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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).


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