Beneficial Effect of Calcium Treatment for Hyperkalemia Is Not Due to "Membrane Stabilization".

OBJECTIVES: Hyperkalemia is a common life-threatening condition causing severe electrophysiologic derangements and arrhythmias. The beneficial effects of calcium (Ca 2+ ) treatment for hyperkalemia have been attributed to "membrane stabilization," by restoration of resting membrane potential (RMP). However, the underlying mechanisms remain poorly understood. Our objective was to investigate the mechanisms underlying adverse electrophysiologic effects of hyperkalemia and the therapeutic effects of Ca 2+ treatment. DESIGN: Controlled experimental trial. SETTING: Laboratory investigation. SUBJECTS: Canine myocytes and tissue preparations. INTERVENTIONS AND MEASUREMENTS: Optical action potentials and volume averaged electrocardiograms were recorded from the transmural wall of ventricular wedge preparations ( n = 7) at baseline (4 mM potassium), hyperkalemia (8-12 mM), and hyperkalemia + Ca 2+ (3.6 mM). Isolated myocytes were studied during hyperkalemia (8 mM) and after Ca 2+ treatment (6 mM) to determine cellular RMP. MAIN RESULTS: Hyperkalemia markedly slowed conduction velocity (CV, by 67% ± 7%; p < 0.001) and homogeneously shortened action potential duration (APD, by 20% ± 10%; p < 0.002). In all preparations, this resulted in QRS widening and the "sine wave" pattern observed in severe hyperkalemia. Ca 2+ treatment restored CV (increase by 44% ± 18%; p < 0.02), resulting in narrowing of the QRS and normalization of the electrocardiogram, but did not restore APD. RMP was significantly elevated by hyperkalemia; however, it was not restored with Ca 2+ treatment suggesting a mechanism unrelated to "membrane stabilization." In addition, the effect of Ca 2+ was attenuated during L-type Ca 2+ channel blockade, suggesting a mechanism related to Ca 2+ -dependent (rather than normally sodium-dependent) conduction. CONCLUSIONS: These data suggest that Ca 2+ treatment for hyperkalemia restores conduction through Ca 2+ -dependent propagation, rather than restoration of membrane potential or "membrane stabilization." Our findings provide a mechanistic rationale for Ca 2+ treatment when hyperkalemia produces abnormalities of conduction (i.e., QRS prolongation).

Patiromer Facilitates Angiotensin Inhibitor and Mineralocorticoid Antagonist Therapies in Patients With Heart Failure and Hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

HARMONIZE Asia: A Phase III Randomized Study to Investigate the Efficacy and Safety of Sodium Zirconium Cyclosilicate in Patients with Hyperkalemia in China.

PURPOSE: Sodium zirconium cyclosilicate (SZC) is an oral potassium (K+)-lowering therapy for adults with hyperkalemia. HARMONIZE Asia (ClinicalTrials.gov identifier: NCT03528681) evaluated the efficacy and safety of SZC in Chinese patients with hyperkalemia. METHODS: This Phase III, randomized, double-blind, placebo-controlled study recruited patients with serum K+ (sK+) ≥5.1 mmol/L at 35 sites in China. Patients received SZC 10 g three times daily (TID) for 24 or 48 hours during an open-label initial phase (OLP). Those patients achieving normokalemia (sK+ 3.5-5.0 mmol/L inclusive) entered a 28-day randomized (2:2:1) treatment phase (RTP) and received SZC 5 g, SZC 10 g, or placebo once daily. The primary endpoint was mean sK+ during RTP Days 8 to 29. Secondary endpoints included mean change in sK+ during the OLP, the proportion of patients who achieved normokalemia at the end of the OLP, the proportion that maintained normokalemia during the RTP, and time to recurrence of hyperkalemia. FINDINGS: In total, 270 patients received SZC 10 g TID during the OLP; 256 (94.8%) completed the OLP. During the OLP, mean sK+ decreased by 1.1 mmol/L from baseline (5.9 mmol/L; P < 0.001) and 87.4% of patients achieved normokalemia. During the RTP, SZC 5 g and 10 g reduced mean sK+ versus placebo in a dose-dependent manner (each P < 0.001); least-squares means (95% confidence interval [CI]) sK+ were 4.9 mmol/L (4.7, 5.0), 4.4 mmol/L (4.3, 4.6), and 5.2 mmol/L (5.1, 5.4) for SZC 5 g, 10 g, and placebo, respectively. At RTP end, the proportions of patients who maintained normokalemia were 58.8% (SZC 5 g; odds ratio vs placebo, 2.5 [95% CI: 1.1, 6.1; P = 0.035]), 76.5% (SZC 10 g; odds ratio vs placebo, 6.3 [95% CI: 2.6, 15.3; P < 0.001]), and 36.8% for placebo. Risk of recurrent hyperkalemia was reduced by 61.0% and 84.0% with SZC 5 g and SZC 10 g, respectively, versus placebo (each P < 0.001). During the RTP, the incidence of adverse events was numerically higher with SZC 5 g (50.0% of patients) and 10 g (44.0%) versus placebo (36.0%); driven primarily by peripheral edema and constipation. IMPLICATIONS: Both SZC doses demonstrated clinically relevant and statistically significant, dose-dependent efficacy in managing sK+ levels in Chinese patients with hyperkalemia, compared with placebo. SZC tolerability was broadly aligned with the known safety profile of SZC.

Current hyperkalemia interventions co-administered with a dextrose 10% solution significantly lower hypoglycemic rates (CHICA-D10).

BACKGROUND: Current protocols which include the administration of a single dextrose dose concomitantly with insulin are inadequate as hypoglycemia commonly occurs 60 min after insulin administration and may persist for up to two hours post-insulin administration. To prevent delayed hypoglycemic events, our institution revised our adult acute hyperkalemia order set to include hypoglycemic preventative measures not currently described in the literature. METHODS: The primary purpose of this retrospective study was to determine if the new adult acute hyperkalemia order set resulted in lower rates of hypoglycemia (glucose <70 mg/dL) compared to the old order set in patients with impaired renal clearance and lower pre-insulin glucose values. In addition to reducing the IV regular insulin dose from 10 to 5 units, the new order set recommends patients receive a 250 mL dextrose 10% solution over two hours in addition to a 50 mL dextrose 50% IV push concomitantly with IV regular insulin if their pre-insulin glucose is ≤250 mg/dL. Patients were included if they were adults, received IV regular insulin from the order set within six hours of presenting to the ED, had a pre-insulin potassium >5.5 mmol/L, had a pre-insulin glucose ≤250 mg/dL, and had impaired renal clearance [creatinine clearance (CrCl) < 30 mL/min or dialysis dependent]. RESULTS: 100 patients were included in each arm. The median pre-insulin potassium levels were 6.4 mmol/L and 6.3 mmol/L in the old and new groups, respectively (p = 0.133). The median pre-insulin glucose levels were 120 mg/dL and 107.5 mg/dL in the old and new groups, respectively (p = 0.013). Twenty (20%) patients in the old group developed hypoglycemia, whereas six (6%) patients in the new group developed hypoglycemia (p = 0.003). There was no significant difference between the two groups in number of patients who achieved a post-insulin potassium level ≤ 5.5 mmol/L. CONCLUSION: Our study found that our approach of additionally administering a 250 mL dextrose 10% solution upon therapy initiation is associated with significantly lower rates of hypoglycemia. Our findings indicate that hypoglycemia rates can be significantly reduced in vulnerable populations if additional preventative measures are employed.

Balancing acute medical management of acute kidney injury and hyperkalaemia versus medicines optimisation for long-term Cardio-Renal-Metabolic (CaReMe) diseases: a narrative review.

Cardio-Renal-Metabolic (CaReMe) diseases, in the form of heart failure, chronic kidney disease and diabetes mellitus, justify prescription of multiple prognostically beneficial medications, specifically renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 inhibitors. Use of these medications is complicated by association with adverse effects, particularly acute kidney injury and hyperkalaemia. Balancing risk and benefit is a common dilemma in acute medicine, with increasingly frequent and complex treatment decisions. Physicians should contemplate adjustments to medications within the context of not just acute illness but also long-term benefit. In the setting of hyperkalaemia, potassium-binding medications can be utilised. At hospital discharge optimisation of therapy can be achieved through clear safety netting advice, scheduled biochemical follow-up, and planned clinical review.

Efficacy and safety analysis of sodium zirconium cyclosilicate and calcium polystyrene sulfonate on rapid reduction of potassium in moderate to severe hyperkalemia patients with chronic kidney disease without dialysis.

BACKGROUND: Hyperkalemia is a common complication of chronic kidney disease (CKD). This study aims to investigate the efficacy and safety of sodium zirconium cyclosilicate and calcium polystyrene sulfonate in reducing potassium in patients with acute and severe hyperkalemia in CKD who are not undergoing dialysis. MATERIALS AND METHODS: A retrospective real-world study was conducted among 73 patients with non-dialysis chronic kidney disease who were hospitalized in the First Affiliated Hospital of Chengdu Medical College from June 2020 to June 2022. 33 patients treated with sodium zirconium cyclosilicate were categorized as SZC group, and the other 40 patients treated with calcium polystyrene sulfonate were categorized as CPS group. Serum potassium, serum sodium, magnesium, calcium, and phosphorus levels were examined. Adverse reactions were recorded during medication. RESULTS: Significantly decreased serum potassium was observed in both groups, whereas the potassium reduction was higher in the SZC group than in the CPS group at 2, 4, 24, and 48 hours after medication while there was no statistically significant difference in the serum potassium level between the two groups at 72 hours. For those people whose initial potassium exceeded 6 mmol/L, the potassium reduction was more obvious in the SZC group than in the CPS group at 2 and 4 hours after medication. The control rate of hyperkalemia in the SZC group was significantly higher than in the CPS group at 4, 24, and 48 hours. No distinct change was observed in serum sodium, calcium, magnesium, and phosphorus before and 72 hours after medication. No severe adverse reactions occurred. CONCLUSION: Sodium zirconium cyclosilicate has a more obvious effect on reducing potassium particularly for those patients with moderate to severe hyperkalemia who need rapid potassium reduction.

Beneficial Effect of Calcium Treatment for Hyperkalemia Is Not Due to "Membrane Stabilization".

OBJECTIVES: Hyperkalemia is a common life-threatening condition causing severe electrophysiologic derangements and arrhythmias. The beneficial effects of calcium (Ca 2+ ) treatment for hyperkalemia have been attributed to "membrane stabilization," by restoration of resting membrane potential (RMP). However, the underlying mechanisms remain poorly understood. Our objective was to investigate the mechanisms underlying adverse electrophysiologic effects of hyperkalemia and the therapeutic effects of Ca 2+ treatment. DESIGN: Controlled experimental trial. SETTING: Laboratory investigation. SUBJECTS: Canine myocytes and tissue preparations. INTERVENTIONS AND MEASUREMENTS: Optical action potentials and volume averaged electrocardiograms were recorded from the transmural wall of ventricular wedge preparations ( n = 7) at baseline (4 mM potassium), hyperkalemia (8-12 mM), and hyperkalemia + Ca 2+ (3.6 mM). Isolated myocytes were studied during hyperkalemia (8 mM) and after Ca 2+ treatment (6 mM) to determine cellular RMP. MAIN RESULTS: Hyperkalemia markedly slowed conduction velocity (CV, by 67% ± 7%; p < 0.001) and homogeneously shortened action potential duration (APD, by 20% ± 10%; p < 0.002). In all preparations, this resulted in QRS widening and the "sine wave" pattern observed in severe hyperkalemia. Ca 2+ treatment restored CV (increase by 44% ± 18%; p < 0.02), resulting in narrowing of the QRS and normalization of the electrocardiogram, but did not restore APD. RMP was significantly elevated by hyperkalemia; however, it was not restored with Ca 2+ treatment suggesting a mechanism unrelated to "membrane stabilization." In addition, the effect of Ca 2+ was attenuated during L-type Ca 2+ channel blockade, suggesting a mechanism related to Ca 2+ -dependent (rather than normally sodium-dependent) conduction. CONCLUSIONS: These data suggest that Ca 2+ treatment for hyperkalemia restores conduction through Ca 2+ -dependent propagation, rather than restoration of membrane potential or "membrane stabilization." Our findings provide a mechanistic rationale for Ca 2+ treatment when hyperkalemia produces abnormalities of conduction (i.e., QRS prolongation).

Cost analysis of patiromer vs sodium zirconium cyclosilicate for the treatment of hyperkalemia in Spain and the UK.

BACKGROUND: Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Published data have shown that potassium-binding polymer patiromer (Veltassa) is associated with reduced rates of severe edema and hospitalization for heart failure compared with sodium zirconium cyclosilicate (SZC, Lokelma) when treating hyperkalemia. The aim of this study was to evaluate the possible costs associated with these interventions in the Spanish and UK settings. METHODS: A cost-analysis model was developed in Microsoft Excel to compare the costs associated with patiromer and SZC for the management of hyperkalemia. Clinical event rates were taken from a published real-world comparative study, with the base case capturing the statistically significant reduction in severe edema with patiromer vs SZC and a sensitivity analysis also including the non-statistically significant reduction in hospitalization for heart failure. Country-specific costs, expressed in 2022 Euros (EUR) and British pounds sterling (GBP), were evaluated from a healthcare payer perspective and included pharmacy costs and costs of clinical events. RESULTS: Patiromer may be associated with cost savings of EUR 107 and GBP 630 per patient-year of treatment vs SZC in Spain and the UK, respectively. The majority of cost savings were due to the possible lower daily cost of patiromer compared with SZC. Including the difference in heart failure hospitalization rates in a sensitivity analysis led to greater cost savings with patiromer over SZC, increasing to EUR 460 and GBP 902 in Spain and the UK, respectively. Extrapolation of patient-level economic outcomes to a population level found that patiromer was associated with annual cost savings of EUR 30.6 million in Spain, and GBP 801.7 million in the UK vs SZC. CONCLUSIONS: Patiromer has the potential to be cost saving vs SZC for the treatment of hyperkalemia in Spain and the UK based on the results of a real-world evidence analysis.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure.

Objective Variations are present in common clinical practices regarding best practice in managing hyperkalaemia (HK), there is therefore a need to establish a multi-specialty approach to optimal renin-angiotension-aldosterone system inhibitors (RAASi) usage and HK management in patients with chronic kidney disease (CKD) & heart failure (HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and the management of HK in patients with CKD and HF. Methods A steering expert group of cardiology and nephrology experts across China were convened to discuss challenges to HK management through a nominal group technique. The group then created a list of 41 statements for a consensus questionnaire, which was distributed for a further survey in extended panel group of cardiologists and nephrologists across China. Consensus was assessed using a modified Delphi technique, with agreement defined as "strong" (≥75% and <90%) and "very strong" (≥90%). The steering group, data collection, and analysis were aided by an independent facilitator. Results A total of 150 responses from 21 provinces across China were recruited in the survey. Respondents were comprised of an even split (n=75, 50%) between cardiologists and nephrologists. All 41 statements achieved the 75% consensus agreement threshold, of which 27 statements attained very strong consensus (≥90% agreement) and 14 attained strong consensus (agreement between 75% and 90%). Conclusion Based on the agreement levels from respondents, the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. OBJECTIVES: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). METHODS: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). RESULTS: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. CONCLUSIONS: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646).

Reducing the harm associated in treating hyperkalaemia with insulin and dextrose.

Inpatient treatment of hyperkalaemia with insulin and dextrose can be complicated by iatrogenic hypoglycaemia. We sought to assess the incidence of hypoglycaemia in hospitalised patients with renal disease and assess the impact of the introduction of a local guideline incorporating the use of sodium zirconium cyclosilicate (SZC) for patients with moderate hyperkalaemia. After establishing a significant burden of hypoglycaemia in the initial observation period, a requirement for hourly capillary blood glucose monitoring (for up to 6 h) following the administration of insulin for hyperkalaemia was incorporated into the guidelines. The two-fold introduction of SZC alongside changes in patient care after the administration of insulin/dextrose resulted in more appropriate use of insulin/dextrose, as well as a significant (73%) reduction in the iatrogenic burden of hypoglycaemia (P = 0.04).

Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

INTRODUCTION: Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. OBJECTIVE: The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. METHOD: In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. RESULTS: Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. CONCLUSION: Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

Evaluation of Insulin Dosing Strategies for Hyperkalemia Management at an Academic Medical Center.

PURPOSE: While intravenous (IV) insulin is often administered at a fixed dose of 10 units for acute hyperkalemia, optimal dosing for minimizing hypoglycemia while effectively reversing hyperkalemia has not been established. The purpose of this analysis was to evaluate the effect of insulin dosing strategies on hypoglycemia in patients with hyperkalemia. METHODS: Adult patients presenting to an academic medical center who received IV insulin for hyperkalemia between 2016 and 2020 were retrospectively identified. Patients treated with 10 units of insulin (fixed) were compared to those who received < 10 units (reduced). The primary outcome was the incidence of hypoglycemia (blood glucose < 70 mg/dL) within 12 hours of insulin administration. Secondary outcomes included the incidence of severe hypoglycemia (blood glucose < 40 mg/dL) and change in potassium. Multivariable analyses were used to assess for risk factors for hypoglycemia and severe hypoglycemia. FINDINGS: Of the 2576 patients included, 305 (11.8%) received reduced dosing and 2271 (88.2%) received fixed dosing. Hypoglycemia occurred in 16.7% of the reduced group and 15.9% of the fixed group (P = 0.70). Severe hypoglycemia occurred in 2.3% of the reduced group and 2.5% of the fixed group (P = 0.86). Median potassium reduction from baseline to first check post-insulin was less with reduced dosing (-0.6 mEq/L vs -0.8 mEq/L, P < 0.001). On multivariable regression analysis, greater weight-based insulin dose and ED location were significant predictors for hypoglycemia and severe hypoglycemia. Location in the intensive care unit was associated with a decreased risk of hypoglycemia. Higher pre-insulin glucose was protective for hypoglycemia and severe hypoglycemia. IMPLICATIONS: The incidence of hypoglycemia was similar among both groups. Greater weight-based insulin dose was a significant risk factor for hypoglycemia, while higher baseline glucose levels were associated with a decreased risk, indicating that patient-specific insulin dosing for hyperkalemia may be warranted.

Myelotoxicity and kidney dysfunction related to the use of trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia: a case report of severe adverse events with a common drug.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are common side effects, with hyperkalemia being uncommon in patients without kidney dysfunction, and myelotoxicity being even rarer. We present the case of a male patient with hypertension and a recent diagnosis of non-Hodgkin lymphoma, undergoing rituximab treatment for two months. He was admitted to the intensive care unit due to dyspnea, tachypnea, and pleuritic pain, requiring mechanical ventilation. Chest computed tomography showed bilateral and multilobed ground-glass opacities, compromising more than 80% of the lung parenchyma. Pulmonary tuberculosis and COVID-19 were ruled out. An angiotomography and Doppler ultrasound revealed an extensive pulmonary thrombus and deep venous thrombosis. Empiric treatment with TMP-SMX for PCP was initiated, but within four days, the patient experienced metabolic acidosis and severe hyperkalemia, necessitating hemodialysis. He also presented with progressive pancytopenia and critical levels of leukopenia and thrombocytopenia. The hypothesis of TMP-SMX-induced myelotoxicity was suspected. Considering the unavailability of an alternative treatment, it was opted to continue TMP-SMX and initiate a granulocyte-colony-stimulating factor. However, the patient maintained medullary deterioration, becoming refractory to the transfusion of blood derivates. On the 17th day of treatment, a clinical decision was made to suspend TMP-SMX, leading to improvements within 48 hours in marrow and kidney functions, metabolic acidosis, and hyperkalemia. Despite all efforts, the patient died after 35 days of hospitalization due to hospital-acquired infections. This case highlights the importance of clinicians recognizing potential myelotoxicity with TMP-SMX and promptly discontinuing the drug if necessary.

Impact of a Hyperkalemia Protocol Tailored to Glucose Concentration and Renal Function on Insulin-Induced Hypoglycemia in Patients with Low Pretreatment Glucose.

BACKGROUND: Hyperkalemia is a common electrolyte abnormality that requires urgent treatment. Insulin is an effective treatment for hyperkalemia, but risk factors for developing insulin-induced hypoglycemia exist (e.g., low pretreatment glucose or renal impairment). OBJECTIVE: This study evaluated the impact of a hyperkalemia protocol tailored to glucose concentration and renal function on insulin-induced hypoglycemia. METHODS: This was a retrospective cohort study of emergency department patients with glucose ≤ 100 mg/dL treated with insulin for hyperkalemia. The primary outcome was incidence of hypoglycemia in patients treated prior to (July 1, 2018-June 30, 2019) vs. after (January 1, 2020-December 31, 2020) the protocol update, which individualized insulin and dextrose doses by glucose concentration and renal function. Secondary outcomes included change in potassium and protocol safety. We assessed factors associated with hypoglycemia using multiple logistic regression. RESULTS: We included 202 total patients (preimplementation: 114, postimplementation: 88). Initial insulin dose was lower in the postimplementation group (p < 0.001). We found a nonsignificant reduction in hypoglycemia in the postimplementation group (42.1% vs. 30.7%, p = 0.10). Degree of potassium reduction was similar in patients who received insulin 5 units vs. 10 units (p = 0.72). Higher pretreatment glucose (log odds ratio [OR] -0.05, 95% confidence interval [CI] -0.08 to -0.02) and additional insulin administration (log OR -1.55, 95% CI -3.01 to -0.25) were associated with reduced risk of developing hypoglycemia. CONCLUSION: A hyperkalemia protocol update was not associated with a significant reduction in hypoglycemia, and the incidence of hypoglycemia remained higher than anticipated. Future studies attempting to optimize treatment in this high-risk population are warranted.

Managing hyperkalemia in patients with heart failure on guideline-directed medical therapy: challenges and opportunities.

Heart failure is a chronic and invalidating syndrome that affects tens of millions of people worldwide with significant socio-economic ramifications for the health care systems. Significant progress in the understanding of the pathophysiology of heart failure has allowed the gradual introduction of several drug classes for the management of such patients. Beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor neprilysin inhibitors, and sodium-glucose-cotransporter 2 inhibitors are all considered pillars of the guideline-directed medical therapy for heart failure. Despite remarkable improvements in the morbidity and mortality of heart failure, however, many patients still develop clinically significant hyperkalemia during combined treatment with those four pharmacological pillars. The consequence is often a down-titration or discontinuation of one or more crucial drugs, which in turns leads to a considerable increase in the risk of cardiovascular events, dialysis, and all-cause mortality. This paper will explore novel approaches for the management of hyperkalemia in heart failure, including closer monitoring of potassium levels, early review of drugs that might increase the risk of hyperkalemia, and pharmacological treatment of hyperkalemia, with a special emphasis on sodium-glucose-cotransporter 2 inhibitors and potassium-binding agents, including patiromer and sodium zirconium cyclosilicate.

Cost-effectiveness of sodium zirconium cyclosilicate for advanced chronic kidney patients in Singapore.

INTRODUCTION: Hyperkalaemia (HK) is prevalent among patients with chronic kidney disease (CKD) and chronic heart failure, especially if they are treated with renin-angiotensin-aldosterone system inhibitors (RAASi). This study evaluated the cost-effectiveness of a newly developed anti-HK therapy, sodium zirconium cyclosilicate (SZC), to the current standard of care for treating HK in advanced CKD patients from the Singapore health system perspective. METHODS: We adapted a global microsimulation model to simulate individual patients' potassium level trajectories with baseline potassium ≥5.5 mmol/L, CKD progression, changes in treatment, and other fatal and non-fatal events. Effectiveness data was derived from ZS-004 and ZS-005 trials. Model parameters were localised using CKD patients' administrative and medical records at the Singapore General Hospital Department of Renal Medicine. We estimated the lifetime cost and quality-adjusted life years (QALYs) of each HK treatment, and the incremental cost-effectiveness ratio of SZC. RESULTS: SZC demonstrated cost-effectiveness with an incremental cost-effectiveness ratsio of SGD 45 068 per QALY over a lifetime horizon, below the willingness-to-pay threshold of SGD 90 000 per QALY. Notably, SZC proved most cost-effective for patients with less severe CKD who were concurrently using RAASi. Sensitivity analyses confirmed the robustness of the findings, accounting for alternative parameter values and statistical uncertainty. CONCLUSION: This study establishes the cost-effectiveness of SZC as a treatment for HK, highlighting its potential to mitigate the risk of hyperkalaemia and optimise RAASi therapy. These findings emphasise the value of integrating SZC into the Singapore health system for improved patient outcomes and resource allocation.

Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing with Sodium Zirconium Cyclosilicate.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) is an approved oral treatment for hyperkalemia that selectively binds potassium (K+) in the gastrointestinal tract and removes K+ from the body through increased fecal excretion. Here, we describe the population pharmacodynamic (PopPD) response of serum K+ concentration in patients with hyperkalemia who are treated with SZC, estimate the impact of patients' intrinsic and extrinsic factors, and compare predicted serum K+ responses between 5 g alternate daily (QOD) and 2.5 g once daily (QD) maintenance doses. METHODS: PopPD analysis was based on pooled data from seven phase II and III clinical trials for SZC. A semi-mechanistic longitudinal mixed-effects (base) model was used to characterize serum K+ concentration after SZC dosing. Indirect-response, virtual pharmacokinetics-pharmacodynamics (PK-PD) modeling was used to mimic the drug exposure compartment. Full covariate modeling was used to assess covariate impact on the half-maximal effective concentration of drug (EC50), placebo response, and Kout. Models were evaluated using goodness-of-fit plots, relative standard errors, and visual predictive checks, and data were stratified to optimize model performance across subgroups. Covariate effects were evaluated based on the magnitude of change in serum K+ between baseline and end of correction phase dosing (48 h, SZC 10 g three times a day) and maintenance phase dosing (28 days, SZC 10 g QD) using a reference subject. RESULTS: The analysis data set included 2369 patients and 25,764 serum K+ observations. The mean (standard deviation) patient age was 66.0 (12) years, 61% were male, 68% were White, 34% had congestive heart failure, and 62% had diabetes. Mean (standard deviation) serum K+ at baseline was 5.49 (0.43) mmol/L. Both the base and full covariance models adequately described observed data. In the final model, there was a sigmoid exposure response on Kin, with EC50 of 32.8 g and a Hill coefficient of 1.36. The predicted placebo-adjusted dose-responses of serum K+ change appeared nearly linear in the correction and maintenance phases. No clinically meaningful difference in placebo-adjusted serum K+ change from baseline at 28 days was observed between maintenance regimens of SZC 5 g QOD and 2.5 g QD. A greater SZC treatment response was associated with high serum K+ at baseline, advanced age, lower body weight, lower estimated glomerular filtration rate, and Black/African American and Asian race, compared with the reference patient. The impact of heart failure status and diabetes status was only minor. CONCLUSIONS: The PopPD model of SZC adequately described changes in serum K+ concentration during correction and maintenance phase dosing. A greater treatment response was associated with various covariates, but the impact of each was modest. Overall, these findings suggest that no adjustment in SZC dose is needed for any of the covariates evaluated.