Management of Hyperkalemia in Renin-Angiotensin-Aldosterone System Inhibitor: Strategies to Maintain Chronic Kidney Disease Patients with Type II Diabetes on Therapy.

BACKGROUND: According to the Centers for Disease Control and Prevention (CDC), diabetes affects approximately 37.3 million individuals in the USA, with another estimated 96 million people having a prediabetic state. Furthermore, one or two out of three adult Americans exhibit metabolic syndrome or an insulin-resistant state, depending on their age group. SUMMARY: Chronic kidney disease (CKD) represents a complication often associated with type II diabetes or the insulin-resistant condition, typically identifiable through proteinuria. Proteinuria serves as both a marker and a contributing factor to kidney damage, and it significantly heightens the risk of cardiovascular (CV) events, including atherosclerosis, heart attacks, and strokes. Renin-angiotensin-aldosterone system inhibitors (RAASis) have demonstrated clinical efficacy in lowering blood pressure, reducing proteinuria, and slowing CKD progression. However, hyperkalemia is a common and serious adverse effect associated with using RAASi. KEY MESSAGES: It is imperative to establish personalized management strategies to enable patients to continue RAASi therapy while effectively addressing hyperkalemia risk. Healthcare professionals must be careful not to inadvertently create a low renal perfusion state, which can reduce distal nephron luminal flow or luminal sodium concentration while using RAASi. Nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), such as finerenone, are demonstrated to delay CKD progression and reduce CV complications, all while mitigating the risk of hyperkalemia. Additionally, maintaining a routine monitoring regimen for serum potassium levels among at-risk patients, making dietary adjustments, and considering the adoption of newer potassium-binding agents hold promise for optimizing RAASi therapy and achieving more effective hyperkalemia management.

Hyperkalemia treatment Standard.

Hyperkalemia is a common electrolyte disturbance in both inpatient and outpatient clinical practice. The severity and associated risk depends on the underlying cause and rate of K+ increase. Acute hyperkalemia requires immediate attention due to potentially life-threatening manifestations resulting from the rapid rise in plasma K+ concentration. Treatment is initially focused on stabilizing the cardiac membrane, followed by maneuvers to shift K+ into the cell, and ultimately initiating strategies to decrease total body K+ content. Chronic hyperkalemia develops over a more extended period of time and manifestations tend to be less severe. Nevertheless, the disorder is not benign since chronic hyperkalemia is associated with increased morbidity and mortality. The approach to patients with chronic hyperkalemia begins with a review of medications potentially responsible for the disorder, ensuring effective diuretic therapy, and correcting metabolic acidosis if present. The practice of restricting foods high in K+ potassium to manage hyperkalemia is being reassessed since the evidence supporting the effectiveness of this strategy is lacking. Rather, dietary restriction should be more nuanced focusing on reducing intake of non-plant sources of K+. Down titration and/or discontinuation of renin-angiotensin-aldosterone inhibitors should be discouraged since these drugs improve outcomes in patients with heart failure and proteinuric kidney disease. In addition to other conservative measures, K+ binding drugs and SGLT2 inhibitors can assist in maintaining use of these drugs.

Non-steroidal mineralocorticoid antagonists and hyperkalemia monitoring in chronic kidney disease patients associated with type II diabetes: a narrative review.

Chronic kidney disease (CKD) is a prevalent complication of Type II diabetes (T2D). The coexistence of CKD with T2D is comparable to cardiovascular disease (CVD) when the estimated glomerular filtration rate declines below 60 ml/min/1.73 m2. Screening and early detection of people with high risk for CKD would be beneficial in managing CKD progress and the associated complications such as CV complications. Renin-angiotensin-aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression, but they carry the risk of hyperkalemia. Nonsteroidal mineralocorticoid antagonists (nsMRA), such as finerenone, exhibit considerable efficacy in their anti-inflammatory, antifibrotic, and renal protective effects with demonstrable reductions in CV complications. In addition, nsMRAs do not cause significant changes in serum potassium levels compared to traditional steroidal MRA. Ongoing research explores the capacity of the sodium-glucose transport protein 2 inhibitors (SGLT-2i), combined with nsMRA, to produce synergistic renal protective effects and reduce the risk of hyperkalemia. Also, a dedicated renal outcomes study (FLOW study) involving a once-weekly injectable Glucagon-like peptide-1 receptor agonist, semaglutide, was halted early by the data monitoring committee due to having achieved the predefined efficacy endpoint and considerations related to renal disease. In CKD patients with T2D on nsMRA, hyperkalemia management requires a comprehensive approach involving lifestyle adjustments, dietary modifications, regular serum potassium level monitoring, and potassium binders, if necessary. Withholding or down-titration of nsMRAs with close monitoring of serum potassium levels may be required in patients with concerning potassium levels. In light of the current state of knowledge, this review article explores the perspectives and approaches that HCPs may consider when monitoring and managing hyperkalemia in CKD patients with T2D.

Chronic Kidney Disease (CKD) is a common and serious problem among people with Type II Diabetes (T2D). People who have CKD with T2D are at a higher risk for heart disease after normal kidney function declines below certain levels. Renin-angiotensin-aldosterone system inhibitors are a group of medications that can help delay CKD progression but may cause a rise in circulating potassium levels. Nonsteroidal mineralocorticoid antagonist (nsMRA), such as finerenone, can reduce kidney inflammation and damage, with noted cardiovascular benefits, and with less effect on serum potassium levels as compared to their steroid-based counterparts. Researchers are studying whether combining blood sugar medications such as sodium-glucose transport protein-2 inhibitors (SGLT-2i) and finerenone can help protect the kidneys and heart. They also want to see if this combination can prevent high potassium levels. This article talks about ways to check and monitor potassium levels in CKD patients with T2D who may be taking nsMRA. To manage high potassium levels in people with CKD and T2D, doctors may suggest lifestyle changes, dietary adjustments, potassium-lowering medication, or adjustment of other medications with close monitoring of potassium levels.

SGLT2 Inhibition and Kidney Potassium Homeostasis.

Pharmacologic inhibition of the sodium-glucose transporter 2 (SGLT2) in the proximal tubule brings about physiologic changes predicted to both increase and decrease kidney K + excretion. Despite these effects, disorders of plasma K + concentration are an uncommon occurrence. If anything, these drugs either cause no effect or a slight reduction in plasma K + concentration in patients with normal kidney function but seem to exert a protective effect against hyperkalemia in the setting of reduced kidney function or when given with drugs that block the renin-angiotensin-aldosterone axis. In this review, we discuss the changes in kidney physiology after the administration of SGLT2 inhibitors predicted to cause both hypokalemia and hyperkalemia. We conclude that these factors offset one another, explaining the uncommon occurrence of dyskalemias with these drugs. Careful human studies focusing on the determinants of kidney K + handling are needed to fully understand how these drugs attenuate the risk of hyperkalemia and yet rarely cause hypokalemia.

New Insights Into Dietary Approaches to Potassium Management in Chronic Kidney Disease.

Potassium disorders are one of the most common electrolyte abnormalities in patients with chronic kidney disease (CKD), contributing to poor clinical outcomes. Maintaining serum potassium levels within the physiologically normal range is critically important in these patients. Dietary potassium restriction has long been considered a core strategy for the management of chronic hyperkalemia in patients with CKD. However, this has been challenged by recent evidence suggesting a paradigm shift toward fostering more liberalized, plant-based dietary patterns. The advent of novel potassium binders and an improved understanding of gastrointestinal processes involved in potassium homeostasis (e.g., gastrointestinal potassium wasting) may facilitate a paradigm shift and incorporation of heart-healthy potassium-enriched food sources. Nevertheless, uncertainty regarding the risk-benefit of plant-based diets in the context of potassium management in CKD remains, requiring well-designed clinical trials to determine the efficacy of dietary potassium manipulation toward improvement of clinical outcomes in patients with CKD.

The Role of Dietary Potassium in the Cardiovascular Protective Effects of Plant-Based Diets.

Dietary intervention is an essential factor in managing a multitude of chronic health conditions such as cardiovascular and chronic kidney disease. In recent decades, there has been a host of research suggesting the potential benefit of plant-based diets in mitigating the health outcomes of these conditions. Plant-based diets are rich in vegetables and fruits, while limiting processed food and animal protein sources. The underlying physiological mechanism involves the interaction of several macronutrients and micronutrients such as plant protein, carbohydrates, and dietary potassium. Specifically, plant-based foods rich in potassium provide cardiorenal protective effects to include urinary alkalization and increased sodium excretion. These diets induce adaptive physiologic responses that improve kidney and cardiovascular hemodynamics and improve overall metabolic health. A shift toward consuming plant-based diets even in subjects with cardiorenal decrements may reduce their morbidity and mortality. Nonetheless, randomized controlled trials are needed to confirm the clinical benefits of plant-based diets.

Amlodipine in the current management of hypertension.

Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which amlodipine, a dihydropyridine, has unique characteristics that distinguish it from other drugs within this class. This review aims to provide an updated overview of the evidence supporting the use of amlodipine over the past 30 years and highlights its cardiovascular benefits in current hypertension management. Amlodipine has low renal clearance (7 mL/min/mg) and long half-life (35-50 h) and duration of action, which allows it to sustain its anti-hypertensive effect for more than 24 h following a single dose. Additionally, blood pressure (BP) control is maintained even when a dose has been missed, providing continuous protection in case of incidental noncompliance. It has proven to reduce BP variability and successfully lower BP. Amlodipine also controls BP in patients with a systolic/diastolic BP of 130/80 mm Hg or higher, diabetes, or chronic kidney disease without worsening glycemic or kidney function. Additionally, amlodipine is a wise choice for older adults due to its ability to control BP and protect against stroke and myocardial infarction. Side effects of amlodipine include edema, palpitations, dizziness, and flushing, which are more common with the higher dose of 10 mg. Amlodipine is cost effective and predicted to be cost saving when compared with usual care.

The evolutionary impact and influence of oestrogens on adipose tissue structure and function.

Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue 'health'. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023.

The respiratory system plays an integral part in maintaining acid-base homeostasis. Normal ventilation participates in the maintenance of an open buffer system, allowing for excretion of CO2 produced from the interaction of nonvolatile acids and bicarbonate. Quantitatively of much greater importance is the excretion of CO2 derived from volatile acids produced from the complete oxidation of fat and carbohydrate. A primary increase in CO2 tension of body fluids is the cause of respiratory acidosis and develops most commonly from one or more of the following: (1) disorders affecting gas exchange across the pulmonary capillary, (2) disorders of the chest wall and the respiratory muscles, and/or (3) inhibition of the medullary respiratory center. Respiratory alkalosis or primary hypocapnia is most commonly caused by disorders that increase alveolar ventilation and is defined by an arterial partial pressure of CO2 <35 mm Hg with subsequent alkalization of body fluids. Both disorders can lead to life-threatening complications, making it of paramount importance for the clinician to have a thorough understanding of the cause and treatment of these acid-base disturbances.

The hypokalaemia that came from the cold.

While electrolyte disorders are common in nephrologists' clinical practice, hypothermia is a condition that nephrologists rarely encounter. Hypothermia can induce several pathophysiological effects on the human body, including hypokalaemia, which is reversible with rewarming. Despite growing evidence from animal research and human studies, the underlying mechanisms of hypothermia-induced hypokalaemia remain unclear. Boubes and colleagues recently presented a case series of hypokalaemia during hypothermia and rewarming, proposing a novel hypothesis for the underlying mechanisms. In this editorial, we review the current knowledge about hypothermia and associated electrolyte changes with insights into the effects of hypothermia on renal physiology.

Acquired Disorders of Hypomagnesemia.

Magnesium disorders are common in clinical practice and when present can manifest clinically as cardiovascular, neuromuscular, or other organ dysfunction. Hypomagnesemia is far more common than hypermagnesemia, which is largely seen in patients with reduced glomerular filtration rates receiving magnesium-containing medications. In addition to inherited disorders of magnesium handling, hypomagnesemia is also seen with excessive gastrointestinal or renal losses and due to medications such as amphotericin B, aminoglycosides, and cisplatin. Laboratory assessment of body magnesium stores largely relies on the measurement of serum magnesium levels that are a poor proxy for total body stores but does correlate with the development of symptoms. Replacement of magnesium can be challenging, with oral replacement strategies being generally more effective at slowly replacing body stores but intravenous replacement being more effective at treating the more life-threatening and severe cases of hypomagnesemia. We conducted a thorough review of the literature using PubMed (1970-2022) and the search terms magnesium, hypomagnesemia, drugs, medications, treatment, and therapy. In the absence of clear data on optimal management of hypomagnesemia, we have made recommendations on magnesium replacement based on our clinical experience.

A comparative post hoc analysis of finerenone and spironolactone in resistant hypertension in moderate-to-advanced chronic kidney disease.

Background: Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone ± a potassium binder. Methods: In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5 mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17 weeks were compared with 12 weeks from AMBER. Results: In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was -7.1 for finerenone and -1.3 for placebo {between-group difference -5.74 [95% confidence interval (CI) -7.99 to -3.49], P < .0001} versus -11.7 for spironolactone + patiromer and -10.8 for spironolactone + placebo [between-group difference -1.0 (95% CI -4.4-2.4), P = .58]. The incidence of serum [K+] ≥5.5 mmol/L was 12% for finerenone and 3% for placebo versus 35% with spironolactone + patiromer and 64% with spironolactone + placebo. Treatment discontinuation due to hyperkalemia was 0.3% for finerenone and 0% for placebo versus 7% for spironolactone + patiromer and 23% for spironolactone + placebo. Conclusions: In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation.Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049).

Pathophysiology and clinical management of hyperkalemia in chronic kidney disease.

Adaptive increases in kidney and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with chronic kidney disease (CKD) as long as the glomerular filtration rate (GFR) remains >15-20 mL/min. K+ balance is maintained by increased secretion per functioning nephron, which is mediated by elevated plasma K+ concentration, aldosterone, increased flow rate, and enhanced Na+-K+-ATPase activity. Fecal losses of potassium also increase in CKD. These mechanisms are effective in preventing hyperkalemia if urine output is in excess of 600 mL/day and the GFR exceeds 15 mL/min. Development of hyperkalemia with only mild to moderate reductions in GFR should prompt a search for intrinsic disease of the collecting duct, disturbances in mineralocorticoid activity, and/or decreased delivery of sodium to the distal nephron. The initial approach to treatment is to review the patient's medication profile and whenever possible discontinue drugs that impair kidney K+ excretion. Patients should be educated on sources of K+ in the diet and should be strongly encouraged to avoid the use of K+ containing salt substitutes as well as herbal remedies since herbs may be a hidden source of dietary K+. Effective diuretic therapy and correction of metabolic acidosis are effective strategies to minimize the potential for hyperkalemia. Discontinuation or use of submaximal doses of renin-angiotensin blockers should be discouraged given the cardiovascular protective effect these drugs provide. Potassium binding drugs can be useful to enable use of these drugs and potentially allow liberalization of the diet in CKD patients.

Change in albuminuria as a surrogate endpoint for cardiovascular and renal outcomes in patients with diabetes.

For the purpose of predicting clinical outcomes in patients with diabetes and chronic kidney disease, change in albuminuria is a good candidate to be a surrogate marker for future cardiovascular events and progression of kidney disease. Spot urine albumin/creatinine ratio is convenient and recognized as a viable alternative to 24-h albumin, with some limitations. Although there is sufficient evidence to validate its use in clinical trials as a surrogate endpoint for renal outcomes, this is not yet the case for cardiovascular outcomes. While change in albuminuria as a primary or secondary endpoint is trial-specific, its use should be encouraged, nonetheless.

Kidney-Protective Effects of SGLT2 Inhibitors.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors have become an integral part of clinical practice guidelines to slow the progression of CKD in patients with and without diabetes mellitus. Although initially developed as antihyperglycemic drugs, their effect on the kidney is multifactorial resulting from profuse glycosuria and natriuresis consequent to their primary site of action. Hemodynamic and metabolic changes ensue that mediate kidney-protective effects, including ( 1 ) decreased workload of proximal tubular cells and prevention of aberrant increases in glycolysis, contributing to a decreased risk of AKI; ( 2 ) lowering of intraglomerular pressure by activating tubular glomerular feedback and reductions in BP and tissue sodium content; ( 3 ) initiation of nutrient-sensing pathways reminiscent of starvation activating ketogenesis, increased autophagy, and restoration of carbon flow through the mitochondria without production of reactive oxygen species; ( 4 ) body weight loss without a reduction in basal metabolic rate due to increases in nonshivering thermogenesis; and ( 5 ) favorable changes in quantity and characteristics of perirenal fat leading to decreased release of adipokines, which adversely affect the glomerular capillary and signal increased sympathetic outflow. Additionally, these drugs stimulate phosphate and magnesium reabsorption and increase uric acid excretion. Familiarity with kidney-specific mechanisms of action, potential changes in kidney function, and/or alterations in electrolytes and volume status, which are induced by these widely prescribed drugs, will facilitate usage in the patients for whom they are indicated.

An international Delphi consensus regarding best practice recommendations for hyperkalaemia across the cardiorenal spectrum.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) are guideline-recommended therapy for individuals with cardiorenal disease. They are associated with increased risk of hyperkalaemia, a common and life-threatening disorder for this population. RAASi-induced hyperkalaemia often leads to dose reduction or discontinuation, reducing cardiorenal protection. Guideline recommendations differ between specialties for the clinical management of hyperkalaemia. Using a modified Delphi method, we developed consensus recommendations for optimal management of hyperkalaemia in adults with cardiorenal disease. METHODS AND RESULTS: An international steering group of cardiologists and nephrologists developed 39 statements regarding hyperkalaemia care, including risk factors and risk stratification, prevention, correction, and cross-specialty coordination. Consensus was determined by agreement on an online questionnaire administered to cardiorenal specialists across Europe and North America. The threshold for consensus agreement was established a priori by the steering group at 67%. Across November 2021, 520 responses were received from Canada (n = 50), France (n = 50), Germany (n = 54), Italy (n = 58), Spain (n = 57), the UK (n = 49), and the US (n = 202); 268 from cardiologists and 252 from nephrologists. Twenty-nine statements attained very high agreement (≥90%) and 10 attained high agreement (≥67%-<90%), with strong alignment between cardiologists and nephrologists. CONCLUSION: A high degree of consensus regarding hyperkalaemia evaluation and management exists among healthcare professionals. Based on high levels of agreement, the steering group derived six key recommendations for hyperkalaemia prevention and management in people with cardiorenal disease. Future studies examining the quality of hyperkalaemia care delivery are required.

Extrarenal Effects of Aldosterone on Potassium Homeostasis.

The role of aldosterone in regulating K+ excretion in the distal nephron is well established in kidney physiology. In addition to effects on the kidney, aldosterone modulates K+ and Na+ transport in salivary fluid, sweat, airway epithelia, and colonic fluid. More controversial and less well defined is the role of aldosterone in determining the internal distribution of K+ across cell membranes in nontransporting epithelia. In vivo studies have been limited by the difficulty in accurately measuring overall K+ balance and factoring in both variability and secondary changes in acid-base balance, systemic hemodynamics, and other K+-regulatory factors such as hormones and adrenergic activity. Despite these limitations, the aggregate data support a contributory role of aldosterone along with insulin and catecholamines in the normal physiologic regulation of internal K+ distribution. The authors speculate differences in tissue sensitivity to aldosterone may also contribute to differential tissue response of cardiac and skeletal muscle to conditions of total body K+ depletion.