Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug-drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient's medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA.

Pseudohypoaldosteronism type IID (PHA2D) is a rare genetic disorder caused by mutations in the KLHL3 gene, leading to increased activity of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the kidneys. This overactivity promotes excessive sodium and chloride reabsorption, resulting in hyperkalaemia, hyperchloremic metabolic acidosis, and suppressed renin/aldosterone levels, despite preserved renal function. We report the case of a nine-year-old boy presenting with chronic fatigue, muscle aches, and growth failure. Laboratory evaluation revealed severe hyperkalaemia and hyperchloremic metabolic acidosis with a normal glomerular filtration rate and persistent normotension. Due to an initial clinical suspicion of isolated mineralocorticoid deficiency, a diagnostic trial of fludrocortisone was initiated while awaiting definitive results. Although this trial improved biochemical markers, it was discontinued once suppressed renin and aldosterone levels pointed toward PHA2. Subsequent genetic testing identified a novel homozygous splice-site mutation in the KLHL3, confirming autosomal recessive PHA2D. Following confirmation of the diagnosis, treatment was transitioned to the disease-specific therapy, hydrochlorothiazide (0.5 mg/kg/day). While this regimen normalized serum potassium and acid-base status, it induced symptomatic hypotension. The dosage was ultimately titrated to an alternate-day, low-dose regimen (0.25 mg/kg), which successfully maintained metabolic stability while minimizing adverse effects. This case underscores that normotension in PHA2D may delay diagnosis and that standard thiazide dosing may precipitate hypotension in previously normotensive patients, necessitating highly individualized treatment strategies.

Hypokalemia is a rare but important cause of rhabdomyolysis in children. Unlike typical rhabdomyolysis, hyperkalemia may be absent because the triggering factor is hypokalemia, potentially delaying diagnosis. We report a five-year-old boy with hypoplastic left heart syndrome after a Fontan procedure who developed severe hypokalemia and rhabdomyolysis following prolonged diarrhea while receiving loop diuretics. He presented with acute lower extremity weakness and inability to stand. Laboratory evaluation revealed potassium 1.9 mmol/L and creatine kinase 9,013 U/L, peaking at 32,908 U/L. Urinalysis showed myoglobinuria, and electrocardiography demonstrated ST depression and prominent U waves. Intravenous potassium replacement and diuretic adjustment resulted in rapid clinical recovery without acute kidney injury. A review of previously reported pediatric cases suggests that potassium depletion from gastrointestinal losses or renal wasting predisposes children to rhabdomyolysis. Early recognition and prompt electrolyte correction are essential.

Mineralocorticoid receptor antagonists (MRAs) are strongly recommended by various guidelines for the management of patients with heart failure. Present and emerging clinical evidence also supports the beneficial role of MRAs in lowering the risk of heart failure-associated hospitalization and mortality. Loop diuretics play a crucial role in the management of edema associated with heart failure; however, their use has been associated with electrolyte abnormalities, activation of the renin-angiotensin-aldosterone and sympathetic systems, and diuretic resistance. Combined use of loop diuretics along with MRAs can help to overcome the diuretic resistance and improve the efficacy and safety of loop diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are another class of drugs that have shown significant benefits in patients with heart failure and are guideline-recommended for use in these patients. Combination therapy of SGLT2 inhibitors along with MRAs can improve various clinical outcomes in heart failure patients and reduce the risk of hyperkalemia, commonly associated with MRA therapy. Combination therapies can be potential opportunities to improve clinical outcomes and patient adherence in the management of patients with heart failure.

Background: Adherence to current clinical guidelines is crucial for ensuring optimal therapy in patients with heart failure (HF). This study aims to explore how cardiologists, as specialists in heart failure, approach the clinical scenarios encountered in the management of HF patients, in line with the recommended guidelines. A heart failure-focused meeting was organized, during which participating cardiologists engaged actively. During HF meetings in which cardiologists participated, 108 questionnaires were distributed electronically. In total, 57 men and 51 women expressed their opinions regarding the Delphi analysis. Results: A strong consensus on the benefits of beta-blockers in improving prognoses for, and reducing mortality in, patients with HF and reduced systolic function emerged. The majority of cardiologists continue to prefer intravenous therapy with continuous loop-diuretic administration in combination with thiazide diuretics. The use of metolazone elicits fewer preferences, probably due to concerns about side effects. Certainly, SGLT2i is useful in reducing hospitalizations and reducing congestion; however, there is no full consensus on whether MRAi should be discontinued in favor of SGLT2i alone. The majority of participants would discontinue MRAs in the presence of hyperkalemia and worsening renal function, maintaining sacubitril/valsartan, and indicating a priority for renal safety. There was near-unanimous agreement on the early initiation of sacubitril/valsartan after the stabilization of patients hospitalized for heart failure. Conclusions: A significant majority (97%) of cardiologists expressed a preference for utilizing all of the guideline-recommended drug classes in the management of heart failure, even if this meant not always reaching the maximum tolerated dose for each medication. This approach underscores the importance of comprehensive therapy, targeting multiple pathophysiological mechanisms in heart failure. Cardiologists emphasized that while achieving optimal dosing is ideal, flexibility in treatment regimens is often necessary to accommodate individual patient characteristics, tolerance, and clinical status. The findings highlight the need for personalized treatment strategies that align with current guidelines, while also recognizing the challenges and variability in patient responses to therapy.

The effect of diuretics can be limited by stimulation of counter-regulatory mechanisms, eventually leading to diuretic resistance. It is thought that the mineralocorticoid aldosterone might contribute to the development of diuretic resistance. To test this, we challenged genetically modified mice with or without a deletion of the gene coding for the aldosterone synthase (AS) with furosemide, hydrochlorothiazide (HCT) and triamterene. Urinary excretion was studied in metabolic cages; kidneys were studied for expression of sodium transporters. In both genotypes, a 4-day treatment with HCT via drinking water (400 mg/l) induced a similar natriuresis and modest loss of body weight < 10%. In contrast, furosemide (125 mg/l) and triamterene (200 mg/l) via drinking water stimulated a significantly higher natriuresis and body weight loss in AS[-/-] mice and in addition, triamterene caused massive hyperkalemia > 9 mM and acidosis (pH < 7.0). In AS[+/+] mice, plasma aldosterone concentration tended to increase under furosemide and HCT administration, while triamterene induced a robust ~ sixfold increase. In the kidney, apical targeting and proteolytic activation of the epithelial sodium channel ENaC were stimulated in AS[+/+] mice under triamterene treatment, an effect that was diminished in AS[-/-] mice. In conclusion, aldosterone is essentially involved in the development of diuretic resistance to ENaC blockade by triamterene and to a lesser extent to furosemide. In contrast, resistance to HCT was independent of aldosterone.

Diuretic drugs act on electrolyte transporters in the kidney to induce diuresis and are often used in chronic kidney disease (CKD), given that nephron loss creates a deficit in the ability to excrete dietary sodium, which promotes an increase in plasma volume. This rise in plasma volume is exacerbated by CKD-induced systemic and intra-renal activation of the renin-angiotensin-aldosterone-system, which further limits urinary sodium excretion. In the absence of a compensatory decrease in systemic vascular resistance, increases in plasma volume induced by sodium retention can manifest as a rise in systemic arterial blood pressure. Management of sodium and volume overload in patients with CKD is therefore typically based on restriction of dietary sodium intake and the use of diuretic agents to enhance urinary sodium excretion. Thiazide and thiazide-type diuretics are foundational therapies for the management of hypertension, whereas loop diuretics are often needed for volume overload, which might also require combination therapies. Mineralocorticoid receptor antagonists have an important role in the management of diuretic-resistant volume overload or treatment-resistant hypertension. Additionally, diuretics can be used for the diagnosis of kidney diseases and in the management of hyperkalaemia or hypokalaemia, hyponatraemia, hypercalcaemia and hypomagnesaemia.

While there remains no universally accepted definition for resistant edema, it is generally acknowledged as edema that fails to respond to maximally administered doses of diuretics. Nephrotic edema is characterized by high levels of proteinuria, notably urinary concentrations of serine proteases, which possess the ability to activate the epithelial sodium channel (ENaC), resulting in persistent fluid retention. Loop diuretics are typically preferred as first-line therapy for hypervolemia. However, the sustained activation of ENaC channels may lead to resistance to treatment. Consequently, the blockade of ENaC represents a potential therapeutic approach. We report the case of a 36-year-old man presenting with nephrotic edema managed with a combination of furosemide and human albumin. Despite an initially favorable response, the patient subsequently developed oliguria and progressive weight gain. On the third day, a regimen comprising amiloride (5 mg/day) and hydrochlorothiazide (50 mg/day) was initiated, resulting in complete resolution of edema after 11 days. No hyperkalemia was observed, with only a slight elevation in serum creatinine levels. Although clinical trials are limited, mounting evidence from human and animal studies supports the concept of nephrotic syndrome as an overfill phenomenon and underscores the potential benefits of ENaC blockers in the management of nephrotic edema.

This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA.

Heart failure (HF) remains one of the most common causes of hospitalization and mortality among Polish patients. The position of the Section of Cardiovascular Pharmacotherapy presents the currently applicable options for pharmacological treatment of HF based on the latest European and American guidelines from 2021-2022 in relation to Polish healthcare conditions. Treatment of HF varies depending on its clinical presentation (acute/chronic) or left ventricular ejection fraction. Initial treatment of symptomatic patients with features of volume overload is based on diuretics, especially loop drugs. Treatment aimed at reducing mortality and hospitalization should include drugs blocking the renin-angiotensin-aldosterone system, preferably angiotensin receptor antagonist/neprilysin inhibitor, i.e. sacubitril/valsartan, selected beta-blockers (no class effect - options include bisoprolol, metoprolol succinate, or vasodilatory beta-blockers - carvedilol and nebivolol), mineralocorticoid receptor antagonist, and sodium-glucose cotransporter type 2 inhibitor (flozin), constituting the 4 pillars of pharmacotherapy. Their effectiveness has been confirmed in numerous prospective randomized trials. The current HF treatment strategy is based on the fastest possible implementation of all four mentioned classes of drugs due to their independent additive action. It is also important to individualize therapy according to comorbidities, blood pressure, resting heart rate, or the presence of arrhythmias. This article emphasizes the cardio- and nephroprotective role of flozins in HF therapy, regardless of ejection fraction value. We propose practical guidelines for the use of medicines, profile of adverse reactions, drug interactions, as well as pharmacoeconomic aspects. The principles of treatment with ivabradine, digoxin, vericiguat, iron supplementation, or antiplatelet and anticoagulant therapy are also discussed, along with recent novel drugs including omecamtiv mecarbil, tolvaptan, or coenzyme Q10 as well as progress in the prevention and treatment of hyperkalemia. Based on the latest recommendations, treatment regimens for different types of HF are discussed.