#199 NephMadness: Hyperkalemia, Diet, K+ Binders, Exercise

March 16, 2020 | By Elena Gibson

@kidney_boy and friends school us on hyperkalemia in CKD 

NephMadness 2020 is here! Listen as Dr. Ryann Sohaney (@ryannsohaney), Dr. Deborah Clegg and Dr. Joel Topf (@kidney_boy) discuss this year’s first Nephmadness topic, Hyperkalemia in CKD. They will (1) review the use of potassium binders for management of hyperkalemia in CKD (2) identify the potential health benefits of dietary potassium and challenge the use of low-potassium diets in CKD, and (3) describe how exercise influences serum potassium and consider exercise recommendations in CKD.

Check out the regions and fill out your brackets for NephMadness 2020 here! Sign-up as a part of The Curbsiders team!

Show Notes | Subscribe | Spotify | Swag! | Top Picks | Mailing List | thecurbsiders@gmail.com

Credits

Written and Produced by: Elena Gibson MD 

Infographic: Caitlyn Vlasschaert MD 

Cover Art: Elena Gibson MD

Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP   

Editor: Matthew Watto MD, FACP (written materials); Clair Morgan Nodderly.com (audio)

Guest: Ryann Sohaney, MD; Deborah Clegg, PhD; Joel Topf, MD 

Sponsors

AccessMedicine is the acclaimed online medical resource that features Harrison’s Principles of Internal Medicine and more trusted content from the best minds in medicine. Visit  AccessMedicine to learn more: http://bit.ly/MHCurbsiders.

Time Stamps

• 00:00 Sponsor – AccessMedicine.com (McGraw-Hill) http://bit.ly/MHCurbsiders
• 00:20 Intro, disclaimer, guest bio
• 02:55 Guest one-liners; Intro to NephMadness 2020
• 07:28 Sponsor – AccessMedicine.com (McGraw-Hill) http://bit.ly/MHCurbsiders
• 08:15 Hyperkalemia in CKD; Case of hyperkalemia; Meds, supplements and a bit on diet
• 17:07 Patiromer, Sodium zirconium, SPS
• 31:08 Diet and potassium
• 46:00 Exercise and hyperkalemia. Is it safe in CKD?
• 51:51 Take home points and Outro

NephMadness: Hyperkalemia Pearls

Hyperkalemia is the most common electrolyte disturbance in patients with CKD 

CKD patients who would benefit from renin-angiotensin-aldosterone system inhibition are often at high risk of developing hyperkalemia 

Evidence has supported the use of potassium binder medications to allow for ongoing RAASi therapy, but changes in long term outcomes have not been studied yet. 

Low potassium or “renal diets” may not be as beneficial as once thought as fruits and vegetables high in potassium have many health benefits 

Patients at risk of hyperkalemia should be counseled on avoiding salt substitutes (which contain potassium chloride) and processed meats. 

Drs. Clegg and Topf point out that constipation is a common triggers for hyperkalemia in CKD patients because the body relies more heavily on the GI system for potassium clearance as renal function worsens

Hyperkalemia in Chronic Kidney Disease (CKD)

Hyperkalemia is the most common electrolyte disturbance in patients with CKD, occurring in up to 20% of patients (Gilligan 2017). The prevalence of hyperkalemia in CKD increases as GFR decreases (Moranne 2009) Additional risk factors for hyperkalemia in CKD include use of Renin-Angiotensin-Aldosterone System inhibitors (RAASi) and diabetes. Diabetes can lead to hyperkalemia as a result of insulin resistance leading to a hyporeninemic, hypoaldosteronism state and type 4 renal tubular acidosis (Sousa 2016).

Renin-Angiotensin-Aldosterone System Inhibitors (RAASi) 

CKD patients with heart failure and/or diabetes who are likely to benefit from RAASi use, are often at high risk of hyperkalemia (Gilligan 2017, Bakris 2015). In addition to treating hypertension,  RAASi are used to prevent the progression of renal disease in CKD patients, and they provide a mortality benefit in HFrEF patients (KDIGO 2012, Yancy 2017). With the goal of continued RAASi therapy, Dr. Topf suggests first using thiazide and/or loop diuretics to decrease potassium in patients with hyperkalemia. If this is unsuccessful or not possible, potassium binders can be considered. 

Kashlak Pearl: Before using a potassium binder, Dr. Topf ensures consistent medication adherence is possible because missed doses can lead to dangerous hyperkalemia. 

Evidence  for potassium binders

The AMETHYST DN trial randomized patients with diabetic nephropathy receiving RAASi therapy to various patiromer doses, and at 4 and 52 weeks dosing of 8.4 grams twice per day or higher resulted in statistically significant reductions in serum potassium with limited adverse events (Bakris 2015). The AMBER trial randomized CKD patients with resistant hypertension to spironolactone and patiromer vs. spironolactone and placebo. At the end of 12 weeks, there was no difference in the primary outcome of improved blood pressure between the groups, but those on patiromer were able to stay on spironolactone for a longer period of time (Agarwal 2019) . The DIAMOND trial, a study aiming to determine if the use of potassium binders to enable ongoing RAAS inhibitor therapy leads to improved cardiovascular and renal outcomes, is anticipated in 2022. 

Potassium Binder Rundown

Sodium polystyrene sulfonate (SPS), patiromer, and sodium zirconium cyclosilicate are potassium binders used to treat hyperkalemia (Palmer 2019) (Table 1).  SPS and patiromer should not be used to quickly lower potassium as they work in the colon and onset can take hours to days. Patiromer and sodium zirconium cyclosilicate are much more tolerable with lower rates of gastrointestinal discomfort. However, Dr. Sohaney discusses how the cost of patiromer and sodium zirconium cyclosilicate can be prohibitive and recommends asking patients about the out of pocket cost. 

Figure from “Competitors for the Hyperkalemia Region” adapted from: Palmer, B and Clegg D. Physiology and Pathophysiology of potassium homeostasis. Am J Kid Dis. 2019.

Sodium Polystyrene Sulfonate 

SPS is the oldest and least expensive potassium binder available. As discussed in more detail during our prior episode on hyperkalemia, SPS is associated with significant gastrointestinal side effects including more rare cases of bowel ischemia (Harel 2013). 

Patiromer

Approved following the AMETHYST-DN trial in 2015 (Bakris 2015). Check and replace magnesium before starting patiromer, as hypomagnesemia is a common side effect (Bakris 2015).

Sodium zirconium cyclosilicate 

Sodium zirconium cyclosilicate works more quickly and can start to lower potassium in as little as two hours because it works throughout the intestine (Packham 2015) . One unique side effect associated with sodium zirconium cyclosilicate is lower extremity edema (Kosiborod 2014). This could be a result of the sodium load, but studies have not identified a change in blood pressure or dry weight suggesting the possibility of a different mechanism (Fishbane 2019). 

Potassium is Good in CKD?

High potassium diets with fresh fruits and vegetables (think DASH diet) have been associated with reductions in cardiovascular mortality (O’Donnell 2014), blood pressure, stroke risk, and kidney stones. Conversely, Dr. Clegg describes how low-potassium, “renal diets” are often high in meats and processed foods. Observational data of potassium intake in CKD have produced mixed results, with the PREVEND study identifying a higher risk of incident CKD in patients with low potassium intake (Kieneker 2016) and CRIC describing an increased risk of CKD progression with high-potassium intake (He 2016) . 

Benefits of Potassium 

Many foods high in potassium, such as fresh fruits and vegetables, are also high in fiber and alkali. Dr. Clegg and Dr Topf describe how constipation is one of the most common triggers for episodes of hyperkalemia in CKD patients because the body starts to rely more heavily on the gastrointestinal system for potassium clearance as renal function worsens. Similarly the increased alkaline load that comes with many fresh foods high in potassium, can help neutralize the acidosis in CKD and help prevent kidney stones (Ferraro 2016). One study randomized patients with CKD to fruits and vegetables vs. sodium bicarbonate tablets (Goraya 2013). Although fruits and vegetables have a much larger potassium load, no difference in serum potassium levels was identified between groups and both were equally effective in controlling acidosis.

Sources of Potassium and What to Avoid  

Dr. Clegg cautions all patients with CKD and ESRD to avoid high-potassium salt substitutes such as No Salt, Morton’s salt substitute, and Nu-Salt. If patients are looking for another salt substitute, consider Mrs. Dash, an herbal flavoring spice. Additional sources of potassium clinicians and patients should look for include health supplements, weight loss supplements, meat substitutes (vegetable meat burgers), and juices (Noni juice, coconut water). Additional medications other than RAAS inhibitors to look  for include non-steroidal antiinflammatory drugs (NSAIDs), other potassium sparing diuretics (amiloride, triamterene), and trimethoprim.   

Diet Recommendations 

Dr. Sohaney acknowledges that the current data is limited and often excludes CKD patients at highest risk of hyperkalemia, such as those with diabetes or those with a potassium of >4.6. However, in most CKD patients our guests encourage recommending a healthy diet with increased fresh fruits and vegetables, decreased processed meats, and no high-potassium salt substitutes. Aim to focus on the global diet for each patient and individualize a dietary plan for potassium intake. 

Exercise and Hyperkalemia 

Most of the potassium in the body is in the intercellular space and 80% of that is in muscle (Cheng 2013). During exercise,the action potential causes potassium to exit the cell, leading to elevations in potassium up to 8mmoL/L (Medbo 1990). Although high, our guests point out how this transient hyperkalemia seems to be well tolerated. Following exercise, the concentration and activity of Na⁺-K⁺-ATPase pumps are increased and post-exercise potassium decreases below pre-exercise levels for a prolonged period of time (Nielsen 2004). Furthermore,reduced muscle mass is associated with increased insulin resistance (Srikanthan 2011), an independent predictor of hyperkalemia (Kim 2015).

Recommending Exercise in CKD

Dr. Sohaney describes how research for various types of exercise and their influence of potassium regulation in CKD patients is limited. Although there is some evidence of improved potassium regulation with intradialysis exercise (Kong 1999), a systematic review of intradialysis exercises did not find any difference in potassium (Ferreira 2019). Given the known health benefits of exercise, our guests and the KDIGO guidelines recommend patients with CKD exercise for at least 30 minutes 5 times per week (KDIGO 2012). Furthermore, Dr. Clegg suggests focusing on increasing muscle mass could help improve insulin sensitivity. 

Learning objectives

After listening to this episode listeners will…  

1. Recognize when and how to manage hyperkalemia in CKD 
2. Identify when to use potassium binders in CKD 
3. Define the pharmacology, adverse effects and evidence behind different potassium binders 
4. Develop an approach to using renin-angiotensin-aldosterone system inhibitor (RAASi) medications in patients with hyperkalemia
5. Define the potential benefits of high-potassium diets and the potential harms of low-potassium diets
6. Recognize how exercise influences potassium

Links*

1. AJKD Nephmadness Blog 
2. Nephmadness 2020 signup (brackets just opened March 13, 2020)

References

1. Gilligan S, Raphael KL. Hyperkalemia and Hypokalemia in CKD: Prevalence, Risk Factors, and Clinical Outcomes. Adv Chronic Kidney Dis. 2017. [https://www.ncbi.nlm.nih.gov/pubmed/29031358]
2. Moranne O, et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol. 2009;20(1):164-171.[https://www.ncbi.nlm.nih.gov/pubmed/19005010]
3. Sousa AG, et al. Hyporeninemic hypoaldosteronism and diabetes mellitus: Pathophysiology assumptions, clinical aspects and implications for management. World J Diabetes. 2016. [https://www.ncbi.nlm.nih.gov/pubmed/26981183/]
4. Bakris GL, et al. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA. 2015 [https://www.ncbi.nlm.nih.gov/pubmed/26172895]
5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150.
6. Maione, A., Navaneethan, S. D., Graziano, G., Mitchell, R., Johnson, D., Mann, J. F., . . . Strippoli, G. F. (2011). Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials. Nephrol Dial Transplant, 26(9), 2827-2847. doi:10.1093/ndt/gfq792
7. Packham DK, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. [https://www.ncbi.nlm.nih.gov/pubmed/25415807].
8. Kosiborod M, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA.2014[https://www.ncbi.nlm.nih.gov/pubmed/25402495]
9. Fishbane S, 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. [https://www.ncbi.nlm.nih.gov/pubmed/31201218]
10. Agarwal R, et al. Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/31533906]
11. Palmer, B. F., & Clegg, D. J. (2019). Physiology and Pathophysiology of Potassium Homeostasis: Core Curriculum 2019. Am J Kidney Dis, 74. [https://www.ncbi.nlm.nih.gov/pubmed/31227226]
12. O’Donnell M,et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med. 2014.[https://www.ncbi.nlm.nih.gov/pubmed/25119607]
13. Kieneker LM, et al. Urinary potassium excretion and risk of developing hypertension: the prevention of renal and vascular end-stage disease study. Hypertension. 2014. [https://www.ncbi.nlm.nih.gov/pubmed/25047575]
14. Kieneker LM, et al. Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease. Kidney Int. 2016. [https://www.ncbi.nlm.nih.gov/pubmed/27575557]
15. He J,et al. Urinary Sodium and Potassium Excretion and CKD Progression. J Am Soc Nephrol. 2016;[https://www.ncbi.nlm.nih.gov/pubmed/26382905]
16. Ferraro PM, et al. Dietary Protein and Potassium, Diet-Dependent Net Acid Load, and Risk of Incident Kidney Stones. Clin J Am Soc Nephrol. 2016. [https://www.ncbi.nlm.nih.gov/pubmed/27445166]
17. Goraya N,et al. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013.https://www.ncbi.nlm.nih.gov/pubmed/23393104
18. Cheng CJ, et al. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol, 2013.[https://www.ncbi.nlm.nih.gov/pubmed/23953801]
19. Medbo JI, Sejersted OM. Plasma potassium changes with high intensity exercise. J Physiol. 1990. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190075/]
20. McKenna MJ, et al. Sprint training increases human skeletal muscle Na(+)-K(+)-ATPase concentration and improves K+ regulation. J Appl Physiol. 1993. [https://www.ncbi.nlm.nih.gov/pubmed/8397176]
21. Nielsen JJ, et al. Effects of high-intensity intermittent training on potassium kinetics and performance in human skeletal muscle. J Physiol. 2004. [https://www.ncbi.nlm.nih.gov/pubmed/14634198]
22. Kong CH, et al. The effect of exercise during haemodialysis on solute removal. Nephrol Dial Transplant. 1999.[https://www.ncbi.nlm.nih.gov/pubmed/10570099[]
23. Ferreira GD, et al. Does Intradialytic Exercise Improve Removal of Solutes by Hemodialysis? A Systematic Review and Meta-analysis. Arch Phys Med Rehabil. 2019.[https://www.ncbi.nlm.nih.gov/pubmed/30922880]

Disclosures

The Curbsiders report no relevant financial disclosures. Joel Topf lists the following on his blog “I have an ownership stake in a few Davita run dialysis clinics and a vascular access center. Takeda Oncology made a donation to MM4MM the program that is taking me to Mount Everest in 2018.”

Citation

Sohaney R, Gibson E, Clegg D, Topf J, Williams PW, Brigham SK, Watto MF. “#199 NephMadness: Hyperkalemia, Diet, Potassium Binders, Exercise”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. March 16, 2020.