Iperkaliemia Archivi

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

Hyperkalemia-induced acute flaccid paralysis: a case report

Pubblicato il 1 marzo 2021Scarica PDF

Martina D’Ercole

Martina D’Ercole^1,2, Leda Cipriani^1,2, Daniela Picciotto¹, Stefania Bianzina³, Elisa Russo^1,2, Francesca Viazzi^1,2, Pasquale Esposito^1,2

1 Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genova, Italy
2 Department of Internal Medicine, University of Genova, Genova, Italy
3 Neonatal and Pediatric Intensive Care Unit, G. Gaslini Institute, Genova, Italy

Corrispondenza:
Prof. Pasquale Esposito
UO Nefrologia Dialisi e Trapianto, IRCCS Ospedale Policlinico San Martino
Largo Rosanna Benzi 10Vi dei Martiri 20
16132 Genova, Italia
Tel +39 010 5555365
Fax +39 010 5556555
E-mail: pasqualeesposito@hotmail.com

Abstract

Acute flaccid paralysis is a medical emergency that may be caused by primary neuro-muscular disorders, metabolic alterations, and iatrogenic effects. Severe hyperkalemia is also a potential cause, especially in elderly patients with impaired renal function. Early diagnosis is essential for appropriate management.

Here, we report the case of a 78-year-old woman with hypertension and diabetes presenting to the emergency department because of pronounced asthenia, rapidly evolving in quadriparesis. Laboratory examinations showed severe hyperkalemia of 9.9 mmol/L, metabolic acidosis, kidney failure (creatinine 1.6 mg/dl), and hyperglycemia (501 mg/dl). The electrocardiography showed absent P-wave, widening QRS, and tall T-waves. The patient was immediately treated with medical therapy and a hemodialysis session, presenting a rapid resolution of electrocardiographic and neurological abnormalities. This case offers the opportunity to discuss the pathogenesis, the clinical presentation, and the management of hyperkalemia-induced acute flaccid paralysis.

Keywords: hyperkalemia, acute flaccid paralysis, hemodialysis, diabetes

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

Introduction

Hyperkalemia is associated with poor outcomes and a high mortality rate among the general population, and among patients with cardiac and renal disease [1,2]. Hyperkalemia-related clinical complications and deaths are determined mainly by the cardiac electrophysiological effects of elevated potassium levels [3]. Indeed, hyperkalemia may result in ventricular arrhythmias and sudden death. Moreover, hyperkalemia may also cause other physiologic perturbations, such as muscle weakness and paralysis, paraesthesia, and metabolic acidosis.

Here, we report a case of severe hyperkalemia presenting with dramatic neurological manifestations in the form of acute flaccid paralysis (AFP).

Impatto dell’iperkaliemia e della mancata aderenza a SRAAi nei pazienti con scompenso cardiaco o con insufficienza renale cronica

Pubblicato il 9 settembre 2019Scarica PDF

Luca Degli Esposti¹, Valentina Perrone¹, Elisa Giacomini¹, Diego Sangiorgi¹, Davide Alessandrini¹, Antonio Santoro²

1 CliCon S.r.l. Health, Economics & Outcomes Research
2 Scuola di Specializzazione in Nefrologia- Università degli studi di Bologna

Corrispondenza a:
Valentina Perrone
CliCon S.r.l.
Health, Economics & Outcomes Research
Via Salara, 36 - 48121 Ravenna (IT)
Tel +39 (0)544 38393
Fax +39 (0)544 212699

Abstract

La presenza di iperkaliemia (IK) in pazienti con insufficienza renale e/o insufficienza cardiaca costituisce un fattore di rischio aggiuntivo di morte. Con il presente studio abbiamo valutato: i) l’incremento del rischio di eventi cardiovascolari (CV) e mortalità in pazienti con IK e in terapia con inibitori del sistema renina-angiotensina-aldosterone (SRAAi), considerando due coorti di pazienti, una affetta da insufficienza renale cronica (IRC) e l’altra da scompenso cardiaco (SC). Inoltre, nei pazienti con IRC si è valutato l’aumento del rischio di dialisi; ii) la stima dell’incremento del rischio di eventi CV e mortalità dovuto ad una aderenza non ottimale a SRAAi in pazienti iperkaliemici in entrambe le coorti SC e IRC. Lo studio è di tipo retrospettivo, basato su database amministrativi di 5 Aziende Sanitare Locali. Sono stati inclusi tutti i pazienti di età ≥18 anni con prima dimissione per SC (ICD-9-CM:428) o IRC (ICD-9-CM:585) tra gennaio 2010 e dicembre 2017 (periodo di arruolamento). La data della prima dimissione per SC/IRC durante il periodo di arruolamento è stata definita data indice (DI). Sono stati inclusi nell’analisi i soli pazienti con SC/IRC che nel primo trimestre successivo alla DI presentavano almeno una prescrizione di SRAAi. I livelli di potassio sono stati rilevati nei 3 mesi prima o dopo la DI; i pazienti con livello ≥5.5mmol/l sono stati definiti iperkaliemici. I pazienti con IK in trattamento con SRAAi presentavano un rischio aumentato del 46%(SC) e del 31%(IRC) di evento CV, del 88%(SC) e 72%(IRC) di decesso e del 458%(IRC) di dialisi. Dopo l’insorgenza della IK, la mancata aderenza al trattamento ha portato ad un rischio di eventi CV aumentato del 65%(SC) e del 34%(IRC) nonché ad un rischio di decesso aumentato del 127% (SC) e 122%(IRC).

Parole chiave: iperkaliemia, inibitori del sistema renina-angiotensina-aldosterone, insufficienza renale cronica, scompenso cardiaco, farmaci per l’iperpotassiemia, studio real-world

Introduzione

L’iperkaliemia (IK) è un grave disordine elettrolitico, potenzialmente fatale, che si configura con un livello sierico di potassio ≥5.0 mmol/l, superiore al limite massimo del range standard (3.5-5.0 mmol/l) [1, 2]. Tuttavia in generale il quadro clinico si rende manifesto per valori ≥5.5 mmol/l.

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).