistical software package SPSS version 25.0 (Chicago, IL). DISCUSSION: This study will evaluate the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease with chronic heart failure. The results of this experiment will provide a clinical basis for Shenfu injection combined with furosemide in the treatment of coronary heart disease and chronic heart failure. OSF REGISTRATION NUMBER: doi: 10.17605/OSF.IO/27FPM.

The chemical profiling of aqueous soluble fraction from Lagopsis supina and its diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lagopsis supina (Steph.) Ik. -Gal. ex Knorr. has been widely used as a remedy treatment for diuresis and edema in China over 2500 years. Our previous results showed that the aqueous soluble fraction from L. supina (LSB) possessed acute diuretic effect. AIM OF THE STUDY: The aim of this study was to appraise the acute (6 h) and prolonged (7 d) diuretic effects, underlying mechanisms, and chemical profiling of LSB. MATERIALS AND METHODS: The chemical profiling of LSB was performed by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-qTOF-MS/MS). Then, oral administration of LSB (40, 80, 160 and 320 mg/kg) and furosemide (10 mg/kg) once daily for 7 consecutive days to evaluate the diuretic effects in saline-loaded rats. The body weight, food consumption, and water intake were recorded once daily. The urinary volume, pH and electrolyte concentrations (Na+, K+, Cl-, and Ca2+) were measured after administration drugs for acute and prolonged diuretic effects. In addition, the serum levels of Na+-K+-ATPase, angiotensin II (Ang II), anti-diuretic hormone (ADH), aldosterone (ALD), atriopeptin (ANP), aquaporins (AQPs)-1, 2 and 3 were determined by ELISA kits. The mRNA expressions and protein levels of AQPs-1, 2 and 3 were analyzed by real-time quantitative PCR and Western blot assays, respectively. RESULTS: 30 compounds were identified in LSB based on accurate mass and MS/MS fragmentation compared to literature, among which phenylpropanoids and flavonoids could be partly responsible for the major diuretic effect. Daily administration of LSB (160 or 320 mg/kg) prominently increased urinary excretion volume after the 2 h at the first day of treatment, remaining until the 7th day. LSB did not cause Na+ and K+ electrolyte abnormalities, and has minor effect on Cl- and Ca2+ concentrations at 320 mg/kg. Furthermore, LSB observably suppressed renin-angiotensin-aldosterone system (RAAS) activation, including decreased serum levels of Ang II, ADH, and ALD, and prominently increased serum level of ANP in rats. LSB treatment significantly down-regulated the serum levels, mRNA expressions and protein levels of AQP1, AQP2, and AQP3. CONCLUSION: LSB has a prominent acute and prolonged diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats, and support the traditional folk use of this plant. Taken together, LSB might be a potential diuretic agent.

Evaluation of the diuretic effect of crude ethanol and saponin-rich extracts of Herniaria glabra L. in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Herniaria glabra L. popularly known in Morocco as "Herras lehjer" which means "Stonebreaker" in English is a plant that has been used in traditional medicine to treat edema, water retention, urinary diseases and renal problems including kidney stones. AIM OF THE STUDY: The present study aims to investigate the diuretic activity of the crude ethanol extract (CEE) and the saponin-rich extract (SRE) of the Herniaria glabra L. METHODS: CEE and SRE were prepared using maceration. SRE was obtained after using the selective liquid-liquid extraction method with organic solvents. Control (normal saline, 10 ml/kg), reference drug (furosemide 10 mg/kg) and three different doses (10 mg/kg, 50 mg/kg, 200 mg/kg) of the CEE and SRE were administered orally to male Wistar rats. The diuretic activity of the extracts was determined by measuring urine volume, urinary electrolyte and urine pH. The urine output measured at 5 h and 24 h, electrolyte concentration and pH were measured at 24 h duration. Data were analyzed by one way ANOVA followed by Dunnett's t-test. RESULTS: The findings indicated that the CEE significantly increased diuresis at 50 mg/kg and 200 mg/kg. Moreover, the SRE showed significant diuretic effect at all doses. CEE at a dose of 200 mg/kg increases the volume of urine by 81%, while SRE at a dose of 200 mg/kg increases the volume of urine by 114%. SRE demonstrated at 200 mg/kg the highest diuretic properties comparable to the reference drug. Na+, K+ and Cl- urinary excretion was also significantly increased at 50 mg/kg and 200 mg/kg of CEE and at all doses of SRE. HPLC analysis revealed the presence of the saponin aglycones, the main ones are medicagenic acid and oleanolic acid, their content in CEE 3.1 ± 0.4%, 2.4 ± 0.3% respectively and in SRE 7.9 ± 0.2%, 5.9 ± 0.3% respectively. Triterpenoid saponins could be responsible for the diuretic activity of Herniaria glabra. CONCLUSION: This study could make it useful to develop a pharmaceutical product based on purified saponin-rich extract of Herniaria glabra L. as a diuretic agent.

Management of Heart Failure Patient with CKD.

CKD is common in patients with heart failure, associated with high mortality and morbidity, which is even higher in people undergoing long-term dialysis. Despite increasing use of evidence-based drug and device therapy in patients with heart failure in the general population, patients with CKD have not benefitted. This review discusses prevalence and evidence of kidney replacement, device, and drug therapies for heart failure in CKD. Evidence for treatment with ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and sodium-glucose cotransporter inhibitors in mild-to-moderate CKD has emerged from general population studies in patients with heart failure with reduced ejection fraction (HFrEF). ß-Blockers have been shown to improve outcomes in patients with HFrEF in all stages of CKD, including patients on dialysis. However, studies of HFrEF selected patients with creatinine <2.5 mg/dl for ACE inhibitors, <3.0 mg/dl for angiotensin-receptor blockers, and <2.5 mg/dl for mineralocorticoid receptor antagonists, excluding patients with severe CKD. Angiotensin receptor neprilysin inhibitor therapy was successfully used in randomized trials in patients with eGFR as low as 20 ml/min per 1.73 m2 Hence, the benefits of renin-angiotensin-aldosterone axis inhibitor therapy in patients with mild-to-moderate CKD have been demonstrated, yet such therapy is not used in all suitable patients because of fear of hyperkalemia and worsening kidney function. Sodium-glucose cotransporter inhibitor therapy improved mortality and hospitalization in patients with HFrEF and CKD stages 3 and 4 (eGFR>20 ml/min per 1.73 m2). High-dose and combination diuretic therapy, often necessary, may be complicated with worsening kidney function and electrolyte imbalances, but has been used successfully in patients with CKD stages 3 and 4. Intravenous iron improved symptoms in patients with heart failure and CKD stage 3; and high-dose iron reduced heart failure hospitalizations by 44% in patients on dialysis. Cardiac resynchronization therapy reduced death and hospitalizations in patients with heart failure and CKD stage 3. Peritoneal dialysis in patients with symptomatic fluid overload improved symptoms and prevented hospital admissions. Evidence suggests that combined cardiology-nephrology clinics may help improve management of patients with HFrEF and CKD. A multidisciplinary approach may be necessary for implementation of evidence-based therapy.

Ethnopharmacological investigations of the leaves of Cecropia pachystachya Trécul (Urticaceae): A native Brazilian tree species.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia pachystachya Trécul (Urticaceae) is a medicinal plant popularly known as 'embaúba'. In Brazil, the leaves of this species are used for the treatment of various kidney and cardiovascular diseases. However, there are no detailed studies on the renal and cardiovascular activities of this species. No studies on the anatomy or the quality control of this herbal drug is available thus far. AIM: This study was aimed to investigate the ethnopharmacological properties of the leaves of C. pachystachya. MATERIAL AND METHODS: The leaves of C. pachystachya were analyzed by light and scanning electron microscopy for pharmacobotanical and anatomical characterization. The ethanol-soluble fraction of C. pachystachya leaf extract (ESCP) was characterized by high-performance liquid chromatograph equipped with diode array detector and mass spectrometry (HPLC-DAD-MS). The acute oral toxicity of ESCP on female Wistar rats was assessed. The acute and prolonged diuresis and antioxidant effects of ESCP (30, 100, and 300 mg/kg) were evaluated in male Wistar rats. In addition, the hypotensive effects of the ESCP as well as the vasodilatory activity in isolated and perfused mesenteric vascular beds were investigated. RESULTS: The anatomical markers obtained in this study can help in the identification of C. pachystachya, as well as to distinguish it from the other 'embaúbas'. The metabolites found in the ESCP were phenolic compounds, mainly C- and O-glycosylated flavonoids. The ESCP did not exhibit any toxic effects at a dose of 2000 mg/kg. Significant diuretic activities were observed at the doses of 30, 100, and 300 mg/kg. In addition, a significant modulating activity of the tissue redox state was observed after prolonged treatment. On the other hand, no hypotensive or vasodilator activity was observed. CONCLUSION: The key findings of the present study can contribute to the taxonomy, species identification and quality control of C. pachystachya. Chemical studies have shown the presence of glycosylated flavonoids, phenylpropanoid derivative and proanthocyanidins. The pharmacological studies showed significant diuretic and antioxidant effects of C. pachystachya leaf extract, indicating a possible validation of its popular medicinal use.

Antiurolithic effects of medicinal plants: results of in vivo studies in rat models of calcium oxalate nephrolithiasis-a systematic review.

Urolithiasis is one of the oldest diseases affecting humans, while plants are one of our oldest companions providing food, shelter, and medicine. In spite of substantial progress in understanding the pathophysiological mechanisms, treatment options are still limited, often expensive for common people in most parts of the world. As a result, there is a great interest in herbal remedies for the treatment of urinary stone disease as an alternative or adjunct therapy. Numerous in vivo and in vitro studies have been carried out to understand the efficacy of herbs in reducing stone formation. We adopted PRISMA guidelines and systematically reviewed PubMed/Medline for the literature, reporting results of various herbal products on in vivo models of nephrolithiasis/urolithiasis. The Medical Subject Heading Terms (Mesh term) "Urolithiasis" was used with Boolean operator "AND" and other related Mesh Unique terms to search all the available records (July 2019). A total of 163 original articles on in vivo experiments were retrieved from PubMed indexed with the (MeshTerm) "Urolithiasis" AND "Complementary Therapies/Alternative Medicine, "Urolithiasis" AND "Plant Extracts" and "Urolithiasis" AND "Traditional Medicine". Most of the studies used ethylene glycol (EG) to induce hyperoxaluria and nephrolithiasis in rats. A variety of extraction methods including aqueous, alcoholic, hydro-alcoholic of various plant parts ranging from root bark to fruits and seeds, or a combination thereof, were utilized. All the investigations did not study all aspects of nephrolithiasis making it difficult to compare the efficacy of various treatments. Changes in the lithogenic factors and a reduction in calcium oxalate (CaOx) crystal deposition in the kidneys were, however, considered favorable outcomes of the various treatments. Less than 10% of the studies examined antioxidant and diuretic activities of the herbal treatments and concluded that their antiurolithic activities were a result of antioxidant, anti-inflammatory, and/or diuretic effects of the treatments.