patiromer Archivi

Differenza nell’efficacia tra i nuovi e i vecchi chelanti del potassio nei pazienti in dialisi: revisione sistematica e meta-analisi

Pubblicato il 2 agosto 2025Scarica PDF

Fortunata Zirino

DOI: 10.69097/42-04-2025-06

Fortunata Zirino¹, Veronica Maressa², Roberta Maria Messina¹, Maria Rita Stancanelli³, Guido Gembillo², Elisa Longhitano², Giovanni Taverna⁴, Giulio Geraci⁵, Valeria Cernaro², Domenico Santoro², Vincenzo Calabrese⁵*

1 Unit of Nephrology and Dialysis, P.O. Maggiore “Nino Baglieri”, Modica (RG), Italy
2 Unit of Nephrology and Dialysis, Department of clinical and experimental medicine, University Hospital “G. Martino”, Messina, 98100, Italy
3 Unit of Nephrology and Dialysis, Department of Medicine and Surgery, Hospital of Enna “Umberto I”, 94100 Enna, Italy
4 Unit of Cardiology, Department of clinical and experimental medicine, University Hospital “G. Martino”, Messina, 98100, Italy
5 Unit of Nephrology and Dialysis, Department of Medicine and Surgery, University of Enna “Kore”, 94100, Enna, Italy

Corresponding author:
Vincenzo Calabrese,
E-mail: v.calabrese@outlook.it

Abstract

Introduzione. L’iperkaliemia è una complicanza comune e grave nei pazienti dializzati, con un’incidenza e una severità crescenti nel tempo. I nuovi chelanti del potassio, patiromer e cicliosilicato di zirconio sodico (SZC), offrono una migliore tollerabilità rispetto agli agenti più datati. Questa meta-analisi mira a valutare l’efficacia e la sicurezza di questi nuovi chelanti nei pazienti dializzati.
Metodi. È stata condotta una revisione sistematica e meta-analisi di studi controllati randomizzati (RCT), aderendo alle linee guida PRISMA. Sono state effettuate ricerche in MEDLINE, PubMed, CINAHL ed EMBASE fino al 1° novembre 2024. Sono stati inclusi RCT che confrontavano patiromer o SZC con placebo, polistirene sulfonato di sodio (SPS) o polistirene sulfonato di calcio (CPS) in pazienti dializzati. Gli esiti primari erano le differenze nei livelli sierici di potassio. Gli esiti secondari includevano eventi avversi (AE) e mortalità. I dati sono stati analizzati utilizzando modelli a effetti fissi e casuali, e l’eterogeneità è stata valutata.
Risultati. Sono stati inclusi sei RCT, coinvolgendo 3155 pazienti. SZC e SPS hanno ridotto significativamente i livelli di potassio pre-HD rispetto al placebo (differenza media -0,68 mmol/L e -0,62 mmol/L, rispettivamente; p<0,0001). Patiromer non ha mostrato una differenza significativa rispetto al placebo (differenza media -0,17 mmol/L; p=0,16). Tutti i trattamenti hanno dimostrato una riduzione degli eventi di iperkaliemia rispetto al placebo. I dati sugli eventi avversi erano limitati e non statisticamente analizzabili, ma non sono state osservate differenze significative negli AE totali. I dati sulla mortalità erano scarsi, con un solo decesso riportato nel gruppo placebo. È stata osservata un’elevata eterogeneità nel confronto tra i nuovi e i vecchi chelanti/placebo. Conclusione. SZC e SPS riducono efficacemente i livelli di potassio pre-HD nei pazienti dializzati rispetto al placebo. L’effetto del patiromer non è risultato statisticamente significativo. Tutti i chelanti hanno ridotto gli eventi di iperkaliemia. I profili di sicurezza sono apparsi comparabili, ma i dati erano limitati. La mancanza di RCT sufficienti, in particolare quelli che confrontano direttamente i nuovi chelanti, evidenzia una significativa lacuna di conoscenza. Sono necessari ulteriori studi per valutare gli esiti a lungo termine, inclusa la qualità della vita e gli effetti cardiovascolari, e per confrontare direttamente l’efficacia e la sicurezza dei diversi chelanti del potassio in questa popolazione.

Parole chiave: dialisi, patiromer, potassio, ciclosilicato di sodio e zirconio, sodio polistirene solfonato

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

The incidence of hyperkalemia is one of the most common complications of kidney disease. Its incidence increases in patients who previously experienced hyperkalemia, with successively shorter time between the episodes [1].

Patiromer and Sodium Zirconium Cyclosilicate (SZC), new exchange ions polymer resin and exchange ions microporous resin, were recently developed reducing adverse events and improving palatability compared to old potassium binders [2–4].

Furthermore, many studies in conservative CKD demonstrated that these new drugs reduce hyperkalemia in patients treated with RAASIs [5].

Many systematic reviews compared new potassium binders with old potassium binders or placebo, but no one performed it in dialysis patients [6].

The main objective of our metanalysis is to evaluate the difference in serum potassium levels after treatment with SZC and Patiromer compared to placebo, sodium polystyrene sulfonate or calcium polystyrene sulfonate. Furthermore, the safety needs to be evaluated among these potassium binders in this population, due to the different pharmacokinetics that improve them.

Methods

Data source and search strategy

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7] and was conducted according to a pre-published protocol (CRD42024608049) [8, 9]. The literature search was designed and performed by two Authors (V.C. and A.P.). We performed a systematic, highly sensitive search in MEDLINE, PubMed, CINAHL and EMBASE for English-language articles without time or sex restriction up to November 1, 2024. Grey literature was screened through Google Scholar, SCOPUS and clinicaltrials.gov.

Study selection and data extraction

We included any randomized controlled trials (RCTs) testing the effects of potassium binders without sex restriction. Studies were included if provided information on outcomes of interest, such as 1) Differences in serum potassium concentration, 2) Adverse events (AEs), and 3) Mortality.

Studies were excluded if they included oncological patients, acute dialysis or CKD in conservative treatment.

Articles were screened by titles and abstracts by two independent investigators (V.C. and A.F.), excluding studies not pertinent to the topic and, subsequently, assessed the full texts to determine eligibility according to the pre-specified inclusion/exclusion criteria. Any disagreement on study judgments was discussed with a third author (V.M.) who was not involved in the selection process.

Reviews, letters, case reports and studies performed on children (age<18) were excluded from analyses but screened for potential additional references. Ongoing, unpublished trials were searched on the clinicaltrials.gov website. Authors of some of the included studies were contacted for additional information about study methods and unreported data.

Data analysis

Primary analysis will compute serum potassium differences between a network meta-analysis comparing each potassium binder/placebo. Secondary analysis will consist of a comparison between SZC/Patiromer and placebo/sodium polystyrene sulfonate or calcium polystyrene sulfonate.

All data will be analyzed with fixed-effect model or random-effect model based on the heterogeneity of the studies. Mean differences, and 95% confidence interval (CI), will be calculated for continuous outcomes. For dummy outcomes, the Odds Ratio (OR), computing 95% confidence interval (CI), will be computed. Data were pooled using the fixed-effects model and also analyzed with the random-effects method to guarantee the strength of the model. We plan to test for heterogeneity using the χ² statistic related to the degrees of freedom, with a p value of 0.05 used as the cut-off value to determine statistical significance. In addition, the degree of heterogeneity will be investigated by calculating the l² statistics. We will consider l² low if <25%, moderate if 25-50%, moderate-high if 50-75% and very high if >75%. In case of high heterogeneity, we will perform sensitivity analyses to explore sources of heterogeneity, such as study quality, year of publication, intervention or control variables, participants characteristics, and risk of bias. In addition, sub-group analyses will be conducted.

We will assess funnel plot asymmetry and the contour-enhanced funnel plot to explore publication bias, if the number of studies allows it. GRADE System will be used to evaluate the certainty of the evidence and to summarize the study conclusions. We planned to construct a summary table via the GRADEpro-GDT (GRADEpro GDT 2015) [10], reporting a summary of the available outcomes’ findings and the quality of the evidence supporting each outcome.

Statistical analyses were performed using Review Manager (RevMan; Version 5.4.) software and R4.4.0 software to perform the Network meta-analysis of all outcomes.

Quality and risk of bias assessment

The quality of RCTs was assessed by using the checklist developed by the Cochrane Renal Group which evaluates the presence of potential selection bias (random sequence generation and allocation concealment), performance bias (blinding of investigators and participants), detection bias (blinding of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective reporting) and possible other sources of bias.

Results

Search results

The selection process has been summed up in the flowchart (Figure 1). Two hundred and twenty-two references were retrieved. Among these, 95 were duplicates. By screening titles and abstracts, a total of 16 citations were selected for full-text evaluation. Among these, 6 articles were excluded because: 1) dealing with other populations or not reporting outcomes pertinent to the topic (n=7), 2) wrong intervention or no comparator (n=2), 3) duplicate (n=0), 4) various reasons (n=2). One study has been retrieved by Clinicaltrial.gov. Six articles referring to 5 full studies were reviewed in detail and included in the review [11, 15].

Study characteristics

All RCTs employed a parallel design. All studies were published after 2019. The final population analyzed in this review included 3155 patients, but the study sample sizes were variable, ranging from 33 [11] to 2690 [13]. The percentage of male participants varied from 49.3% [14] to 73% [15]. The mean age of patients ranged from 54 [11] to 66 [15] years. Three studies compared SZC to placebo, one study compared Patiromer to placebo, and one crossover study compared Patiromer to both placebo and SPS. The main characteristics of the eight RCTs reviewed are summarized in Table 1.

Trial reference	Study population and its characteristics	Intervention	Comparator	Study duration	Outcome(s)	Results	Notes
NCT03781089	Thrice weekly HD, adults Exclusion: Pregnancies -N=33 -Age (yr)= ~54 – Men (%)= 54.5% – Hispanic = 18.2% Countries= United States (single centre)	Patiromer (8.4mg/die) N=17	SPS (15g) N=16	7 weeks	Delta K	Not reported	Patients were checked up at 3, 5, 10, 14 and 27 weeks after initiation of treatment
					hypekalemia events*	13 in patiromer group vs 41 in SPS group
					AEs	Death: 0 in patiromer group vs 0 SAE: 2 in patiromer group vs 2 (Arrhythmia: 0 in patiromer group vs 1 Infection: 0 in patiromer group vs 1 FAV thrombosis: 1 in patiromer group vs 0 Hospitalization: 1 in patiromer group vs 0)
NCT03 303521	Thrice weekly HD, adults Exclusion: Hemoglobin <9 g/dl Pregnancies -N= 196 -Age (yr)=58 -Men (%)= 58.7% -Hispanic (%)= 52% -Countries= Japan, Russia, US, UK	SZC (5-10 mg) N=97	Placebo N=99	11 weeks	Delta K*	Mean difference between SZC and Placebo groups: − 0.74 mmol/L (95% CI − 0.97/− 0.52)	It is a post-Hoc analysis
					hyperkalemia events	Not reported
					AEs	Hypokalemia (k<2 mmol/L) was not registered in either SZC group or the placebo group
NCT03303521	Thrice weekly HD, adults Exclusion: Hemoglobin <9 g/dl Pregnancies -N= 196 -Age (yr)=58 -Men (%)= 58.7% -Hispanic (%)= 52% -Cauntries= Japan, Russia, US, UK	SZC (5-10 mg) N=97	Placebo N=99	11 weeks	Delta K	Not reported
					hyperkalemia events*	6/97 in SZC group vs 13/99 in placebo group
					AEs	Total AEs: 40/97 vs 46/99 in placebo group GI disorders: 19/97 vs 17/99 in placebo group Infection: 12/97 vs 9/99 in placebo group SAEs: 7/9 vs 8/99 in placebo group
NCT04847232	Recurrent serum K > 5.5 mmol/L in adults thrice weekly HD patients. Exclusion: -Pregnancies -Arrhythmias within 7 days before screening N= 2690 -Age (yr)=56 -Men (%)= NS Countries=Argentina, Austria, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Peru, Poland, Russian Federation, Slovakia, Spain, Taiwan, Thailand, Turkey, Ukraine, the UK, the USA and Vietnam	SZC (5-10mg) N= 1349	Placebo N=1341		Delta K	Not reported	Although the RCT results were completed, data are published but available partially on clinicaltrial.gov
					hyperkalemia events*	125 in SZC group vs 280 in placebo group
					AEs	GI disorders: 251 vs 260 in placebo group Infection: 295 vs 252 in placebo group SAEs: 7/9 vs 8/99 in placebo group
NCT04217590	China adults thrice weekly HD patients with preHD K >5.4 mmol/L Exclusion: Pregnancies -N= 134 -Age (yr)=55 -Men (%)= 49.3%	SZC (5-10 mg) N=67	Placebo N=67	11 weeks	Delta K	Mean difference between SZC and Placebo groups: –0.65 mmol/L (95% CI, –0.81 to –0.48; P < 0.001).
					hyperkalemia events*	40/67 in SZC group vs 56/67 in placebo group
					AEs	No severe hyperkalemia has been registered hypokalemia 2/67 in SZC group vs 0/67 in placebo group AEs 42/67 in SZC group vs 44/67 in placebo group SAEs 6/67 in SZC group vs 8/67 in placebo group Infection 0 in SZC group vs 1/67 in placebo group Death 0 in SZC group vs 1/67 in placebo group GI 6/67 in SZC group vs 9/67 in placebo group
SNCTP000003912	Swiss adults thrice weekly HD patients Exclusion: Pregnancies -N= 51 -Age (yr)=66 -Men (%)= 73% – Caucasian= 82% – Countries= Switzerland (multicentric)	Patiromer (8.4mg/die) N=51	Placebo N=51	8 weeks	Delta K	0.15+0.16 mmol//l in patiromer group vs 0.32+0.06 in placebo group	unblinded two-arm crossover RCTs
					hyperkalemia events*	17% in patiromer group vs 34% in placebo group
					AEs
SNCTP000003912	Swiss adults thrice weekly HD patients Exclusion: Pregnancies -N= 51 -Age (yr)=66 -Men (%)= 73% – Caucasia= 82% -Countries= Switzerland (multicentric)	Patiromer (8.4mg/die) N=51	SPS (15g) N=51	8 weeks	Delta K	0.15+0.16 mmol//l in patiromer group vs -0.3+0.05 in SPS group	unblinded two-arm crossover RCTs
					hyperkalemia events*	17% in patiromer group vs 12% in SPS group
					AEs	GI 26% in Patiromer group vs 24% in SPS group

Table 1. Summary of main characteristics and findings of the RCTs reviewed.

Study quality and risk of bias

Random sequence generation and allocation concealment were detailed in all trials. Three RCTs were double-blind, and one was open-label [15]. Blinding of participants, investigators and outcome assessors was specified in all studies. Attrition bias was low in all studies. The overall dropout rate was lower than 10 % for each study. Reporting bias was high in all studies. No other potential sources of bias were observed in the majority of studies (Figure 2).

Outcome data

Mortality

The three studies that compared SZC to placebo reported 114 deaths in the placebo group and 120 in the SZC group, and data on mortality were available.

Differences in potassium level

Data on pre-HD potassium value as a continuous variable were reported by 3 studies [12, 14, 15]. a pooled analysis involving 432 patients, both SPS and SZC showed a significant reduction in serum potassium levels compared to placebo, with a mean difference of –0.6200 (95% CI: [–0.89 / –0.35]; p < 0.0001) and –0.68 (95% CI: [–0.81 / –0.55]; p < 0.0001), respectively. Conversely, no differences between Patiromer and placebo were found (mean difference -0.17, 95%CI [-0.41/0.07], p=0.16). This collective analysis was not affected by heterogeneity (I²=0%) (Figure 3). The GRADE quality of this analysis was low after downgrading for the small number of the included studies.

Similarly, a meta-analysis comparing the new agent to the old agent/placebo showed a significant reduction of serum potassium in the new binders group (-0.47, 95%CI [-0.91/-0.02], p=0.04), but it revealed the highest heterogeneity (I²=94%).

Figure 3. Forest plot. Comparison between potassium binders on mean difference in serum potassium.

Hyperkalemia events

Hyperkalemia has been reported in all studies. In this case, differences have been found in each group compared to placebo (Patiromer -0.791, 95%CI:[-1-0.078], p=0.030; SPS -0.998, 95%CI [-1-0.250], p=0.009; SZC -0.620, 95%CI [-1-0.220], p=0.002). According to these results, all treatments can avoid pre-dialysis hyperkalemia (K>5.5 mmol/L) compared to placebo (Figure 4). However, it revealed the highest heterogeneity (I²=99%).

Figure 4. Forest plot. Comparison between potassium binders on hyperkalemia incidence.

Adverse Events

Adverse events cannot be statistically analyzed since they are not reported in each study and, where reported, as non-aggregable data. However, no difference has been found for total AEs in the included studies. The same can be assessed either for gastrointestinal events, for infectious or for SAEs. They are detailed in Table 1.

Discussion

Our analysis showed a significant difference in the management of hyperkalemia for each potassium binder compared to the only dialytic treatment with a lower pre-HD potassium concentration for SZC and SPS, without significant hypokalemia recurrence. At the same time, the recurrence of AEs not seem to be higher than only dialytic treatment.

Intradialytic hyperkalemia has been related to mortality and comorbidity, as well as hyperkalemia in conservative CKD [17–19]. Furthermore, the worst management of potassium worsens the intradialytic cardiovascular risk due to the speediest correction, almost obliged in patients with kalemia higher than 6.5 mmol/L. Although diet education, disionemia is not easy to manage in dialysis patients, often due to the lack of alimentary compliance [20].

The higher reduction of serum potassium in SZC patients than in patiromer patients can be easily explained by the speedier efficacy of the first. Indeed, SZC results are speedier in the first 48h than patiromer, and serum potassium in dialysis patients needs management into the 48/72h without dialysis [21]. This difference in speed could be crucial in patients with acute hyperkalemia or those requiring rapid potassium normalization for urgent medical procedures.

As reported in the published protocol, highlighting possible gaps in actual knowledge was one of the aims and this systematic review revealed an important gap: the lack of sufficient RCTs. The crucial relevance of knowing the efficacy and the safety of these new drugs for clinicians should be juxtaposed with enough structured and dialysis-based RCTs. In particular, the lack of studies directly comparing the different potassium binders with each other makes it difficult to establish which is the optimal choice for dialysis patients. Future studies should focus on direct comparisons to provide more robust evidence.

The lack of a sufficient number of RCTs has been reported since the first decade of this century, highlighting the phenomenon of the “Invisible trial” [22]. Even though the Restoring Invisible & About palatability and adherence, no data available from RCTs exist even though the APPETIZE study ended in 2022 [23]. Abandoned Trials (RIAT) initiative on Cochrane evidence products showed a possible solution to this problem, trials for smaller populations are often not enough to generate evidence. Furthermore, the variability of dialysis patient populations, with different comorbidities and dialysis regimens, makes it difficult to generalize the results of existing studies. A personalized approach to hyperkalemia management is needed, taking into account the specific needs of each patient.

Furthermore, some studies compared the cost-effectiveness of new and old potassium binders, with evidence of slightly lower cost in the new K binders, often due to the reduction of hospitalisation [24, 25].

Nowadays, the small number of performed trials on dialysis patients represents the major limit of this systematic review. Indeed, the lack of RCT on hemodialysis did not allow us to give a clear opinion about the use of these drugs on dialysis patients, preventing us from fully understanding if there is one potassium binder more efficient or secure. It is a serious gap in our acknowledgement that needs to be solved. Also, hypokalemia, one of the major adverse events of these drugs, is not reported enough to compute a real risk. The lack of detailed data on adverse events, particularly hypokalemia, limits our ability to fully assess the safety profile of these drugs. Future studies should include a systematic assessment of adverse events, with particular attention to hypokalemia and its clinical consequences. One of the limitations of this systematic review is the highest heterogeneity, perhaps due to the small sample, the small number of included studies and the heterogeneity of the comparisons (SPS and Placebo).

Conclusion

In conclusion, according to our analysis, all potassium binders seem to have more efficacy than placebo and seem to have high safety. However, the knowledge gap cannot be solved due to the need for more RCTs, paying attention that all outcomes are evaluated and reported. Furthermore, it is essential that future studies focus on evaluating the long-term impact of these drugs on the quality of life of dialysis patients and on cardiovascular outcomes. The management of hyperkalemia must be integrated into a comprehensive approach to the care of the dialysis patient, taking into account their specific needs and comorbidities.

Bibliography

Confronto tra i chelanti del potassio nella gestione dell’iperkaliemia nei pazienti in terapia dialitica cronica: protocollo per una revisione sistematica

Pubblicato il 1 febbraio 2025Scarica PDF

Vincenzo Calabrese

DOI: 10.69097/42-01-2025-02

Veronica Maressa ¹, Alessandra Farina ¹, Valeria Cernaro ¹, Guido Gembillo ¹, Elisa Longhitano¹, Giovanni Taverna², Domenico Santoro¹, Vincenzo Calabrese ³*
La revisione del protocollo è stata eseguita dal Porf. Gabriele Donati

1 Unit of Nephrology and Dialysis, Department of clinical and experimental medicine, University Hospital “G. Martino”, Messina, 98100, Italy
2 Unit of Cardiology, Department of clinical and experimental medicine, University Hospital “G. Martino”, Messina, 98100, Italy
3 Unit of Nephrology and Dialysis, Department of Medicine and Surgery, University of Enna “Kore”, 94100, Enna, Italy

Corrispondenza a:
Vincenzo Calabrese,
e-mail: v.calabrese@outlook.it

Abstract

Introduzione. Il trattamento dell’iperkaliemia è uno degli obiettivi principali della terapia di supporto nei pazienti in emodialisi. In questo contesto, la terapia con i nuovi chelanti del potassio è una risorsa promettente.
Scopo. L’obiettivo principale è valutare la differenza nella concentrazione sierica di potassio pre-dialisi nei pazienti in terapia dialitica in trattamento con sodio zirconio ciclosilicato o patiromer comparati con placebo/polistirene sulfonato di sodio/polistirene sulfonato di calcio.
Metodi. La ricerca della letteratura verrà sistematicamente eseguita su PubMed, EMBASE, CINAHLE e verrà esaminata pure la letteratura grigia. Esamineremo RCT su pazienti trattati con SZC o patiromer in emodialisi cronica, senza restrizioni di sesso o età, che includono le differenze nella concentrazione sierica di potassio, eventi avversi (EA) e mortalità come esiti.
Questa revisione sistematica dovrebbe fornire una valutazione completa dell’efficacia e degli effetti avversi dei nuovi chelanti del potassio, rispetto al sodio polistirene sulfonato o al calcio polistirene sulfonato o al placebo, sulla concentrazione sierica di potassio, in un campione di pazienti in emodialisi. Inoltre, possono essere evidenziate possibili lacune nella conoscenza effettiva, suggerendo nuove ricerche.
Conclusioni. Il presente protocollo per una revisione sistematica prenderà in considerazione tutte le prove esistenti da RCT pubblicati sull’efficacia degli dei chelanti del potassio sui pazienti in emodialisi.

Parole chiave: Leganti del potassio, ciclosilicato di sodio e zirconio, patiromer, iperkaliemia, CKD, emodialisi

Ci spiace, ma questo articolo è disponibile soltanto in inglese.

Introduction

The incidence of Hyperkalemia is common in kidney diseases, and its incidence increases in patients who previously experienced hyperkalemia, similarly to patients with diabetes or assuming RAASIs, with successively shorter time between the episodes [1].

Patiromer and Sodium Zirconium Cyclosilicate (SZC), an ion-exchange polymer resin and an ion-exchange microporous resin, were developed in the second decades of the third millennium, reducing adverse events [2–4].

The increased risk of mortality and morbidity in hyperkalemia is well-known [5, 6], as well as their increased incidence in patients treated with RAASIs. It occurs because RAASIs reduce the aldosterone-related potassium excretion that physiologically occurs in the distal and collecting tubule. Despite this, RAASIs showed nephroprotective and cardioprotective action, and it makes RAASIs useful to use. For this, new potassium binders, also aimed to better manage hyperkalemia in patients treated with RAASIs, managing pre-dialysis serum potassium that is considered a risk factor of cardiovascular mortality [7].

Aims and scope

The main objective is to evaluate the difference in serum potassium levels at different time points after treatment with SZC and patiromer compared to placebo, sodium polystyrene sulfonate or calcium polystyrene sulfonate. The rationale for using potassium binders is to reduce pre-HD serum potassium, allowing a mitigation of interdialytic potassium changes and reducing the risk of arrhythmia.

Furthermore, the safety needs to be evaluated among these potassium binders in this population, due to the different pharmacokinetics that improve them.

Methods

Design and registration

This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-P) guidelines [8]. This review protocol will also be registered in the PROSPERO database.

Search strategy

We will perform systematic research in MEDLINE, EMBASE, and CINAHLE, looking for published randomized controlled trials (RCTs). Grey literature will be screened through Google Scholar, Scopus and ClinicalTrials.gov. Only RCTs will be included in the study.

We will search for papers in the English language, and we will include only European and American countries, to avoid heterogeneity in the population. Reference lists from eligible trials and related reviews will also be reviewed, in order to find additional potential eligible studies. Ongoing, unpublished trials or further data from published trials will be researched on ClinicalTrials.gov. Finally, where needed, we will contact the experts in the field.

Search details are summarized in Table 1.

MEDLINE 127

((Potassium binders) OR (lokelma) OR (sodium zirconium cyclosilicate) OR (Veltassa) OR (patiromer)) AND ((Placebo) OR (Kayexalate) OR (sodium polystyrene sulfonate) OR (sorbisterit) OR (calcium polystyrene sulfonate)) AND ((dialysis) OR (Hemodialysis) OR (peritoneal dialysis) OR (CKD) OR (Chronic Kidney Disease)) AND ((Potassium) OR (hyperkalemia)) ‘Filters: Clinical Trial, Randomized Controlled Trial’

CINAHL 8

#1 Potassium Binders

#2 Lokelma

#3 Sodium zirconium cyclosilicate

#4 Veltassa

#5 Patiromer

#6 Placebo

#7 Kayexalate

#8 Sodium polystyrene sulfonate

#9 Sorbisterit

#10 Calcium polystyrene sulfonate

#11 Dialysis

#12 hemodialysis

#13 Peritoneal dialysis

#14 CKD

#15 Chronic Kidney Disease

#16 Potassium

#17 Hyperkalemia

#18 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

#19 #11 OR #12 OR #13 OR # 14 OR #15

#20 # 16 OR #17

#21 #18 AND #19 AND #20 in Trials

EMBASE 87

((‘Potassium binders/exp’ OR ‘lokelma’ OR ‘sodium zirconium cyclosilicate’ OR ‘Veltassa’ OR ‘patiromer’) AND (‘Placebo’ OR ‘Kayexalate’ OR ‘sodium polystyrene sulfonate’ OR ‘sorbisterit’ OR ‘calcium polystyrene sulfonate’) AND (‘dialysis’/exp OR ‘hemodialysis’/exp OR ‘peritoneal dialysis’/exp OR ‘chronic kidney disease’ OR ‘CKD’/exp) AND (‘potassium’ OR ‘hyperkalemia’/exp)) AND (‘Clinical Trial’ OR ‘Randomized Controlled Trial’)

Table 1. Search strategy PubMed and EMBASE.

Eligibility criteria

PICO strategy will be applied as follows:

– Population: we will compare the efficacy and the adverse effects in patients treated with SZC or patiromer. Eligible RCTs will consider subjects with chronic hemodialysis, without sex or age restriction. Exclusion criteria correspond to CKD in conservative treatment, acute hemodialysis, and oncological disorders.

– Intervention: SZC or Patiromer

– Comparator: placebo, sodium polystyrene sulfonate or calcium polystyrene sulfonate.

– Outcome: differences in serum potassium concentration, Adverse events (AEs), and mortality.

– Study design: Randomized clinical trials (RCTs)

Literature screening and study selection

The summary will be shown using the PRISMA flow diagram [9]. Duplicate will be removed.

Studies will be screened first by title and abstracts by two independent authors and any disagreement will be discussed with a third author. All abstracts will be screened using Rayyan software, whereas all full-text articles will be screened using the Mendeley software desktop.

Data extraction

Studies will be screened first by title and abstracts by two independent authors and any disagreement will be discussed with a third author with Rayyan software. Subsequently, the full texts of the selected studies will be read and assessed by two independent authors and any disagreement will be discussed with a third author. Reasons for the exclusion will be reported for each study. The selection process will be described through the PRISMA flow diagram.

The following data will be extracted through a standardized extraction Excel sheet by two independent authors:

General characteristics of the study (design, settings, sample size)
Participant characteristics: inclusion and exclusion criteria; number of participants screened and included; average age; comorbidities; sex; area of recruitment
Intervention characteristics: type and duration of the treatment and the follow-up
Adverse events: number of participants affected by adverse events, description of the adverse events and number of dropouts.

Missing data will be obtained by contacting the included studies’ authors. We will send emails three times in three months.

We will include RCTs to allow a high-grade validity of this systematic review. If needed for insufficient data, we will include non-RCTs and observational studies.

Data items

Identification of the study: this will include the name of the journal, article DOI, article title, authors, publication year, short citation, and country.

Methods: study objectives, study design, inclusion and exclusion criteria, intervention, comparator characteristics, population details and results will be included.

For intervention and comparator will be specified type, dose, duration, frequency, and mode of administration.

For population, detail will be detailed mean age, sex, and number of participants. Results will describe summary statistics, effect estimates, confidence intervals, p-values, subgroup analyses, sensitivity analyses, risk of bias, and GRADE.

We plan to perform subgroup analyses based on age (< or > 18 years), hemodialysis or peritoneal dialysis, and a network analysis for different potassium binders will be performed.

Main findings: this will include patient characteristics and other relevant clinical outcome measures.

Methodological quality assessment

For the systematic review, the method of assessing the risk of bias or study quality, and for the data extraction will be structured as follows: studies will be screened first by title and abstracts by two independent authors and any disagreement will be discussed with a third author with Rayyan software.

Blinding: the study selection, data extraction, and risk of bias assessment will be performed without blinding the assessors to the study authors or the journal of publication.

Strategy for data synthesis: qualitative synthesis of the results based on risk of bias will be performed. If applicable, quantitative synthesis through a meta-analysis will follow. The risk of bias will be assessed independently by two authors, using the ROB 2.0 Tool for each outcome of interest. Any disagreement will be discussed with a third reviewer. RobVis visualization tool will be used to create the RoB graph.

Meta-analysis

Primary analysis will compute serum potassium differences between SZC/Patiromer and placebo/sodium polystyrene sulfonate or calcium polystyrene sulfonate. Secondary analysis will consist on a network metanalysis comparing each potassium binder/placebo. All data will be analyzed with fixed-effect model or random-effect model based on the heterogeneity of the studies. Mean differences, and 95% confidence interval (CI), will be calculated for continuous outcomes. For dummy outcomes, the Odds Ratio (OR), computing 95% confidence interval (CI), will be computed. Data were pooled using the fixed-effects model and also analyzed with the random-effects method to guarantee the strength of the model. We plan to test for heterogeneity using the χ² statistic related to freedom degrees, with a P value of 0.05 used as the cut-off value to determine statistical significance. In addition, the degree of heterogeneity will be investigated by calculating the l² statistics. We will consider l² low if <25%, moderate if 25-50%, moderate-high if 50-75% and very high if >75%. In case of high heterogeneity, we will perform sensitivity analyses to explore sources of heterogeneity, such as study quality, year of publication, intervention or control variables, participants characteristics, and risk of bias. In addition, sub-group analyses will be conducted. We will use RevMan 5.4 software to perform the meta-analysis of all outcomes, and R4.4.0 software to perform the Network meta-analysis of all outcomes.

We will assess funnel plot asymmetry and the contour-enhanced funnel plot to explore publication bias. GRADE System will be used to evaluate the certainty of the evidence and to summarize the study conclusions.

Ethics

This is a systematic review that will use published data and does not require ethical approval, but each included study have to enrol patients after written consent and approval ethical code.

Status of the study and dissemination plan

We are starting the literature search, but the selection has not already started. We expect to complete the project and report it in 12 months. We will follow the updated PRISMA guideline to report the final paper and we will upload the progress on the PROSPERO website. Furthermore, we hope to publish a systematic review in a Nephrological journal.

Discussion

Serum potassium levels deviation from the normal range increases morbidity and mortality, both in conservative CKD [10, 11] and dialysis patients [12].

Considering that levels both lower or upper normal range are related to increased mortality and morbidity, hyperkalemia seems to significantly increase mortality and morbidity [5, 6]. This can be explained by the higher risk of arrhythmia in patients with rapid potassium intradialytic oscillations. About this, guaranteeing normal serum potassium on interdialytic days is needed to avoid rapid intradialytic oscillation [13].

The hyperkalemic effect of RAASIs can be physiologically explained, by a reduced urinary potassium excretion in the distal and collecting tubule, as well as by an increased potassium movement through the extracellular space [14].

It is well known that RAASIs are able to reduce fibrosis [15] and that they can reduce mortality and hospitalization [16], for this is needed to find a solution to manage hyperkalemia RAASIs-related.

Indeed, new potassium binders allow for better management of RAASI treatment in CKD patients, as well as reduced hypokalemia as an adverse effect compared to old potassium binders. For these reasons, an inclusive systematic review is needed to evaluate the efficacy and safety of each potassium binder.

Conclusion

This protocol deeply describes the methods and criteria used to perform a systematic review of the literature, including selection, extraction, biases evaluation, and synthesis of data from published RCTs evaluating the efficacy and safety of various potassium binders. We hope that this systematic review will increase the current knowledge and will hypothesize possible future research to overpass current gaps.

Bibliography

Iperkaliemia nel paziente con Malattia Renale Cronica in trattamento conservativo: overview sui nuovi chelanti e sui possibili approcci terapeutici

Pubblicato il 31 agosto 2018Scarica PDF

Toni De Stefano

Toni De Stefano, Silvio Borrelli, Carlo Garofalo, Michele Provenzano, Luca De Nicola, Roberto Minutolo, Giuseppe Conte

Affiliazione: Cattedra di Nefrologia-Università degli studi della Campania “Luigi Vanvitelli”; P.O. S.M.d.P. Incurabili, Napoli

Autore Corrispondente:
Dott. De Stefano Toni
Cattedra di Nefrologia, Università degli studi della Campania “Luigi Vanvitelli”
Dip. Scienze Mediche, Chirurgiche, Metaboliche e dell’invecchiamento
Piazza Miraglia, 80138 Napoli
Tel/Fax: 0812549409
E-mail: toni-ds@live.it

Abstract

Abstract in italiano

L’iperkaliemia è una condizione clinica di frequente riscontro nei pazienti con malattia renale cronica (CKD) che si associa a debolezza, paralisi, aritmie e aumento del rischio di mortalità e rappresenta uno dei motivi più frequenti che spingono a iniziare il trattamento sostitutivo negli stadi avanzati della CKD. L’iperkaliemia è associabile anche in maniera indiretta alla progressione della CKD, in quanto spesso il riscontro di valori elevati di potassio è causa di sospensione del trattamento con farmaci inibenti il sistema renina angiotensina, che costituiscono il trattamento nefro-protettivo di prima scelta. Diventa fondamentale quindi individuare i pazienti a rischio di sviluppare iperkaliemia e attuare interventi terapeutici volti a prevenire e trattare questa complicanza della CKD, quali modifiche della dieta, diuretici, chelanti del potassio. Fra queste, le uniche attualmente disponibili in Italia sono il Sodio-polistirensolfonato (SPS) ed il calcio-polistirensolfonato (CPS) che si sono dimostrate negli anni relativamente poco efficaci e sicure. Le nuove resine (Patiromer e ZS-9) costituiscono un significativo miglioramento nell’armamentario terapeutico del nefrologo per il trattamento dell’iperkaliemia, e negli studi fin qui condotti mostrano un buon profilo di efficacia e sicurezza. Gli effetti collaterali sembrerebbero meno frequenti e meno severi rispetto a SPS, con l’ulteriore vantaggio di una maggiore selettività per il potassio. Patiromer potrebbe rivelarsi molto utile nel cronico, data anche la totale assenza di sodio nella molecola; ZS-9 potrebbe invece svolgere un ruolo preponderante anche nel trattamento della iperpotassiemia acuta.

Parole chiave: Iperkaliemia, chelanti di K, SPS, CPS, Patiromer, ZS-9

L’iperkaliemia (o iperpotassiemia) è uno dei più comuni disturbi elettrolitici osservabili in pazienti con malattia renale cronica (CKD) o scompenso cardiaco congestizio. In accordo con la letteratura corrente, non c’è una definizione univoca: si può parlare di iperkaliemia sia quando il livello di potassio (K) nel sangue supera il cut-off di 5,0 mEq/L (1–3) sia quando supera il cut-off di 5,5 mEq/L (4, 5).

L’iperkaliemia è piuttosto rara nella popolazione generale poiché una funzione renale conservata consente una regolazione fine ed efficace l’omeostasi del potassio (6).

L’iperkalemia un fattore limitante nell’utilizzo dei farmaci che bloccano il Sistema Renina Angiotensina Aldosterone (SRAA)

Pubblicato il 9 maggio 2018Scarica PDF

Antonio Santoro¹, Marcora Mandreoli²

¹ Divisione di Nefrologia, Dialisi ed Ipertensione, Policlinico S.Orsola-Malpighi Azienda Ospedaliero-Universitaria di Bologna
² UOC Nefrologia e Dialisi, Ospedale S. Maria della Scaletta, Imola

Autore corrispondente:
Antonio Santoro
Divisione di Nefrologia, Dialisi ed Ipertensione
Policlinico S.Orsola-Malpighi
Azienda Ospedaliero-Universitaria di Bologna
Via P. Palagi,9
40138 Bologna
E-mail: antonio.santoro@unibo.it

Abstract

Gli inibitori dell’enzima di conversione dell’angiotensina (ACE-I) ed i bloccanti dei recettori dell’angiotensina (ARB) hanno dimostrato una reale efficacia nel ridurre la pressione arteriosa,la proteinuria, nel rallentare la progressione della malattia renale cronica (MRC) e nel miglioramento clinico. in pazienti con insufficienza cardiaca, diabete mellito e cardiopatia ischemica. Il loro utilizzo è però limitato da alcuni effetti collaterali come l’aumento del potassio (K) sierico,che assume carattere di severità nei pazienti con insufficienza renale. Nei 23.000 pazienti seguiti nell’ambito del progetto PIRP della Regione Emilia-Romagna, l’iperkaliemia alla prima visita (K>5,5 mEq/L) era presente complessivamente nel 7% circa di tutti i pazienti. La prevalenza di valori di K > 5.5 mEq/L aumentava in relazione allo stadio CKD, raggiungendo l’11% nei pazienti in stadio 4 e 5. Tra i pazienti con valori di K >5.5 al baseline, il 44.8% era in terapia con ACE-I/ARB inibitori, il 3.8% con diuretici anti-aldosteronici ed un ulteriore 3.9% assumeva contestualmente farmaci bloccanti il SRAA e risparmiatori di K. Le contro-misure per evitare l’insorgenza di iperkalemia in corso di terapie con farmaci che bloccano i SRAA vanno dalla dieta povera di K, ai diuretici ed infine a farmaci che favoriscono l’eliminazione fecale del K. Tra questi i polistirene sulfonati che hanno più di 50 anni di vita scambiano il K con il sodio o con il calcio. Questi farmaci però, nell’uso cronico, possono determinare dei sovraccarichi di sodio o di calcio e causare delle pericolose necrosi intestinali. Recentemente sono stati introdotti sul mercato due nuovi farmaci estremamente promettenti nel trattamento dell’iperkalemia, il patiromer ed il sodio zirconio ciclosilicato. Il patiromer, che è uno scambiatore potassio-calcio, agisce a livello del colon dove vi è una maggiore concentrazione di K e dove il farmaco è maggiormente ionizzato. Il Sodio zirconio ciclosilicato (ZS-9) è un a resina che sfrutta per intrappolare il K dei micropori di ben definite dimensioni collocati nella struttura cristallina del silicato di zirconio. Il K intrappolato viene scambiato con altri protoni e con il sodio. Anche questi farmaci dovranno però, dimostrare la loro efficacia e sicurezza nel lungo periodo per ritenersi dei veri partners dei bloccanti del SRAA in alcune categorie di pazienti.

Parole chiave: potassio, iperkalemia, sartani, ace-inibitori, insufficienza renale, patiromer, sodio zieconio ciclosilato, ZS-9, kayexalate

Introduzione

Il timore verso gli effetti avversi dei bloccanti del Sistema Renina Angiotensina Aldosterone (SRAA), spesso comporta una loro sottoutilizzazione o un sottodosaggio, in particolare nei sottogruppi di pazienti che sono maggiormente a rischio di sviluppare complicanze. Uno studio turco che si è occupato di valutare le barriere che limitano l’uso di ACE-I e ARB in pazienti con insufficienza renale cronica, ha riconosciuto nell’iperkalemia, l’elemento principale che porta alla sospensione dei bloccanti il SRAA (6). Anche lo studio di Shirazian ha evidenziato che l’iperkalemia rappresenta la causa principale di sottoutilizzo di ACE-I e ARB (7).