Potassium responses to sodium zirconium cyclosilicate in hyperkalemic hemodialysis patients: post-hoc analysis of DIALIZE.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) is an effective and well-tolerated treatment for hyperkalemia in maintenance hemodialysis patients. In post-hoc analyses of the phase 3b DIALIZE study, we examined the spectrum of potassium responses to SZC. METHODS: Post-hoc analyses with SZC and placebo included: the number of long interdialytic interval (LIDI) visits during the 4-week evaluation period where patients attained pre-dialysis serum potassium (sK+) concentrations of 4.0-5.0 and 4.0-5.5 mmol/L; potassium gradient (the difference between pre-dialysis sK+ and dialysate potassium) at days 36, 43, 50, and 57, and change from baseline to the end of treatment (EOT) using categories of potassium gradient (1 to < 2, 2 to < 3, 3 to < 4, and ≥ 4 mmol/L). RESULTS: A greater proportion of patients achieved the ranges of pre-dialysis sK+ concentration with SZC versus placebo for ≥1, ≥ 2, ≥ 3, and 4 LIDI visits over 4 weeks; 23.7 and 48.5% of patients in the SZC group achieved pre-dialysis sK+ concentrations of 4.0-5.0 and 4.0-5.5 mmol/L, respectively, at all 4 LIDI visits. Baseline mean potassium gradient was similar with SZC and placebo. At day 57, mean (standard deviation) potassium gradient was 2.78 (0.08) mmol/L with SZC and 3.52 (0.08) mmol/L with placebo; mean difference (95% confidence interval) was - 0.74 mmol/L (- 0.97 to - 0.52). A greater reduction in potassium gradient category from baseline towards lower-risk categories at EOT was observed with SZC versus placebo. CONCLUSIONS: These analyses expand our knowledge of the spectrum of potassium responses with SZC in hyperkalemic hemodialysis patients. TRIAL REGISTRATION: NCT03303521 .

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.

The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure.

BACKGROUND: CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. METHODS: We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants' RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George's Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. DISCUSSION: This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. TRIAL REGISTRATION: EudraCT number 2020-002946-18. Registered on 08 June 2020. Online record pending.

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.

Advances in the management of hyperkalemia in chronic kidney disease.

PURPOSE OF REVIEW: Patients with chronic kidney disease (CKD) have an increased risk of hyperkalemia that increases both short-term and long-term mortality. Historically, managing hyperkalemia has relied upon dietary modifications, augmentation of urinary potassium excretion and enhanced enteral potassium elimination. This review discusses current treatments and their limitations and summarizes the evidence supporting novel agents for potassium lowering in patients with CKD. RECENT FINDINGS: The introduction of two novel ion exchange resins represents the first new pharmacologic therapies for hyperkalemia in the last 50 years. Patiromer, which was recently approved for use in the United States, has been shown to be well tolerated and effective for decreasing serum potassium in patients with CKD when taken for up to a year. Sodium zirconium cyclosilicate for which approval is pending has also shown promise in treating both acute and chronic hyperkalemia in patients with CKD. Both medications have been well tolerated with minimal adverse events in relatively short-term follow-up. SUMMARY: Novel ion exchange resins have the potential to provide new strategies for safely and effectively managing hyperkalemia in the CKD population. This may decrease morbidity and mortality associated with hyperkalemia and allow more broad use of medications whose use is otherwise limited by hyperkalemia.

[Assessment of the population at risk of hyperkalemia]. / Évaluation de la population à risque d'hyperkaliémie.

Potassium is involved in the voltage and excitability of the myocytes. Its homeostasis is dependent on dietary intake and its predominant renal elimination. The renin-angiotensin-aldosterone system regulates its elimination. Acute and chronic hyperkalemia is a risk factor for cardiac mortality. Chronic renal failure and heart failure are the major comorbidities. RAAS inhibitor therapies are the major iatrogenic factors in hyperkalemia. Approximately 90% of patients with hyperkalemia are over 50 years of age and 43% are over 75 years of age. Only 4.9% of hyperkalemias are managed with resin therapy. One-third of patients have 3 comorbidities, and 14% have 5 or more comorbidities. The main comorbidities are hypertension (74.0%), dyslipidemia (56.3%), renal failure (55.2%), diabetes (44.7%), coronary artery disease such as angina and myocardial infarction (23.3%) and heart failure (12%). It should be noted that 2/3 of the patients receiving resins were also receiving ARBSIs and tended to have more co-morbidities. Hyperkalemia is underestimated and requires strict monitoring in patients with renal failure or heart failure. Resins are not suitable for long-term adherence and new therapies such as patiromer would reduce the risk of hyperkalemia.

Reduction of dioxins and polychlorinated biphenyls (PCBs) in human body.

The accumulation of persistent lipophilic organic pollutants like dioxins and PCBs in human body is of great concern since many of these compounds may elicit adverse health effects on humans. To reduce dioxins and PCBs with long half-lives that are absorbed into the human body, we need to work actively to minimize accumulation of dioxins and PCBs taken. Lot of manner has been tested such as foods containing dietary fibers and chlorophyll, lipids (squalane etc) and anion exchange resins. Cholestyramine, a cholesterol lowering agent, was no efficacy in humans. Authors have conducted a pilot study to demonstrate the effect lowering dioxin in human bodies using colestimide. Nine patients on cdestimide for 6 months, showed mean 20% decrease respectively in both dioxin and PCB levels, and the maximum percentage decrease was approximately 40%. From a standpoint to avoid the influence on high-risk group and high-risk life stage other than next generation, the world-wide cooperation for reducing environmental chemicals is greatly appealed.

Controlled trial of nicotine polacrilex gum with supportive measures.

In a placebo-controlled, double-blind, 2-year prospective study, 182 smokers were given either nicotine polacrilex gum containing 4 mg of nicotine (n = 92) or a placebo (n = 90). The number of participants abstinent at 2-year follow-up was 41 (44.6%) of 92 in the nicotine group vs 28 (31.1%) of 90 in the placebo group. Abstinence rates for daily nicotine gum users (n = 64) at 12 months and again at 24 months remained 48.4%, as compared with 26.1% and 31.9% for the daily placebo gum users (n = 69). Of participants with a high nicotine-dependence score, those allotted to the nicotine group rather than to the placebo group were 13 times more likely to be abstaining at the 2-year follow-up. Use of nicotine polacrilex gum, therefore, can substantially aid in stopping smoking, particularly among highly dependent smokers.

The bile acid binding and hypocholesterolemic action of two water-soluble polymers.

The in vitro bile acid binding properties of 2 water-soluble, linear, cationic resins, poly-[(dimethylimino)trimethylene chloride] or 3,3-ione C1, and poly-diallyldimethylammonium chloride) or CAT-FLOC were determined. Both polymers were substantially more active than cholestyramine. All were compared for hypocholesterolemic effect in normo-cholesterolemic dogs. CAT-FLOC and 3,3-ionene C1, administered at 1.8 and 1.2 g/day, respectively, exhibited cholesterol-lowering action equivalent to cholesteryramine given at 12 g/day. The results of this study suggest that effective reduction of plasma cholesterol may be achieved with significantly lower doses of bile acid sequestrants.

Treatment of hypercholesterolemia with Secholex. A long-term clinical trial and comparison with cholestyramine.

The efficacy of an anion-exchange gel, Secholex, as a hypocholesterolemic agent was assessed in 46 patients in 4 different studies and the effects were compared with those of cholestyramine. All patients had severe Type II-a or II-b hyperlipoproteinemia. In short-term metabolic studies Secholex (15 g/day) and cholestyramine (16 g/day) decreased serum cholesterol levels and increased total fecal sterol output and serum methyl sterol concentration to a similar extent, but cholestyramine was more effective than Secholex in increasing fecal bile acid excretion. In crossover studies, the two drugs appeared to be equally effective in lowing serum cholesterol levels but the patients mostly preferred Secholex. Twenty patients were treated with Secholex over a two-year period. The average decrease in serum cholesterol levels from the mean pretreatment value of 406 mg/100 ml was 15% during the first year, and 13% during the second year. In 5 patients the serum cholesterol was permanently lowered by more than 20% (good responders), while in 7 patients the average reduction of serum cholesterol level during Secholex administration was less than 10% (non-responders). The serum triglyceride level was slightly decreased by Secholex in Type II-b patients but was unaltered in Type II-a patients. At the end of the treatment period, serum iron and vitamin B12 levels were normal but the serum folic acid concentration was reduced in eight of 20 patients. A dose--response study indicated that a similar cholesterol-lowering effect was obtained with daily doses of 9 and 15 g of Secholex. It is concluded that Secholex is a relatively safe drug which effectively reduces serum cholesterol levels in two-thirds of patients with severe hypercholesterolemia.

Effect of sodium cellulose phosphate therapy on crystallization of calcium oxalate in urine.

Effects of oral sodium cellulose phosphate therapy (5 g three times a day with meals for 4 days) on renal excretion of oxalate and on the crystallization of calcium oxalate in urine were examined in six patients with absorptive hypercalciuria on a constant metabolic dietary regimen. During treatment, urinary oxalate increased by 9-50 mg/day. However, urinary calcium decreased by 138-225 mg/day (50%-70%). Thus, the state of saturation of urine with respect to calcium oxalate decreased or did not change significantly. There was no consistent or significant change in the formation product ratio (limit of metastability) or in the crystal growth of calcium oxalate in urine.

Clinical pharmacology of sodium cellulose phosphate.

The safety and effectiveness of sodium cellulose phosphate (SCP) in the treatment of calcium urolithiasis of absorptive hypercalciuria was explored. Eighteen patients with absorptive hypercalciuria with intestinal hyperabsorption of calcium, normal or suppressed parathyroid function, and active stone disease received 10 to 15 Gm SCP daily (2.5 to 5 Gm with meals) and 2 to 3 Gm magnesium gluconate daily (1 to 1.5 Gm twice daily orally separately from SCP) for eight to 54 months, while maintained on a moderate calcium and oxalate restriction. During treatment, serum calcium, immunoreactive parathyroid hormone, and urinary cyclic AMP remained within the normal range. Serum alkaline phosphatase and bone density (measured by photon absorptiometry) did not change significantly or remained within normal limits. Serum concentrations of magnesium, copper, zinc, and iron and blood hematocrit were not significantly altered by therapy. However, urinary calcium returned toward normal, and incidence of renal stone formation markedly decreased. The results suggest that SCP is a safe and an effective drug for absorptive hypercalciuria.

Cation exchange resin preparation in recurrent calcium urolithiasis.

The efficacy of the cation exchange preparation, Campanyl, was studied in animal experiments and also in patients with absorptive hypercalciuria suffering from recurrent calcium stones, both in short-term studies on several treatment groups and with long-term maintenance dosage. In a dose of 15 Gm daily, taken with the main meal, the preparation was well tolerated and no serious side effects occurred. The frequency of stone passage, compared with that in the pretreatment period, was reduced by more than half, and urinary calcium excretion was considerably reduced. Litholysis was not observed. Campanyl is considered to be especially useful in patients with hyperabsorptive hypercalciuria. Dosage should be adjusted individually according to urinary calcium concentration.

Pharmacologic treatment of calcium calculi.

Selective pharmacologic therapy of calcium nephrolithiasis is highly effective in preventing new stone formation. A remission rate of greater than 80 per cent and overall reduction in individual stone formation rate of greater than 90 per cent can be obtained in patients with calcium nephrolithiasis. In patients with mild-to-moderate severity of stone disease, virtually total control of stone disease can be achieved as evidenced by remission rates of greater than 95 per cent. The need for stone removal may be dramatically reduced by an effective prophylactic program. Selective pharmacologic therapy of calcium nephrolithiasis also encompasses the advantages of overcoming the nonrenal manifestations of conditions that cause stone formation as well as averting certain side effects that may be caused by nonselective medical therapy. Despite these advantages, selective medical therapy clearly cannot provide total control of stone disease. A satisfactory response requires continued, dedicated compliance by patients to the recommended program and a commitment of the physician to provide long-term follow-up and care.

Effective therapy of enteric hyperoxaluria: in vitro binding of oxalate by anion-exchange resins and aluminum hydroxide.

Hyperabsorption of dietary oxalate is a major factor in the pathogenesis of enteric hyperoxaluria and a frequent complication of inflammatory bowel disease and ileojejunal bypass surgery. Successful treatment requires reduction in oxalate intake or inhibition of absorption of dietary oxalate by oral ingestion of oxalate binding agents. To identify such agents, oxalate binding by anion-exchange resins, gums, and aluminum hydroxide was measured under conditions that simulated those present in the intestinal lumen. Of the agents tested, those that bound oxalate best were colestipol and aluminum hydroxide. Strongly basic anion-exchange resins readily bound oxalate only in the absence of chloride. These results suggest that colestipol and aluminum hydroxide administration might reduce dietary oxalate absorption in patients with enteric hyperoxaluria.

Smoking cessation strategies: what works, what doesn't.

Health professionals can effectively help patients quit smoking with a minimal, intervention-oriented, office-based treatment program. Clear-cut, unequivocal, unambiguous, stop-smoking advice can produce sustained, 1-year abstinence rates in the 5% range. This capability has been clearly documented for physicians. Dental literature increasingly supports the same conclusion for dentists. These studies show that although the yield from such brief advice may seem small, it is 17 times greater than the yield which results from saying nothing. Moreover, because dentists and physicians see so many patients during the course of 1 year, the potential impact of such intervention is staggering. More than 3.5 million patients could be cured of tobacco dependence annually. While specialized smoking cessation treatment programs can achieve 1 year sustained abstinence rates as high as 70%, they reach relatively few patients and can only achieve such high success rates because of the intensive, time-consuming nature of their interventions. The impact of basic dental advice can be increased during regular follow-up visits, when "teachable moments" in dental health often occur. Impact of advice on the 1-year sustained abstinence rates can be increased by arranging to see the patient at regular follow-up visits after the target quit date has been set, making certain that the medication, nicotine polacrilex, is used correctly.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychopharmacologic treatment of cigarette smoking.

In summary, the entrance of the dental community into this area of treatment may have a significant impact on the reduction of smoking in our society. Dentists may be seeing smokers before the onset of disease and when they are ready to quit. Repeated patient visits offer a unique opportunity for follow-up. Presently, nicotine polacrilex is the only approved pharmacological FDA treatment. This is an ideal treatment for dentists to pursue because it is orally administered and effective through a proper chewing action. Other pharmacological agents (for example, antihypertensives) may require the followup of the physician. There are three key demands on the practitioner treating smokers: an understanding of the role of nicotine dependence in compulsive smoking; how to prescribe and educate in the proper use of nicotine polacrilex; and sympathy and a basic awareness of withdrawal and the psychological needs of patients undergoing cessation from smoking. This paper covers the rationale for development and use of nicotine polacrilex as well as some of the evidence for its effectiveness (relief of nicotine withdrawal) and efficacy (short and long term). The specifics of proper use have been described along with a brief overview of the psychosocial skills needed to succeed. The dentist offers a unique opportunity to reach enormous numbers of smokers in the battle against tobacco-induced disease and death.

Potassium. The intracellular cation.

Normally the concentration of potassium in the extracellular space is maintained within relatively narrow bounds; in disease, these boundaries may be exceeded. Hyperkalemia and sometimes hypokalemia must be considered medical emergencies, to be treated promptly, effectively, and appropriately.

Composition and structure of renal and ureteral calculi in patients under covalitin therapy.

We examined the composition and texture of 53 urinary calculi from patients receiving Covalitin therapy. The texture of the infection stones and of concrements containing mainly apatite showed no changes as compared to concrements from control groups receiving no such therapy. Calcium oxalate stones more often showed a whewellite texture (Type 2) and a less frequent occurrence of weddellite (Type 4) as compared to the control groups. Surface or marginal changes indicating a possible litholysis could not be shown.