Lubiprostone, a novel laxative, might improve hyperphosphatemia without water dilution
© The Author(s) 2016
Received: 15 March 2016
Accepted: 20 August 2016
Published: 10 October 2016
Hemodialysis patients often develop constipation due to dietary restriction and the use of phosphate and/or potassium binders. Lubiprostone is a novel laxative that promotes defecation by activating the chloride ion channel 2 (ClC-2) in the gastrointestinal tract. While lubiprostone has been reported to be useful in bowel control of dialysis patients, no studies have examined changes in electrolyte levels following administration of lubiprostone.
We prospectively compared stool frequency and electrolyte levels before and after treatment with lubiprostone in 28 hemodialysis patients treated with the drug for at least 3 months in our hospital.
Mean ± standard deviation of stool frequency was significantly increased from 1.8 ± 1.3 times/week before treatment to 4.3 ± 1.8 times/week at Month 1, 4.9 ± 1.9 times/week at Month 2, and 4.5±1.5 times/week at Month 3 (p < 0.001, p < 0.001, and p < 0.001, respectively). With regard to electrolyte levels, only serum inorganic phosphorus (IP) level was significantly decreased, from 4.7 ± 1.5 mg/dL at baseline to 4.5 ± 1.6 mg/dL at Month 1, 4.0 ± 1.3 mg/dL at Month 2, and 3.8 ± 1.1 mg/dL at Month 3 (p = 0.123, p < 0.001, and p < 0.001, respectively). Lubiprostone not only improved bowel control, but also decreased serum IP levels in hemodialysis patients.
Lubiprostone may improve prognosis of hemodialysis patients through bowel control and a decrease in serum IP.
KeywordsHemodialysis Lubiprostone Serum phosphorus level
Hemodialysis patients have a higher prevalence of constipation than patients with normal renal function, due to dietary restriction, fluid restriction, and use of phosphate and/or potassium binders . Given the risk of hypermagnesemia due to the use of magnesium oxide preparations, which are saline laxatives , hemodialysis patients often use sennosides, which are stimulant laxatives. However, chronic use of these compounds can result in difficulties with bowel control due to resistance .
Lubiprostone is a novel laxative that promotes defecation by activating the chloride ion channel 2 (ClC-2) on the apical membrane of the small intestinal epithelium, thereby increasing water secretion into the intestinal lumen to soften feces and enhance intestinal transit. While some studies have reported the usefulness of lubiprostone in bowel control of dialysis patients , none have examined associated changes in electrolyte levels in these patients.
Here, we investigated changes in electrolyte levels in hemodialysis patients after treatment with lubiprostone.
Among 396 patients who underwent hemodialysis in our hospital between August 2014 and August 2015, 44 (9 %) patients were administered lubiprostone to treat constipation. After excluding 16 patients who dropped out for reasons such as nausea and loss of appetite, 28 who had used the compound for at least 3 months and gave informed consent to participate were included in the study. This prospective observational study was approved by the Ethics Review Board of Saitama Sekishinkai Hospital.
Even after starting treatment with lubiprostone, patients continued to take any oral laxatives they had been using before treatment, with no changes in dosage. Lubiprostone was started at an initial dose of 24 μg once daily after dinner and was then adjusted based on defecation frequency. The following parameters at months 1, 2, and 3 of treatment with lubiprostone were compared with those before treatment (baseline): mean weekly stool frequency; stool consistency (Bristol Stool Form Scale); serum levels of sodium (Na), potassium (K), corrected calcium (Ca), and inorganic phosphorus (IP); and Geriatric Nutritional Risk Index (GNRI) for nutritional assessment .
Serum levels were determined via laboratory tests performed at the start of each week, and corrected Ca was calculated using Payne’s formula. No changes were made to any non-laxative oral drug doses or dialysis condition throughout the study.
All data are presented as mean ± standard deviation. The Wilcoxon signed-rank test was used to compare two groups (continuous variables) at a significance level of 0.05. All statistical analyses were performed using SPSS Version 22.0 (IBM, Tokyo, Japan).
Baseline characteristics of patients
Number of enrolled patients (men/women)
69.4 ± 14.2
Duration of dialysis, years
7.7 ± 9.1
Underlying disease of renal failure
Diabetic nephropathy, 11 patients
Chronic glomerulonephritis, 3 patients
Nephrosclerosis, 5 patients
Autosomal dominant polycystic kidney disease, 1 patient
Primary hyperparathyroidism, 1 patient
Unknown, 7 patients
Stimulant laxative, 17 patients
Sugar laxative, 1 patient
Calcium carbonate, 8 patients
Lanthanum carbonate, 12 patients
Bixalomer, 2 patients
Ferric citrate hydrate, 1 patient
Cinacalcet, 4 patients
Comparison of stool and serum parameters of hemodialysis patients before and 1, 2, and 3 months after treatment with lubiprostone
Mean ± SD
Mean ± SD
Mean ± SD
Mean ± SD
Stool frequency (times/month)
1.8 ± 1.3
4.3 ± 1.8
p < 0.001
4.9 ± 1.9
p < 0.001
4.5 ± 1.5
p < 0.001
Bristol Stool Form Scale
2.3 ± 1.0
3.4 ± 0.7
p < 0.001
3.5 ± 0.8
p < 0.001
3.6 ± 0.6
p < 0.001
Serum Na (mEq/L)
137.3 ± 3.3
137.5 ± 3.0
p = 0.963
138.2 ± 3.5
p = 0.070
138.2 ± 4.0
p = 0.180
Serum Cl (mEq/L)
102.6 ± 4.0
103.0 ± 3.0
p = 0.434
103.1 ± 3.6
p = 0.504
103.0 ± 3.2
p = 0.743
Serum K (mEq/L)
4.4 ± 0.7
4.4 ± 0.7
p = 0.873
4.3 ± 0.6
p = 0.415
4.3 ± 0.6
p = 0.626
Serum Ca (mg/dL)
9.2 ± 0.6
9.1 ± 0.6
p = 0.159
9.2 ± 0.6
p = 0.608
9.2 ± 0.6
p = 0.499
Serum IP (mg/dL)
4.7 ± 1.5
4.5 ± 1.6
p = 0.123
4.0 ± 1.3
p < 0.001
3.8 ± 1.1
p < 0.001
Geriatric nutritional risk index
85.6 ± 12.8
85.4 ± 11.9
p = 0.501
86.2 ± 11.9
p = 0.220
86.4 ± 11.1
p = 0.061
This study showed that lubiprostone not only improved bowel control but also decreased serum IP levels in hemodialysis patients.
Hemodialysis patients have a high prevalence of constipation due to dietary restriction, fluid restriction, and use of phosphate binders . It has been reported that constipation is associated with an increased risk of death from cardiovascular disease (CVD) , suggesting the importance of bowel control in dialysis patients, who have a high risk of death from CVD . Lubiprostone is a novel laxative that promotes defecation by activating ClC-2 on the apical membrane of the small intestinal epithelium, thereby increasing water secretion into the intestinal lumen to soften feces and enhance intestinal transit. In the present study, lubiprostone increased the mean weekly stool frequency and the Bristol Stool Form Scale score, showing its usefulness in bowel control of dialysis patients.
Lubiprostone decreased serum IP levels in hemodialysis patients. A report evaluating the safety of lubiprostone in patients with chronic constipation found no change in serum electrolytes, including Na, K, and Cl, before and after administration, although serum IP values were not measured . In a study in mice, urinary toxins including BUN, indoxyl sulfate, and hippurate were reported to decrease with lubiprostone administration , which the authors speculated was due to lubiprostone-induced recovery of imbalances in the gut microbiota. The decrease in serum IP values in our study might have involved similar effects. Alternatively, the decrease might have been due to improved adherence to oral phosphate binders associated with improved bowel control following administration of lubiprostone, albeit that the oral intake of phosphorus adsorption drugs before and after lubiprostone administration was not confirmed. Decreased food intake and/or nutritional status due to nausea and/or anorexia caused by lubiprostone might also have been responsible for the decrease in serum IP, but this is implausible given the lack of change from baseline in GNRI after treatment with lubiprostone.
Since it has been reported that constipation was associated with an increased risk of death from CVD , bowel control may decrease the risk of death from CVD in dialysis patients. In addition, hyperphosphatemia not only induces secondary hyperparathyroidism and related abnormal bone metabolism but also increases the risk of cardiovascular complications and death through vascular calcification . Serum IP control is therefore recommended to improve prognosis . As such, lubiprostone may improve long-term life prognosis if it is indeed effective in controlling serum IP levels.
Several limitations of the present study warrant mention. First, our study was not designed to compare treated and untreated patients, as all patients received lubiprostone. Second, the study was a small, single-center study with a short follow-up. A definitive conclusion on the utility of lubiprostone in hemodialysis patients will require larger, longer-term studies.
Lubiprostone not only improved bowel control but also decreased serum IP levels in hemodialysis patients. Lubiprostone may improve the prognosis of hemodialysis patients by improving bowel control and decreasing serum IP.
SG planned the study, searched the literature, and prepared the article. KN and NI assisted in the article preparation. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
This prospective observational study was approved by the Ethics Review Board of Saitama Sekishinkai Hospital, and the study protocol conformed to the provisions outlined in the Declaration of Helsinki (as revised in Tokyo 2004).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Yasuda G, Shibata K, Takizawa T, Ikeda Y, Tokita Y, Umemura S, et al. Prevalence of constipation in continuous ambulatory peritoneal dialysis patients and comparison with hemodialysis patients. Am J Kidney Dis. 2002;39:1292–9.View ArticlePubMedGoogle Scholar
- Guerrera MP, Volpe SL, Mao JJ. Therapeutic uses of magnesium. Am Fam Physician. 2009;80:157–62.PubMedGoogle Scholar
- Locke 3rd GR, Pemberton JH, Phillips SF. AGA technical review on constipation. American Gastroenterological Association. Gastroenterology. 2000;119:1766–78.View ArticlePubMedGoogle Scholar
- Yoshida T, Furukubo T, Tanaka C, Miyake M, Sumino K, Tanaka R, et al. Clinical efficacy of lubiprostone for constipation in patients undergoing maintenance hemodialysis. J Osaka Soc Dial Ther. 2014;32:29–32.Google Scholar
- Bouillanne O, Morineau G, Dupomt C, Coulombel I, Vincent JP, Nicolis I. Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr. 2005;82:777–83.PubMedGoogle Scholar
- Honkura K, Tomata Y, Sugiyama K, Kaiho Y, Watanabe T, Zhang S, et al. Defecation frequency and cardiovascular disease mortality in Japan: the Ohsaki cohort study. Atherosclerosis. 2016;246:251–6.View ArticlePubMedGoogle Scholar
- Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol. 1998;9:S16–23.PubMedGoogle Scholar
- Lembo AJ, Johanson JF, Parkman HP, Rao SS, Miner Jr PB, Useno R. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci. 2011;56:2639–45.View ArticlePubMedPubMed CentralGoogle Scholar
- Mishima E, Fukuda S, Shima H, Hirayama A, Akiyama Y, Takeuchi Y, et al. Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD. J Am Soc Nephrol. 2015;26:1787–94.View ArticlePubMedGoogle Scholar
- Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcome and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2008;52:519–30.View ArticlePubMedGoogle Scholar
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76:S1–130.Google Scholar