Adverse Gastrointestinal Effects with Kayexalate or Kalimate: A Comprehensive Review

Introduction

Patients suffering from chronic kidney disease (CKD) may exhibit hyperkalemia, a commonly seen adverse event of electrolyte imbalance that can lead to fatal cardiac arrhythmias.¹ Hyperkalemia is commonly treated by a cation-exchange resin called sodium polystyrene sulfonate (Kayexalate).^2–4 This drug acts as an exchange resin between sodium and potassium ions in the large intestine for accelerating potassium removal in the stool.⁵ However, its use has been reportedly related to colonic necrosis besides other fatal adverse events of gastrointestinal (GI) tract.⁶ An analog of Kayexalate, Kalimate (calcium polystyrene sulfonate), is also employed for treating hyperkalemia in clinical practice. However, there are not many incidences of Kalimate-induced GI tract injuries.⁷ Thus, our present study aimed to assess the clinical characteristics, risk factors, and outcomes of GI adverse events induced by Kayexalate or Kalimate from the published case reports in the literature.

Materials and Methods

Study Population

We considered articles to be eligible that presented a case report or case series of GI adverse events associated with the use of Kayexalate or Kalimate. Any unfavorable or damaging effect on the GI tract in relation to the use of Kayexalate or Kalimate is considered as a GI adverse event. The age, sex, symptoms, GI injury location, and risk factors of enrolled patients were analyzed. If there is no information available for any case series from the original authors, those cases were excluded from this study.

Literature Sources

We searched databases including PubMed and Medline (n = 136), Cochrane Library (n = 35), Clinical Key (n = 203), and Google Scholar (n = 2134) (Figure 1. Flow diagram of included studies) (1948 to March 31, 2020) for the case reports, considered eligible, of GI adverse events associated with Kayexalate and Kalimate use. Language-related restrictions were not enforced in this study.

Figure 1 Flow diagram of included studies.

Statistical Analysis

The published reports contained 29 case reports, 11 case series, and 1 systematic review. The clinical characteristics of all enrolled patients were described using mean ± standard deviation for continuous variables with abnormal distribution and number (percent) for categorical variables. Categorical variables were expressed as the number of cases and a percentage. These variables were compared using the T-test. A P value less than 0.05 indicates statistical significance.

Ethics Considerations

The present study was approved by the institutional review board of the Research Ethics Committee of China Medical University Hospital, in Taiwan (CMUH109-REC-01-049).

Results

A total of 2508 relevant articles were identified from our literature search. Following the application of the defined exclusion criteria, 41 articles describing 135 cases of GI adverse events induced by Kayexalate or Kalimate use were enrolled in our present study (Kayexalate: 103 cases; Kalimate: 32 cases). The enrolled patients were found in 29 case reports, 11 case series, and 1 systematic review (Figure 1).^5–52 Three cases out of the 135 reported cases in our present study were reported before 1990, 24 cases were reported during 1990 to 2000, and another 108 cases were reported after 2000.

Table 1 presents the clinical characteristics of all enrolled patients who experienced GI adverse events. The mean age of these patients was 55.5 ± 20.2 years (mean ± standard deviation) with a range from 27 weeks of gestation to 91 years. In addition, 71.9% of them aged 55 years or more (n = 97), while 28.1% aged below 55 years (n = 38). The differences between these two age groups were found to be statistically significant (P < 0.001). Regarding sex distribution, 54.8% of them were male (n = 74), whereas 45.2% were women (n = 61). The differences between the male and female groups were found to be statistically significant (P < 0.001).

Table 1 Summary of Clinicopathologic Findings of Patients with Kayexalate or Kalimate-Associated Gastrointestinal Injury in the Literature and the Present Case

Moreover, 55.6% of all enrolled patients used Kayexalate or Kalimate with sorbitol concomitantly, whereas 44.4% used either of the drugs without sorbitol. A statistically significant difference was found between the sorbitol group and without-sorbitol group (P < 0.001). In the analysis of predisposing factors for hyperkalemia, 87.7% had a history of CKD (n = 114) and 53.1% had end-stage renal disease (ESRD) requiring dialysis (n = 69), 30.0% had hypertension (n = 39), and 18.5% had a prior solid transplant (n = 24). The differences were statistically significant (P < 0.001). The mean usage time of Kayexalate or Kalimate causing GI adverse events was 19.84 days (0.5 days to 1 year). Only 27 patients (33.3%) received Kayexalate for more than 1 month. Kayexalate or Kalimate was administered orally in 67.8% of patients, rectally in 88.5%, and via the nasogastric route in 2.5%. The difference in administration routes was statistically significant (P < 0.001).

The results of GI adverse events associated with Kayexalate or Kalimate use are summarized in Table 2 in our present study. The presenting GI symptoms of all enrolled patients were abdominal pain (n = 59, 68.6%), nausea or vomiting (n = 6, 7.0%), diarrhea (n = 18, 20.9%), and black stool or bloody stool (n = 48, 55.8%). A statistically significant difference was found between different symptoms (P < 0.001). The colon was the most commonly involved site of the GI tract (n = 103, 76.3%), followed by the small intestine and duodenum (25.2%), rectum (14.8%), stomach (7.4%) and esophagus (3.0%). The differences between these various sites were significant (P < 0.001).

Table 2 Results of Gastrointestinal Adverse Events Associated with the Use of Kayexalate or Kalimate (n = 135)

Histopathological findings associated with Kayexalate or Kalimate use were intestinal-wall ulcerations (83.7%), necrosis (60.0%), and perforation (31.9%). The differences between these histological findings were statistically significant (P < 0.001). In our present study, crystals of Kayexalate or Kalimate were demonstrated histopathologically in 95.5% of all patients. Meanwhile, mortality caused by GI injuries was reported in 20.7% of all patients in our present study.

Discussion

Kayexalate has been widely used for acute and chronic hyperkalemia management. It was subsequently approved by the FDA in the United States in 1958.⁷ Kalimate is a calcium-exchange resin with similar pharmacological action as that of Kayexalate, and it is also used for treating acute or chronic hyperkalemia. Kayexalate or Kalimate, which is a cation-exchange resin, can be introduced into the lower GI tract employing an enema preparation. This resin can also be introduced either orally or by nasogastric tube into the upper GI tract. When the resin is administered orally or by nasogastric tube into the stomach region, at first sodium or calcium cations are released from the resin in exchange with hydrogen ions in the stomach’s acidic milieu. As the resin traverses the intestines, there is an exchange of hydrogen with potassium, followed by its excretion through the feces along with the remainder of the altered resin. Thus, the serum levels of potassium decrease over a period of hours to days.^7,8

Conventionally, Kayexalate was given as a water suspension. Because of the concerns of fecal impaction and constipation, it became a common practice to administer Kayexalate together with hypertonic sorbitol.² Sorbitol is a cathartic agent that has been reported to be associated with the development of intestinal injury rather than Kayexalate itself. The pathophysiological processes may be potentiated by the concomitant use of sorbitol with Kayexalate or Kalimate. Sorbitol, by elevating prostaglandin levels, causes a direct damage to the intestinal mucosa and leads to vasospasm and exacerbation of inflammation, and ultimately vascular injury.⁵ Histopathological lesions of these drugs-induced injuries vary from patchy inflammation to frank necrosis.⁸ This toxic effect of sorbitol on the GI tract has been proposed to potentially cause local ischemia and hypotension, in association with uremia and elevated renin levels in these patients, thereby adding to the severity of the injury. The susceptibility of uremic versus non-uremic rats to injury induced by Kayexalate–sorbitol enema indicates that uremia may in fact predispose to Kayexalate-induced mucosal injury.⁹ However, an increasing number of case reports have shown that severe adverse events, such as colonic necrosis, are linked with the Kayexalate treatment without or with only a small amount of sorbitol.⁷ Our present study included numerous cases using Kayexalate or Kalimate without sorbitol who experienced similar GI adverse events.^10,11 Moreover, Singhania N et al reported a case of colonic intestinal necrosis after co-administration of Kayexalate and activated charcoal.¹²

Furthermore, Kayexalate or Kalimate crystals were often seen to aggregate inside the damaged parts of the GI tract specimens, examined histopathologically. The presence of Kayexalate crystals in injured GI tract segments may represent a “footprint” of its use, indicating that Kayexalate itself may be pathogenic.⁸ Previous reports have postulated several risk factors for GI adverse events, including CKD, ESRD, solid organ transplantation, immunosuppression, and postoperative status; these factors lead to GI injury associated with Kayexalate or Kalimate treatment by different mechanisms.^{5,6,8,13–16,21,22} Renal transplant recipients are at increased risk for various adverse events, including infection, graft rejection, and medication adverse effects, in the early post-transplant period.⁸ Indeed, many of these risk factors were noted in most cases reviewed in the present study. Remarkably, 87.7% of all enrolled patients in this reviewing study had a history of ESRD, acute kidney injury or CKD. As shown in Table 1, the difference between these groups of comorbidities was statistically significant.

The increased renin levels, often seen in patients with renal diseases, place them at high risk to non-occlusive mesenteric ischemia via angiotensin II-mediated vasoconstriction.¹⁶ As noticed from our findings, this risk may be elevated during the postoperative period, possibly caused by ileus-induced colonic distension (resulting in lowered blood flow to colon), simultaneous hypotension and reduced gut motility as a result of opioid use, uremia, and constipation.^5,17,18 Patients who recently had transplantation are at a particularly elevated risk of these complications due to the administration of immunosuppressive drugs that negatively influence the normal protective and reparative capacity of GI cells.^18,19

The increase of inflammatory cytokines and prostaglandins may further impair local hemodynamic mechanisms, resulting in vascular injury and subsequent mucosal injury in the GI tract of individuals at high risk, such as those suffering with CKD or vascular disease, and patients’ solid organ transplant recipients. Given our present results, the pathogenesis of GI injury related to Kayexalate or Kalimate crystals is probably more complex than what we know presently and may represent a histopathologic injury in response to different heterogeneous insults.

It is difficult to define the etiology for colonic necrosis in patients with several health issues with elevated susceptibility to mucosal injury. Combined histologic, laboratory, clinical and examinations are necessary to eliminate the commonly seen causes of mucosal necrosis and also to correctly diagnose the mucosal necrosis associated with Kayexalate- or Kalimate.^{15,18,20–22,29–53} However, the observation of Kayexalate or Kalimate angulated crystals with a specific mosaic pattern is critical for diagnosing Kayexalate- or Kalimate-related mucosal necrosis. Histologically, cholestyramine crystals (used to decrease high blood cholesterol levels or to treat itching due to biliary tract blockage) should be distinguished from Kayexalate crystals. The cholestyramine crystals are more basophilic, opaque without a mosaic pattern, and rhomboid in shape compared with the Kayexalate crystals.¹⁸ The microscopic features of Kalimate crystals and of Kayexalate crystals are the same.^20,22

The colon is the most common site of Kayexalate- or Kalimate-induced GI injuries. Injury caused by Kayexalate may appear in more proximal sections of the GI tract.^15,18 As shown in Table 2, various locations of GI adverse events were statistically different, contradicting the severe adverse events in the lower GI tract from numerous case reports. Intestinal necrosis and perforation are potential complications of Kayexalate and may present in a delayed stage up to 2 months.^28,51–53 However, Kayexalate- or Kalimate-related toxicities in the upper GI tract have been rarely described in the literature.^20,22

Most of these cases do have simultaneous damage to colon. This change may possibly be due to the trend for the use of oral, instead of rectal Kayexalate or Kalimate.^{5,22–28,51–53} However, regardless of the location of Kayexalate or Kalimate-associated injury, mortality remains high. The elevated mortality may be a result of aggravated damage along with the large comorbid disease burden of affected patients.⁵ In the current study, we also found safety complications associated with Kayexalate or Kalimate usage, either with or without concomitant sorbitol.^5–53

This study has certain limitations. First, all results were inferred from case reports and case series. Similar to other reports concerning suspected adverse drug reactions, the relationship between Kayexalate or Kalimate and the described GI adverse events presented in our review remains uncertain. Second, this study was limited by some missing information, the absence of a standardized method of reporting adverse effects, and also possible selection and publication biases. Finally, Kayexalate- or Kalimate-associated GI adverse effects that are small in severity likely never reported and thus not recorded clinically, thereby limiting the quantification of the incidence of these events and evaluating the risk factors.

Conclusions

The use of Kayexalate or Kalimate, both with and without sorbitol, may be associated with fatal GI injuries. The most common high-risk groups of Kayexalate- or Kalimate-induced GI injuries are patients with CKD and ESRD, followed by patients with hypertension and organ transplantations. However, Kayexalate or Kalimate is given primarily to CKD or ESRD patients because those are the patients who suffer from hyperkalemia. Therefore, it would be expected that GI adverse effects of Kayexalate or Kalimate are observed in these patients. Moreover, the most common site of GI injuries induced by Kayexalate or Kalimate is the colon. Therefore, physicians should carefully assess the patient’s intestinal motility and medication history, multiple medical problems, comorbidity, and surgery before prescribing Kayexalate or Kalimate for hyperkalemia management, mainly in patients with ESRD. Physicians should also consider other safer agents when appropriate. Furthermore, detecting Kayexalate or Kalimate crystals is important for pathologists to reach a correct diagnosis.