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.
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
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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 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).
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.
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.
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.
|Sodium polystyrene sulfonate
|Sodium zirconium cyclosilicate
|Mechanism of action
|Na+/K+ exchange resin, often given with sorbitol, also binds Ca2+and Mg2+
|Exchanges Ca2+ for K+, also binds Mg2+
|Binds K+ in exchange for H+ and Na+
|Time of onset
|Variable (hours to days)
|Entire intestinal tract
|Commonly reported adverse reactions and precautions
|Diarrhea, metabolic alkalosis, volume overload, rarely colonic necrosis; must separate from other oral drugs by at least 3 hours
|Constipation, diarrhea, flatulence, hypomagnesemia; may need to separate from some oral drugs by 3 hours
|Constipation, diarrhea, edema; can increase gastric pH potentially interfering the drugs having pH dependent solubility; should be separated from other oral drugs by 2 hours
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.
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).
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).
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) .
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.
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.
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.
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).
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.
After listening to this episode listeners will…
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.”
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.
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