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NDT Advance Access published online on November 7, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn617
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Intestinal bacterial overgrowth in CAPD patients with hypokalaemia

Kuo-Hsiung Shu1,2, Chi-Sen Chang2,3, Ya-Wen Chuang1, Cheng-Hsu Chen1, Chi-Hung Cheng1,2, Ming-Ju Wu1,2 and Tung-Min Yu1

1 Division of Nephrology 2 Department of Medicine 3 Division of Gastroenterology, Taichung Veterans General Hospital, Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan

Correspondence and offprint requests to: Kuo-Hsiung Shu, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. Tel: +886-4-23592525, Ext. 3040; Fax: +886-4-23594980; E-mail: khshu{at}vghtc.gov.tw



   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Objective. We have previously demonstrated that hypokalaemia is a risk factor for enteric peritonitis in CAPD patients. The underlying mechanism is unclear, and there have been no similar reports. We hypothesized that hypokalaemia may result in dysmotility of the intestinal tract and in turn cause bacterial overgrowth and subclinical translocation of enteral bacteria.

Methods. Uraemic patients undergoing CAPD in our hospital were enrolled in the study. Hypokalaemia was defined as a serum potassium (K) level ≤ 3.5 mEq/L despite treatment for 1 month. A breath hydrogen test (BHT) was performed to detect if intestinal bacterial overgrowth was present. Blood samples were also collected for the study of inflammatory cytokines, including interleukin 1 (IL1), IL2, IL6, IL8, TNF-{alpha} and {gamma}-IFN.

Results. A total of 68 patients were recruited. Hypokalaemia was present in 18 cases (26.5%, group 1), while 50 cases (group 2) had normal serum K levels. A higher prevalence of abnormal BHT was found in group 1 (27.8%), compared with group 2 (8.0%, P = 0.048). There was a trend towards a higher prevalence of abnormal BHT in diabetes mellitus (DM) patients with hypokalaemia (80.0%) compared with normal kalaemia (22.2%, P = 0.09), while no similar trends were found in non-DM hypokalaemic patients (7.7 versus 4.9%). When comparisons were made among different subgroups, patients with DM and hypokalaemia had a significantly higher prevalence of abnormal BHT compared to non-DM, normokalaemic patients (P < 0.0004) and non-DM, hypokalaemic patients (P = 0.008). Multivariate logistic regression analysis revealed that DM was an independent risk factor for abnormal BHT (odds ratio: 12.39, 95% CI: 2.25–68.20, P = 0.004). There was no significant difference in serum albumin, Kt/V, weekly creatinine clearance, pattern of peritoneal equilibrium test, C-reactive protein and various inflammatory cytokines between the two groups.

Conclusion. CAPD patients with hypokalaemia may have intestinal bacterial overgrowth. While both DM and hypokalaemia might contribute to this abnormality, only DM appeared to be the independent risk factor.

Keywords: diabetes mellitus; hypokalaemia; intestinal bacterial overgrowth; peritoneal dialysis



   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
Hypokalaemia, rarely found in HD patients, is relatively common among CAPD patients, and the prevalence ranges between 10 and 36% [1–3]. In our hospital, the prevalence of hypokalaemia among CAPD was between 21.6% and 26.4% in the past 3 years, while 8.2–11.3% of patients had serum potassium levels lower than 3.0 mEq/L [4]. The aetiology of hypokalaemia was multifactorial and might include an intracellular shift, loss via dialysate and poor nutrition [5–7]. In a previous study [8], we have shown that the fasting insulin level was significantly higher in CAPD patients with hypokalaemia. The consequences of hypokalaemia are multiple and may be associated with increased morbidity and mortality [7]. We have previously demonstrated that CAPD patients with hypokalaemia may have an increased incidence of peritonitis; in particular, the bacteria are mostly originated from the intestine [9]. Because hypokalaemia is usually associated with malnutrition [7], defence against bacteria may be dampened. On the other hand, hypokalaemia may compromise intestinal motility that in turn causes bacterial overgrowth. Therefore, we hypothesized that bacteria may translocate from intestinal lumen to the peritoneal cavity and predispose to the occurrence of peritonitis in CAPD patients with hypokalaemia. The aim of the current study was to test if hypokalaemia results in intestinal bacterial overgrowth and if a state of inflammation exists in these patients.



   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
Uraemic patients undergoing CAPD for more than 3 months with regular follow-up in our hospital were enrolled for the study. Informed consent was obtained from each patient, and the study was approved by the institutional review board. The exclusion criteria were (1) active infection, (2) malignancy, (3) taking drugs that interfere with gastrointestinal motility, (4) intestinal obstruction and (5) scleroderma and other diseases that would be expected to affect gastrointestinal motility. A persistent serum potassium level ≤ 3.5 mEq/L despite treatment with potassium chloride tablets and/or encouraging taking potassium-rich food for 1 month was defined as hypokalaemia. The serum potassium level was checked monthly along with other biochemical studies in our hospital. Most of the patients had four exchanges per day, using the Dianeal® solution (Baxter Healthcare, Singapore) with various glucose concentrations depending on clinical situation. Icodextrin®(Baxter Healthcare), given in the night, was added to the prescription in patients with ultrafiltration failure. Patients were routinely followed up every month and blood samples obtained for biochemistry, glucose and complete blood counts. A peritoneal equilibration test (PET) was routinely performed 1 month after the initiation of CAPD and every 6 months thereafter.

A breath hydrogen test (BHT) was conducted for each patient. This procedure has been previously described [10]. Briefly, patients were asked to avoid foods with high complex carbohydrates such as bread and pasta in the evening before the test. After overnight fasting, two basal samples of end-expiratory breath were collected 15 min apart before the test meal. The test meal consisted of 50 g of glucose in 100 mL water. Once the subject had finished the test meal, breath samples were collected at 15-min intervals for 3 h. The samples were obtained in duplicates and analysed by gas chromatography (Mode 12 Microlyzer, Quintron Instrument, Milwaukee, WI, USA). The concentrations of hydrogen expressed in ppm were recorded for each sample. An abnormal BHT was defined as an increase in breath hydrogen excretion of at least 12 ppm above the baseline, as well as increased breath hydrogen levels in the fasting state.

Fasting venous blood samples were also taken for the determination of high-sensitive C-reactive protein (hs-CRP) by particle-enhanced immunonephelometry (Dade Behring, Germany) and interlukin 1 (IL-1), IL-2, IL-6, IL-8, tumour necrosis factor-{alpha} and interferon-{gamma} by using commercially available ELISA kits (eBioscience, CA, USA).

For statistical analysis, data were expressed as mean with standard deviation unless otherwise specified. Categorical data were compared between hypokalaemic and normokalaemic groups using the chi-square test with Yates’ correction or Fisher's exact test. Continuous data were compared with the t-test or the Mann–Whitney U-test as appropriate. Multivariate logistic regression analysis was performed to evaluate the independent risk factors contributing to abnormal BHT. A P-value of <0.05 was considered significant.



   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
This study was carried out over a 3-month period in late 2006. The total number of prevalent CAPD patients was 97. Seventeen patients did not give their consents for the study due to various reasons; 12 cases were excluded due to active infection (n = 7), malignancy (n = 1) and taking drugs that might affect gastrointestinal motility (n = 4). The remaining 68 patients (male:female = 29:39) were enrolled in the study. The demographic data are shown in Table 1. There was no statistically significant difference between the two groups in terms of gender distribution, age, CAPD duration, presence of diabetes mellitus (DM), prevalence of hepatitis B or C virus infection, peritoneal membrane transport characteristics, Kt/V, weekly creatinine clearance, serum albumin and use of drugs that might affect serum potassium level (i.e. diuretics, angiotensin converting enzyme inhibitor and angiotensin receptor blocker). In addition to encouraging taking potassium-rich food in all hypokalaemic patients, 55.6% of this group also received potassium chloride supplement. The hypokalaemic group had significantly lower serum phosphorus levels (4.57 ± 0.96 versus 5.33 ± 1.21 mg/dL, P = 0.019). The data of inflammatory biomarkers are depicted in Table 2. There was no statistically significant difference between the two groups in the blood levels of CRP, IL-1, IL-2, IL-6, IL-8, tumour necrosis factor-{alpha} and interferon-{gamma}. The hypokalaemic group had a significantly higher prevalence of abnormal BHT (27.8 versus 8.0%, P = 0.048, Figure 1). When patients without DM (n = 54) were analysed, there was no significant difference in the prevalence of abnormal BHT between hypokalaemic and normal kalaemic group (7.7 versus 4.9%, Figure 1). However, when DM patients (n = 14) were analysed, a trend towards a higher prevalence of abnormal BHT in the hypokalaemic group was found (80.0 versus 22.2%, P = 0.09, Figure 1). When comparisons were made among subgroups with different status of DM and serum potassium levels, patients with DM and hypokalaemia had a significantly higher prevalence of abnormal BHT compared to non-DM, normokalaemic patients (P < 0.0004) and non-DM, hypokalaemic patients (P = 0.008) (Figure 2). Multivariate logistic regression analysis revealed that only DM was the independent predictor of abnormal BHT (odds ratio: 12.39, 95% CI: 2.25–68.20, P = 0.004, Table 3).


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  		Table 1 Demographic data

 

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  		Table 2 Bioinflammatory markers

 

Figure 1
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  		Fig. 1 Prevalence of the abnormal breath test among CAPD patients with hypo- and normokalaemia. P-values were obtained separately in each populations, i.e. total case, DM and non-DM.

 

Figure 2
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  		Fig. 2 Comparison of the prevalence of the abnormal breath test among CAPD patients with different status of DM and serum potassium levels.

 

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  		Table 3 Multiple logistic regression analysis for BHT (n = 68)

 


   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
BHT has been studied in various gastrointestinal functional diseases and is a useful tool to determine if there is intestinal bacterial overgrowth [11]. In liver cirrhosis patients with spontaneous bacterial peritonitis, abnormal intestinal motility and bacterial overgrowth have been well documented [10,12]. Furthermore, selective intestinal discontamination with oral antibiotics markedly reduces the recurrence of spontaneous bacterial peritonitis in these patients [13]. Gastrointestinal motility is also impaired in chronic kidney diseases [14,15] and uraemic patients on CAPD [16]. Our previous study [9] showed that CAPD patients with hypokalaemia were associated with a higher peritonitis rate, and interestingly, most of the causative organisms were of intestinal origin. This led to a hypothesis that hypokalaemia might facilitate the translocation of bacteria from intestinal lumen to peritoneal cavity. The association of constipation, hypokalaemia and CAPD peritonitis in a previous report also supports this assumption [17]. The present study showed that hypokalaemic CAPD patients had a slightly higher prevalence of abnormal BHT, implying a state of intestinal bacterial overgrowth. This is compatible with our working hypothesis that hypokalaemia in CAPD patients may have an adverse effect on intestinal motility and cause bacterial overgrowth. However, when non-DM patients were analysed separately, there was no significant difference in the prevalence of abnormal BHT in the hypokalaemic group (7.7%) compared to the normal kalaemic group (4.9%) (Figure 1). Interestingly, when DM patients were analysed, a high prevalence (80.0%) of abnormal BHT was identified in hypokalaemic patients, compared to normokalaemic patients (22.2%), although the difference was not statistically significant (P = 0.09, Figure 1). As the case number was relatively small, it is possible that a significant P-value could be obtained if more patients were enrolled. Nevertheless, it appeared that both DM and serum potassium levels were contributing factors to intestinal bacterial overgrowth in our patients. Indeed, when comparisons were made among different subgroups, DM patients with hypokalaemia had a much higher prevalence of abnormal BHT, compared to non-DM patients with or without hypokalaemia (P = 0.008 and P < 0.0004, respectively, Figure 2). The multivariate logistic regression analysis revealed that DM was the only independent risk factor for abnormal BHT (odds ratio: 12.39, 95% CI: 2.25–68.20, P = 0.004, Table 3). Gastrointestinal dysmotility is a relatively common complication of DM and has been attributed to autonomic nervous system involvement and hyperglycaemia [18]. A previous study also demonstrated abnormal BHT in DM patients [19]. On the other hand, there was no report addressing BHT in hypokalaemic patients before. Hypokalaemia may lead to both structural and functional abnormalities in the gastrointestinal tract [20]. Structurally, oedema of intestinal mucosa and submucosa with lymphocytic engorgement of villi and invasion of Peyer's patches with mononuclear phagocytes can be seen. Functionally, decreased motility and propulsive activity of the intestine is a common consequence of hypokalaemia and may lead to paralytic ileus. Figure 1 showed a big difference, although not statistically significant, in the prevalence of abnormal BHT between hypokalaemic and normokalaemic DM patients that argues for the importance of hypokalaemia in the pathogenesis of intestinal bacterial overgrowth in DM patients. In multivariate regression analysis, the odds ratio for abnormal BHT in hypokalaemic patients was 4.37, although the P-value was 0.09, which was not statistically significant. Because the case number of the hypokalaemic group was relatively small (n = 18), the clinical significance of hypokalaemia needs to be tested in the future with a larger population.

There was no statistically significant difference in CRP and various inflammatory cytokines between the two groups. Intestinal bacterial overgrowth may not necessarily result in bacterial translocation. All of our patients were in a stable condition without any sign of peritonitis; hence, bacterial translocation was negligible if it existed. It is possible that a subtle stimulus may not trigger a bright immune response, and therefore no significant increase in cytokine production can be detected. Nevertheless, a more sensitive method of measurement such as mRNA expression in the peritoneal effluent may give a more meaningful result.

In conclusion, we have demonstrated that a significant proportion of DM and hypokalaemia CAPD patients had abnormal BHT, implying a status of intestinal bacterial overgrowth. While DM is an independent predictor for this abnormality, the role of hypokalaemia may need to be examined with a larger population. A further study to demonstrate the direct evidence of bacterial translocation in such patients is warranted to support our hypothesis.



   Acknowledgments
 
This work was supported by a research grant from Taichung Veterans General Hospital, TCVGH-963602C. The authors wish to express their thanks to the biostatistics task force, Taichung Veterans General Hospital, Taichung, Taiwan, ROC, for their assistance in statistical analysis.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

  1. Khan AN, Bernardini J, Johnston JR, et al. Hypokalemia in peritoneal dialysis patients. Perit Dial Int (1996) 16:652–653.[Free Full Text]
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  3. Rostand SG. Profound hypokalemia in continuous ambulatory peritoneal dialysis. Arch Intern Med (1983) 143:377–378.[Abstract/Free Full Text]
  4. Annual report on Dialysis, 2005–2007. Division of Nephrology, Taichung Veterans General Hospital, Taiwan.
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  6. Newman LN, Weiss MF, Berger J, et al. The law of unintended consequences in action: increase in incidence of hypokalemia with improved adequacy of dialysis. Adv Perit Dial (2000) 16:134–137.[Medline]
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  8. Wang C-L, Yang T-C, Shu K-H, et al. Hypokalemia in patients undergoing continuous ambulatory peritoneal dialysis. Acta Nephrologica (2008) 22:16–19.
  9. Chuang Y-W, Chen C-H, Cheng C-H, et al. Hypokalemia is a risk factor for enteric peritonitis in patients undergoing continuous ambulatory peritoneal dialysis. Acta Nephrologica (2007) 21:104–111.
  10. Chang CS, Chen GH, Lien HC, et al. Small intestinal dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology (1998) 28:1187–1190.[CrossRef][Web of Science][Medline]
  11. Simrén M, Stotzer PO. Use and abuse of hydrogen breath tests. Gut (2006) 55:297–303.[Abstract/Free Full Text]
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  16. Stompór T, Hubalewska-Hola A, Staszczak A, et al. Association between gastric emptying rate and nutritional status in patients treated with continuous ambulatory peritoneal dialysis. Perit Dial Int (2002) 22:500–505.[Abstract/Free Full Text]
  17. Singharetnam W, Holley JL. Acute treatment of constipation may lead to transmural migration of bacteria resulting in Gram-negative, polymicrobial, or fungal peritonitis. Perit Dial Int (1996) 16:423–425.[Free Full Text]
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  19. Urita Y, Ishihara S, Akimoto T, et al. Seventy-five gram glucose tolerance test to assess carbohydrate malabsorption and small bowel bacterial overgrowth. World J Gastroenterol (2006) 12:3092–3095.[Web of Science][Medline]
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Received for publication: 29. 2.08
Accepted in revised form: 8.10.08


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