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SGLT2 Inhibition and Kidney Potassium Homeostasis.
Palmer, BF, Clegg, DJ
Clinical journal of the American Society of Nephrology : CJASN. 2024;(3):399-405
Abstract
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.
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Oestrogens, adipose tissues and environmental exposures influence obesity and diabetes across the lifecycle.
Bardhi, O, Dubey, P, Palmer, BF, Clegg, DJ
The Proceedings of the Nutrition Society. 2024;:1-8
Abstract
Endogenous oestrogens regulate essential functions to include menstrual cycles, energy balance, adipose tissue distribution, pancreatic β-cell function, insulin sensitivity and lipid homeostasis. Oestrogens are a family of hormones which include oestradiol (E2), oestrone (E1) and oestriol (E3). Oestrogens function by binding and activating oestrogen receptors (ERs). Phytoestrogens are plant-derived compounds which exhibit oestrogenic-like activity and can bind to ERs. Phytoestrogens exert potential oestrogenic-like benefits; however, their effects are context-dependent and require cautious consideration regarding generalised health benefits. Xenoestrogens are synthetic compounds which have been determined to disrupt endocrine function through binding to ERs. Xenoestrogens enter the body through various routes and given their chemical structure they can accumulate, posing long-term health risks. Xenoestrogens interfere with endogenous oestrogens and their functions contributing to conditions like cancer, infertility, and metabolic disorders. Understanding the interplay between endogenous and exogenous oestrogens is critical in order to determine their potential health consequences and requires further investigation. This manuscript provides a summary of the role endogenous oestrogens have in regulating metabolic functions. Additionally, we discuss the impact phytoestrogens and synthetic xenoestrogens have on biological systems across various life stages. We highlight their mechanisms of action, potential benefits, risks and discuss the need for further research to bridge gaps in understanding and mitigate exposure-related health risks.
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Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023.
Palmer, BF, Clegg, DJ
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2023;(3):347-359
Abstract
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.
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New Insights Into Dietary Approaches to Potassium Management in Chronic Kidney Disease.
Sumida, K, Biruete, A, Kistler, BM, Khor, BH, Ebrahim, Z, Giannini, R, Sussman-Dabach, EJ, Avesani, CM, Chan, M, Lambert, K, et al
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2023;(6S):S6-S12
Abstract
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.
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Metabolic Flexibility and Its Impact on Health Outcomes.
Palmer, BF, Clegg, DJ
Mayo Clinic proceedings. 2022;(4):761-776
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Abstract
A metabolically flexible state exists when there is a rapid switch between glucose and fatty acids during the transition between the fed and fasting state. This flexibility in fuel choice serves to prevent hyperglycemia following a meal and simultaneously ensures an adequate amount of blood glucose is available for delivery to the brain and exclusively glycolytic tissues during fasting. The modern era is characterized by chronic overnutrition in which a mixture of fuels is delivered to the mitochondria in an unabated manner thereby uncoupling the feast and famine situation. The continuous influx of fuel leads to accumulation of reducing equivalents in the mitochondria and an increase in the mitochondrial membrane potential. These changes create a microenvironment fostering the generation of reactive oxygen species and other metabolites leading to deleterious protein modification, cell injury, and ultimately clinical disease. Insulin resistance may also play a primary role in this deleterious effect. The imbalance between mitochondrial energy delivery and use is made worse with a sedentary lifestyle. Maneuvers that restore energy balance across the mitochondria activate pathways that remove or repair damaged molecules and restore the plasticity characteristic of normal energy metabolism. Readily available strategies to maintain energy balance across the mitochondria include exercise, various forms of caloric restriction, administration of sodium-glucose cotransporter-2 inhibitors, cold exposure, and hypobaric hypoxia.
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Associations of Glycemic Index and Glycemic Load with Cardiovascular Disease: Updated Evidence from Meta-analysis and Cohort Studies.
Dwivedi, AK, Dubey, P, Reddy, SY, Clegg, DJ
Current cardiology reports. 2022;(3):141-161
Abstract
PURPOSE OF REVIEW Diet and lifestyle patterns are considered major contributory factors for cardiovascular disease (CVD) and mortality. In particular, consuming a diet higher in carbohydrates (not inclusive of fruits and vegetables, but more processed carbohydrates) has been associated with metabolic abnormalities that subsequently may increase the risk of CVD and related mortality. Glycemic index (GI) and glycemic load (GL) are values given to foods based on how fast the body converts carbohydrates into glucose also referred to as the glycemic burden of carbohydrates from foods. Conflicting associations of how high GI and GL influence CVDs have been observed even in high-quality meta-analysis studies. We synthesize and report the associations of high GI and GL with various CVDs by sex, obesity, and geographical locations using an updated review of meta-analysis and observational studies. RECENT FINDINGS We identified high GI or high GL is associated with an increased risk of CVD events including diabetes (DM), metabolic syndrome (MS), coronary heart disease (CHD), stroke, and stroke mortality in the general population, and the risk of CVD outcomes appears to be stratified by sex, obesity status, and preexisting CVD. Both high GI and GL are associated with DM and CHD in the general population. However, high GI is strongly associated with DM/MS, while high GL is strongly associated with an increased risk of CHD in females. In addition, high GL is also associated with incident stroke, and appears to be associated with CVD mortality in subjects with preexisting CVD or high BMI and all-cause mortality in non-obese DM subjects. However, high GI appears to be associated with CVD or all-cause mortality only in females without CVD. High GI/GL is an important risk factor for CVD outcomes in the general population. High GI seems to be markedly associated with DM/MS, and it may enhance the risk of CVD or all-cause mortality in both sexes and predominately females. Although both high GI and high GL are risk factors for CHD in females, high GL is associated with CVD outcomes in at-risk populations for CVD. These data suggest that while high GI increases the propensity of CVD risk factors and mortality in healthy individuals, high GL contributes to the risk of severe heart diseases including CVD or all-cause mortality, particularly in at-risk populations. These data indicate dietary interventions designed for focusing carbohydrate quality by lowering both GI and GL are recommended for preventing CVD outcomes across all populations.
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Can Novel Potassium Binders Liberate People with Chronic Kidney Disease from the Low-Potassium Diet? A Cautionary Tale.
St-Jules, DE, Clegg, DJ, Palmer, BF, Carrero, JJ
Clinical journal of the American Society of Nephrology : CJASN. 2022;(3):467-472
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Abstract
The advent of new potassium binders provides an important breakthrough in the chronic management of hyperkalemia for people with CKD. In addition to the direct benefits of managing hyperkalemia, many researchers and clinicians view these new medications as a possible means to safely transition patients away from the low-potassium diet to a more healthful eating pattern. In this review, we examine the mechanisms of potassium binders in the context of hyperkalemia risk related to dietary potassium intake in people with CKD. We note that whereas these medications target hyperkalemia caused by potassium bioaccumulation, the primary evidence for restricting dietary potassium is risk of postprandial hyperkalemia. The majority of ingested potassium is absorbed alongside endogenously secreted potassium in the small intestines, but the action of these novel medications is predominantly constrained to the large intestine. As a result and despite their effectiveness in lowering basal potassium levels, it remains unclear whether potassium binders would provide protection against hyperkalemia caused by excessive dietary potassium intake in people with CKD. Until this knowledge gap is bridged, clinicians should consider postprandial hyperkalemia risk when removing restrictions on dietary potassium intake in people with CKD on potassium binders.
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Diet-microbiome interactions in cancer treatment: Opportunities and challenges for precision nutrition in cancer.
Greathouse, KL, Wyatt, M, Johnson, AJ, Toy, EP, Khan, JM, Dunn, K, Clegg, DJ, Reddy, S
Neoplasia (New York, N.Y.). 2022;:100800
Abstract
Dietary patterns contribute to cancer risk. Separately, microbial factors influence the development of several cancers. However, the interaction of diet and the microbiome and their joint contribution to cancer treatment response needs more research. The microbiome significantly impacts drug metabolism, immune activation, and response to immunotherapy. One of the critical factors affecting the microbiome structure and function is diet. Data demonstrate that the diet and microbiome composition affects the immune response. Moreover, malnutrition is a significant confounder to cancer therapy response. There is little understanding of the interaction of malnutrition with the microbiome in the context of cancer. This review aims to address the current knowledge of dietary intake patterns and malnutrition among cancer patients and the impact on treatment outcomes. Second, this review will provide evidence linking the microbiome to cancer treatment response and provide evidence of the potentially strong effect that diet could have on this interaction. This review will formulate critical questions that will need further research to understand the diet-microbiome relationship in cancer treatment response and directions for future research to guide us to precision nutrition therapy to improve cancer outcomes.
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Extrarenal Effects of Aldosterone on Potassium Homeostasis.
Palmer, BF, Clegg, DJ
Kidney360. 2022;(3):561-568
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Abstract
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.
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10.
Starvation Ketosis and the Kidney.
Palmer, BF, Clegg, DJ
American journal of nephrology. 2021;(6):467-478
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Abstract
BACKGROUND The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the clinician better insight into many clinical conditions characterized by ketoacidosis. SUMMARY The body adapts to long-term fasting by conserving nitrogen, as the brain increasingly utilizes keto acids, sparing the need for glucose. This shift in fuel utilization decreases the need for mobilization of amino acids from the muscle for purposes of gluconeogenesis. Loss of urinary nitrogen is initially in the form of urea when hepatic gluconeogenesis is dominant and later as ammonia reflecting increased glutamine uptake by the kidney. The carbon skeleton of glutamine is utilized for glucose production and regeneration of consumed HCO3-. The replacement of urea with NH4+ provides the osmoles needed for urine flow and waste product excretion. Over time, the urinary loss of nitrogen is minimized as kidney uptake of filtered ketone bodies becomes more complete. Adjustments in urine Na+ serve to minimize kidney K+ wasting and, along with changes in urine pH, minimize the likelihood of uric acid precipitation. There is a sexual dimorphism in response to starvation. Key Message: Ketoacidosis is a major feature of common clinical conditions to include diabetic ketoacidosis, alcoholic ketoacidosis, salicylate intoxication, SGLT2 inhibitor therapy, and calorie sufficient but carbohydrate-restricted diets. Familiarity with the pathophysiology and metabolic consequences of ketogenesis is critical, given the potential for the clinician to encounter one of these conditions.