PRESENTED BY
CAROL POLLOCK, JUAN JESUS CARRERO, DEB CLEGG AND KIERAN MCCAFFERTY

Click HERE to view the Symposium on the Virtual Meeting

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Change IME

Hyperkalaemia (HK) is a potentially life-threatening condition with serious clinical and economic consequences. There is a U-shape relationship between serum potassium (K+) levels, mortality and major adverse cardiovascular events in patients with chronic kidney disease (CKD), (1, 2). HK can have a negative impact on clinical decisions for patients with CKD. For example, as renin-angiotensin-aldosterone system inhibitor (RAASi) use is associated with an increased risk of HK, a common treatment response to HK is to down-titrate or discontinue RAASi therapy. However, suboptimal doses are associated with increased mortality thereby creating a therapeutic and clinical dilemma (3,4,5).

The prevalence of this condition calls for close attention and raises important questions for practice. These questions have now been addressed at a virtual panel meeting convened as part of the ERA-EDTA’s first virtual conference, held on 7th June 2020 and chaired by Professor Carol Pollock and Professor Loreto Gesualdo. The meeting assembled the leading experts in the field, Professor Juan Jesus Carrero, Dr Deborah Clegg and Dr Kieran McCafferty, to share their views on the problem.

K+ again and again: Hyperkalaemia occurrence, recurrence and persistence in CKD; the perfect storm?

HK is common in CKD patients and may appear even in CKD stage 3, marking the inability to compensate for K+ retention (6). Further decline in kidney function is associated with increased risk of HK, becoming six to 11 times higher than in individuals with preserved kidney function (7, 8). Furthermore, age and other comorbidities commonly present in CKD patients, as well as certain therapeutic interventions, can also increase the risk of HK (9).

Even a single HK event is associated with increased risk of hospitalisation, adverse outcomes and mortality in both non-dialysis and dialysis patients (10-12). HK recurrence receives relatively little attention in the literature, even though it has been shown to occur in up to 30% of predialysis and 40% of dialysis patients (11-13). Patients with CKD stage 4 usually experience a mild increase in serum K+ levels for 13–30% of the time. In patients who have experienced ≥1 HK event, serum K+ concentrations decrease more slowly and tend not to reach pre-HK concentrations compared with patients with a single HK event (14). Furthermore, there is currently little guidance on how to successfully manage persistently elevated serum K+ levels.

The clinical consequences of HK chronicity are not yet elucidated. Persistent HK is associated with a higher risk of CKD progression to end-stage renal disease and a higher risk of death (15, 16). Even so, it is commonly perceived that CKD patients are in some way adapted to higher K+ levels and are able to tolerate them better than is the general population (8). Several studies have shown significantly lower mortality risk in hyperkalaemic CKD patients compared with healthy individuals, which raises the question of the reference range for serum K+ in patients with renal failure (6). Based on the observed association between the mortality risk and K+ levels in the CKD population, patients with CKD can tolerate plasma K+ levels that are on average 0.4 mmol/L higher than in individuals with normal renal function before reaching a comparable risk of mortality (Figure 1). Nevertheless, serum K+ levels above 5.5 mmol/L are still associated with higher mortality risk, even in CKD patients, and should prompt clinical intervention (6).

Figure 1. Association between K+ levels and relative mortality risk (6, 17)

K+ restriction: The patient’s dilemma
Dietary management of HK in CKD patients may represent a considerable challenge. The modern diet has shifted from traditionally high intake of K+ and low intake of sodium (Na+), which was typical for prehistoric humans, to high intake of Na+ and a low intake of K+, due to the use of fire and later introduction of processed food (18). The current recommendation of the Food and Nutrition Board of the US National Academy of Sciences Institute of Medicine is daily K+ intake of 4700 mg, which is three times lower than in prehistoric times (9). The actual K+ intake is even lower, and, according to the US National Health and Nutrition Examination Survey (NHANES) stands at 2290 mg/day for women and 3026 mg/day for men in the USA, which is in line with the current recommendations for K+ intake in CKD patients (Figure 2) (20-23). However, the K+ absorption profile is somewhat different in CKD patients compared with that in healthy individuals. Besides the higher baseline serum level, its decrease following the ingestion of K+-rich food is more gradual than in the general population, and is further delayed by the use of RAASi therapies, thus keeping the patient in the hyperkalaemic state (19).

Figure 2. Recommended K+ intake in healthy population and patients with renal impairment (9, 19)

Common dietary sources of K+ include certain fruits and vegetables, as well as cereals and unprocessed meat and fish. Nevertheless, the bioavailability of K+ differs between various sources, and is highest from salt substitutes and K+-containing additives (24, 25). The net base-producing plant-based foods high in K+ may boost cellular K+ uptake due to alkaline milieu and by stimulating the release of endogenous insulin (26). This enhances K+ uptake by the cells, thus attenuating the rise of serum K+. Furthermore, it may promote K+ removal by the stool, by increasing faecal bulk (27). The myth that consumption of K+-rich plant-based diet should be avoided has been refuted by recent studies that have demonstrated an association between such a diet and lower mortality in CKD patients, as long as urinary K+ excretion is preserved (28-33). Moreover, the well-known renoprotective effect of K+ in the general population is currently being investigated in a randomised, double-blind, placebo-controlled study including patients with CKD stages 3b to 4 (33-37). The hope is that novel K+ binders will enable the consumption of plant-based heart-healthy diets in CKD patients.

Interdialytic hyperkalaemia: A step towards optimal care
HK is prevalent in 30–50% of long-term haemodialysis patients, and higher serum potassium levels are associated with an increased risk of mortality in these patients (38-40). In the first hour of dialysis, there is a rapid fall in K+ levels; however, HK returns within 6 hours after haemodialysis (41-45). It has been demonstrated that almost three quarters of all arrhythmias occurred during or immediately after dialysis, and this is assumed to be related to the changes in K+ levels which occur during the dialysis sessions (46). In patients on haemodialysis, dietary K+ restriction is associated with a high rate of non-adherence, malnutrition, and increased morbidity and mortality (27, 47-49). Traditional potassium binders such as sodium polystyrene sulphonate (SPS) can be used for the management of HK; however, the long-term efficacy of these treatments has yet to be robustly demonstrated in patients on dialysis (47, 50-52). SPS is also poorly tolerated due to its unpleasant taste and texture (50). Data on how to optimally manage HK in patients on dialysis are limited. However, newer K+ binders may improve the management of a broad spectrum of patients at all stages of CKD (53-55). DIALIZE is the first randomised, placebo-controlled trial to evaluate the efficacy and safety of a novel K+ binder, sodium zirconium cyclosilicate (SZC), for the treatment of HK in patients on haemodialysis. The study results have demonstrated that SZC reduced serum K+ levels and sustained K+ control in haemodialysis patients. There were no differences between SZC and placebo in interdialytic weight gain, which is a marker of sodium and fluid retention. SZC was also well tolerated, with most adverse events being mild or moderate in intensity, and the adverse event profiles between the treatment groups were similar, including gastrointestinal events and hypokalaemia (56-61).

References

1. Luo J, Brunelli SM, Jensen DE, Yang A. Association Between Serum Potassium and Outcomes in Patients With Reduced Kidney Function. Clin J Am Soc Nephrol 2016;11(1):90-100.

2. Collins AJ, Pitt B, Reaven N, et al. Association of Serum Potassium With All-Cause Mortality in Patients With and Without Heart Failure, Chronic Kidney Disease, and/or Diabetes. Am J Nephrol 2017;46(3):213-221.

3. Yildrim T, Arici M, Piskinpasa S, et al. Major Barriers Against Renin-Angiotensin-Aldosterone System Blocker Use in Chronic Kidney Disease Stages 3-5 in Clinical Practice: A Safety Concern? Ren Fail. 2012;34(9):1095-9.

4. Epstein M, Reaven NL, Funk SE, et al. Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin-Aldosterone System Inhibitors. Am J Manag Care 2015 Sep;21(11 Suppl):S212-20.

5. Kim K, Thomsen RW, Nisolaisen SK, Hasvold LP, Palaka E, Sorensen HT. Healthcare Resource Utilisation and Cost Associated With Elevated Potassium Levels: A Danish Population-Based Cohort Study. BMJ Open 2019 Apr 1;9(4):e026465.

6. Gasparini A, Evans M, Barany P, et al. Plasma Potassium Ranges Associated With Mortality Across Stages of Chronic Kidney Disease: The Stockholm CREAtinine Measurements (SCREAM) Project. Nephrol Dial Transplant 2019;34(9):1534-1541.

7. Nilsson E, Gasparini A, Arnlov J, et al. Incidence and Determinants of Hyperkalemia and Hypokalemia in a Large Healthcare System. Int J Cardiol 2017;245:277-284.

8. Einhorn LM, Zhan M, hsu VD, et al. The Frequency of Hyperkalemia and Its Significance in Chronic Kidney Disease. Arch Intern Med 2009;169(12):1156-62.

9. Clase CM, Carrero JJ, Ellison DH, et al. Potassium Homeostasis and Management of Dyskalemia in Kidney Diseases: Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2020;97(1):42-61.

10. Luo J, Brunelli SM, Jensen DE, Yang A. Association Between Serum Potassium and Outcomes in Patients With Reduced Kidney Function. Clin J Am Soc Nephrol 2016;11(1):90-100.

11. Thomsen RW, Nicolaisen SK, Hasvold P, et al. Elevated Potassium Levels in Patients With Chronic Kidney Disease: Occurrence, Risk Factors and Clinical Outcomes-A Danish Population-Based Cohort Study. Nephrol Dial Transplant 2018;33(9):1610-1620.

12. Brunelli SM, Du Mond C, Oestreicher N, Rakov V, Spiegel DM. Serum Potassium and Short-term Clinical Outcomes Among Hemodialysis Patients: Impact of the Long Interdialytic Interval. Am J Kidney Dis 2017;70(1):21-29.

13. Rossignol P, Lamiral Z, Frimat L, et al. Hyperkalaemia Prevalence, Recurrence and Management in Chronic Haemodialysis: A Prospective Multicentre French Regional Registry 2-year Survey. Nephrol Dial Transplant 2017;32(12):2112-2118.

14. Adelborg K, Nicolaisen SK, Hasvold P, et al. Predictors for Repeated Hyperkalemia and Potassium Trajectories in High-Risk Patients – A Population-Based Cohort Study. PLoS One 2019;14(6):e0218739.

15. Provenzano M, Minutolo R, Chiodini P, et al. Competing-Risk Analysis of Death and End Stage Kidney Disease by Hyperkalaemia Status in Non-Dialysis Chronic Kidney Disease Patients Receiving Stable Nephrology Care. J Clin Med 2018;7(12):499.

16. Matsushita K, Sang Y, Yang C, et al. Dyskalemia, Its Patterns, and Prognosis Among Patients With Incident Heart Failure: A Nationwide Study of US Veterans. PLoS One 2019;14(8):e0219899.

17. Carrero JJ. K+ again and again: Hyperkalaemia occurrence, recurrence and persistence in CKD; the perfect storm? Presented at the 57th European Reanla Association – European Dialysis Transplantation Association Congress (fully virtual), June 7, 2020. Available at: https://www.era-edta.org/en/virtual-meeting/#!resources/k-again-and-again. Accessed June 30, 2020.

18. Palmer BF, Clegg DJ. Achieving the Benefits of a High-Potassium, Paleolithic Diet, Without the Toxicity. Mayo Clin Proc. 2016;91(4):496-508.

19. Clegg D. K+ restriction: The patient’s dilemma. Presented at the 57th European Reanla Association – European Dialysis Transplantation Association Congress (fully virtual), June 7, 2020. Available at: https://www.era-edta.org/en/virtual-meeting/#!resources/k-restriction-the-patient-s-dilemma. Accessed June 30, 2020.

20. Linus Pauling institute, Oregon State University. Potassium. Available at: https://lpi.oregonstate.edu/mic/minerals/potassium (Accessed March 2020);

21. Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC, USA: The National Academies Press; 2005.

22. US Department of Health and Human Services and US Department of Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at: https://health.gov/our-work/food-and-nutrition/2015-2020-dietary-guidelines/ (Accessed March 2020).

23. US Department of Agriculture, Agriculture Research Service 2010. What we eat in America, NHANES 2007–2008. Available at: http://www.ars.usda.gov/ba/bhnrc/fsrg (Accessed March 2020).

24. Cupisti A, Kovesdy CP, D’Alessandro C, Kalantar-Zadeh K. Dietary Approach to Recurrent or Chronic Hyperkalaemia in Patients With Decreased Kidney Function. Nutrients 2018;10(3):261.

25. Parpia AS, Goldstein MB, Acand J, Cho F, L’Abbe MR, Darling PB. Sodium-Reduced Meat and Poultry Products Contain a Significant Amount of Potassium From Food Additives. J Acad Nutr Diet 2018;118(5):878-885.

26. Allon M, Dansby L, Shanklin N. Glucose Modulation of the Disposal of an Acute Potassium Load in Patients With End-Stage Renal Disease. Am J Med 1993;94(5):475-482.

27. 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(5):282-7.

28. Kalantar-Zadeh K, Tortorici AR, Chen JLT, et al. Dietary Restrictions in Dialysis Patients: Is There Anything Left to Eat? Semin Dial 2015;28(2):159-68.

29. Chen X, wei G, Jalili T, et al. The Associations of Plant Protein Intake With All-Cause Mortality in CKD. Am J Kidnea Dis 2016;67(3):423-30.

30. Noori N, Kalantar-Zadeh K, Kovesdy CP, et al. Dietary Potassium Intake and Mortality in Long-Term Hemodialysis Patients. Am J Kidney Dis 2010;56(2):338-47.

31. Lewonberg-Yoo AK, Tighiouart H, Levey AS, Beck GJ, Sarnak MJ. Urine Potassium Excretion, Kidney Failure, and Mortality in CKD. Am J Kidney Dis 2017;69(3):341-349.

32. Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott P, Cappuccio FP. Effect of Increased Potassium Intake on Cardiovascular Risk Factors and Disease: Systematic Review and Meta-Analyses. BMJ 2013;346:f1378.

33. Gritter M, Vogt L, Yeung SMH, et al. Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease. Nephron 2018;140(1):48-57.

34. Gritter M, Rotmans JI, Hoorn EJ. Role of Dietary K + in Natriuresis, Blood Pressure Reduction, Cardiovascular Protection, and Renoprotection. Hypertension 2019;73(1):15-23.

35. Kendrick J, Linas S. Approaches to and Clinical Benefits of Reducing Dietary K in CKD. Clin J Am Soc Nephrol 2017;12(10):1559-1560.

36. ClinicalTrials.gov. NCT03253172. Available at: https://clinicaltrials.gov/ct2/show/NCT03253172 (Accessed March 2020)

37. Palmer BF. Potassium Binders for Hyperkalemia in Chronic Kidney Disease-Diet, Renin-Angiotensin-Aldosterone System Inhibitor Therapy, and Hemodialysis. Mayo Clin Proc 2020;95(2):339-354.

38. Karaboyas A, Zee J, Brunelli SM, et al. Dialysate Potassium, Serum Potassium, Mortality, and Arrhythmia Events in Hemodialysis: Results From the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2017;69(2):266-277.

39. Xu H, Ashfaq A, Karaboyas A, et al. Prevalence of hyperkalaemia in DOPPS: a real-world, international cohort of haemodialysis patients. Presentation at the 54th European Renal Association – European Dialysis Transplantation Association Congress, June 3-6, 2017, Madrid, Spain. Poster MP 371. Nephrol Dial Transpl 2017;32(Suppl3):iii563.

40. Kovesdy C, Regidor DL, Mehrotra R, et al. Serum and Dialysate Potassium Concentrations and Survival in Hemodialysis Patients. Clin J Am Soc Nephrol 2007;2(5):999-1007.

41. Blumberg A, Roser HW, Zehnder C, Muller-Brand J. Plasma Potassium in Patients With Terminal Renal Failure During and After Haemodialysis; Relationship With Dialytic Potassium Removal and Total Body Potassium. Nephrol Dial Transplant 1997;12(8):1629-34.

42. Pun PH, Middleton JP. Dialysate Potassium, Dialysate Magnesium, and Hemodialysis Risk. J Am Soc Nephrol 2017;28(12):3441-3451.

43. Canaud B, Ponce P, Parisotto MT, et al. Vascular Access Management for Haemodialysis: A Value-Based Approach from NephroCare Experience. In: Vascular Access Surgery – Tips and Tricks. Berezin A. ed. InTech Open, 2019.

44. Leypoldt JK, Agar BU, Bernardo AA, Culleton BF. Prescriptions of Dialysate Potassium Concentration During Short Daily or Long Nocturnal (High Dose) Hemodialysis Hemodial Int 2016;20(2):218-225.

45. Brunelli SM, Spiegel DM, Du Mond C, Oestreicher N, Winklemayer WC, Kovesdy CP. Serum-to-dialysate Potassium Gradient and Its Association With Short-Term Outcomes in Hemodialysis Patients. Nephrol Dial Transplant 2018;33(7):1207-1214.

46. Wan C, Herzog CA, Zareba W, Szymkiewicz SJ. Sudden Cardiac Arrest in Hemodialysis Patients With Wearable Cardioverter Defibrillator. Ann Noninvasive Electrocardiol 2014;19(3):247-57.

47. Chaaban A, Abouchacra S, Gebran N, et al. Potassium Binders in Hemodialysis Patients: A Friend or Foe? Ren Fail. 2013;35(2):185-8.

48. Palmer SC, Ruospo M, Campbell KL, et al. Nutrition and Dietary Intake and Their Association With Mortality and Hospitalisation in Adults With Chronic Kidney Disease Treated With Haemodialysis: Protocol for DIET-HD, a Prospective Multinational Cohort Study. BMJ Open 2015;5(3):e006897.

49. Khouiery G, Waked A, Goldman M, et al. Dietary Intake in Hemodialysis Patients Does Not Reflect a Heart Healthy Diet. J Ren Nutr 2011;21(6):438-47.

50. Chaitman M, Dixit D, Bridgeman MB. Potassium-Binding Agents for the Clinical Management of Hyperkalemia. P T 2016;41(1):43-50.

51. Sanofi Aventis. Resonium Prescribing Information, 2014.

52. Zann V, McDermott J, Jacobs JW, et al. Palatability and Physical Properties of Potassium-Binding Resin RDX7675: Comparison With Sodium Polystyrene Sulfonate. Drug Des Devel Ther 2017;11:2663-2673

53. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of Structure and Function of ZS-9, a K+ Selective Ion Trap. PLoS One 2014;9(12):e114686

54. PubChem. Sodium zirconium cyclosilicate. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/91799284#section=Top (Accessed October 2019).

55. Vifor Pharma. Patiromer US Prescribing Information 2016.

56. Fishbane S, Ford M, Fukagawa M, et al. A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia. J Am Soc Nephrol 2019;30(9):1723-1733.

57. Fishbane S, et al. A Phase 3, Randomized, Double-Blind, Placebo-Copntrolled Study of the Efficacy and Safety of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Pre-Dialysis Hyperkalaemia (DIALIZE). Presented at 56th Congress of the European Renal Association – European Dialysis and Transplant Association; June 13-16, 2019; Budapest, Hungary.

58. Fishbane S, et al. Sodium Zirconium Cyclosilicate (SZC) Improves Potassium Balance in Hyperkalemic Hemodialysis Patients: Results from the Phase 3b, Randomized, Placebo-Controlled DIALIZE Study. Presented at American Society of Nephrology Kidney Week 2019; 5th–10th November 2019; Washington, DC, USA.

59. ClinicalTrials.gov. NCT03781089. Available at: https://clinicaltrials.gov/ct2/show/NCT03781089 (Accessed March 2020);

60. ClinicalTrials.gov. NCT03740048. Available at: https://clinicaltrials.gov/ct2/show/NCT03740048 (Accessed March 2020)

61. Kovesdy CP, Rowan CG, Conrad A, et al. Real-World Evaluation of Patiromer for the Treatment of Hyperkalemia in Hemodialysis Patients. Kidney Int Rep 2018;4(2):301–309.

NDT-E Summary Articles