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1.
Physiol Rep ; 12(9): e16033, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38740564

RESUMO

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.


Assuntos
Furosemida , Insuficiência Cardíaca , Rim , Peptídeo Natriurético Encefálico , Sódio , Volume Sistólico , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/metabolismo , Masculino , Feminino , Idoso , Projetos Piloto , Furosemida/farmacologia , Furosemida/administração & dosagem , Sódio/metabolismo , Sódio/urina , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/metabolismo , Rim/metabolismo , Rim/fisiopatologia , Rim/efeitos dos fármacos , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Diuréticos/farmacologia , Diuréticos/administração & dosagem , GMP Cíclico/metabolismo , GMP Cíclico/urina , Idoso de 80 Anos ou mais
2.
J Hypertens ; 42(6): 1086-1093, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690907

RESUMO

BACKGROUND: Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term. METHODS: In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status. RESULTS: Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm [ß 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3] than those born term (ß 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002. CONCLUSION: We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals.


Assuntos
Nascimento Prematuro , Sódio , Estresse Psicológico , Humanos , Feminino , Masculino , Adulto Jovem , Estresse Psicológico/fisiopatologia , Estresse Psicológico/urina , Adolescente , Sódio/urina , Estudos Prospectivos , Nascimento Prematuro/fisiopatologia , Pressão Sanguínea/fisiologia , Recém-Nascido , Creatinina/urina , Adulto , Natriurese
3.
Am J Physiol Renal Physiol ; 326(5): F737-F750, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38482554

RESUMO

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.


Assuntos
Angiotensina II , Hipertensão , Natriurese , Trocador 3 de Sódio-Hidrogênio , Animais , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Feminino , Trocador 3 de Sódio-Hidrogênio/metabolismo , Natriurese/efeitos dos fármacos , Diuréticos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fatores Sexuais , Simulação por Computador , Sódio/metabolismo , Ratos , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Caracteres Sexuais , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia
4.
Hypertens Res ; 47(4): 998-1016, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38302775

RESUMO

The aim was to evaluate the effects of renal denervation (RDN) on autoregulation of renal hemodynamics and the pressure-natriuresis relationship in Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF)-induced heart failure (HF). RDN was performed one week after creation of ACF or sham-operation. Animals were prepared for evaluation of autoregulatory capacity of renal blood flow (RBF) and glomerular filtration rate (GFR), and of the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. Their basal values of blood pressure and renal function were significantly lower than with innervated sham-operated TGR (p < 0.05 in all cases): mean arterial pressure (MAP) (115 ± 2 vs. 160 ± 3 mmHg), RBF (6.91 ± 0.33 vs. 10.87 ± 0.38 ml.min-1.g-1), urine flow (UF) (11.3 ± 1.79 vs. 43.17 ± 3.24 µl.min-1.g-1) and absolute sodium excretion (UNaV) (1.08 ± 0.27 vs, 6.38 ± 0.76 µmol.min-1.g-1). After denervation ACF TGR showed improved autoregulation of RBF: at lowest RAP level (80 mmHg) the value was higher than in innervated ACF TGR (6.92 ± 0.26 vs. 4.54 ± 0.22 ml.min-1.g-1, p < 0.05). Also, the pressure-natriuresis relationship was markedly improved after RDN: at the RAP of 80 mmHg UF equaled 4.31 ± 0.99 vs. 0.26 ± 0.09 µl.min-1.g-1 recorded in innervated ACF TGR, UNaV was 0.31 ± 0.05 vs. 0.04 ± 0.01 µmol min-1.g-1 (p < 0.05 in all cases). In conclusion, in our model of hypertensive rat with ACF-induced HF, RDN improved autoregulatory capacity of RBF and the pressure-natriuresis relationship when measured at the stage of HF decompensation.


Assuntos
Síndrome Cardiorrenal , Fístula , Insuficiência Cardíaca , Hipertensão , Ratos , Animais , Ratos Transgênicos , Pressão Sanguínea , Natriurese , Rim , Circulação Renal , Simpatectomia , Taxa de Filtração Glomerular
5.
Chem Biodivers ; 21(4): e202400175, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38345349

RESUMO

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.


Assuntos
Hipertensão , Urolitíase , Ratos , Feminino , Masculino , Animais , Ratos Endogâmicos SHR , Natriurese/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Diurese/fisiologia , Urolitíase/tratamento farmacológico , Urolitíase/prevenção & controle
6.
Sci Rep ; 14(1): 5002, 2024 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424466

RESUMO

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.


Assuntos
Diabetes Mellitus , Insuficiência Renal , Humanos , Natriurese/fisiologia , Pressão Sanguínea/fisiologia , Renina , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Aldosterona/farmacologia , Rim , Fator Natriurético Atrial
8.
Cardiorenal Med ; 14(1): 58-66, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38228113

RESUMO

BACKGROUND: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics. SUMMARY: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms. KEY MESSAGE: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF.


Assuntos
Síndrome Cardiorrenal , Insuficiência Cardíaca , Túbulos Renais Proximais , Sódio , Humanos , Túbulos Renais Proximais/fisiopatologia , Túbulos Renais Proximais/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Síndrome Cardiorrenal/fisiopatologia , Síndrome Cardiorrenal/metabolismo , Sódio/metabolismo , Doença Aguda , Natriurese/fisiologia , Diuréticos/uso terapêutico
11.
Circ Heart Fail ; 17(1): e011105, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38179728

RESUMO

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.


Assuntos
Diuréticos , Insuficiência Cardíaca , Humanos , Diuréticos/uso terapêutico , Natriurese , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Diurese , Sódio , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos
12.
J Intensive Care Med ; 39(2): 146-152, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37632128

RESUMO

PURPOSE: Acute kidney injury is a frequent complication of acute respiratory distress syndrome (ARDS). We aim to study the evolution of kidney function in patients presenting severe ARDS and requiring veno-venous extracorporeal membrane oxygenation (VV ECMO). METHODS: We conducted a multicenter retrospective study, including adult patients requiring VV ECMO for ARDS. The primary outcome was the evolution of the serum creatinine level after VV ECMO initiation. Secondary outcomes were change in urine output, and urine biochemical parameters after VV ECMO initiation. RESULTS: One hundred and two patients were included. VV ECMO was initiated after a median of 6 days of mechanical ventilation, mainly for ARDS caused by COVID-19 (73%). Serum creatinine level did not significantly differ after VV ECMO initiation (P = .20). VV ECMO was associated with a significant increase in daily urine output (+6.6 mL/kg/day, [3.8;9.3] P < .001), even after adjustment for potential confounding factors; with an increase in natriuresis. The increase in urine output under VV ECMO was associated with a reduced risk of receiving kidney replacement therapy (OR 0.4 [0.2;0.8], P = .026). CONCLUSIONS: VV ECMO initiation in severe ARDS is associated with an increase in daily urine output and natriuresis, without change in glomerular filtration rate.


Assuntos
Oxigenação por Membrana Extracorpórea , Síndrome do Desconforto Respiratório , Adulto , Humanos , Estudos Retrospectivos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Creatinina , Natriurese , Síndrome do Desconforto Respiratório/etiologia , Rim
13.
Cardiovasc Diabetol ; 22(1): 197, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37533009

RESUMO

Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks' duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1-2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.


Assuntos
Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diuréticos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Natriurese , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
14.
Am Heart J ; 265: 121-131, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37544492

RESUMO

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919.


Assuntos
Insuficiência Cardíaca , Humanos , Resultado do Tratamento , Insuficiência Cardíaca/diagnóstico , Diuréticos/uso terapêutico , Diurese , Natriurese
15.
Hypertens Res ; 46(10): 2340-2355, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37592042

RESUMO

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.


Assuntos
Insuficiência Cardíaca , Hipertensão , Ratos , Animais , Angiotensina II/farmacologia , Natriurese , Rim , Pressão Sanguínea , Ratos Transgênicos , Circulação Renal , Sódio , Homeostase
16.
Am J Physiol Renal Physiol ; 325(4): F426-F435, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37560772

RESUMO

Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial Na+ channel (ENaC). The present nonrandomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na+ excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin-to-creatinine ratio > 300 mg/g, n = 7, and <30 mg/g, n = 7, respectively) were included and ingested a diet with fixed Na+ content (150 mmol/day) for 5 days. On the last day, amiloride at 10 mg was administered twice. Body weight, 24-h urine electrolyte excretion, body water content, and ambulatory blood pressure as well as plasma renin, angiotensin II, and aldosterone concentrations were determined before and after amiloride. Amiloride led to a significant decrease in body weight, increase in 24-h urinary Na+ excretion, and decrease in 24-h urinary K+ excretion in both groups. Urine output increased in the nonalbuminuric group only. There was no change in plasma renin, aldosterone, and angiotensin II concentrations after amiloride, whereas a significant decrease in nocturnal systolic blood pressure and increase in 24-h urine aldosterone excretion was observed in albuminuric KTRs only. There was a significant correlation between 24-h urinary albumin excretion and amiloride-induced 24-h urinary Na+ excretion. In conclusion, ENaC activity contributes to Na+ and water retention in KTRs with and without albuminuria. ENaC is a relevant pharmacological target in KTRs; however, larger and long-term studies are needed to evaluate whether the magnitude of this effect depends on the presence of albuminuria.NEW & NOTEWORTHY Amiloride has a significant natriuretic effect in kidney transplant recipients (KTRs) that relates to urinary albumin excretion. The epithelial Na+ channel may be a relevant direct pharmacological target to counter Na+ retention and hypertension in KTRs. Epithelial Na+ channel blockers should be further investigated as a mean to mitigate Na+ and water retention and to potentially obtain optimal blood pressure control in KTRs.


Assuntos
Hipertensão , Transplante de Rim , Desequilíbrio Hidroeletrolítico , Humanos , Amilorida/farmacologia , Amilorida/uso terapêutico , Albuminúria , Natriurese , Transplante de Rim/efeitos adversos , Renina , Aldosterona , Angiotensina II , Monitorização Ambulatorial da Pressão Arterial , Sódio/metabolismo , Redução de Peso , Peso Corporal , Água , Canais Epiteliais de Sódio
17.
Nat Med ; 29(10): 2625-2632, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37640861

RESUMO

Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l-1. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .


Assuntos
Insuficiência Cardíaca , Natriurese , Feminino , Humanos , Masculino , Doença Aguda , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Sódio/urina , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico
18.
Hypertension ; 80(11): 2265-2279, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37503660

RESUMO

Screening of compounds comprising 8-substituted guanine revealed that 8-aminoguanosine and 8-aminoguanine cause diuresis/natriuresis/glucosuria, yet decrease potassium excretion. Subsequent investigations demonstrated that 8-aminoguanosine's effects are mediated by its metabolite 8-aminoguanine. The mechanism by which 8-aminoguanine causes diuresis/natriuresis/glucosuria involves inhibition of PNPase (purine nucleoside phosphorylase), which increases renal interstitial inosine levels. Additional evidence suggests that inosine, via indirect or direct adenosine A2B receptor activation, increases renal medullary blood flow which enhances renal excretory function. Likely, 8-aminoguanine has pleiotropic actions that also alter renal excretory function. Indeed, the antikaliuretic effects of 8-aminoguanine are independent of PNPase inhibition. 8-Aminoguanine is an endogenous molecule; nitrosative stress leads to production of biomolecules containing 8-nitroguanine moieties. Degradation of these biomolecules releases 8-nitroguanosine and 8-nitro-2'-deoxyguanosine which are converted to 8-aminoguanine. Also, guanosine and guanine per se may contribute to 8-aminoguanine formation. 8-Aminoinosine, 8-aminohypoxanthine, and 8-aminoxanthine likewise induce diuresis/natriuresis/glucosuria, yet do not reduce potassium excretion. Thus, there are several pharmacologically active 8-aminopurines with nuanced effects on renal excretory function. Chronic treatment with 8-aminoguanine attenuates hypertension in deoxycorticosterone/salt rats, prevents strokes, and increases lifespan in Dahl salt-sensitive rats on a high salt diet and attenuates the metabolic syndrome in rats; 8-aminoguanosine retards progression of pulmonary hypertension in rats and anemia and organ damage in sickle cell mice. 8-Aminoguanine reverses age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines represent a new class of agents (and potentially endogenous factors) that have beneficial effects on the cardiovascular system and kidneys and may turn back the clock in age-associated diseases.


Assuntos
Sistema Cardiovascular , Guanina , Ratos , Camundongos , Animais , Ratos Endogâmicos Dahl , Guanina/metabolismo , Guanina/farmacologia , Natriurese , Sistema Cardiovascular/metabolismo , Potássio , Inosina/farmacologia
19.
Endocrinol Metab (Seoul) ; 38(4): 359-372, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37482684

RESUMO

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Natriurese , Retroalimentação , Glucose , Sódio/metabolismo
20.
J Neurosurg ; 139(6): 1657-1663, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37209066

RESUMO

OBJECTIVE: Oxytocin (OXT) secretion has been shown to be abnormally elevated in patients who develop syndrome of inappropriate secretion of antidiuretic hormone (SIADH)-related hyponatremia after transsphenoidal pituitary surgery (TPS). While OXT was previously reported to increase natriuresis in the kidney, a potential role for this hormone in postoperative sodium balance and dysnatremias has not been studied. The objective of this study was to analyze the correlation between patients' urinary output of OXT and natremia and natriuresis after TPS. METHODS: The authors measured and correlated the urinary output of OXT with natriuresis and natremia in 20 consecutive patients who underwent TPS. RESULTS: The ratio of urinary secretion of OXT between days 1 and 4 showed a strong, significant correlation with patient natriuresis at day 7 after pituitary surgery. Concomitantly, patient natremia showed a moderate, inverted correlation with OXT secretion in the urine. CONCLUSIONS: Together, these results show for the first time that urinary OXT secretion correlates with patient natriuresis and natremia after pituitary surgery. This observation suggests a notable role for this hormone in sodium balance.


Assuntos
Hiponatremia , Síndrome de Secreção Inadequada de HAD , Doenças da Hipófise , Humanos , Natriurese , Ocitocina , Síndrome de Secreção Inadequada de HAD/etiologia , Hiponatremia/etiologia , Sódio
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