DKD expert meeting highlights: Prevention and management of hyperkalaemia in patients on RASIs

Hyperkalaemia or concerns regarding potential hyperkalaemia may contribute to dose reduction or discontinuation of renin-angiotensin system inhibitors (RASIs). At a recent diabetic kidney disease (DKD) expert meeting chaired by Professor Juliana Chan of the Department of Medicine and Therapeutics, the Chinese University of Hong Kong (CUHK), and Professor Sydney Tang of the Department of Medicine, the University of Hong Kong (HKU), a panel of clinical pharmacologists, endocrinologists and nephrologists shared insights into personalized potassium management and provided practical guidance on RASI optimization.

Importance of optimal RASI therapy
Cardiorenal benefits of RASIs and finerenone (a new class of non-steroidal mineralocorticoid antagonist [nsMRA]) have been well established in clinicals trials. “To maximize these benefits, uptitration to the maximum tolerated dose is required,” highlighted Tang. [Eur Heart J 2022;43:474-484; N Engl J Med 2001;345:861-869; Ann Intern Med 2003;138:542-529]

“Based on real-world evidence, RASI discontinuation is associated with significantly higher risks of major adverse cardiovascular events [MACE; hazard ratio (HR), 1.27; 95 percent confidence interval (CI), 1.08–1.49], heart failure [HF; HR, 1.85; 95 percent CI, 1.53–2.25], and end-stage kidney disease [ESKD; HR, 1.30; 95 percent CI, 1.17–1.43] vs RASI continuation in patients with type 2 diabetes mellitus [DM] and advanced chronic kidney disease [CKD],” noted Professor Elaine Chow of the Department of Medicine and Therapeutics, CUHK. [EClinicalMedicine 2022;55:101751]

Hyperkalaemia: Barrier to RASI optimization
Treatment with RASIs may induce hyperkalaemia, a potentially life-threatening disorder, although this can often be prevented by dose adjustment or avoidance of factors that may worsen kidney function or cause hyperkalaemia. [Eur Heart J Suppl 2021;26:891-896; Kidney international 2022;102:990-999] The panellists agreed that owing to fears of hyperkalaemia, suboptimal use of RASIs remains common in clinical practice, especially in the context of fragmented care in the public healthcare system, which limits optimal use of RASIs, thereby offsetting their cardiorenal benefits. [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

Although a universal definition of hyperkalaemia is currently lacking, the panellists agreed on serum potassium levels >5.0–5.5 mmol/L as a threshold for hyperkalaemia. “A U-shaped relationship can be seen for serum potassium level and all-cause mortality in patients with HF, CKD and/or DM, with mortality rate increasing from potassium levels >5.0 mmoL/L,” noted Tang. [Eur J Emerg Med 2020;27:329-337; Am J Nephrol 2017;46:213-221]

How to identify patients at risk of hyperkalaemia?
Most of the panellists noted that ≤15 percent of their patients with DKD on RASI therapy have serum potas­sium levels >5.0 mmol/L, while ≤10 percent have serum potassium levels >5.5 mmol/L. Of note, hyperkalaemia is not always induced by RASIs. Clinicians are advised to consider risk factors that cause or aggravate hyperkalaemia. (Table 1) [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

How to mitigate risk of hyperkalaemia?
According to the experts, patients with hyperkalaemia or elevated se­rum potassium levels should be que­ried about their diet, since transient hyperkalaemia can be attributed to potassium-rich food, especially ba­nana, kiwi fruits and double-stewed soup with potassium-enriched broth that leaches from boiled vegetables. (Table 1) However, the panellists ac­knowledged that a low-potassium diet is pragmatically difficult to follow. “The key is portion control. Patients tend to consume a lot of ‘healthy’ foods or overeat during holidays. Clinicians should educate them to eat sensibly and take a weight-maintaining diet with balanced nutrients. If they are over­weight or obese, cutting portion size of their usual diets will help. Patients with CKD, especially those treated with potassium-sparing medication such as RASIs and MRAs, should avoid taking excessive potassium-rich foods,” sug­gested Prof Chan. [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

“The combination of spironolactone and RASIs further increases the risk of hyperkalaemia, but it is widely used in patients with DM comorbid HF,” point­ed out Professor Kathryn Tan of the Department of Medicine, HKU, and Dr Vincent Yeung, Specialist in Endocrinol­ogy, Diabetes & Metabolism in private practice. “In my experience, hyperka­laemia rarely occurs in patients treat­ed with low-dose spironolactone [ie, ≤25.0 mg daily],” shared Dr Tai-Pang Ip of the Tung Wah Hospital. The panellists pointed out that while coadministration of drugs known to promote hyperkalae­mia is not an absolute contraindication, this should prompt frequent monitoring of serum potassium levels, particularly in patients receiving high-dose spi­ronolactone (ie, 50–100 mg daily) plus RASIs. (Table 1) [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

Moreover, increased fluid intake (except in patients with fluid overload), tight glycaemic control and use of loop or thiazide diuretics and sodium-glucose cotransporter 2 (SGLT2) in­hibitors can reduce the risk of hyper­kalaemia. (Table 2) [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023] “Increasing use of SGLT2 inhibitors in recent years may lead to a lower risk of hyperkalaemia in patients treated with RASIs and/or finerenone,” commented Chow. Notably, finerenone has a good and predictable safety margin (differ­ence in mean serum potassium at 4 months, +0.21 mmol/L) with a low dis­continuation rate due to hyperkalaemia. [Eur Heart J 2022;43:474-484]

Management of hyperkalaemia
The pharmacological treatment threshold for hyperkalaemia is serum potassium ≥5.5 mmol/L. Before initi­ating treatment, blood test should be repeated to rule out pseudohyperka­laemia. The latter is due to leakage of potassium from red blood cells with dif­ficult venipuncture or if collected blood samples are not immediately spun down. [The Renal Association, Clinical Practice Guidelines Treatment of Acute Hyperkalaemia in Adults, June 2020] “If readily available, electrocardiography [ECG] is helpful in assessing severity of hyperkalaemia, especially in patients with serum potassium levels >6 mmol/L pending repeat serum potassium lev­el measurement,” said Dr Chung-Ping Ho, Specialist in Nephrology in pri­vate practice. “Any characteristic ECG changes [ie, peaked T waves, flattened P wave and prolonged QRS interval] should warrant hyperkalaemia management.”

Importantly, hyperkalaemia treatment should be individualized and guided by several factors, including baseline serum potassium level, how rapidly serum potassium level rises, and patient’s medical history. (Table 3) [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

“Chronic hyperkalaemia is common in patients with stage ≥3 CKD, particularly in pre-haemodialysis [pre-HD] patients,” noted Tang and Dr John Chan, Specialist in Nephrology. “Patients with CKD often have better tolerance of elevated potassium levels vs patients without CKD. Nevertheless, a potassium level >5.5 mmol/L is a red flag that warrants treatment, regardless of whether hyperkalaemia is chronic or acute.”

“Patients with hyperkalaemia should be monitored closely for rapid deterioration in kidney function [eg, acute kidney injury (AKI)] indicated by a sudden surge of serum creatinine. In that setting, the treatment threshold for hyperkalaemia is much lower,” said Dr Chun-Yu Yung of the Pok Oi Hospital. Additionally, COVID-19 may increase the risk of developing AKI and can therefore be problematic. [Ren Fail 2023;45:2170809]

“Identifying and addressing the underlying cause of hyperkalaemia and sudden deterioration of kidney function are crucial for effective treatment,” suggested Tan. (Table 3)

“In case of suspected hyperkalaemia, dietary intervention should be initiated between the first and second serum potassium tests, while reassessment of concomitant medications and addition of loop or thiazide diuretics and/or SGLT2 inhibitors can be started after ruling out pseudohyperkalaemia in the second serum potassium test,” said Chow. The panellists also suggested additional treatments including potassium binders (if potassium level >5.5 mmol/L), insulin dextrose or dialysis (if potassium level >6 mmol/L), and sodium bicarbonate (if metabolic acidosis). Of note, new potassium binders (eg, sodium zirconium cyclosilicate) are better tolerated and have a faster onset of action vs traditional potassium binders, although they are associated with higher costs. (Table 3) [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]

“Importantly, RASI discontinuation should be the very last resort after all possible interventions have been exhausted, especially in patients with heavy proteinuria,” highlighted Chow and Ho. (Table 3) “If short-term discontinuation of RASIs is deemed necessary, it should be carefully reintroduced as soon as possible.”

Once hyperkalaemia has been corrected, the panellists recommended reinitiation of cardiorenal-protective drugs (eg, RASIs and finerenone) and gradual uptitration to the maximum tolerated dose if possible in patients with CKD. In patients with serum creatinine <500 μmol/L, RASIs should be restarted at the lowest dose and potassium level should be closely monitored. However, the panellists voiced their reservations about reinitiating RASIs in patients without proteinuria or those with serum creatinine level >500 μmol/L. [Chan JCN, Tang SCW, et al, DKD expert meeting, 2023]