- Email: [email protected]
Managing Hyperkalemia: Another Benefit of Exercise in People With Chronic Kidney Disease?
REVIEW ARTICLE
Managing Hyperkalemia: Another Benefit of Exercise in People With Chronic Kidney Disease? David E. St-Jules, RD, PhD,* Meredith Marinaro, MS, RD, CSR,† David S. Goldfarb, MD,‡ Laura D. Byham-Gray, PhD, RDN,§ and Kenneth R. Wilund, PhD{ People with chronic kidney disease (CKD) are at increased risk of hyperkalemia, an electrolyte abnormality that can cause serious, sometimes fatal, cardiac arrhythmias. Muscle contraction causes potassium to be released from cells, increasing serum potassium concentrations. However, these effects are transient, and the long-term impact of exercise training on hyperkalemia risk in CKD patients is largely unknown. In this review, we examine the effects of exercise on factors affecting potassium balance in people with CKD, highlighting the potential benefits of regular exercise on hyperkalemia risk in this population. Although regular exercise is already recommended for people with CKD, research examining this hypothesis may lead to novel therapeutic treatments for this life-threatening condition. Ó 2019 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
P
ATIENTS WITH CHRONIC kidney disease (CKD) are advised to engage in moderate intensity exercise at least 3-5 times per week.1,2 The most salient benefit of regular exercise is improved physical function, but many other benefits have been identified. In this article, we will review possible mechanistic links between exercise and potassium balance as another potential benefit of exercise in this population (Fig. 1).
Internal Potassium Balance The majority of body potassium is found in the intracellular fluid, having an intracellular:extracellular potassium concentration gradient of approximately 35:1. The internal balance of potassium is vital for generating action potentials in muscle cells, and is maintained through the action of
* Department of Population Health, New York University School of Medicine, New York, New York. † Natural Sciences Department, Concordia University Chicago, River Forest, Illinois. ‡ Division of Nephrology, New York University School of Medicine, New York, New York. § Department of Clinical and Preventive Nutrition Sciences, Rutgers University, New Brunswick, New Jersey. { Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Champaign, Illinois. Financial Disclosure: D.E.S and D.S.G. are investigators on an InvestigatorSponsored Trial from Relypsa, Inc. (ClinicalTrials.gov Identifier: NCT03183778). M.M. is a full time employee of Akebia Therapeutics. Address correspondence to David E. St-Jules, RD, PhD, Center for Healthful Behavior Change, New York University School of Medicine, 713-180 Madison Avenue, New York, NY 10016. E-mail: [email protected] Ó 2019 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 https://doi.org/10.1053/j.jrn.2019.10.001
Journal of Renal Nutrition, Vol -, No - (-), 2019: pp 1-4
sodium-potassium ATPase (NKA). Insulin-mediated increases in NKA action are primarily responsible for the rapid uptake of potassium into cells following a meal.3 As one of the main buffering sites of potassium in the body, muscles have a key role in adaptation to dietary potassium deficiency and excess. During potassium depletion, NKA activity and potassium uptake in muscle are dramatically reduced to help prevent hypokalemia, while potassium excretion by the kidneys is reduced.4 Conversely, during increased potassium intake, NKA activity and potassium uptake in muscle are dramatically increased, and are likely responsible for the extrarenal protection against potassium toxicity seen with high-potassium feeding, until excretion by the kidneys occurs.5,6 Regulation of NKA is also affected by physical activity. During muscle contraction, potassium leaks from muscles into the extracellular fluid. This effect decreases the potassium concentration gradient and membrane potential of muscle cells, reducing contractility. Although potassium leak from cells causes a transient increase in extracellular potassium, muscle cells adapt by increasing NKA activity to take up the potassium.7,8 This adaptation is thought to enhance physical endurance by slowing membrane depolarization from potassium leakage; however, it may also have an indirect effect on internal potassium balance. In addition to increasing muscle NKA activity, exercise may improve internal potassium balance in people with CKD by reducing insulin resistance. Although insulin has been shown to have distinct effects on potassium and glucose homeostasis,4,9 diabetes and insulin resistance are associated with higher serum potassium concentrations and hyperkalemia risk, independent of CKD status and serum glucose concentration.10,11 The reason for the apparent contradictory findings is unclear, and it remains
1
2
ST-JULES ET AL
Potassium Buffering and Storage Another key aspect of exercise adaptation is building muscle. Assuming a potassium concentration of 140 mEq/L and 70% water content, 1 kg of muscle contains approximately 3,800 mg of potassium, which is more potassium than most people consume in a day, or nearly twice the amount of potassium in the entire extracellular fluid compartment. As a result, interventions to build and/or preserve muscle mass may improve the potassiumbuffering capacity of the intracellular compartment, particularly insulin-mediated potassium uptake in the postprandial period. However, any potassium-buffering benefit is likely to be small, as the effect of exercise on relative muscle mass in patients with advanced CKD (if any) is limited,12 and the additional energy intake required to support exercise, and growth and maintenance of muscle, are likely to cause a proportional increase in dietary potassium intake. Potassium Losses in Sweat A small amount of potassium is lost each day in sweat (usually ,500 mg/d). Exercise and heat exposure to induce sweating has been shown to increase potassium losses in sweat to more than 1,000 mg/d, and substantial potassium depletion has been described under extreme exercise and heat conditions.13-15 However, acclimation generally occurs within days, and potassium losses in sweat appear to return to near-normal levels.14 As a result, potassium losses in sweat from regular exercise are unlikely to have a major effect on external potassium balance and serum potassium concentrations in people with CKD. Potassium Losses in Stool In end-stage kidney disease, the amount of potassium excreted in stool increases dramatically.16,17 Apart from residual kidney function, the primary determinant of fecal potassium excretion is the amount of stool produced.16,17 Given the high prevalence of constipation reported in this population,18 factors that can increase stool output have been proposed as a potential treatment for hyperkalemia in people with advanced CKD.19 Physical activity, along with fluids and dietary fiber, are part of the classic triad of lifestyle recommendations for managing of constipation in people with normal kidney function.20,21 However, despite being a well-known treatment for constipation, the evidence linking physical activity to constipation is considered inconsistent or limited quality (level B).20
Intake ICF ECF
K
K
Urine
Stool
Figure 1. Features of potassium homeostasis and balance that may be affected by exercise. ECF, Extracellular Fluid, ICF, Intracellular Fluid.
ated some promising, albeit mixed results regarding serum potassium (20.45 [20.58, 20.31]; I2 5 85%).22 In terms of exercise on nondialysis days, Mustata et al.23 conducted a single-group, pre-post study of 2 hourly sessions per week of supervised aerobic training for 3 months in 11 HD patients. Although the primary outcomes of interest in this study were arterial stiffness and insulin resistance, they reported a clinically relevant trend toward reduced serum potassium concentrations (Fig. 2).23 Of interest, the intervention had no effect on insulin resistance or body weight.23 The use of a supervised exercise program, and the apparent sustained clustering of serum potassium concentrations within the normal range throughout the intervention in Mustata et al.23 (Fig. 2) provide preliminary support for this research hypothesis. However, these findings should be interpreted with caution, as this study was not designed or powered to look at hyperkalemia as an outcome. Although the baseline serum potassium concentrations appear to reflect a study sample with mild hyperkalemia 6
Serum Potassium (mEq/L)
possible that reducing insulin resistance could reduce hyperkalemia through an indirect, unknown mechanism.
5.5
5
4.5
Discussion To our knowledge, the hypothesis that exercise may help manage hyperkalemia in people with CKD has not been proposed previously, so clinical trial data are limited. Several studies have examined the effect of intradialytic exercise on solute removal during hemodialysis (HD), and have gener-
4 Baseline
1 Month
2 Months
3 Months
Figure 2. Effect of aerobic exercise on serum potassium concentrations in hemodialysis patients. Mean 6 standard deviation presented based on data from Mustata et al.23
3
EXERCISE AND HYPERKALEMIA
at baseline, it is more likely that the population mean was driven upwards by a limited number of participants who had moderate-severe hyperkalemia, a conclusion that is supported by the larger standard deviation at baseline (0.3 mEq/L) compared to follow-up (0.2 mEq/L) (Fig. 2). Unfortunately, the data from this study are no longer available for analysis, but the primary author notes that, to his recollection, medication use (e.g., Kayexalate) did not explain the apparent decrease in serum potassium concentrations (personal communication).
Practical Application Sedentary lifestyle is a major issue in the general population, and even more so among people with CKD. Physical activity and physical function decline substantially as CKD progresses, with nearly two-thirds of US adults with CKD (estimated glomerular filtration rate ,60 mL/min/ 1.73 m2) reporting insufficient or inactive levels of activity,24 and the vast majority (85%) of ESKD patients assessed in the Chronic Renal Insufficiency Cohort study being rated as pre-frail or frail.25 Patients with CKD, particularly those on dialysis, experience a variety of barriers to exercise related to their disease (e.g., anemia), co-occurring conditions (e.g., heart failure), and treatments (e.g., in-center HD) that make it difficult for them to engage in regular, moderate-intensity exercise.26,27 Unfortunately, these issues are worsened by the lack of support for and unnecessary restrictions imposed on exercise in the CKD population.28 Indeed, healthcare teams rarely have staff available who can deliver safe and effective exercise programs, especially to those with conditions that require clinical judgment (e.g., hypertension, fluid overload).28 Despite being relatively inactive, plenty of observational and clinical trial evidence supports the fact that many people with CKD can and do engage in clinically meaningful physical activity. The impact of exercise on potassium balance will depend on the type, intensity, dose, and timing of exercise, as well as the characteristics of the patient, in addition to a variety of other factors (e.g., diet, potassium binders). For example, the anabolic effects of resistance training may be blunted in hypercatabolic states or when following a low protein diet. Based on the proposed mechanisms of action (Fig. 1), both endurance and resistance training have the potential to reduce the risk of hyperkalemia (Table 1), although exercises for balance and flexibility may also benefit patients by preventing injury and maintaining mobility.2 Although there are plenty of good reasons for CKD patients to follow recommendations to engage in regular physical activity,24 managing hyperkalemia, if found to be true, would provide a measurable monthly reminder to help motivate patients. Moreover, mechanistic insights into potassium homeostasis and balance in CKD may lead to novel therapeutic treatments for hyperkalemia. Clinical
Table 1. Potential Effects of Endurance and Resistance Training on Factors Related to Potassium Balance in People With CKD Factor 29
NKA activation Insulin resistance30 Muscle mass31 Sweat Stool32
Endurance
Resistance
O O O O O
O O O O O
CKD, chronic kidney disease; NKA, sodium-potassium ATPase.
trials evaluating various exercise programs across CKD populations are needed to make any firm conclusions. However, we echo prior sentiments that the most effective exercise is likely to be the type that the patient will stick with.28
References 1. Milan RH. Exercise guidelines for chronic kidney disease patients. J Ren Nutr. 2016;26:e23-e25. 2. National Kidney Foundation. Staying fit with kidney disease. National Kidney Foundation Website, https://www.kidney.org/atoz/content/stayfit;. Accessed March 27, 2019. 3. McDonough AA, Thompson CB, Youn JH. Skeletal muscle regulates extracellular potassium. Am J Physio Ren Physiol. 2002;282:F967-F974. 4. Choi CS, Thompson CB, Leong PKK, McDonough AA, Youn JH. Short-term K1 deprivation provokes resistance of cellular K1 uptake revealed with the K1 clamp. Am J Physiol Ren Physiol. 2001;280:F95-F102. 5. Alexander EA, Levinsky NG. An extrarenal mechanism of potassium adaptation. J Clin Invest. 1968;47:740-748. 6. Blanchley JD, Crider BP, Johnson JH. Extrarenal potassium adaptation: role of skeletal muscle. Am J Physiol. 1986;251:F313-F318. 7. McKenna MJ, Schmidt TA, Hargreaves M, Cameron L, Skinner SL, Kjeldsen K. Sprint training increases human skeletal muscle Na1-K1-ATPase concentration and improves K1 regulation. J Appl Physiol. 1993;75:173-180. 8. Green HJ, Chin ER, Ball-Burnett M, Ranney D. Increases in human skeletal muscle Na1-K1-ATPase concentration with short-term training. Am J Physiol. 1993;264:C1538-C1541. 9. Nguyen TQ, Maalouf NM, Sakhaee K, Moe OW. Comparison of insulin action on glucose versus potassium uptake in humans. Clin J Am Soc Nephrol. 2011;6:1533-1539. 10. Takaichi K, Takemoto F, Ubara Y, Mori Y. Analysis of factors causing hyperkalemia. Intern Med. 2007;46:823-829. 11. Kim HW, Lee DH, Lee SA, Koh G. A relationship between serum potassium concentration and insulin resistance in patients with type 2 diabetes mellitus. Int Urol Nephrol. 2015;47:991-999. 12. Johansen KL, Painter PL, Sakkas GK, Gordon P, Doyle K, Shubert T. Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: a randomized, controlled trial. J Am Soc Nephrol. 2006;17:2307-2314. 13. National Academies of Sciences, Engineering, and Medicine. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press; 2019. 14. Consolazio CF, Matoush LO, Nelson RA, Harding RS, Canham JE. Excretion of sodium, potassium, magnesium and iron in human sweat and the relation of each to balance and requirements. J Nutr. 1962;79:407-415. 15. Institute of Medicine Committee on Military Nutrition Research. Fluid replacement and heat stress. Washington (DC): The National Academies Press; 2019.
4
ST-JULES ET AL
16. Hayes CP Jr, Robinson RR. Fecal potassium excretion in patients on chronic intermittent hemodialysis. Trans Am Soc Artif Intern Organs. 1965;11:242-246. 17. Hayes CP Jr, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic kidney failure. Trans Assoc Am Physicians. 1967;80:207-216. 18. Murtagh FEM, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis. 2007;14:82-89. 19. St-Jules DE, Goldfarb DS, Sevick MA. Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients. J Ren Nutr. 2016;26:282-287. 20. Leung L, Riutta T, Kotecha J, Rosser W. Chronic constipation: an evidence-based review. J Am Board Fam Med. 2011;24:436-451. 21. Constipation. NIDDK website. https://www.niddk.nih.gov/ health-information/digestive-diseases/constipation. Accessed March 27, 2019. 22. Ferrerira GD, Bohlke M, Correa CM, Dias EC, Orcy RB. Does intradialytic exercise improve removal of solutes by hemodialysis? A systematic review and meta-analysis. Arch Phys Med Rehabil. 2019. In Press. 23. Mustata S, Chan C, Lai V, Miller JA. Impact of an exercise program on arterial stiffness and insulin resistance in hemodialysis patients. J Am Soc Nephrol. 2004;15:2713-2718.
24. Beddhu S, Baird BC, Zitterkoph J, Neilson J, Greene T. Physical activity and mortality in chronic kidney disease (NHANES III). Clin J Am Soc Nephrol. 2009;4:1901-1906. 25. Reese PP, Cappola AR, Shults J, et al. Physical performance and frailty in chronic kidney disease. Am J Nephrol. 2013;38:307-315. 26. Delgado C, Johansen KL. Barriers to exercise participation among dialysis patients. Nephrol Dial Transpl. 2012;27:1152-1157. 27. Jhamb M, McNulty ML, Ingalsbe G, et al. Knowledge, barriers and facilitators of exercise in dialysis patients: a qualitative study of patients, staff and nephrologist. BMC Nephrol. 2016;17:192. 28. Wilund KR, Jeong JH, Greenwood SA. Addressing myths about exercise in hemodialysis patients. Semin Dial. 2019;32:297-302. 29. Clausen T. Na1-K1 pump regulation and skeletal muscle contractility. Physiol Rev. 2003;83:1269-1324. 30. Keshel TE, Coker RH. Exercise training and insulin resistance: a current review. J Obes Weight Loss Ther. 2014;5(Suppl 5). S5-003. 31. Konopka AR, Harber MP. Skeletal muscle hypertrophy after aerobic exercise training. Exerc Sport Sci Rev. 2014;42:53-61. 32. Gao R, Tao Y, Zhou C, et al. Exercise therapy in patients with constipation: a systematic review and meta-analysis of randomized controlled trial. Scand J Gastroenterol. 2019;54:169-177.
Managing Hyperkalemia: Another Benefit of Exercise in People With Chronic Kidney Disease? David E. St-Jules, RD, PhD,* Meredith Marinaro, MS, RD, CSR,† David S. Goldfarb, MD,‡ Laura D. Byham-Gray, PhD, RDN,§ and Kenneth R. Wilund, PhD{ People with chronic kidney disease (CKD) are at increased risk of hyperkalemia, an electrolyte abnormality that can cause serious, sometimes fatal, cardiac arrhythmias. Muscle contraction causes potassium to be released from cells, increasing serum potassium concentrations. However, these effects are transient, and the long-term impact of exercise training on hyperkalemia risk in CKD patients is largely unknown. In this review, we examine the effects of exercise on factors affecting potassium balance in people with CKD, highlighting the potential benefits of regular exercise on hyperkalemia risk in this population. Although regular exercise is already recommended for people with CKD, research examining this hypothesis may lead to novel therapeutic treatments for this life-threatening condition. Ó 2019 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
P
ATIENTS WITH CHRONIC kidney disease (CKD) are advised to engage in moderate intensity exercise at least 3-5 times per week.1,2 The most salient benefit of regular exercise is improved physical function, but many other benefits have been identified. In this article, we will review possible mechanistic links between exercise and potassium balance as another potential benefit of exercise in this population (Fig. 1).
Internal Potassium Balance The majority of body potassium is found in the intracellular fluid, having an intracellular:extracellular potassium concentration gradient of approximately 35:1. The internal balance of potassium is vital for generating action potentials in muscle cells, and is maintained through the action of
* Department of Population Health, New York University School of Medicine, New York, New York. † Natural Sciences Department, Concordia University Chicago, River Forest, Illinois. ‡ Division of Nephrology, New York University School of Medicine, New York, New York. § Department of Clinical and Preventive Nutrition Sciences, Rutgers University, New Brunswick, New Jersey. { Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Champaign, Illinois. Financial Disclosure: D.E.S and D.S.G. are investigators on an InvestigatorSponsored Trial from Relypsa, Inc. (ClinicalTrials.gov Identifier: NCT03183778). M.M. is a full time employee of Akebia Therapeutics. Address correspondence to David E. St-Jules, RD, PhD, Center for Healthful Behavior Change, New York University School of Medicine, 713-180 Madison Avenue, New York, NY 10016. E-mail: [email protected] Ó 2019 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 https://doi.org/10.1053/j.jrn.2019.10.001
Journal of Renal Nutrition, Vol -, No - (-), 2019: pp 1-4
sodium-potassium ATPase (NKA). Insulin-mediated increases in NKA action are primarily responsible for the rapid uptake of potassium into cells following a meal.3 As one of the main buffering sites of potassium in the body, muscles have a key role in adaptation to dietary potassium deficiency and excess. During potassium depletion, NKA activity and potassium uptake in muscle are dramatically reduced to help prevent hypokalemia, while potassium excretion by the kidneys is reduced.4 Conversely, during increased potassium intake, NKA activity and potassium uptake in muscle are dramatically increased, and are likely responsible for the extrarenal protection against potassium toxicity seen with high-potassium feeding, until excretion by the kidneys occurs.5,6 Regulation of NKA is also affected by physical activity. During muscle contraction, potassium leaks from muscles into the extracellular fluid. This effect decreases the potassium concentration gradient and membrane potential of muscle cells, reducing contractility. Although potassium leak from cells causes a transient increase in extracellular potassium, muscle cells adapt by increasing NKA activity to take up the potassium.7,8 This adaptation is thought to enhance physical endurance by slowing membrane depolarization from potassium leakage; however, it may also have an indirect effect on internal potassium balance. In addition to increasing muscle NKA activity, exercise may improve internal potassium balance in people with CKD by reducing insulin resistance. Although insulin has been shown to have distinct effects on potassium and glucose homeostasis,4,9 diabetes and insulin resistance are associated with higher serum potassium concentrations and hyperkalemia risk, independent of CKD status and serum glucose concentration.10,11 The reason for the apparent contradictory findings is unclear, and it remains
1
2
ST-JULES ET AL
Potassium Buffering and Storage Another key aspect of exercise adaptation is building muscle. Assuming a potassium concentration of 140 mEq/L and 70% water content, 1 kg of muscle contains approximately 3,800 mg of potassium, which is more potassium than most people consume in a day, or nearly twice the amount of potassium in the entire extracellular fluid compartment. As a result, interventions to build and/or preserve muscle mass may improve the potassiumbuffering capacity of the intracellular compartment, particularly insulin-mediated potassium uptake in the postprandial period. However, any potassium-buffering benefit is likely to be small, as the effect of exercise on relative muscle mass in patients with advanced CKD (if any) is limited,12 and the additional energy intake required to support exercise, and growth and maintenance of muscle, are likely to cause a proportional increase in dietary potassium intake. Potassium Losses in Sweat A small amount of potassium is lost each day in sweat (usually ,500 mg/d). Exercise and heat exposure to induce sweating has been shown to increase potassium losses in sweat to more than 1,000 mg/d, and substantial potassium depletion has been described under extreme exercise and heat conditions.13-15 However, acclimation generally occurs within days, and potassium losses in sweat appear to return to near-normal levels.14 As a result, potassium losses in sweat from regular exercise are unlikely to have a major effect on external potassium balance and serum potassium concentrations in people with CKD. Potassium Losses in Stool In end-stage kidney disease, the amount of potassium excreted in stool increases dramatically.16,17 Apart from residual kidney function, the primary determinant of fecal potassium excretion is the amount of stool produced.16,17 Given the high prevalence of constipation reported in this population,18 factors that can increase stool output have been proposed as a potential treatment for hyperkalemia in people with advanced CKD.19 Physical activity, along with fluids and dietary fiber, are part of the classic triad of lifestyle recommendations for managing of constipation in people with normal kidney function.20,21 However, despite being a well-known treatment for constipation, the evidence linking physical activity to constipation is considered inconsistent or limited quality (level B).20
Intake ICF ECF
K
K
Urine
Stool
Figure 1. Features of potassium homeostasis and balance that may be affected by exercise. ECF, Extracellular Fluid, ICF, Intracellular Fluid.
ated some promising, albeit mixed results regarding serum potassium (20.45 [20.58, 20.31]; I2 5 85%).22 In terms of exercise on nondialysis days, Mustata et al.23 conducted a single-group, pre-post study of 2 hourly sessions per week of supervised aerobic training for 3 months in 11 HD patients. Although the primary outcomes of interest in this study were arterial stiffness and insulin resistance, they reported a clinically relevant trend toward reduced serum potassium concentrations (Fig. 2).23 Of interest, the intervention had no effect on insulin resistance or body weight.23 The use of a supervised exercise program, and the apparent sustained clustering of serum potassium concentrations within the normal range throughout the intervention in Mustata et al.23 (Fig. 2) provide preliminary support for this research hypothesis. However, these findings should be interpreted with caution, as this study was not designed or powered to look at hyperkalemia as an outcome. Although the baseline serum potassium concentrations appear to reflect a study sample with mild hyperkalemia 6
Serum Potassium (mEq/L)
possible that reducing insulin resistance could reduce hyperkalemia through an indirect, unknown mechanism.
5.5
5
4.5
Discussion To our knowledge, the hypothesis that exercise may help manage hyperkalemia in people with CKD has not been proposed previously, so clinical trial data are limited. Several studies have examined the effect of intradialytic exercise on solute removal during hemodialysis (HD), and have gener-
4 Baseline
1 Month
2 Months
3 Months
Figure 2. Effect of aerobic exercise on serum potassium concentrations in hemodialysis patients. Mean 6 standard deviation presented based on data from Mustata et al.23
3
EXERCISE AND HYPERKALEMIA
at baseline, it is more likely that the population mean was driven upwards by a limited number of participants who had moderate-severe hyperkalemia, a conclusion that is supported by the larger standard deviation at baseline (0.3 mEq/L) compared to follow-up (0.2 mEq/L) (Fig. 2). Unfortunately, the data from this study are no longer available for analysis, but the primary author notes that, to his recollection, medication use (e.g., Kayexalate) did not explain the apparent decrease in serum potassium concentrations (personal communication).
Practical Application Sedentary lifestyle is a major issue in the general population, and even more so among people with CKD. Physical activity and physical function decline substantially as CKD progresses, with nearly two-thirds of US adults with CKD (estimated glomerular filtration rate ,60 mL/min/ 1.73 m2) reporting insufficient or inactive levels of activity,24 and the vast majority (85%) of ESKD patients assessed in the Chronic Renal Insufficiency Cohort study being rated as pre-frail or frail.25 Patients with CKD, particularly those on dialysis, experience a variety of barriers to exercise related to their disease (e.g., anemia), co-occurring conditions (e.g., heart failure), and treatments (e.g., in-center HD) that make it difficult for them to engage in regular, moderate-intensity exercise.26,27 Unfortunately, these issues are worsened by the lack of support for and unnecessary restrictions imposed on exercise in the CKD population.28 Indeed, healthcare teams rarely have staff available who can deliver safe and effective exercise programs, especially to those with conditions that require clinical judgment (e.g., hypertension, fluid overload).28 Despite being relatively inactive, plenty of observational and clinical trial evidence supports the fact that many people with CKD can and do engage in clinically meaningful physical activity. The impact of exercise on potassium balance will depend on the type, intensity, dose, and timing of exercise, as well as the characteristics of the patient, in addition to a variety of other factors (e.g., diet, potassium binders). For example, the anabolic effects of resistance training may be blunted in hypercatabolic states or when following a low protein diet. Based on the proposed mechanisms of action (Fig. 1), both endurance and resistance training have the potential to reduce the risk of hyperkalemia (Table 1), although exercises for balance and flexibility may also benefit patients by preventing injury and maintaining mobility.2 Although there are plenty of good reasons for CKD patients to follow recommendations to engage in regular physical activity,24 managing hyperkalemia, if found to be true, would provide a measurable monthly reminder to help motivate patients. Moreover, mechanistic insights into potassium homeostasis and balance in CKD may lead to novel therapeutic treatments for hyperkalemia. Clinical
Table 1. Potential Effects of Endurance and Resistance Training on Factors Related to Potassium Balance in People With CKD Factor 29
NKA activation Insulin resistance30 Muscle mass31 Sweat Stool32
Endurance
Resistance
O O O O O
O O O O O
CKD, chronic kidney disease; NKA, sodium-potassium ATPase.
trials evaluating various exercise programs across CKD populations are needed to make any firm conclusions. However, we echo prior sentiments that the most effective exercise is likely to be the type that the patient will stick with.28
References 1. Milan RH. Exercise guidelines for chronic kidney disease patients. J Ren Nutr. 2016;26:e23-e25. 2. National Kidney Foundation. Staying fit with kidney disease. National Kidney Foundation Website, https://www.kidney.org/atoz/content/stayfit;. Accessed March 27, 2019. 3. McDonough AA, Thompson CB, Youn JH. Skeletal muscle regulates extracellular potassium. Am J Physio Ren Physiol. 2002;282:F967-F974. 4. Choi CS, Thompson CB, Leong PKK, McDonough AA, Youn JH. Short-term K1 deprivation provokes resistance of cellular K1 uptake revealed with the K1 clamp. Am J Physiol Ren Physiol. 2001;280:F95-F102. 5. Alexander EA, Levinsky NG. An extrarenal mechanism of potassium adaptation. J Clin Invest. 1968;47:740-748. 6. Blanchley JD, Crider BP, Johnson JH. Extrarenal potassium adaptation: role of skeletal muscle. Am J Physiol. 1986;251:F313-F318. 7. McKenna MJ, Schmidt TA, Hargreaves M, Cameron L, Skinner SL, Kjeldsen K. Sprint training increases human skeletal muscle Na1-K1-ATPase concentration and improves K1 regulation. J Appl Physiol. 1993;75:173-180. 8. Green HJ, Chin ER, Ball-Burnett M, Ranney D. Increases in human skeletal muscle Na1-K1-ATPase concentration with short-term training. Am J Physiol. 1993;264:C1538-C1541. 9. Nguyen TQ, Maalouf NM, Sakhaee K, Moe OW. Comparison of insulin action on glucose versus potassium uptake in humans. Clin J Am Soc Nephrol. 2011;6:1533-1539. 10. Takaichi K, Takemoto F, Ubara Y, Mori Y. Analysis of factors causing hyperkalemia. Intern Med. 2007;46:823-829. 11. Kim HW, Lee DH, Lee SA, Koh G. A relationship between serum potassium concentration and insulin resistance in patients with type 2 diabetes mellitus. Int Urol Nephrol. 2015;47:991-999. 12. Johansen KL, Painter PL, Sakkas GK, Gordon P, Doyle K, Shubert T. Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: a randomized, controlled trial. J Am Soc Nephrol. 2006;17:2307-2314. 13. National Academies of Sciences, Engineering, and Medicine. Dietary Reference Intakes for Sodium and Potassium. Washington, DC: The National Academies Press; 2019. 14. Consolazio CF, Matoush LO, Nelson RA, Harding RS, Canham JE. Excretion of sodium, potassium, magnesium and iron in human sweat and the relation of each to balance and requirements. J Nutr. 1962;79:407-415. 15. Institute of Medicine Committee on Military Nutrition Research. Fluid replacement and heat stress. Washington (DC): The National Academies Press; 2019.
4
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16. Hayes CP Jr, Robinson RR. Fecal potassium excretion in patients on chronic intermittent hemodialysis. Trans Am Soc Artif Intern Organs. 1965;11:242-246. 17. Hayes CP Jr, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic kidney failure. Trans Assoc Am Physicians. 1967;80:207-216. 18. Murtagh FEM, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis. 2007;14:82-89. 19. St-Jules DE, Goldfarb DS, Sevick MA. Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients. J Ren Nutr. 2016;26:282-287. 20. Leung L, Riutta T, Kotecha J, Rosser W. Chronic constipation: an evidence-based review. J Am Board Fam Med. 2011;24:436-451. 21. Constipation. NIDDK website. https://www.niddk.nih.gov/ health-information/digestive-diseases/constipation. Accessed March 27, 2019. 22. Ferrerira GD, Bohlke M, Correa CM, Dias EC, Orcy RB. Does intradialytic exercise improve removal of solutes by hemodialysis? A systematic review and meta-analysis. Arch Phys Med Rehabil. 2019. In Press. 23. Mustata S, Chan C, Lai V, Miller JA. Impact of an exercise program on arterial stiffness and insulin resistance in hemodialysis patients. J Am Soc Nephrol. 2004;15:2713-2718.
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