Sodium polystyrene sulfonate (SPS) is commonly prescribed for the management of hyperkalemia, a critical electrolyte imbalance contributing to over 800000 annual visits to emergency departments.

To conduct a systematic review of documented cases of SPS-induced colitis and assess its associated prognosis.

Following the PRISMA-P guidelines, our study employed Medical Subject Headings and Health Sciences Descriptors, skillfully combined using Boolean operators, to conduct comprehensive searches across various electronic databases, including Scopus, Web of Science, MEDLINE (PubMed), BIREME (Biblioteca Regional de Medicina), LILACS (Latin American and Caribbean Health Sciences Literature), SciELO (Scientific Electronic Library Online), Embase, and Opengray.eu. Language criteria were confined to English, Spanish, and Portuguese, with no limitations on the publication date. Additionally, we manually scrutinized the reference lists of retrieved studies. To present our findings, we utilized simple descriptive analysis.

Our search strategy yielded a total of 442 references. After rigorous evaluation, we included 51 references, encompassing 59 documented cases of colitis. Predominant clinical presentations included abdominal pain, observed in 35 (60.3%) cases, and bloating, reported in 18 (31%) cases. The most frequently affected sites of inflammation were the cecum, rectum, and small intestine, accounting for 31%, 25.8%, and 22.4% of cases, respectively. Colonoscopy findings were described in 28 (48.2%) cases, and 29 (50%) of patients required surgical intervention. Among the subset of patients for whom outcome data was available, 39 (67.2%) experienced favorable outcomes, while 12 (20.6%) unfortunately succumbed to the condition. The mean time required for resolution was 36.7 d, with a range spanning from 1 to 120 d.

SPS demonstrates the capacity to effectively lower serum potassium levels within 24 h. However, this benefit is not without the risk of bowel injury. Our study highlights the absence of high-quality data pertaining to the incidence of adverse events associated with SPS usage, making it challenging to determine whether the potential risks outweigh the benefits. However, a significant mortality rate related to SPS-induced colitis was noted. Future investigations should prioritize randomized controlled trials with a sufficiently large patient cohort to ascertain the true utility and safety profile of this medication.

Adverse drug events span a broad spectrum of clinical presentations, affecting various organ systems. Recognizing and understanding these medication-related effects is essential for mitigating associated morbidity and mortality[1]. Sodium Polystyrene Sulfonate (SPS) has found a specific niche in the management of hyperkalemia, a life-threatening electrolyte disturbance that leads to over 800000 emergency department visits annually[2]. This therapeutic agent gained approval from the United States Food and Drug Administration (FDA) in 1958, four years prior to the implementation of the Kefauver–Harris Drug Amendments, legislation designed to ensure drug efficacy and safety[3].

The effective management of hyperkalemia is of paramount importance for preserving life, as it serves as a protective barrier against potentially fatal arrhythmias by either facilitating potassium translocation from the serum into cells or enhancing renal potassium excretion[4]. SPS, a cation exchange resin, can be administered orally or rectally, primarily exerting its effects within the colon by facilitating the exchange of sodium ions for potassium ions[1,4,5]. Nevertheless, it is crucial to note that this drug is not without its share of side effects[6]. Historically, it has been co-administered with sorbitol, an osmotic laxative, to mitigate the risk of severe constipation or fecal impaction, which can occur when SPS is administered in isolation[1]. The FDA, in 2009, issued a black box warning to underscore the heightened risk of intestinal necrosis associated with this combination therapy[3].

Typically, gastrointestinal adverse effects manifest as mild symptoms, such as nausea and constipation[7]. However, more severe and potentially fatal complications, including colonic ulceration, severe colitis, and necrosis, have been linked to SPS therapy[7,8]. Notably, the severity of these complications tends to correlate with the overall clinical condition of patients, particularly those with a history of organ transplantation, chronic kidney failure, or individuals in the postoperative period[4].

One of the most widely accepted theories regarding the mechanism of injury revolves around the presence of renin in high concentrations among patients with renal failure. The activation of renin and subsequent splanchnic vasoconstriction may lead to non-occlusive mesenteric ischemia, predisposing the colonic mucosa to injuries and electrolyte disturbances. However, it remains unclear why patients with renal failure are more susceptible to this catastrophic complication. It is possible that they are more prone to hyperkalemia, necessitating higher doses of SPS treatment than other patient groups[4].

Typically, the colon represents the gastrointestinal tract most frequently affected by SPS-induced complications. These lesions necessitate endoscopic or colonoscopic analysis with biopsy to rule out differential pathologies such as cancer. While gastric involvement is less common, it was identified in only two cases in our comprehensive review. Biopsy results typically reveal intestinal necrosis, ulcers, or perforations, with more than 90% of tissue samples exhibiting an accumulation of SPS crystals. The presence of kayexalate crystals in pathology specimens distinguishes kayexalate-induced necrosis from ischemic necrosis. Histological evidence of angulated crystals of sodium polystyrene sulfate in areas of mucosal erosions, ulcerations, or frank necrosis strongly suggests the diagnosis. Additional related findings include inflammatory exudates, pseudomembrane formation, and acute/chronic serositis. These crystals are typically identified adhered to the mucosa or embedded within the inflammatory milieu and ulcerations. Thus, in reaching a diagnosis, it is imperative to rule out conditions that can mimic SPS-induced effects, such as neoplasms, inflammatory diseases, and infectious diseases[4].

The objective is to conduct a systematic review of documented cases of SPS-induced colitis and to assess the overall prognosis associated with this condition.

This systematic review delves into the analysis of documented cases of SPS-induced colitis, shedding light on the importance of collecting data on medication-related adverse events to enhance healthcare safety. Hyperkalemia, if left untreated, poses significant threats such as severe arrhythmias, cardiac arrest, and fatality[11]. The use of SPS for managing hyperkalemia has a historical legacy dating back to the 1960s[12], even though robust evidence substantiating its safety and efficacy remains scant[2].

Notably, mild adverse effects associated with SPS include symptoms like diarrhea, constipation, abdominal pain, bloating, nausea, and vomiting[13]. In the systematic review, bloating was reported in 31% of cases as a minor adverse effect, while vomiting occurred in 7% of patients. However, it is crucial to distinguish these relatively well-tolerated mild effects from severe adverse outcomes potentially linked to SPS use, which can significantly increase morbidity and mortality[14]. Such severe outcomes encompass colitis, ischemic colonic necrosis, seizures, confusion, irregular heartbeat, and pneumoperitoneum[13]. This systematic review reveals that all the cases included presented with colitis, and some cases developed more severe consequences.

Interestingly, descriptions of intestinal lesions first emerged in 1987 when catastrophic colonic necrosis was documented in five cases[15,16]. Subsequently, in 2012, a cohort study involving 2194 inpatients identified colonic necrosis in 82 cases related to SPS use[17]. Studies have reported varying incidences of colon necrosis after drug administration, ranging from 0.14% to 1.8%, with a higher incidence observed in the postoperative period[5,18]. Additionally, other concerning findings associated with SPS use, such as the three cases of pneumoperitoneum requiring urgent laparotomy, have been reported[19,20]. The characteristics of the patients are detailed in Tables 1 and 2.

Although these cases, though less common, are often detected early due to patients' complaints of increased abdominal pain and distention[5]. Typically, the time to the initial manifestation is around two days. A retrospective cohort study involving 19530 adults found that new users and users receiving the recommended dose 'per label' had a higher risk of adverse effects compared to chronic users and those on lower doses[21,22]. After adjusting for 26 covariates, SPS use was associated with hospitalization or death due to intestinal ischemia/thrombosis or gastrointestinal ulcers and perforation (HR 1.25, 95%CI 1.05-1.49)[21,22]. Therefore, the threshold dose for deleterious effects has yet to be determined, and caution is advised when prescribing this medication, especially for more fragile patients[4].

In a prior systematic review, 91% of included cases had a history of renal disease, a proportion slightly higher than the 75.8% observed in this study[4]. This aligns with expectations, as SPS is commonly used in patients with renal conditions. Other common comorbidities identified in our work included hypertension and diabetes mellitus, both of which are associated with chronic kidney disease[8,23,24]. In the literature, potential risk factors associated with deleterious adverse effects include uremia, hypovolemia, peripheral vascular disease, and immunosuppressive therapy, all of which were also evident in the cases reviewed[18,25-28].

Typically, the colon is the gastrointestinal segment most frequently affected by SPS-induced complications. These lesions necessitate endoscopic/colonoscopy analysis with biopsy to rule out differential diagnoses, such as cancer[16]. Gastric involvement is less common and was identified in only two cases in our review[29,30]. Biopsy results typically reveal intestinal necrosis, ulcers, or perforations, with an accumulation of SPS crystals in more than 90% of tissue samples[5]. The presence of kayexalate crystals in pathology specimens differentiates kayexalate-induced necrosis from ischemic necrosis[5]. Histologic evidence of angulated crystals of sodium polystyrene sulfate in areas of mucosal erosions, ulcerations, or frank necrosis strongly suggests the diagnosis[31]. Other associated findings include inflammatory exudates, pseudomembrane formation, and acute/chronic serositis[32]. These crystals are typically identified adhered to the mucosa or embedded within the inflammatory milieu and ulcerations[5]. Thus, to arrive at a definitive diagnosis, it is imperative to rule out conditions that can mimic SPS-induced effects, such as neoplasms, inflammatory diseases, and infectious diseases[16]. These histological characteristics are summarized in Table 2.

However, the pathophysiological mechanism underlying these lesions remains incompletely understood[4]. One of the most widely accepted theories suggests that the presence of renin in high concentrations among patients with renal failure plays a pivotal role. Activation of renin and subsequent splanchnic vasoconstriction can lead to non-occlusive mesenteric ischemia, predisposing the colonic mucosa to injuries and electrolyte disturbances[32,33]. Nevertheless, it remains unclear why patients with renal failure are more susceptible to this catastrophic complication. It may simply be attributed to their higher likelihood of being hyperkalemic, necessitating treatment with higher doses of SPS than other patients[33].

Alternative theories propose that polystyrene's high water affinity leads to bulk formation with shear-thickening flow behavior, resulting in clumping and resin clogging, particularly in patients with compromised gastrointestinal motility[34]. This leads to resin impaction, subsequent gut obstruction, ischemic necrosis, and perforation, analogous to findings in stercoral colonic perforation[35]. Details about the drug are available in Table 3.

Despite the relatively common use of SPS, there is limited evidence regarding its effectiveness and safety in the literature. Therefore, vigilance is warranted regarding the drug's adverse effects[36]. A previous systematic review published in 2013 reported serious adverse reactions associated with colonic necrosis, which occupied a prominent position and resulted in a mortality rate of 33% among affected patients, higher than the 21% mortality rate observed in our study[4]. Conversely, in a double-blind, randomized, placebo-controlled trial, colonic necrosis was not reported[3]. However, the trial involved only 31 participants who were followed for a short period (7 d) and were less ill than the general patients who typically receive the medication[32]. Therefore, prescribing SPS should be a carefully considered decision, taking into account each patient's specific circumstances, especially in cases of sicker patients, such as older individuals and those with gastrointestinal hypomotility. Higher mortality rates have been observed in colitis induced by SPS. Therefore, it is essential to consider alternative approaches for controlling hyperkalemia. If alternative options are not available, it is strongly advised to implement routine monitoring to enable early detection of potential complications[19,36].

In the adapted quality assessment tool, the majority of cases were classified as having moderate quality (96.6%)[10]. None of the cases were categorized as high quality. This was primarily due to causality questions, which, for example, implicate the danger of reexposing the patient to SPS. Additionally, none of the cases met the criteria to score in question one, as the authors did not specify whether the cases were unique in their centers. Nonetheless, only two cases were classified as low quality[34,37]. Further details can be found in Supplementary material.

The primary limitations of our study were the limited number of available cases (n = 59) and the scarcity of data in many of the reviewed cases. Despite our efforts, some full articles could not be located, even after contacting the authors, which could be attributed to the publication year. The inclusion of articles was restricted to those published in English, Spanish, French, or Portuguese, potentially resulting in the omission of articles in other languages. Despite these limitations, most of the variables presented in Tables 1 and 2 provide valuable insights into the characteristics of the patients.

Considering that observational trials suggest that SPS may lower serum potassium levels, but not without the risk of bowel injury[2] and death resulting from hyperkalemia is an unacceptable outcome[38], alternative options for addressing elevated potassium levels should be explored, and SPS should be considered a drug of last resort[39]. Some authors argue that despite many decades of experience with SPS and its low cost, it would be premature to abandon it in favor of more expensive alternatives with similar side effects or undefined long-term toxicity[17]. When evaluating patients exposed to SPS with diarrhea, it is essential to always consider a broad range of potential differential diagnoses for colitis and diarrhea in this group of patients, such as inflammatory bowel disease[40-42], infectious enteritis and colitis[43-45], angiotensin II receptor blocker induced sprue-like enteropathy[46], celiac disease[47,48], foreign body ingestion or food poisoning[49], neoplasm[50] or pellagra[51].

In conclusion, alternative methods such as hemodialysis or glucose, insulin, or bicarbonate injections may be more effective in controlling hyperkalemia[18]. There is currently insufficient high-quality data to estimate the number of adverse events associated with SPS use, making it challenging to determine whether the benefits outweigh the risks[2,38]. Moreover, it is crucial to acknowledge that the mortality rate was notably significant, standing at 20.6% in this review. Therefore, future studies should ideally involve randomized controlled trials with an adequate number of patients to investigate the real risks and benefits of this drug.