Urea, TMAO, betaine and other osmolytes as endogenous diuretics in heart failure and hypertension

Abstract

Diuretics are essential for managing fluid overload in heart failure (HF) and controlling blood pressure in hypertension. However, their use is often associated with complications such as electrolyte imbalances and neurohormonal dysregulation, which can limit their effectiveness and contribute to adverse outcomes. These challenges underscore the need for alternative or adjunctive strategies to better manage fluid retention and congestion. Osmolytes are small molecules that help counteract increases in extracellular osmotic and hydrostatic pressure and are naturally present at high concentrations in the renal medulla. Notably, elevated serum levels of osmolytes such as trimethylamine N-oxide (TMAO) and betaine have been observed in patients with HF, although their role in the pathophysiology of the disease remains unclear. Given the known diuretic properties of osmolytes such as urea—historically used in the management of HF—it is plausible that other osmolytes may similarly modulate diuresis and volume status. This review examines the biological actions of several key osmolytes, including urea, TMAO, betaine, and taurine. Emerging evidence supports the need for further preclinical and clinical studies to investigate the potential diuretic and cytoprotective effects of TMAO, betaine, and taurine in the prevention and treatment of HF and hypertension.

Introduction

Heart failure (HF) is a progressing condition that represents a major global healthcare challenge. It affects more than 20 million people and results in over one million hospital admissions annually in the USA and Europe, imposing a huge economic burden on these healthcare systems. Additionally, the prevalence of HF is rising in low-income countries, creating growing challenges for already resource-limited healthcare infrastructures[1–3].

HF is categorized based on the left ventricular ejection fraction (LVEF) into three groups: (I) Heart Failure with reduced ejection fraction (HFrEF, LVEF < 40%), (II) Heart Failure with mildly reduced ejection fraction (HFmrEF, LVEF 40–49%), and (III) Heart Failure with preserved ejection fraction (HFpEF, LVEF ≥ 50%).

However, the above classification represents a significant oversimplification and fails to encapsulate the full spectrum of HF phenotypes.

Nevertheless, the common characteristic shared among all HF phenotypes is the occurrence of fluid retention and congestion at some stage of the disease. This underscores the critical need for individualized management strategies that address underlying congestion and fluid imbalance.

Diuretics, especially loop agents (such as furosemide, torsemide, bumetanide) have been a mainstay of managing congestion in patients with worsening HF across the spectrum of LVEF. Also, despite limited data supporting this recommendation, sodium restriction is oftentimes advised to HF patients as a self-care strategy (class 2a recommendation), since sodium excess might be associated with fluid retention [4–6].

Back in 1925, Crawford and collaborators first described the use of urea as a diuretic agent in advanced HF. A daily dose of between 30 and 60 g resulted in a significant, dose-dependent increase in urine output and improvement in edema [7]. Since then, numerous studies on the use of diuretics for the treatment of salt and water retention in cardiac disease have been conducted. Despite known challenges such as diuretic resistance and neurohormonal activation, diuretics remain a cornerstone of decongestive therapy for patients with HF [8].

It is worth stressing that virtually all fundamental drugs recommended in HF like angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), or sodium glucose co-transporter 2 inhibitors (SGLT2-i) [9, 10], also affect water and/or sodium homeostasis.

In this paper, we review existing evidence on the diuretic properties of endogenously produced osmolytes such as urea, trimethylamine N-oxide (TMAO), betaine, and taurine.

Current diuretic and decongestive therapies in HF management

The majority of patients suffering from HF will, at some point, experience signs and symptoms of congestion (e.g., peripheral edema, dyspnea, dyspnea on exertion, or orthopnea) and seek urgent medical care for that reason. Congestion (accumulation of extracellular fluid with increased cardiac filling pressures) results from decreased efficacy of the heart as a pump and increased neurohormonal activation, leading to increased sodium and water retention and/or redistribution of fluids within the body compartments. Importantly, while body sodium levels in HF patients are often increased, plasma sodium concentrations might be low due to disproportionate water retention. To remove excessive sodium, forced diuresis and natriuresis are used [11, 12].

Current European (2021/2023) and American (2022) guidelines present diuretics as class I recommendation drugs to relieve congestion, improve symptoms, and prevent worsening of HF in all phenotypes of the disease [6, 9]. Diuretics, compared to placebo, have been shown to reduce the risk of worsening HF along with improved exercise capacity [13]. The absence of large randomized controlled trials directly assessing their impact on survival in HF patients limits our understanding of long-term outcomes [14–16]. According to both guidelines, diuretics should be added to disease-modifying drugs in all patients with symptoms and/or signs of congestion [9, 17]. In fact, most patients with chronic disease will require a maintenance dose of diuretics in order to avoid volume overload and remain clinically stable [10].

Unfortunately, the use of diuretics remains challenging because of frequent resistance, electrolyte disturbances associated with increased urine excretion, as well as worsening renal function due to volume depletion, especially in individuals with ischemic nephropathy. Diuretic resistance, a failure to reduce the fluid overload despite the proper diuretic regimen, is associated with adverse outcomes [18]. Factors contributing to diuretic resistance include poor compliance, and those that interfere with the diuretic mechanism of action, such as sympathetic nervous system activation, renin-angiotensin system (RAS) activation (loop diuretics up-regulate RAS), renal dysfunction due to reduced renal blood flow, and altered drug pharmacokinetics and pharmacodynamics [11, 12, 19–21]. Administration of diuretics and the following increase in sodium delivered to the distal convoluted tubule stimulate nephrons to adapt to high NaCl concentrations, further increasing the rate of sodium reabsorption and lowering the efficacy of such treatment [22]. Thus, to overcome diuretic resistance in HF, combination (sequential) nephron blockade by adding thiazides or thiazide-like diuretics on top of loop diuretics has been recommended [23, 24]. This strategy is based on the pathophysiology of diuretic resistance and uses the synergistic effect of agents that act upon different segments of the nephron [25, 26]. Furthermore, adding SGLT2 inhibitors to loop diuretics in HF patients enhances natriuresis and allows for a reduction in loop diuretic dosage, suggesting a synergistic effect [27]. Additional possible strategies include incorporating acetazolamide, which inhibits sodium reabsorption [28]. High-dose MRAs, when combined with loop diuretics, have been shown to improve outcomes in HF patients by reducing morbidity and mortality [29].

Identifying patients with diuretic resistance may help improve outcomes by enabling more targeted and aggressive decongestive therapy [30, 31]; however, the use of high-dose diuretics in HF patients is associated with potentially life-threatening electrolyte imbalances, including hypo- or hyperkalemia and hyponatremia [32].

Recently, some new natriuretic and diuretic drugs targeting vasopressin-receptors and urea transporters have been investigated in clinical trials with the hope to find effective alternatives to conventional diuretic therapy [33–35].

Nevertheless, novel effective drugs and approaches to achieve satisfactory decongestion in both acute and chronic HF are still needed. Development of safer and perhaps less expensive diuretic agents with different mechanisms of action to the currently used, could ultimately help overcome diuretic resistance and improve maintenance of euvolemia.

Current diuretic therapies in hypertension management

Hypertension, characterized by chronically elevated arterial blood pressure (BP) and often associated with excessive fluid retention, imposes increased afterload on the heart resulting in structural and functional cardiac adaptations. These adaptations, including left ventricular hypertrophy and myocardial fibrosis, play a critical role in the development and progression of HF.

The 2024 guidelines issued by the European Society of Cardiology (ESC) and the 2017 guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) continue to endorse that diuretics, as well as ACEIs, angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are a first-line option for initial antihypertensive therapy based on their efficacy in reducing BP and documented benefit in reducing clinical outcomes [36, 37]. Notably, all recommended first classes of antihypertensive medications, including diuretics, are similarly effective in preventing cardiovascular disease, except in cases of heavy proteinuria or advanced kidney disease, where RAS inhibitors are specifically indicated [36]. First-line diuretic classes include thiazides, thiazide-like diuretics, and potassium-sparing diuretics [37]. Among these, thiazide-like diuretics, such as chlorthalidone and indapamide, are preferred due to their longer duration of action compared to traditional thiazides, making them particularly effective for managing hypertension. Importantly, for patients with resistant hypertension, diuretics are essential at maximally tolerated doses as part of a multidrug regimen [36, 37]. Excessive dietary salt intake and salt and water retention are major contributors to treatment resistance, underscoring the critical role of diuretics in overcoming these challenges [38].

Interstitial congestion in HF

The interstitial compartment is a critical regulator of extracellular fluid homeostasis, mediating bidirectional exchange of water, osmolytes, and macromolecules between the intravascular and intracellular spaces. Under normal physiological conditions, the equilibrium between capillary hydrostatic, osmotic, and oncotic pressures, coupled with efficient lymphatic drainage, maintains low interstitial hydrostatic pressure. In HF, elevated venous pressures increase capillary hydrostatic forces, leading to excessive fluid transudation into the interstitium and resultant tissue congestion, often in the absence of overt intravascular volume expansion [39, 40].

Interstitial fluid accumulation exhibits organ-specific patterns due to heterogeneity in capillary permeability, interstitial matrix composition, and lymphatic clearance [41]. Pulmonary congestion arises from elevated left atrial pressures and compromised lymphatic drainage, impairing alveolar-capillary gas exchange [42]. Renal venous congestion reduces glomerular filtration and natriuretic capacity, thereby perpetuating volume overload. Peripheral edema, frequently perceived as a benign finding, in fact reflects significant lymphatic dysfunction and correlates with adverse clinical outcomes. Splanchnic venous congestion disrupts mucosal barrier integrity, facilitates microbial translocation, and contributes to systemic inflammation and cardiac cachexia [43–45].

Understanding the regional pathophysiology of interstitial fluid accumulation supports the rationale for individualized decongestive strategies and may explain variability in diuretic responsiveness.

Osmolytes

Osmolytes are small molecules which counteract increased extracellular osmotic and hydrostatic pressure. These molecules can be categorized into four classes (i) methylamines (TMAO, betaine, glycerophosphocholine), (ii) amino acids (proline, taurine, glycine, arginine, beta alanine), (iii) carbohydrates (sorbitol, glycerol, myo-inositol) and (iv) urea [46]. Osmolyte concentrations vary among species and tissues [47], being found mainly in the kidneys but also in the epithelium of the urinary bladder, intestines, and liver [48–50]. Their concentration in the kidney varies, reaching their highest levels near the tip of the renal papilla [51, 52].

A variety of eukaryotic cells are exposed to a harsh environment characterized by hyperosmolar conditions, particularly in marine organisms that inhabit saline waters. In humans, cells in the renal medulla undergo extreme osmotic stress due to the accumulation of sodium chloride and urea, substances that are critical in the urine concentration process. Organisms have developed complex mechanisms to protect cells from such extraordinary conditions [53].

There are two primary pathways for cell volume restoration under conditions of heightened osmotic or hydrostatic extracellular pressure. The first pathway involves the transmembrane movement of inorganic ions, followed by water’s influx or efflux, which might perturb protein integrity. The second pathway employs organic solutes known as osmolytes, including TMAO, betaine, myo-inositol, taurine, sorbitol and glycerophosphocholine. These molecules are accumulated within mammalian cells to counteract increased extracellular osmotic and hydrostatic pressures. In contrast to inorganic salts, osmolytes do not alter protein conformation [54]. In fact, organic osmolytes such as betaine serve as chaperones by stabilizing proteins in their folded, functional form [55, 56].

Accumulating evidence suggests that osmolytes have a role in the cardiovascular system, and disturbances in osmolyte levels may either lead to or result from water and electrolyte imbalances in HF and hypertension. Future research into the mechanisms of osmolytes’ biological actions could bring us closer to fully understanding the role of these molecules in HF.

Osmolytes as diuretics

Urea

Urea, an organic compound that functions as an osmolyte, is characterized by its small, polar structure featuring two amino groups and has a molecular weight of 60 g/mol. It is one of the most abundant waste products of metabolism that must be excreted by the kidneys. However, nearly half of the filtered urea is passively reabsorbed from the tubules in order to create an osmotic pressure gradient in the kidney medulla. Since urea does not permeate as easily as water, in some regions of the nephron, especially in the medullary collecting duct, its reabsorption is facilitated by urea transporters. These are regulated by urinary solute urea and vasopressin and play a key role in urine concentration by increasing urea concentration in the renal medulla [57, 58].

Diuretic properties of urea were explored well before loop diuretics were approved for human use. The oral administration of urea as a decongestive agent in advanced HF was proposed in the early twentieth century [7, 59]. Furthermore, it has also been shown that dietary urea reduces BP in hypertensive rats partially through its diuretic effect [60].

Urea is the primary end-product of protein catabolism and is commonly measured as blood urea nitrogen (BUN). Elevated BUN levels are observed in patients with congestive HF, attributable to prerenal kidney dysfunction [61]. Persistent high BUN levels are predictors of increased cardiovascular and all-cause mortality [62, 63]. Moreover, serum urea itself appears to be an independent risk factor for cardiac mortality in chronic HF and can be used as a predictor for hospital readmissions [64]. There is also evidence that urea can be formed in cardiac tissue itself [65]. According to Duchesne et al., urea production increases with cardiac hypertrophy, presumably due to high polyamine synthesis from ornithine [66]. The authors have identified urea transporters type A (UT-A) in rat and human hearts and reported their increased expression in HF and hypertension.

Notably, urea is used in the treatment of hyponatremia, particularly in cases associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [67]. It acts as an osmotic diuretic, promoting the excretion of free water while minimizing sodium loss [68]. This mechanism is particularly beneficial in SIADH, where water retention leads to dilutional hyponatremia [69]. Several studies suggest that urea has demonstrated comparable efficacy to vaptans in normalizing serum sodium levels [67, 70, 71].

Biological and clinical effects of urea are summarized in Table 1.

Table 1.

Physiological Actions and Associated Biological and Clinical Effects of Urea. Urea exerts both beneficial and adverse biological and clinical effects—ranging from osmotic diuresis to insulin resistance and gut barrier dysfunction—that are dose- and concentration-dependent

Mechanis of Action	Biological/Clinical importance	References
Increases renal tubular osmolarity	Promotes osmotic diuresis and water excretion	[67, 72]
-	Marker of neurohormonal activation (RAS, vasopressin, sympathetic nervous system)	[63]
Crosses blood–brain barrier, creating osmotic gradient	Lowering of Intracranial Pressure	[73]
Induces oxidative stress in renal tubular cells	Renal tubular injury and dysfunction	[74]
Stimulates reactive oxygen species (ROS) production in adipose tissue	Enhances insulin resistance	[75]
Elevates oxidative stress in pancreatic β-cells	Decreases insulin secretion	[76]
Urea and its breakdown products increase gut-blood barrier permeability	Intestinal barrier dysfunction	[77, 78]
Systemic toxicity of urea metabolites	Uremic encephalopathy Vomiting, diarrhea, nausea, weakness	[79, 80]

Taurine

Taurine is an osmolyte known to be present in most animal tissues in high levels, regulated by hypertonicity [81, 82]. Dietary sources of this semi-essential amino acid include meat and seafood, as well as commercially available energy drinks [83]. A number of animal experiments reported natriuretic and diuretic potential of taurine. For example, Mozaffari and colleagues described diuretic and natriuretic properties of taurine in a study on taurine-depleted and taurine-supplemented rats. Adding taurine to isotonic saline infusion significantly increased renal excretory response to saline load [84]. In another study by this group, chronic treatment with taurine protected the kidneys from an age-dependent decline in excretory function [85]. Furthermore, Horiuchi et al. also reported increased urine volume and urinary sodium excretion in rats drinking 3% taurine [86]. In stroke-prone hypertensive rats, taurine also improved renal function and reduced ventricular hypertrophy [87]. Findings from animal studies have been supported by the results from investigation performed on cirrhotic patients with ascites. Intravenous taurine significantly increased both diuresis and sodium excretion in this cohort [88].

Considering its diuretic effect and beyond, multiple experimental and epidemiological studies report beneficial role of taurine in cardiovascular system and conclude that its supplementation could contribute to prevention of cardiovascular disease [89]. Several authors discussed potential role of taurine in management of HF. A clinical trial conducted in 1985 evaluated addition of taurine to conventional HF therapy [90]. Compared with placebo, taurine significantly improved New York Heart Association (NYHA) functional class in patients with congestive HF. Later, a randomized single-blind placebo-controlled clinical trial on taurine supplementation in patients with HF (NYHA class II and III) on standard medical treatment showed that taurine was able to improve exercise capacity [91]. In another small study in HF patients oral supplementation improved cardiac electric activity following exercise and enhanced functional capacity [92]. In contrast, McGurk et al. performed a meta-analysis which did not show any significant association between the level of taurine and HF [93].

Additionally taurine, a conditionally essential amino sulfonic acid, exhibits antioxidant, anti-inflammatory, and membrane-stabilizing properties [94], in animal models and limited human studies, taurine supplementation has been associated with improvements in cardiac function, reduced oxidative stress, and modulation of calcium homeostasis [95].

Finally, taurine has long been recognized for its hypotensive effect and impact on vascular function in both hypertensive animal models and in humans [94, 96–99]. For example, taurine was showed to reduce renal dysfunction and hypertension associated with administration of Cyclosporine A in rats [100]. Furthermore, in experiments performed on rats with fructose-induced hypertension, taurine combined with physical exercise improved exercise capacity and prevented development of hypertension [101]. Several human studies support these findings. Waldron and collaborators collectively reviewed literature on oral supplementation of taurine in humans and reported a significant reduction in BP with no adverse effects associated with its ingestion in their meta-analysis [102].

TMAO

TMAO is an osmolyte produced in the liver through the oxidation of TMA, a toxic and odorous byproduct of gut microbiota metabolism of choline and L-carnitine. Alternatively, fish and other seafood provide a direct source of TMAO [103]. TMAO is characterized by fast turnover in the circulation, with little of the dose absorbed by extrahepatic tissue and most of it excreted in the urine within 24 h [104].

Apart from its protective effects on proteins [105], the results of our recent experiments showed that a moderate increase in plasma TMAO exerted beneficial effects in HF rats, which was associated with long-term diuretic, natriuretic and hypotensive response [106]. We also found that intravenous TMAO significantly increased short-term diuresis (osmotic diuresis) in anesthetized rats compared to the control group, which received the same volume of normal saline. We hypothesize that the diuretic potential of TMAO could be responsible for its favorable effect in HF rats [106].

In the recent years, TMAO has gained considerable attention due to its possible impact on human health. A number of papers re-evaluated that issue [107, 108]. Multiple clinical studies showed a positive correlation between plasma TMAO and cardiovascular risk. A study by Trøseid and colleagues revealed high levels of TMAO and its metabolites, such as betaine, in patients with HF [109]. Increased TMAO was associated with NYHA class, ischemic etiology, and adverse outcomes in this study. Elevated TMAO levels were yet again associated with poor prognosis in acute HF and combined with the N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) predicted death at 1 year in another investigation [110]. Higher levels of TMAO have been reported in HF patients [111], including the subgroup of patients with HFpEF [112]. It is though worth mentioning that loop diuretics increase plasma TMAO concentration by decreasing its urinary excretion rate [113, 114] and thus their use should be considered a potential confounder in TMAO studies, especially in HF patients, who usually receive high-dose diuretic therapy. On the contrary, some studies do not support the correlation between TMAO levels and cardiovascular death, all-cause death or acute HF leading to hospitalization [115]. Recently, the responsiveness of TMAO levels to treatment was investigated in the BIOSTAT-CHF study [116]. The study showed no response of TMAO to guideline-based pharmacological treatment. On the other hand, SGLT2-i in patients after acute myocardial infarction increase the level of plasma TMAO [117].

Even though some authors consider TMAO to be a novel therapeutic target for HF [118], data on the pathological role of TMAO are contradictory. Some animal experiments showed negative effect of TMAO in HF. For example, 1 or 2-week-long intraperitoneal treatment with TMAO induced cardiac hypertrophy and cardiac fibrosis in Sprague Dawley rats [119]. In cultured cardiomyocytes, TMAO stimulated cardiac hypertrophy. Further, in mice fed a diet containing 0.12% TMAO for 15 weeks, myocardial fibrosis was significantly greater compared to control group [120]. On the other hand, research on the impact of TMAO on cardiac damage on cellular level did not confirm the hypothesis that TMAO is hazardous for cell viability [121, 122]. Moreover, 56-week treatment with low-dose dietary TMAO reduced left ventricular end-diastolic pressure and cardiac fibrosis in hypertensive rats [123].

Whether TMAO is a mediator of cardiovascular disease, or simply a surrogate marker is a topic of ongoing debate. In fact, it is surprising that the discussion on the adverse cardiovascular effects focuses on TMAO rather than TMA, its precursor, which for decades has been known for its significant toxicity [124]. TMA’s presence in the environment and its known harmful impact on proteins, along with its cytotoxic effects on cardiomyocytes and vascular smooth muscle cells, raises a question whether it is rather TMA that is more destructive to the cardiovascular system than its metabolite TMAO [108, 125]. Moreover, TMAO, in contrast to TMA, is able to actually preserve protein structure and counteract osmotic stress [108, 126], which could be beneficial in a setting of increased blood osmotic and hydrostatic pressures in HF or hypertension.

In addition, recent research indicates that at low concentrations, TMAO may positively influence mitochondrial bioenergetics, especially under stress conditions. In isolated perfused mouse hearts, acute exposure to TMAO at physiological concentrations (10–100 µM) improved mitochondrial oxygen consumption rates via respiratory chain complexes I and II. It significantly raised both maximal and spare respiratory capacity, despite a decrease in mechanical function, pointing to a compensatory activation of oxidative metabolism [127]. In a chronic model of right ventricular failure induced by monocrotaline in rats, long-term oral supplementation with TMAO preserved fatty acid oxidation and mitochondrial adenosine triphosphate (ATP) production, and supported cardiac function, likely by stabilizing mitochondrial oxidative phosphorylation under pressure overload [128].

However, research on the association between TMAO and BP is still fairly limited. Ge and collaborators [129] analyzed correlation between circulating TMAO concentrations and prevalence of hypertension, reporting that high TMAO levels correlate with higher prevalence of the disease. However, spontaneously hypertensive rats receiving TMAO with drinking water for 12 weeks [123] did not differ significantly from the controls in terms of BP. Furthermore, studies from our laboratory showed that although TMAO prolongs the hypertensive effect of angiotensin II, it does not affect BP in normotensive rats when administered alone [130] whereas TMA—but not TMAO—increases BP in normotensive rats [131].

Betaine

Betaine is a derivative of methyl amino acids found in a variety of organisms, ranging from plants to mammals. In humans, betaine is partly derived from dietary sources and partly from endogenous synthesis in the liver. It was first isolated by Scheibler in the 1860 s from sugar beets (Beta vulgaris) [132] and, since then, has received a lot of scientific attention due to its potential health benefits [133]. Physiological role of betaine in transmethylation as well as osmolytic and protein stabilizing properties of this molecule, have been widely discussed in the literature, and several excellent reviews of these aspects have been published thus far [134–136].

Data from animal studies, although limited, provide evidence that betaine has diuretic properties. In our recent work, acute administration of betaine increased diuresis without significantly affecting arterial BP [137]. However, in the study on hyperuricemic mice, 7 days of betaine supplementation did not influence 24-h diuresis despite apparent nephroprotective effects [138]. Therefore, its diuretic effect needs to be elucidated in chronic conditions.

A few experimental studies provide evidence of the cardioprotective effect of betaine. For example, betaine protected against cardiac oxidative stress in two different models of heart injury, in myocardial infarction [139] and after water-pipe smoke exposure [140]. Also, in a study on apolipoprotein E-deficient mice betaine exerted an anti-atherogenic effect by inhibiting inflammatory response [141].

Despite promising results from experimental studies, the clinical significance of betaine has not yet been fully worked out. An increase in betaine serum concentration was related to a relative risk of acute and chronic HF [142]. Investigation of betaine concentrations in patients with chronic systolic HF revealed an association between elevated betaine, and high plasma NT-pro-BNP levels as well as left ventricular diastolic (but not systolic) dysfunction. These indices were also prognostic for worse 5-year adverse clinical outcomes in HF [143]. Furthermore, in patients with diabetes, high serum betaine levels were associated with a greater risk of hospitalization for HF [144]. On the other hand, recent meta-analysis does not support the association between plasma betaine and elevated cardiovascular risk [145] or correlation between betaine and cardiovascular death, all-cause death, acute HF leading to hospitalization [115], and there are data suggesting that betaine insufficiency indicates an increased risk of HF after an acute coronary event [146].

Considering the effect of betaine on BP, several lines of evidence suggest that it could counteract hypertension. 12-week supplementation of betaine to obese patients led to an insignificant decrease in diastolic BP compared to the control [147]. Another study, performed on 7074 individuals [148], revealed a negative correlation between serum betaine levels and both systolic and diastolic pressure. Furthermore, Wang et al. showed that reduced circulating betaine was associated with high systolic and diastolic BP in hemodialysis patients [149].

Essentially no clinical studies directly tested supplementation of betaine in terms of its ability to improve cardiovascular or renal health. In particular, the impact of betaine on BP regulation and diuresis requires more research.

The effect of osmolytes on cardiovascular system and water-electrolyte balance has been summarized in Table 2.

Table 2.

Effects of osmolytes on hemodynamics and water-electrolyte balance in HF patients

Osmolyte	BP	HR	Diuresis	Serum Na⁺	Serum K⁺	Serum Cl⁺	Renal Function	Serum levels in HF	References
Urea	↓, -	-	↑	↑	-	-	↑	↑	[60, 67, 68, 150, 151]
Taurine	↓,↑	↑, -	↑	↓	↓	↓	↑	↓	[85–88, 91, 152–155]
TMAO	↓,↑, -	↑, ↓	↑	-	-	-	↓	↑	[106, 109, 110, 123, 130, 131, 156–158]
Betaine	↓, -	-	↑	-	-	-	↑	↑	[137, 143, 144, 147–149, 159]

↓, lowering effect or decreased levels; ↑, heightening effect or elevated levels; -, no effect; BP, blood pressure; HF, heart failure; HR, heart rate; TMAO, trimethylamine N-oxide;

Potential mechanisms underlying the diuretic effects of osmolytes

There are several possible mechanisms through which osmolytes may exert a diuretic effect. Below, we present the two with the most supporting evidence.

Firstly, endogenous osmolytes may directly change the osmotic pressure gradient in the kidney nephron. Alongside vasopressin, the osmotic pressure gradient between the filtrate and the kidney medulla is the key factor driving water reabsorption [160]. Therefore, the increase of osmolyte concentration in the filtrate should result in greater water loss in the urine. Apart from urea, the osmolytes we discussed do not move passively between the filtrate and the renal interstitium and require a secondary active transportation system. Although this is not thoroughly explored, the literature suggests that betaine, taurine, and urea are reabsorbed from filtrate via SIT1 (sodium-dependent amino acid transporter) [161], TauT (taurine transporter) [162], urea transporter A1 (UT-A1), and urea transporter A1 (UT-A3) [163, 164], respectively (see Fig. 1). Arguably, inhibiting these transporters may produce a diuretic effect. In fact, UTs have already become a target of novel diuretic therapy that has recently been investigated [165]. Inhibition of these transporters essentially retains urea in the renal collecting duct, thereby stimulating osmotic diuresis without disrupting electrolyte balance. Therefore, they could potentially act as salt-sparing diuretics (aquaretics), which may have fewer side effects compared to other available diuretics that primarily target salt channels [166–168]. We hypothesize that other osmolyte transporters may be a target of new aquaretics, which would be a viable alternative to natriuretics in individuals with hyponatremia. Considering TMAO, it is generally believed that, in addition to glomerular filtration, TMAO is actively secreted in the kidneys [169] via Organic Cation Transporter 2 (OCT2, an uptake transporter) and efflux transporters like Breast Cancer Resistance Protein (BCRP) or Multidrug Resistance Protein 1 (MDR1) [169, 170]. Additionally, research by Gessner et al. suggests that Multidrug and Toxin Extrusion Protein 1 (MATE1) contributes to the transcellular transport of TMAO [171]. This active secretion occurs in the proximal tubule, and currently, there is no data on the transport of TMAO in the renal medulla. However, in mammalian tissues, TMAO is found in the highest concentration in the kidney medulla [172]. Recent data suggest that the expression of enzymes producing TMAO (FMO, Flavin-containing monooxygenase 1, 3, and 5) does not differ between the kidney cortex and the medulla [173]. Therefore, it can be speculated that there are transporters localized in the loops of Henle or the medullary collecting ducts, causing TMAO reabsorption, analogous to urea, which are responsible for TMAO accumulation in the medulla. Figure 1 summarizes the osmolytes transport in the kidney nephron and possible targets of diuretic therapy.

Fig. 1.

Osmolytes transport in kidney nephron and possible targets of diuretic therapy. UT-A1 — urea transporter A1, UT-A3 — urea transporter A3, TauT — taurine transporter, OCT2 — Organic Cation Transporter 2, BCRP — Breast Cancer Resistance Protein, MDR1 — Multidrug Resistance Protein 1, MATE1 — Multidrug and Toxin Extrusion Protein 1, SIT1 — sodium-dependent amino acid transporter

Another mechanism by which endogenous osmolytes may exert a diuretic effect is altering neurohormonal homeostasis. Crucial regulators of the water-electrolyte balance include the neuroendocrine hypothalamo-neurohypophysial system synthesizing vasopressin (anti-diuretic hormone, ADH) [174] as well as complex axes of RAS acting locally in tissues and systemic circulation [175]. In this regard, Wang et al. reported that 28-day betaine supplementation to high-salt stressed rats decreased ADH levels [176]. Considering taurine, its diuretic and natriuretic effects were associated with a decrease in plasma renin activity and aldosterone, but not atrial natriuretic peptide and vasopressin, suggesting that the diuretic effect of taurine is mainly dependent on the inhibition of the RAS [88]. However, taurine also exerts modulatory action on the osmosensitivity of supraoptic neurons and therefore affects vasopressin release [177]. In one of our studies on TMAO, healthy rats supplemented with TMAO exhibited higher ADH plasma concentration. In HF rats, this effect was not observed, presumably due to pathological neurohormonal activation and ADH increase due to HF. Nonetheless, the diuretic effect of TMAO in each experimental setting was observed, regardless of elevated ADH. Our study revealed that TMAO causes a favorable shift in the RAS, towards angiotensin converting enzyme 2-MAS (ACE2-MAS) axis, which activation is generally associated with a natriuretic and diuretic response [178].

Summary

There is an urgent need for innovative strategies to manage fluid retention in HF and hypertension, driven by the high rates of hospitalization and mortality associated with HF.

Emerging evidence suggests that elevated levels of renal osmolytes, such as TMAO and betaine, may reflect underlying volume overload and disturbances in water-electrolyte balance. Yet, the precise mechanisms linking HF to altered osmolyte profiles remain poorly defined, highlighting a critical gap in our understanding and a compelling area for future investigation.

Particularly promising is the exploration of osmolyte transporters beyond the well-characterized urea channels as potential targets for novel aquaretic therapies. This approach could open new pathways for managing diuretic resistance and addressing persistent congestion in HF. Beyond acute decompensation, these agents may offer benefits in earlier HF stages, where subtle neurohormonal and volume changes precede overt symptoms. For patients on loop diuretics, adjunctive use of osmolytes such as urea or taurine could enhance diuretic response, reduce resistance, and mitigate electrolyte disturbances.

Moreover, the multifaceted properties of osmolytes—including antioxidant, anti-inflammatory, and metabolic regulatory effects—position them as attractive candidates for comprehensive cardiorenal modulation. Carefully designed clinical trials are needed to assess their efficacy and safety across diverse HF phenotypes and stages.

Abbreviations

ACC/AHA

American College of Cardiology/American Heart Association

ACE2-MAS

Angiotensin converting enzyme 2-MAS

ACEI

Angiotensin-converting enzyme inhibitors

ADH

Antidiuretic hormone

ARB

Angiotensin receptor blockers

ARNI

Angiotensin receptor neprilysin inhibitor

ATP

Adenosine triphosphate

BCRP

Breast Cancer Resistance Protein

BGT1

Betaine-GABA transporter 1

BP

Blood pressure

BUN

Blood urea nitrogen

CCBs

Calcium channel blockers

DMB

3-Dimethyl-1-butanol

ESC

European Society of Cardiology

FMO

Flavin-containing monooxygenase

GABA

Gamma-aminobutyric acid

HF

Heart failure

HFmrEF

Heart failure with mildly reduced ejection fraction

HFpEF

Heart failure with preserved ejection fraction

HFrEF

Heart failure with reduced ejection fraction

LDH

Lactate dehydrogenase

LVEF

Left ventricular ejection fraction

MATE1

Multidrug and Toxin Extrusion Protein 1

MDR1

Multidrug Resistance Protein 1

MRAs

Mineralocorticoid receptor antagonists

NT-pro-BNP

N-terminal prohormone of brain natriuretic peptide

NYHA

New York Heart Association (Functional Classification)

OCT2

Organic Cation Transporter 2

RAS

Renin-angiotensin system

ROS

Reactive oxygen species

SGLT2-I

Sodium glucose co-transporter 2 inhibitors

SIADH

Syndrome of inappropriate antidiuretic hormone secretion

SIT1

Sodium-dependent imino acid transporter

TauT

Taurine transporter

TMA

Trimethylamine

TMAO

Trimethylamine N-oxide

UT-A1

Urea transporter A1

UT-A3

Urea transporter A3

Author contribution

Authors'contributions M.U., I.M., W.K., K.J. and Z.A. performed the literature search and drafted the manuscript, M.U. conceptualized the idea for the article and provided critical revisions.

Funding

The study was supported by the National Science Centre, Poland (2018/31/B/NZ5/00038).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.