New Insights Into Dietary Approaches to Potassium Management in Chronic Kidney Disease

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.

Introduction

Potassium is the most abundant cation in the human body, with approximately 2% being located in extracellular fluid (3.5–5.0 mEq/L) and 98% being in the intracellular compartment (140 mEq/L).^1,2 Potassium plays a crucial role in normal cell membrane electrophysiology in neurons, muscle, and cardiac cells.¹ Abnormal serum potassium concentrations can therefore result in electrophysio-logical perturbations in neuromuscular and cardiac systems, contributing to various adverse clinical outcomes, such as muscular weakness, hypertension, ventricular arrhythmias, and mortality.^2,3

Since the physiological mechanisms involved in potassium homeostasis (e.g., renin-angiotensin-aldosterone system [RAAS], insulin secretion, and urinary clearance) are gradually impaired as kidney function declines, chronic kidney disease (CKD) has been the most common predis-posing condition for hyperkalemia in clinical practice.⁴ Therefore, patients with advanced stages of CKD are at a high risk of experiencing recurrent episodes of hyperkalemia and its related adverse outcomes, often in combination with one or more exacerbating factors, such as concurrent use of RAAS inhibitors and pre-existing metabolic acidosis.² As a result, several approaches have been recommended for the management of chronic hyperkalemia in patients with CKD, among which dietary potassium restriction is a core strategy.⁵ This seemingly rational dietary intervention, however, is supported by limited evidence and the idea that hyperkalemia in CKD results from either excessive potassium intake, impaired potassium excretion, or potassium redistribution from the intracellular to extracellular space.^5,6

Emerging evidence from observational studies has now challenged this widely accepted practice by showing minimal risks and more favorable outcomes associated with higher (vs. lower) dietary potassium intake even in patients with CKD.^7–10 This in turn raises the possibility of a paradigm shift from restricting dietary potassium toward fostering more liberalized, plant-based dietary intake to improve cardio-renal outcomes as these foods are often rich in potassium. In this review, we summarize the current understanding of dietary approaches to potassium management in patients with CKD and discuss the impact of emerging potassium binders and potentially novel gut-targeted “potassium wasting” strategies on dietary potassium manipulation in patients with CKD.

Mechanisms of Hyperkalemia in Chronic Kidney Disease

Normal potassium homeostasis is maintained primarily by the kidneys through the electrogenic secretion of potassium in the distal convoluted tubule and the proximal collecting duct.¹¹ When damage to tubulointerstitial lesions progresses and kidney function starts to decline, the kidneys can adjust to the decreased number of nephrons by increasing potassium secretion in residual functioning nephrons and thereby maintaining serum potassium levels within a physiologically normal range (i.e., normokalemia).¹² However, the effectiveness of this adaptation is increasingly hampered as CKD progresses toward advanced stages, resulting in the development of hyperkalemia.^1,4 In addition to the tubulointerstitial damage and kidney function decline that prevent the kidneys from maintaining normokalemia, several conditions predispose patients with CKD to hyperkalemia.⁴ These include the use of medications promoting hyperkalemia (e.g., RAAS inhibitors, potassium-sparing diuretics, and beta blockers), the high prevalence of hyperkalemia-inducing comorbidities (e.g., diabetes mellitus, acute kidney injury, and congestive heart failure), and CKD-related factors, such as metabolic acidosis and anemia requiring blood transfusion.⁴

Dietary Sources and Intake of Potassium

Meat, poultry, fish, milk and dairy products, nuts and legumes, and fruits and vegetables are major sources of dietary potassium, as well as of dietary fibers and of essential micronutrients, such as antioxidant vitamins.¹³ As food patterns vary widely around the world, dietary potassium sources and potassium intake also vary globally, ranging from~2.0 g/day (~52 mmol/day) in China to ~4.8 g/day (~123 mmol/day) in Spain where a typical Mediterranean diet is consumed.^14,15 The dietary sources of potassium are also important in terms of the bioavailability of ingested potassium and the acid-base balance.¹⁰ Compared with high-potassium meat which is low in fiber and enhances net acid production through its metabolism, high-potassium fruits and vegetables, which are high in fiber and enhance net base production, may facilitate fecal potassium excretion (by decreasing intestinal transit time) and intracellular potassium distribution, potentially contributing to lower extracellular potassium concentrations.⁵ Hence, even when prescribing potassium-restricted diets, the lower bioavailability (50%–60%) of plant potassium might be advantageous by enabling patients with CKD to benefit from the other salutary effects of plant-based diets (e.g., higher amount of antioxidants, vitamins, fiber, flavonoids, carotenoids, salicylates, and alkali content; improved glycemic control; and gut microbiota modulation; Figure 1) without precipitating hyperkalemia.^16–18 However, more research is needed to determine if dietary fiber can lower potassium bioavailability.¹⁹

Figure 1.

Plant-based diet and multifaceted health benefits, Abbreviation: CKD, chronic kidney disease.

The intake of foods with potassium additives, such as ultraprocessed foods, and those containing low-sodium salt substitutes or potassium preservatives is an important hidden source of potassium. A 100-g intake of enhanced meat could add 300–575 mg of potassium because of its preservatives.^20–22 Of note, the bioavailability of ingested potassium from potassium additives is reported to be as high as 100%.²³ It may also be important to note that the food manufacturers may be incentivized to use potassium additives with the addition to potassium to nutrition fact labels. Due to the major emphasis on sodium restriction in patients with CKD, some patients switch to low-sodium salt substitutes, not realizing that these can contain potassium salts.⁴ Moreover, dietary counseling emphasizing the restrictions of fruits and vegetables may lead patients to replace unprocessed or minimally processed foods with ultraprocessed foods containing potassium additives. Hence, these foods require special attention when practicing dietary potassium monitoring for potassium management in CKD.¹⁷

Dietary Potassium Restriction–Historical Approach

Restricting the amount of dietary potassium intake has long been considered a reasonable strategy for chronic potassium management in patients with CKD. Thus, this strategy has been widely used in clinical practice for more than a half century (Table 1). A low potassium diet is typically defined as a dietary potassium intake of 2–3 g/day (~50–77 mmol/day),²⁴ although the exact amount to which dietary potassium should be limited is ill-defined.⁶ The current Kidney Disease Outcomes Quality Initiative clinical practice guideline for nutrition in CKD states that it is reasonable to adjust dietary potassium intake to maintain serum potassium within the normal range in adults with CKD 3–5D or post-transplant (based on expert opinion), without specifying the limit of dietary potassium amount.²⁵ Given the inherent nonuniformity of dietary strategies, the suggested individualized approach seems reasonable and practical. However, the key rationale behind this apparently less restrictive opinion-based statement is the scarcity of compelling scientific evidence supporting the effectiveness of dietary potassium restriction in maintaining normokalemia, let alone its ability to improve relevant clinical outcomes in patients with CKD.^6,25 Of note, the original potassium balance studies which are the core evidence for potassium restricted diets were short-term kinetic studies using large boluses of potassium salts—highly bioavailable and not a food constituent—in a fasted state, assessing transient changes in serum potassium over several hours, not accumulation of potassium over time.^26,27 It is also important to note that not all patients with CKD require a low-potassium diet.

Table 1.

Potential Benefits and Challenges of Dietary Potassium Manipulation in Chronic Kidney Disease

Dietary Approaches	Benefits	Challenges
Traditional approach
Dietary potassium restriction	Reduce dietary potassium loads Decrease the intake of ultraprocessed foods with high content of potassium additives and of low-sodium with potassium salts May help reduce plasma potassium concentrations and prevent hyperkalemia	Low fiber and alkali intake Slow intestinal transit and impairment of fecal potassium excretion Increase in net acid load and aggravation of metabolic acidosis Reduces dietary variety Educate patients on food sources with potassium additives and potassium salts
Novel approach
Liberalized plant-based diet	Increase fiber and alkali intake Facilitate intestinal transit and increase fecal potassium excretion Reduce net acid production and mitigate metabolic acidosis Increase dietary variety	High dietary potassium loads
(with/without) Gut-targeted interventions
Novel potassium binders (i.e., patiromer sorbitex calcium and sodium zirconium cyclosilicate)	Increase fecal potassium excretion Reduce plasma potassium concentrations Prevent hyperkalemia	Drug adverse effects Limited effect on postprandial hyperkalemia Increase pill burden
Gastrointestinal potassium wasting (e.g., laxatives)	Increase fecal potassium excretion Reduce plasma potassium concentrations Prevent hyperkalemia	Malnutrition/loss of water soluble vitamins Hypokalemia Increase pill burden

Dietary Potassium Restriction and Clinical Outcomes

In a recent meta-analysis including 2 randomized controlled trials and 5 observational studies in patients with CKD, a restricted (1,295 mg/d) (vs. unrestricted [1,570 mg/d]) potassium diet significantly lowered serum potassium levels by a mean of −20.22 mEq/L (albeit with very-low-quality evidence from only 2 small trials, one of which used oral nutritional supplements [100% liquid nutrition from potassium salts] as an intervention and accounted for 92% of this estimate)²⁸ but was not associated with the risk of CKD progression and mortality.²⁹ In a recent randomized feeding trial examining the effects of higher (3.9 g [100 mmol]/day) versus lower (1.6 g [40 mmol]/day) dietary potassium intake on serum potassium and blood pressure levels in 29 adults with CKD (baseline mean estimated glomerular filtration rate and serum potassium of 54.5 mL/min/1.73 m² and 4.5 mmol/L, respectively), the higher versus lower potassium diet was associated with a 2.5-fold higher risk of hyperkalemia (serum potassium ≥ 5.5 mmol/L, documented at prespecified study visits) but did not change 24-h ambulatory blood pressure over the 4-week feeding period.³⁰ Of note, two participants developed confirmed hyperkalemia (serum potassium > 5.5 mmol/L), both during the high potassium feeding period, but had nondietary reasons (one used tacrolimus and had a rise in serum creatinine and the other used both an angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor).³⁰ These observations may reinforce the importance of recommending dietary potassium restriction for preventing chronic hyperkalemia and its potentially life-threatening sequelae in CKD. Nevertheless, the impact of restricting dietary potassium intake on long-term clinical outcomes among patients with advanced stages of CKD is still questionable, particularly for the outcomes that are not directly linked to hyperkalemia (e.g., noncardiovascular outcomes) but could be benefited from the aforementioned salutary effects of high potassium-containing food groups.²⁴

In this context, the results from a recent large observational study investigating the association of dietary potassium intake with clinical outcomes in 8,043 patients on hemodialysis may be worth mentioning.⁷ In this study, the researchers found no association of dietary potassium intake with serum potassium levels, with prevalence of hyperkalemia, or with all-cause or cause-specific mortality, suggesting that dietary potassium intake may not raise serum potassium to the degree originally thought in this population. They also detected no evidence for mediation effects of serum potassium in the dietary potassium-mortality association, while showing a significant association of higher serum potassium levels with a greater risk of cardiovascular mortality. Of interest, they observed a significantly lower risk of noncardiovascular mortality associated with higher potassium intake when adjusting for various clinical characteristics, which was attenuated to null after further adjustment for food groups, implying that the favorable association was confounded by the beneficial effects of certain potassium-rich food groups (e.g., net base production and constipation alleviation) that can also mitigate the impact of their high potassium content on serum potassium concentrations.

Plant-Based Diets–New Perspectives in Dietary Potassium Management

Plant-based diets are based on plant-dominant foods, including the Mediterranean, Dietary Approaches to Stop Hypertension, Plant-Dominant Low-Protein Diet, vegan, vegetarian, and whole-plant–based diets. Some of these plant-based diets include small amounts of lean animal-based protein sources. One of the most frequently stated concerns about fostering a plant-based diet in patients with CKD is the perceived risk of hyperkalemia, which is not supported by current scientific evidence.^9,10,31–34 In a series of clinical trials examining the effect of fruit and vegetable intake (vs. oral sodium bicarbonate) on kidney-related and cardiovascular-related biochemical parameters in patients with CKD, Goraya et al.^31–33 demonstrated an intervention of approximately 2 to 4 cups of fruits and vegetables, such as apples, oranges, carrots, and tomatoes, did not cause hyperkalemia. Importantly, participants with baseline plasma potassium > 4.6 mEq/L were excluded from the trials. A similar finding was reported in a trial of 22 patients with CKD stages G3–4 who consumed a pure vegan diet for 3 months.³⁴ In terms of clinical outcomes associated with plant-based diets, a recent meta-analysis of cohort studies showed that healthy dietary intake of fruits and vegetables was consistently associated with better survival in patients with CKD.³⁵ Nevertheless, with intrinsic limitations of these reported studies (e.g., limited generaliz-ability and lack of information about postprandial plasma potassium levels), questions remain whether the high-potassium plant-based diets can really be promoted in patients with CKD, particularly given the scarcity of interventional data on long-term clinical outcomes (Table 1). In this context, it may be worth noting that the Mediterranean and Dietary Approaches to Stop Hypertension diets were not associated with cardiovascular or all-cause mortality in patients on hemodialysis enrolled in the DIET-HD study, a multinational, prospective cohort study.³⁶

Novel Potassium Binders in Potassium Management

The advent of novel potassium binders (i.e., patiromer sorbitex calcium [patiromer] and sodium zirconium cyclo-silicate [SZC]) has provided an important breakthrough for the chronic potassium management in CKD. Patiromer is a nonabsorbable polymer that binds potassium in exchange for calcium in the colon, while SZC is a high-specificity inorganic crystal that entraps potassium in the intestinal tract, both allowing pharmacological lowering of plasma potassium concentration by increasing fecal potassium excretion. With their improved long-term safety profiles compared to sodium polystyrene sulfonate,³⁷ many clinicians and researchers have viewed these new drugs as a possible means to safely transition patients with CKD from low-potassium diets toward more liberalized, plant-based, heart-healthy eating patterns.^38,39 The practicality of this concept may be validated in an ongoing clinical trial testing the feasibility of prescribing high potassium-containing foods with the use of SZC in patients with CKD stages 4 and 5 with hyperkalemia (ClinicalTrials.gov identifier: NCT04207203). A recent clinical trial showing the effectiveness of chronic patiromer use in preventing hyperkalemia and reducing the rate of RAAS inhibitor discontinuation in patients with heart failure and hyperkalemia may further support the concept.⁴⁰

Notwithstanding the positive impact brought by the novel potassium binders on potassium management in CKD, questions remain whether all patients with CKD consuming plant-based diets need to be on these medications and whether their use can effectively suppress the possible postprandial rise in plasma potassium concentrations following a high-potassium meal. In the absence of definitive trial evidence regarding the efficacy of newer potassium binders on liberalized plant-based diets in patients with CKD, these medications may be used judiciously among those with risk factors for hyperkalemia (e.g., history of hyperkalemia and concomitant use of RAAS inhibitors) with careful consideration of their cost-benefit balance and close monitoring of serum potassium concentrations, including those in the postprandial period.

Gastrointestinal Potassium Wasting–Potential Future Approaches

Under physiologic circumstances, approximately 90% of potassium consumed is excreted by the kidneys and the remaining 10% is accounted for by intestinal excretion via the large conductance calcium-activated potassium channel subunit alpha 1 (KCa1.1, also known as BK channel) expressed on the apical surface of colonic epithelial cells.⁴¹ As kidney function declines, the gut becomes especially important for maintaining potassium homeostasis primarily by enhancing potassium secretion through an increase in BK channel expression.⁴² In patients on hemodialysis, for example, fecal potassium excretion increases by ~30% of dietary potassium intake,^43,44 which can reach up to ~80% (3,000 mg/day).⁴⁵ It is therefore conceivable that slow intestinal transit and inadequate fecal potassium excretion can enhance potassium bio-accumulation, leading to hyperkalemia, whereas conditions with faster intestinal transit, such as diarrhea, can enhance intestinal potassium excretion, helping to prevent hyperkalemia or sometimes leading to hypokalemia.⁴⁶ Supporting this concept, a recent observational study showed that the use (vs. nonuse) of laxatives was associated with significantly lower risk of hyperkalemia in patients with advanced CKD transitioning to dialysis.⁴⁷ The theoretical safety concerns related to laxative use (e.g., dehydration, progressive loss of kidney function, and hypokalemia) in patients with CKD may be alleviated by reported associations of laxative use with a clinically negligible change in estimated glomerular filtration rate and with no risk of hypokalemia in these patients.^47,48 Given the high prevalence of constipation in patients with CKD (due in part to low-potassium and consequently low-fiber diets to avoid hyperkalemia) and its associations with several adverse clinical outcomes,^49–51 this so-called “gastrointestinal potassium wasting” by enhancing intestinal transit seems particularly relevant to patients with CKD and, with a careful consideration for the risk-benefit profiles, may provide a new therapeutic potential for optimal potassium management in these patients (Table 1).

Conclusion

With the growing importance of heart-healthy dietary patterns in reducing morbidity and mortality, evidence is accumulating that challenges the prevailing dogma of dietary potassium restriction but instead supports more liberalized, plant-based diets in patients with CKD. However, questions remain regarding the risks of plant-based diets, as well as the clinical utility of novel potassium binders and “gastrointestinal potassium wasting” in the context of liberalizing diets. Regardless, there is a renewed urgency to determine the efficacy of recommending dietary restriction of potassium rich foods in the context of the benefits these same foods provide to cardiometabolic health. Perhaps the time has arrived to begin to reassess our recommendations of potassium-restricted diets and consider more personalized dietary approaches for our patients with CKD. Well-designed clinical trials are needed to test the validity of dietary potassium intake with or without additional gut-targeted interventions toward optimal potassium management and ultimate improvement of clinical outcomes in patients with CKD.