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Purpose: Sodium polystyrene sulfonate (SPS) is a cation-exchanging resin that has been widely used for several decades as first-line therapy of mild chronic hyperkalemia in patients with chronic kidney disease (CKD). However, evidence to prove the long-term tolerability and efficacy of SPS for the treatment of this condition is still missing. Methods: In this retrospective, observational study, we enrolled 26 outpatients with stages 3-4 CKD who received oral therapy with low-dose SPS for mild chronic hyperkalemia in the Outpatient Nephrology clinic of our Department during 2010-2016. We obtained medical records on side effects potentially attributable to SPS use, and we analyzed the changes in serum electrolytes before and after the initiation of SPS therapy. Results: Serum potassium levels fell from 5.9 ± 0.4 to 4.8 ± 0.5 mmol/l ( P < 0.001) over a median follow-up of 15.4 months (range 3-27 months). SPS use was associated with a slight, but significant elevation in serum sodium levels (139.5 ± 2.9 vs 141.2 ± 2.4, P = 0.006), whereas serum calcium and phosphate remained unchanged before and after the initiation of SPS. We recorded ten episodes of recurrent serum potassium elevation ≥ 5.5 mmol/l, none of which required hospitalization or acute dialysis. No episode of colonic necrosis or any other serious drug-related adverse event was observed. SPS therapy was well-tolerated, since only 1 out of 26 patients discontinued SPS at 3 months due to gastrointestinal intolerance. Conclusion: This study suggests that low-dose SPS is well-tolerated and can effectively normalize elevated serum potassium over several weeks in CKD outpatients with mild chronic hyperkalemia. [ABSTRACT FROM AUTHOR]