Sodium zirconium cyclosilicate for the management of chronic hyperkalemia in kidney disease, a novel agent.

INTRODUCTION: Hyperkalemia is a common finding in patients with advanced kidney disease for multiple reasons. Renin-Angiotensin-Aldosterone-System Inhibitors (RAASi) that are indicated for slowing down progression of kidney disease are often associated with hyperkalemia which becomes a limiting factor in their use and titration to the maximum dose. Having a safe, effective, tolerable, and affordable potassium binder can help optimize RAAS inhibition in the setting of kidney disease. AREAS COVERED: Although sodium polystyrene sulfonate has been a mainstay of acute management of hyperkalemia for decades, evidence regarding its efficacy is limited, and its chronic use is not routinely recommended for concerns regarding toxicity. The concern of gastrointestinal (GI) adverse effects with sodium polystyrene sulfonate has spurred the development of alternatives. Sodium zirconium cyclosilicate (SZC) is a promising agent that selectively binds potassium in the gut and eliminates it, while being safe for chronic use based on 1 year of data. Even though we do not have head-to-head studies among the three currently available binders, SZC stands out in rapidity of onset and efficacy. EXPERT OPINION: In this review, we summarize the general management of hyperkalemia, including new agents. We review the pre-clinical and clinical data relating to sodium zirconium cyclosilicate.

Effects and Safety of a Novel Oral Potassium-Lowering Drug-Sodium Zirconium Cyclosilicate for the Treatment of Hyperkalemia: a Systematic Review and Meta-Analysis.

BACKGROUND: Oral sodium zirconium cyclosilicate (SZC) is a novel potassium binder capable of achieving a rapid reduction of serum potassium (sK+) and maintaining a long-term normokalemia. We undertook a meta-analysis to summarize and evaluate the effects surrounding SZC in patients with hyperkalemia. METHOD: We searched data sources from MEDLINE (from 1950 to Sep 2020), EMBASE (from 1970 to Sep 2020), and the Cochrane Library database (from 1950 to Sep 2020) for eligible studies. All randomized controlled trials (RCTs) regarding comparison of therapeutic effects of SZC in hyperkalemia participants were included. RESULTS: Seven studies, including 1697 patients with hyperkalemia, were analyzed. SZC significantly reduced mean sK+ (-0.42 mmol/L; 95% CI: -0.63 to -0.20 mmol/L, p = 0.0001) compared with placebo, with a significantly greater proportion of patients with normokalemia (RR 3.48, 95% CI 1.49 to 8.11, p = 0.004). Subgroup analyses showed that the longer durations of SZC treatment, the greater magnitudes of potassium reduction when compared with those of placebo (p between subgroups = 0.01) at correction phase. Besides, it also demonstrated sK+ tended to decrease more in patients who got longer treatment or larger dosage of SZC at maintenance phase; however, the difference did not reach statistical significance. Additionally, the drug was equally effective in studies with larger than 50% of patients with chronic kidney disease (CKD) or diabetes or patients using renin-angiotensin aldosterone system inhibitor (RAAS) inhibitors (all p < 0.05). The risk of edema (4.30, 1.17 to 15.84; p = 0.03) in SZC group was higher than those of placebo group. No statistically significant differences in the risks of other adverse events were observed between the two groups. CONCLUSIONS: SZC effectively decreased the sK+ level in patients with hyperkalemia within 48 h and had benefits in the long-term control of serum potassium in patients who continued to receive SZC with a favorable safety profile from available data.

Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥ 5.5 mmol/L: pooled analysis from two phase 3 trials.

BACKGROUND: Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤ 48 h in patients with baseline serum potassium level ≥ 5.5 mmol/L. METHODS: Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤ 5.5 and ≤ 5.0 mmol/L, and proportion achieving potassium level ≤ 5.5 and ≤ 5.0 mmol/L at 4, 24, and 48 h. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. RESULTS: At baseline, 125 of 170 patients (73.5%) had potassium level 5.5-< 6.0, 39 (22.9%) had potassium level 6.0-6.5, and 6 (3.5%) had potassium level > 6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1 h post-initial dose. By 4 and 48 h, 37.5% and 85.0% of patients achieved potassium level ≤ 5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤ 5.5 and ≤ 5.0 mmol/L were 2.0 (1.1-2.0) and 21.6 (4.1-22.4) h, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. CONCLUSIONS: SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: ZS-003: NCT01737697 and HARMONIZE: NCT02088073.

Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE.

BACKGROUND: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the -HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. METHODS: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5-6.2 mmol/L received once-daily SZC 5-10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). RESULTS: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5-15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. CONCLUSION: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia.

BACKGROUND: Patients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients. METHODS: In the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0-5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium. RESULTS: In total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia. CONCLUSIONS: Sodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.

Colesevelam and colestipol: novel medication resins in the gastrointestinal tract.

We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (H&E) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on H&E and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on H&E and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.

[Hiperkalemia]. / Hiperpotasemia.

Hyperkalemia is a common and potentially lethal clinical problem. It may be caused by several drugs, especially those which target the renin-angiotensin--aldosterone system, inability of kidney to excrete potassium, a shift of these ions into the extracellular fluid, or a combination of those mechanisms. It can be also spurious, caused by hemolysis after blood drawing. In the article the conditions associated with hyperkalemia, its diagnosis and the management are reviewed.

Hipercalcemia como efecto secundario de los quelantes de potasio / Hypercalcaemia as a side effect of potassium binding agents

La hipercalcemia es un efecto adverso potencial de las resinas cálcicas de intercambio iónico, de uso frecuente en el tratamiento y la prevención de la hiperpotasemia en la enfermedad renal crónica (ERC). Describimos una serie de siete pacientes con ERC moderada de la consulta de Nefrología Clínica (filtrado glomerular medio estimado por CKD-EPI: 41,29 ± 10,83 ml/min/1,73 m2), que presentan hipercalcemia leve en relación con el tratamiento con poliestireno sulfonato cálcico. El calcio sérico se elevó de media 0,91 ± 0,46 mg/dl, con un descenso paralelo de los niveles de hormona paratiroidea intacta (iPTH) de 49,29 ± 52,24 ng/dl de media. Tras la retirada o la reducción de la dosis, se objetivó una recuperación de las cifras de calcio e iPTH séricos. Los quelantes cálcicos de potasio se deben incluir en el diagnóstico diferencial de la hipercalcemia en pacientes con ERC no avanzada (AU)

Hypercalcaemia is a potential adverse effect of calcium-containing ion exchange resins, often used in the treatment and prevention of hyperkalaemia in chronic kidney disease (CKD). We describe a series of seven outpatients with moderate CKD (mean glomerular filtration rate estimated with the CKD-EPI formula: 41.29±10.83mL/min/1.73m2), presenting mild hypercalcaemia in relation to the treatment with calcium polystyrene sulfonate. Serum calcium increased a mean of 0.91±0.46mg/dL, with a mean concomitant decrease of serum intact parathormone (iPTH) of 52.24±49.29ng/dL. After treatment withdrawal or dose reduction, we observed a recovery of serum calcium and iPTH values. Treatment with calcium-based potassium binders should be included in the differential diagnosis of hypercalcaemia in patients with moderate CKD (AU)

Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective?

Sodium polystyrene sulfonate (SPS), an ion-exchange resin designed to bind potassium in the colon, was approved in 1958 as a treatment for hyperkalemia by the US Food and Drug Administration, 4 years before drug manufacturers were required to prove the effectiveness and safety of their drugs. In September 2009, citing reports of colonic necrosis, the Food and Drug Administration issued a warning advising against concomitant administration of sorbitol, an osmotic cathartic used to prevent SPS-induced fecal impaction and to speed delivery of resin to the colon, with the powdered resin; however, a premixed suspension of SPS in sorbitol, the only preparation stocked by many hospital pharmacies, is prescribed routinely for treatment of hyperkalemia. We can find no convincing evidence that SPS increases fecal potassium losses in experimental animals or humans and no evidence that adding sorbitol to the resin increases its effectiveness as a treatment for hyperkalemia. There is growing concern, however, that suspensions of SPS in sorbitol can be harmful. It would be wise to exhaust other alternatives for managing hyperkalemia before turning to these largely unproven and potentially harmful therapies.

Comparison of sevelamer hydrochloride and sevelamer carbonate: risk of metabolic acidosis and clinical implications.

Hyperphosphatemia is highly prevalent in patients with chronic kidney disease (CKD), particularly in those with advanced or end-stage renal disease. Sevelamer hydrochloride is an ion-exchange resin that reduces serum phosphorus concentrations. The agent also produces favorable lipid profile effects and does not cause hypercalcemia. However, reported drawbacks of this agent are metabolic acidosis, high pill burden, and a relatively low affinity and selectivity for phosphate anions. Sevelamer carbonate is a new buffered formulation that does not increase the risk of metabolic acidosis. To determine the roles of these two agents in the treatment of hyperphosphatemia in patients with CKD, we performed a MEDLINE search (June 1995-June 2008) focusing on the mechanism of action of resin binding with phosphate and the development of metabolic acidosis. We also reviewed studies that evaluated the effects of sevelamer hydrochloride or sevelamer carbonate on serum bicarbonate concentrations. Several studies in patients with CKD and hyperphosphatemia who received hemodialysis or peritoneal dialysis found decreases in serum bicarbonate concentrations with the use of sevelamer hydrochloride, whereas sevelamer carbonate did not have this negative effect on bicarbonate concentrations. Both drugs appear to be equivalent in their abilities to lower serum phosphorus concentrations. However, as sevelamer carbonate does not decrease serum bicarbonate levels, it may be more appropriate for patients at risk for metabolic acidosis who require phosphate binders that do not contain calcium or aluminum.

[Evolution in vitamin D treatment after debut of sevelamer hydrochloride in chronic renal failure patients].

Newly developed sevelamer hydrochlorid (Sev-HCl) has been recognized to show the effective control of the hyperphosphatemia in chronic renal failure patients, without elevation of serum Ca, Mg, and Al as well. Then, Sev-HCl has been expected to evolute the vitamin D treatment, and to reduce the ectopic calcifications through lowering Ca x P products. Although, relatively high frequent abdominal adverse effects in Sev-HCl treatment were reported, including life-threatening bowel occlusions or bowel perforations. It is important to use the appropriate dose of Sev-HCl avoiding the abdominal adverse effects.

Role of colestipol in the treatment of hyperthyroidism.

The enterohepatic circulation of thyroxine (T4) and triiodothyronine (T3) is higher in thyrotoxicosis. Bile-salt sequestrants bind iodothyronines and thereby increase their fecal excretion. We, therefore, evaluated the effect of colestipol-hydrochloride administration on clinical and biochemical indices of patients with hyperthyroidism. In a prospective, controlled trial, ninety-two adult volunteers with Graves' disease, toxic autonomous nodule or toxic multinodular goiter were randomly assigned into the following treatment protocols: Group 1, 30 mg of methimazole (MMI) and 20 g of colestipol-hydrochloride (COL) daily; Group 2, 30 mg of MMI daily; and Group 3, 15 mg of MMI 20 g of COL daily. The patients were further classified into Group A, severe hyperthyroidism (baseline levels of total T3 (TT3) > or =5 nmol/l) and Group B, mild to moderate thyrotoxicosis (baseline levels of TT-3<5 nmol/l). Crook's clinical index, serum free T4 (FT4), TT3 and thyroid stimulating hormone (TSH) levels were determined before (WO), following one week (W1) and two weeks (W2) of treatment. Serum TT3 level decreased (mean+/-SE) at W1 by 40.8+/-2.6% of WO in Group1 and by 29.2+/-2.4% in Group 2 (p<0.001), and down further to 47.8+/-3.0% at W2 in Group 1, and 40.6+/-2.8% in Group 2 (p=0.01). Serum FT4 level decreased (mean+/-SE) from WO to W1 by 31.7+/-2.7% in Group 1 and by 16.2+/-3.1% in Group 2 (p=0.005), and down to 49.1+/-2.8% of WO at W2 in Group 1 and to 38.7+/-3.5% in Group 2 (p=0.07). In sub groups B COL was not effective in reducing thyroid hormone levels nor in ameliorating the clinical status of the patients. However, in Group A3 COL lowered FT4 (p=0.001) and TT3 (p=0.05) levels as compared to group A2. At W2 the clinical hyperthyroidism score improved faster in Group A1 (p<0.001) and Group A3 (p=0.012) as compared to the control Group A2. In conclusion, COL is an effective and well tolerated adjunctive agent in the treatment of hyperthyroidism. Its main effect is in severe cases of thyrotoxicosis, and in the first phase of treatment. As adjunctive COL treatment in hyperthyroidism allows reducing MMI dosage it may decrease the rate of dose dependent MMI side effects.

Mixture risk assessment: a case study of Monsanto experiences.

Monsanto employs several pragmatic approaches for evaluating the toxicity of mixtures. These approaches are similar to those recommended by many national and international agencies. When conducting hazard and risk assessments, priority is always given to using data collected directly on the mixture of concern. To provide an example of the first tier of evaluation, actual data on acute respiratory irritation studies on mixtures were evaluated to determine whether the principle of additivity was applicable to the mixture evaluated. If actual data on the mixture are unavailable, extrapolation across similar mixtures is considered. Because many formulations are quite similar in composition, the toxicity data from one mixture can be extended to a closely related mixture in a scientifically justifiable manner. An example of a family of products where such extrapolations have been made is presented to exemplify this second approach. Lastly, if data on similar mixtures are unavailable, data on component fractions are used to predict the toxicity of the mixture. In this third approach, process knowledge and scientific judgement are used to determine how the known toxicological properties of the individual fractions affect toxicity of the mixture. Three examples of plant effluents where toxicological data on fractions were used to predict the toxicity of the mixture are discussed. The results of the analysis are used to discuss the predictive value of each of the above mentioned toxicological approaches for evaluating chemical mixtures.