Optimization of RAASi Therapy with New Potassium Binders for Patients with Heart Failure and Hyperkalemia: Rapid Review and Meta-Analysis

(1) Background: The objective of this rapid review is to assess whether new potassium binders (NPBs) could enable the optimization of RAASi therapy more than usual care or placebo in patients with or at risk of heart failure and hyperkalemia. (2) Methods: We searched for RCTs that included patients with or at risk of hyperkalemia and patients treated with Patiromer or sodium zirconium cyclosilicate (ZSC). The comparators were placebo, usual care, and potassium binders with different doses or different treatment protocols. We searched the Cochrane CENTRAL, MEDLINE, and ClinicalTrials.gov databases. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. Data were pooled using the random effects model, and the fixed effects model was used for sensitivity analysis. (3) Results: We included 12 studies with 2800 enrolled patients. Only three of these trials (412 patients) were included in the meta-analysis. NPBs seemed to have an effect on the optimization of MRA therapy, with an RR (95% CI) of 1.24 (1.09, 1.42) (moderate certainty evidence); Patiromer seemed to have an effect on MRA optimization, with an RR (95% CI) or 1.25 (1.08, 1.45) (high certainty evidence). ZSC seemed to have no effect on enabling MRA therapy, with an RR (95% CI) of 1.19 (0.89, 1.59) (low certainty evidence). The AEs in HF patients with hyperkalemia treated with Patiromer were GI disorders and hypomagnesemia. ZSC The AEs included chronic cardiac failure, hypokalemia, and edema. (4) Conclusions: This meta-analysis included three studies with a small number of patients and a short follow-up period (1–3 months). The evidence of the effect of NPBs on MRA optimization had a moderate certainty for imprecision. Data on the effect on MRA optimization and less severe AEs in long-term treatment seem to suggest the use of Patiromer for the optimization of MRA therapy in patients with or at risk of heart failure and hyperkalemia. Future adequately powered RCTs are needed to assess the benefits and potential harms of potassium binders.

An unusual recurrent ileocolonic injury

Potassium binders (Kayexalate® and Sorbisterit®) are commonly used to treat hyperkaliemia. They are made of sodium or calcium polystyrene sulfonate. Their use is associated with multiple adverse effects including ileocolonic (or more rarely upper digestive tract) injuries which can lead to necrosis or perforations. This side effect is mostly seen in patients with chronic kidney disease or constipation. It presents with abdominal pain, diarrhea or hematochezia. The diagnosis is made when the histo-logical analysis of samples from the erythematous or ulcerated digestive wall finds polystyrene sulfonate crystals embedded in the mucosa. This diagnosis can be suspected by taking a careful initial drug inventory, if the clinician is aware of this rare but serious adverse effect. The lack of specificity of clinical symptoms and endoscopic lesions makes this inventory even more essential. Treatment is mainly supportive and requires cessation of the drug, while surgery is inevitable in the most severe cases.

Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial

Background Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin aldosterone system (RAAS), particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. Purpose We sought to assess the effect of canagliflozin on hyperkalaemia and other potassium-related outcomes in people with T2DM and CKD by conducting a post-hoc analysis of the CREDENCE trial. Methods The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post-hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. Results At baseline the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin angiotensin system blockade. Canagliflozin reduced the risk of investigator-reported hyperkalaemia or initiation of potassium binders (HR 0.78, 95% CI 0.64–0.95, p=0.014; Figure 1). The incidence of laboratory-determined hyperkalaemia was similarly reduced (HR 0.77, 95% CI 0.61–0.98, p=0.031; Figure 2); the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, p=0.53) was not increased. Mean serum potassium over time with canagliflozin was similar to that of placebo. Conclusion Among patients treated with RAAS inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Patiromer in a Patient with Severe Hyperkalemia on Incremental Hemodialysis with 1 Session per Week: A Case Report and Literature Review

Hyperkalemia is common in patients with ESRD, undergoing hemodialysis (HD), and is associated with an increase in hospitalization and mortality. Residual kidney function in long-term dialysis patients is associated with lower morbidity and mortality in HD patients. Although the 2015 National Kidney Foundation-Kidney Disease Outcomes Quality Initiate (NKD-KDOQI) guidelines allow the reduction in the weekly HD dose for patients with a residual kidney urea clearance (Kur) >3 mL/min/1.73 m², very few centers adjust the dialysis dose based on these criteria. In our center, the pattern of incremental hemodialysis (iHD) with once-a-week schedule (1 HD/W) has been an option for a group of patients showing very good results. This pattern is maintained as long as residual diuresis is >1,000 mL/24 h, Kur is >4 mL/min, and there is no presence of edema or volume overload, as well as no analytical parameters persistently outside the advisable range (serum phosphorus >6 mg/dL or potassium [K⁺] >6.5 mmol/L). Management of hyperkalemia in HD patients includes reduction of dietary intake, dosing of medications that contribute to hyperkalemia, and use of cation-exchange resins such as calcium or sodium polystyrene sulfonate. Two newer potassium binders, patiromer sorbitex calcium and sodium zirconium cyclosilicate, have been safely used for potassium imbalance treatment in patients with ESRD in HD with a conventional regimen of thrice weekly, but has not yet been studied in 1 HD/W schedules. We present the case of a 76-year-old woman in iHD (1 HD/W) treated with patiromer for severe HK and describe her clinical characteristics and outcomes. In addition, we review the corresponding literature. Based on these data, it can be anticipated that the use of patiromer may overcome the risk of hyperkalemia in patients with incident ESRD treated with less-frequent HD regimens.

Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options

Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).

MO218ALTERNATING EPISODES OF TRUE HYPERKALEMIA AND PSEUDOHYPERKALEMIA IN ADULT SICKLE CELL DISEASE - A NEPHROLOGIST'S DILEMA

Background and Aims To illustrate the phenomenon of alternating true hyperkalemia and pseudohyperkalemia in adult sickle cell disease. Method Case Report Results Sickle cell disease (SCD) predisposes the patient to recurrent episodes of acute painful hemolytic crisis. Sickle cell nephropathy (SCN) is not uncommon in adult patients. The presence of sickled erythrocytes in the renal medullary vessels is the hallmark of the disease and renal manifestations include renal ischemia, microinfarcts, renal papillary necrosis and renal tubular abnormalities with variable clinical presentations. Furthermore, acute hemolytic crisis can be complicated by sepsis. Hemolysis, specifically, intravascular hemolysis, can produce hyperkalemia. Additionally, reduced glomerular filtration rate from SCN predisposes to hyperkalemia. Pseudo-hyperkalemia was first reported by Hartmann and Mellinkoff in 1955 as a marked elevation of serum potassium levels in the absence of clinical evidence of electrolyte imbalance. In pseudohyperkalmia, simultaneously estimated serum potassium exceeds plasma potassium by >0.4 mmol/L. This is often associated with moderate to severe thrombocytosis or leukocytosis. Clearly, hyperkalemia is a potentially lethal condition. At the same time, the institution of inappropriate treatment of pseudo-hyperkalemia leading to hypokalemia is also equally potentially lethal. We describe a 40-yo African American male patient with sickle cell anemia who exhibited alternating episodes of hyperkalemia and pseudo-hyperkalemia, during consecutive hospital admissions. Pseudohyperkalemia was associated with severe thrombocytosis complicating sepsis. EKG was normal despite measured serum potassium of 6.7 mmol/L (Figure). Conclusion We believe that this is the first report of adult SCD demonstrating alternating cycles of true hyperkalemia and pseudo-hyperkalemia at different times. We must draw attention to the new availability of the new potassium binders, Patiromer and sodium zirconium cyclosilicate. We would advocate for caution in the use of these potent potassium binders and to always give consideration to the presence of pseudo-hyperkalemia under appropriate clinical scenarios. We posit that providers managing adult patients with sickle cell disease must be aware of such a phenomenon to avoid the dangers of overtreatment of episodes of pseudo-hyperkalemia in such patients.

MO493PATTERNS OF HYPERKALEMIA AND ASSOCIATED ADVERSE HEALTH OUTCOMES IN PERSONS WITH CHRONIC KIDNEY DISEASE

Background and Aims Patients with CKD are often described as having chronic hyperkalemia, but earlier studies have relied on a single potassium measurement. Whether the hyperkalemia in CKD is chronic or transient, and whether temporal patterns have different outcome implications, is unknown. Method Observational study from the Stockholm Creatinine Measurements (SCREAM) project of patients with confirmed CKD G3-5. We extracted all data on potassium measured during routine outpatient care and estimated its longitudinal trajectories. At each month, we created a rolling assessment of the proportion of time in which potassium was abnormal during the previous year, defining patterns of normokalemia (100% of time with potassium 3.5-5.0 mmol/L), transient (<50% of time with potassium >5.0 mmol/L) and chronic hyperkalemia (≥50% of time with potassium >5.0 mmol/L). We described the presence of chronic and transient hyperkalemia throughout the spectrum of CKD G3-5 and identified clinical predictors by logistic regression. Through time-dependent Cox models we examined whether previous hyperkalemia patterns offer prognostic gain beyond that of the current potassium value. Results We included 36,511 participants (56% women) with confirmed CKD G3-5, median age 81 years, and eGFR 46 ml/min/1.73 m2. During 3-year-median follow-up, patterns of transient and chronic hyperkalemia were observed in 15% and 4% of patients with CKD G3a, increasing to 50% and 17% of patients with CKD G5. Factors associated with chronic hyperkalemia were younger age, male sex, more severe CKD category, presence of diabetes or heart failure, use of renin-angiotensin system inhibitors, and use of potassium binders. Major cardiovascular events (MACE) occurred in 13,104 (36%) patients and 13,570 (37%) died. In time-dependent models, independent of identified confounders and of time-updated potassium values, compared with the normokalemic pattern, patients with transient (HR 1.37, 95% CI 1.29-1.46) or chronic (HR 1.17, 95% CI 1.04-1.32) hyperkalemia patterns were at higher risk of MACE. Transient hyperkalemia pattern (HR 1.43, 95% CI 1.35-1.52) and time-updated elevated potassium, but not a state of chronic hyperkalemia (HR 1.07, 95% CI 0.95-1.20), predicted the risk of death. Conclusion Chronic hyperkalemia occurs in 4-17% of patients with CKD G3-5. We did not observe a clear dose-response for the association between hyperkalemia pattern (normal, transient, chronic) with either MACE or death. There was modest incremental information in the previous potassium pattern, beyond potassium measured at a single time point.

Alternating and Concurrent True Hyperkalemia and Pseudohyperkalemia in Adult Sickle Cell Disease

Sickle cell disease (SCD) predisposes the patient to recurrent episodes of acute painful hemolytic crisis. Sickle cell nephropathy (SCN) is not uncommon in adult patients, and renal manifestations of SCN include renal ischemia, microinfarcts, renal papillary necrosis, and renal tubular abnormalities with variable clinical presentations. Intravascular hemolysis and reduced glomerular filtration rate with renal tubular dysfunction predispose to true hyperkalemia. Hemolytic crisis can be complicated by sepsis, leading to significant degrees of thrombocytosis, and thrombocytosis is a well-defined cause of pseudohyperkalemia. We describe a 40-year-old African American male patient with sickle cell anemia who exhibited alternating episodes of true hyperkalemia and pseudohyperkalemia, during consecutive hospital admissions. Clearly, true hyperkalemia is a potentially lethal condition. At the same time, the institution of inappropriate and intensive treatment of pseudohyperkalemia leading to severe hypokalemia is also potentially lethal. The need for this caution is most imperative with the recent introduction of the safer and more potent potassium binders, patiromer and sodium zirconium cyclosilicate.

Practical guidance for the use of potassium binders in the management of hyperkalaemia in patients with heart failure and/or chronic kidney disease

Given the critical physiological role of potassium, it is understandable that the development of severe hyperkalaemia requires effective management to reduce its effects, which include muscle weakness, paralysis and cardiac arrhythmias. Hyperkalaemia most often results from the failure of renal adaptation to potassium imbalance. Patients who are most susceptible to the development of hyperkalaemia include those with chronic kidney disease and those with heart failure. These patients are often treated with renin–angiotensin–aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers, but the development of hyperkalaemia can require down-titration or cessation of RAAS inhibitors. This presents a significant challenge to nephrologists, cardiologists and healthcare professionals treating these patients as this can prevent them from receiving maximum guideline-directed RAAS inhibitor therapy. Panellists in this roundtable discussion shared their clinical experiences of using potassium binders to manage hyperkalaemia in patients with chronic kidney disease and patients with heart failure (illustrated with case studies) in Northern Ireland and considered recommendations for the implementation and maintenance of chronic potassium-lowering treatment.