Abstract
Purpose
Bowel habits may affect the prognosis in the chronic kidney disease (CKD) patients. This study aimed to explore the association of bowel habits with cardiovascular and all-cause mortality in CKD.
Methods
2460 CKD patients in the National Health and Nutrition Examination Survey (NHANES) from 2005 through 2010 without missing data for bowel habits and mortality were enrolled. Bowel habits including bowel movements (BMs) per week and stools consistency were obtained by standard interview. Mortality status and cause of death were determined by NHANES-linked National Death Index records through 31 December 2015. Cox proportional hazard models and Kaplan-Meier analysis were used to evaluate the association of bowel habits with cardiovascular and all-cause mortality.
Results
A total of 2460 CKD patients with an average age of 60.80 ± 0.57 years were enrolled. During an average follow-up of 87.47 ± 0.98 months, 144 cardiovascular and 669 all-cause deaths were documented. Reporting 3 or fewer BMs per week was associated with cardiovascular (HR = 1.83, 95% CI: 1.06, 3.17) and all-cause mortality (HR = 1.71, 95% CI: 1.20, 2.43). More than 10 BMs per week also increased the risk of all-cause mortality (HR = 1.21, 95% CI: 1.01, 1.45). Hard stools consistency increased the risk of all-cause mortality (HR= 2.00, 95% CI: 1.48, 2.70) compared with those reporting normal stools.
Conclusion
Low stool frequency and hard stool consistency were associated with an increased risk of mortality in patients with CKD.
Keywords: Bowel habits, defecation, stool, chronic kidney disease, mortality
1. Introduction
Chronic kidney disease (CKD) is characterized as a condition of renal structural and functional abnormalities. It has been reported that more than 14% of US adults have CKD, and the prevalence is still increasing [1]. In addition, the public health and significant economic burden of CKD is growing rapidly worldwide. As kidney function declines, CKD patients can develop anemia, mineral and bone disorders, acidosis, and other complications [2]. The exploration of risk factors for poor prognosis in CKD patients holds immense significance due to the potential for early detection and intervention, which can effectively mitigate complications and extend survival time.
Gastrointestinal disturbances are commonly observed in CKD, particularly constipation. Several clinical features of CKD patients may lead to an increased prevalence of constipation, such as a severely restricted diet, limited intake of liquid, frequent use of phosphate binders and other constipation-inducing medications, alteration of intestinal flora, and accumulation of uremic toxins [3,4]. Ruszkowski et al. discovered a high occurrence of constipation among non-dialysis CKD patients, with prevalence rates of 31.8% in CKD stage 1–2, 29.8% in CKD stage 3, and 38.8% in CKD stage 4–5 [5]. They also observed that self-reported constipation consistently correlated with poorer health-related quality of life, while the presence of hard stool consistency was linked to elevated levels of uremic toxins [5]. In CKD patients undergoing dialysis, the gastrointestinal symptoms that were found to be most prevalent included constipation, indigestion, abdominal pain, and reflux. Notably, constipation was observed to be more frequently experienced by individuals undergoing hemodialysis compared to those undergoing peritoneal dialysis [6]. In veterans with normal kidney function, constipation increased the risk of coronary heart disease, ischemic stroke and all-cause mortality by 11%, 19% and 12%, respectively [7]. In addition, Sumida et al. documented a positive correlation between constipation and the occurrence of chronic kidney disease (CKD), end-stage renal disease (ESRD), as well as the progressive decline in estimated glomerular filtration rate (eGFR) [8]. All these results indicated that bowel habits could affect renal health, whereas it is still unclear whether bowel habits could affect the prognosis of CKD patients.
To our knowledge, the association between bowel habits, including the frequency of bowel movements (BMs) and stool consistency, and prognosis in the CKD population has never been studied. Thus, using data from the National Health and Nutrition Examination Survey (NHANES), we aimed to explore the association between bowel habits with cardiovascular and all-cause mortality in CKD patients in the United States. We hypothesized that both lower stool frequency and hard stool consistency could increase the risk of mortality.
2. Methods
2.1. Survey population
NHANES is a national health survey conducted by the National Center of Health Statistics, Centers for Disease Control and Prevention. It evaluated the nutrition and health status of a noninstitutionalized civilian population in the US with a complex, multistage, probability cluster design. Nationally representative health-related data were obtained by in-home interviews, physical examinations and laboratory tests in a mobile examination center (MEC). All detailed NHANES study designs and data are publicly available at www.cdc.gov/nchs/nhanes/.
The NHANES survey cycle from 2005 to 2010 enrolled 31034 participants in total. Our study included all participants who underwent an in-home interview about bowel habits and had complete data to determine CKD status at first (n = 13774). We further excluded participants without CKD (n = 11314) for a final sample size of 2460 CKD patients with complete data about bowel habits and their mortality status, which represented approximately 24.06 million noninstitutionalized residents of the United States.
The National Center of Health Statistics ethics review broad approved all NHANES study protocols, and written informed consent was obtained from each participant.
2.2. Diagnosis of Chronic kidney disease
Blood specimens and random urine samples were obtained from participants in MEC. Serum creatinine was determined using the modular chemistry side of a Beckman Coulter DxC800 with the Jaffe reaction method (kinetic alkaline picrate) [9]. It was noting that the correction of creatinine concentrations from 2005–2006 NHANES data was used as recommended by NHANES. Standard creatinine (mg/dL) was calculated as −0.016 + 0.978*(NHANES 05-06 uncalibrated serum creatinine, mg/dL). Urinary creatinine by the Jaffe rate reaction and urinary albumin by solid-phase fluorescent immunoassay were used to calculate the urinary albumin: creatinine ratio (ACR) [10]. Data about age, gender, race and serum creatinine were used to calculate eGFR according to the CKD Epidemiology Collaboration (CKD-EPI) equation for each participant [11]. CKD was defined as the presence of either albuminuria (ACR >30 mg/g) or low-eGFR (eGFR <60 mL/min/1.73m2) according to Kidney Disease: Improving Global Outcomes 2012 recommendations [12].
2.3. Measurement of bowel habits
Bowel habits were assessed using the question ‘How often do you usually have bowel movements?’ (stool frequency) and the Bristol Stoll Form Scale, which asked participants to identify their typical stool type using a visual card (stool consistency) through an in-home standard interview by NHANES trained staff. We categorized stool frequency per week into low (3 or fewer bowel movements), intermediate (4 to 10 bowel movements) and high (more than 10 bowel movements) according to previous studies [13]. Stool consistency was categorized into hard stools (types 1 and 2), normal stools (types 3 and 4) and loose stools (types 5, 6 and 7) based on the Bristol Stool Form Scale [14].
2.4. Definitions of covariates
Demographic covariates in our study included gender (male/female), age (years), race (Mexican American/other Hispanic/non-Hispanic White/non-Hispanic Black/other races), education level (less than high school/high school or general educational development/above high school/others) and family income-poverty ratio (<1, 1–2.9, ≥3). Body mass index (BMI, kg/m2) was calculated as weight in kilograms divided by height in meters squared. We categorized BMI as <25, 25–29.9 and ≥30 kg/m2, which corresponded to normal weight, overweight and obese populations [15]. Triglycerides (mg/dL) was determined by a timed-endpoint method using a Beckman Coulter DxC800. Hemoglobin Alc (%) was measured by calculating the change in absorbance at 415 nm using A1c 2.2 Plus Glycohemoglobin Analyzer (Tosoh Medics, Inc., So. San Francisco) in NHANES 2005-2006 and A1c G7 HPLC Glycohemoglobin Analyzer (Tosoh Medics, Inc., So. San Francisco, Ca 94080.) in NHANES 2007–2010. Smoking status was classified as never or former or current according to the responses to the questions ‘Have you smoked at least 100 cigarettes during your entire life?’ and ‘Do you smoke cigarettes now?.’ The health condition variables composed of hypertension (yes/no) and diabetes (yes/no) were also included. Diabetes was defined as self-reported, doctor-diagnosed diabetes or a hemoglobin A1c level ≥6.5%. Hypertension was defined as self-reported, doctor-diagnosed hypertension or having three consecutive systolic blood pressure measurements ≥140 mmHg or diastolic blood pressure ≥ 90 mmHg. All detailed measurement processes of these variables are publicly available at www.cdc.gov/nchs/nhanes/.
2.5. Ascertainment of all-cause and cardiovascular mortality
Mortality status for each participant was ascertained by the death certificate records from the National Death Index. This linked mortality file for NHANES included follow-up time and underlying cause of death for participants aged ≥18 years through 31 December 2015. Cardiovascular mortality was defined as any death related to heart disease or cerebrovascular disease (International Statistical Classification of Diseases and Related Problems, Tenth Revision codes I00 to I09, I11, I13, I20 to I51, and I60 to I69). A detailed description of the linkage method and analytic guidelines are publicly available at www.cdc.gov/nchs/data/datalinkage/public-use-2015-linked-mortality-files-data-dictionary.pdf.
2.6. Statistical analysis
Accounting for the complex sampling design of NHANES, all analyses incorporated sampling weights to obtain estimates from the complex NHANES survey that were generalizable to the U.S. population. In descriptive analyses, continuous variables were represented as the means with standard error (SE), and categorical parameters were presented as proportions according to both diabetes and PN status. Either a weighted Student’s t test (for continuous variables) or weighted chi-square test (for categorical variables) was employed to evaluate the differences among participants grouped by their mortality status. Kaplan-Meier survival curves and log-rank tests for cardiovascular and all-cause mortality stratified by stool frequency and stool consistency were employed with the adjustment of age, race, education level, family income-poverty ratio, body mass index, triglycerides, hemoglobin A1c, eGFR, smoking, hypertension and diabetes status. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between bowel habits and cardiovascular and all-cause mortality in CKD adults. Intermediate stool frequency (4 to 10 bowel movements per week) and normal stools (types 3 and 4) were set as a reference for calculating HRs. All models were adjusted for age, race, education level, family income-poverty ratio, body mass index, triglycerides, hemoglobin A1c, eGFR, smoking, hypertension and diabetes status. Missing values were imputed by themedian for continuous variables or mode for categorical variables of existing cases of those variables. All analyses were performed using R version 3.6.3 (http://www.R-project.org, The R Foundation) and Empower software (www. empowerstats.com; X&Y Solutions, Inc., Boston MA). A two-sided p < 0.05 was considered statistically significant.
3. Results
3.1. Baseline Characteristics of participants
A total of 2460 CKD participants with an average age of 60.80 ± 0.57 years were enrolled, of whom 43.10% were male and 56.90% were female, which represented approximately 24.06 million residents in the US. Participants who were still alive were more likely to be younger, female, have an above-high school education, have a family income-poverty ratio ≥ 3, have a higher eGFR and a lower urinary ACR. Participants who died were also more commonly former smokers, overweight, hypertension and diabetes. The baseline characteristics of the study CKD population are shown in Table 1. The number (unweighted) and prevalence (weighted) of stool frequency and stool consistency according to CKD stages are shown in Table 2. The prevalence of constipation (low stool frequency and hard stool consistency) was highest in end-stage CKD, especially in CKD G5 (low stool frequency: 16.14%, hard stool consistency: 14.46%) and G4-5 A3 (low stool frequency:19.22%, hard stool consistency: 8.74). More detailed stool frequency according to CKD stages are shown in Supplementary Table 1.
Table 1.
Baseline Characteristics of participants who were still alive versus deceased by 31 December 2015.
| Overall | Still alive | Deceased | p value | |
|---|---|---|---|---|
| No. (Unweighted) | 2460 | 1791 | 669 | |
| Age (years), ± SE | 60.80 ± 0.57 | 57.27 ± 0.60 | 72.38 ± 0.58 | <0.001 |
| Gender, % (SE) | ||||
| Male | 43.10 (1.21) | 41.13 (1.29) | 49.58 (2.11) | <0.001 |
| Female | 56.90 (1.21) | 58.87 (1.29) | 50.42 (2.11) | |
| Race, % (SE) | ||||
| Mexican American | 6.90 (1.00) | 7.90 (1.08) | 3.63 (0.90) | <0.001 |
| Other Hispanic | 4.07 (0.61) | 4.81 (0.69) | 1.63 (0.69) | |
| Non-Hispanic White | 73.70 (1.98) | 71.16 (2.14) | 82.05 (2.22) | |
| Non-Hispanic Black | 11.60 (1.16) | 11.86 (1.22) | 10.76 (1.59) | |
| Other Races | 3.73 (0.55) | 4.28 (0.69) | 1.93 (0.66) | |
| Education level, % (SE) | ||||
| Less than high school | 25.46 (1.36) | 23.10 (1.44) | 33.23 (1.67) | <0.001 |
| High school or GED | 27.03 (1.56) | 26.66 (1.66) | 28.26 (2.07) | |
| Above high school | 47.51 (2.01) | 50.25 (2.11) | 38.51 (2.43) | |
| Family income-poverty ratio, % (SE) | ||||
| < 1 | 13.25 (0.92) | 12.86 (0.95) | 14.53 (1.86) | <0.001 |
| 1-2.9 | 45.26 (1.46) | 41.72 (1.46) | 57.03 (2.37) | |
| ≥ 3 | 41.49 (1.70) | 45.42 (1.68) | 28.43 (2.94) | |
| Smoking status, % (SE) | ||||
| Never | 51.56 (1.23) | 54.73 (1.49) | 41.15 (2.48) | <0.001 |
| Former | 31.60 (1.16) | 28.46 (1.15) | 41.92 (2.53) | |
| Current | 16.84 (0.94) | 16.81 (1.07) | 16.93 (1.45) | |
| Body mass index, % (SE) | ||||
| Normal Weight | 26.60 (1.09) | 26.11 (1.38) | 28.29 (1.96) | 0.03 |
| Overweight | 30.86 (1.14) | 29.69 (1.47) | 34.80 (2.20) | |
| Obese | 42.54 (1.19) | 44.20 (1.45) | 36.91 (2.15) | |
| Hypertension, % (SE) | 67.38 (1.16) | 62.01 (1.41) | 85.01 (1.30) | <0.001 |
| Diabetes, % (SE) | 27.60 (1.31) | 25.02 (1.44) | 36.09 (2.00) | <0.001 |
| Triglycerides (mg/dL), ± SE | 175.78 ± 3.56 | 177.88 ± 4.25 | 168.82 ± 5.23 | 0.2 |
| Hemoglobin Alc (%), ± SE | 6.01 ± 0.04 | 5.98 ± 0.04 | 6.11 ± 0.06 | 0.06 |
| eGFR (ml/min/1.73 m2) | 71.33 ± 0.92 | 75.96 ± 1.07 | 56.09 ± 1.10 | <0.001 |
| urinary albumin/creatinine ratio (mg/g), ± SE | 185.21 ± 16.67 | 146.26 ± 13.70 | 313.29 ± 53.69 | 0.004 |
Abbreviations: SE: standard error; GED: general educational development; eGFR: estimate glomerular filtration rate.
Table 2.
The no. (unweighted) and prevalence (weighted) of stool frequency and stool consistency according to CKD stages.
| Stool frequencya |
Stool consistencyb |
|||||
|---|---|---|---|---|---|---|
| Low | Intermediate | High | Hard | Normal | Loose | |
| CKD stages according to eGFRc. No., % (SE) | ||||||
| G1 | 57, 9.67 (1.19) | 326, 51.15 (2.47) | 274, 39.18 (2.47) | 44, 6.61 (0.98) | 464, 70.66 (2.63) | 149, 22.72 (2.28) |
| G2 | 37, 7.20 (1.47) | 334, 61.61 (2.27) | 177, 31.19 (2.02) | 50, 8.13 (1.50) | 393, 74.74 (2.01) | 105, 17.13 (2.36) |
| G3 | 98, 9.22 (1.13) | 693, 63.38 (1.36) | 343, 27.40 (1.40) | 86, 7.34 (0.99) | 854, 77.71 (1.63) | 194, 14.95 (0.97) |
| G4 | 10, 9.56 (2.97) | 58, 67.11 (6.05) | 22, 23.33 (4.91) | 5, 6.04 (2.53) | 67, 74.23 (6.56) | 18, 19.73 (5.27) |
| G5 | 4, 16.14 (8.08) | 17, 55.16 (10.62) | 10, 28.70 (9.87) | 6, 14.46 (6.00) | 18, 63.02 (9.21) | 7, 22.53 (8.49) |
| P for trend | 0.78 | <0.01 | <0.01 | 0.58 | 0.07 | 0.01 |
| CKD stages according to urinary albumin/creatinine ratiod. No., % (SE) | ||||||
| A1 | 71, 9.48 (1.24) | 528, 63.92 (1.49) | 244, 26.60 (1.66) | 64, 7.58 (1.13) | 638, 77.98 (1.84) | 141, 14.45 (1.20) |
| A2 | 107, 8.20 (0.85) | 751, 56.97 (1.47) | 492, 34.82 (1.47) | 107, 7.37 (0.86) | 959, 72.45 (1.78) | 284, 20.18 (1.64) |
| A3 | 28, 11.44 (2.60) | 149, 58.32 (3.88) | 90, 30.24 (3.54) | 20, 6.22 (1.05) | 199, 76.67 (2.80) | 48, 17.10 (2.68) |
| P for trend | 0.93 | 0.01 | 0.01 | 0.60 | 0.14 | 0.01 |
| CKD stages according to both eGFR and urinary albumin/creatinine ratio. No., % (SE) | ||||||
| G1-2 A2 | 80, 8.40 (0.93) | 574, 55.75 (1.70) | 393, 35.85 (1.66) | 85, 7.65 (1.04) | 730, 71.26 (2.04) | 232, 21.09 (1.93) |
| G1-2 A3 | 14, 9.90 (3.12) | 86, 56.28 (4.94) | 58, 33.82 (4.35) | 9, 4.49 (1.90) | 127, 82.02 (3.51) | 22, 13.49 (3.18) |
| G3 A1 | 68, 9.56 (1.29) | 502, 63.60 (1.50) | 234, 26.84 (1.74) | 61, 7.59 (1.23) | 608, 77.98 (1.91) | 135, 14.42 (1.21) |
| G3 A2 | 23, 7.41 (1.89) | 153, 61.82 (3.81) | 90, 30.77 (3.18) | 19, 5.85 (1.49) | 201, 78.60 (2.69) | 46, 15.55 (2.32) |
| G3 A3 | 7, 10.90 (4.50) | 38, 66.07 (6.42) | 19, 23.02 (5.39) | 6, 9.25 (3.56) | 45, 69.91 (8.98) | 13, 20.84 (8.28) |
| G4-5 A1 | 3, 7.37 (2.84) | 26, 72.16 (7.03) | 10, 20.47 (6.96) | 3, 7.17 (4.37) | 30, 77.79 (9.00) | 6, 15.04 (6.50) |
| G4-5 A2 | 4, 6.73 (3.90) | 24, 66.63 (6.71) | 9, 26.64 (6.10) | 3, 7.90 (4.79) | 28, 72.58 (9.52) | 6, 19.52 (8.64) |
| G4-5 A3 | 7, 19.22 (7.83) | 25, 54.11 (8.91) | 13, 26.67 (7.55) | 5, 8.74 (3.87) | 27, 64.49 (7.53) | 13, 26.78 (7.64) |
| P for trend | 0.33 | <0.01 | <0.01 | 0.95 | 0.17 | 0.12 |
Stool frequency per week was categorized into low (3 or fewer bowel movements), intermediate (4 to 10 bowel movements) and high (more than 10 bowel movements).
Stool consistency was categorized into hard stools (types 1 and 2), normal stools (types 3 and 4) and loose stools (types 5, 6 and 7) according to the Bristol Stool Form Scale.
CKD G1: eGFR ≥ 90 mL/min/1.73 m2; G2: 60 mL/min/1.73 m2 ≤ eGFR < 90 mL/min/1.73 m2; G3: 30 mL/min/1.73 m2 ≤ eGFR < 60 mL/min/1.73 m2; G4: 15 mL/min/1.73 m2 ≤ eGFR < 30 mL/min/1.73 m2; G5: eGFR < 15 mL/min/1.73 m2.
CKD A1: urinary albumin/creatinine ratio < 30 mg/g; A2: 30 mg/g ≤ urinary albumin/creatinine ratio < 300 mg/g; A3: urinary albumin/creatinine ratio > 300 mg/g.
3.2. Follow-up and Outcomes
During an average follow-up of 87.47 ± 0.98 months, 669 all-cause deaths were documented, of which 144 were due to cardiovascular causes. The overall outcomes and detailed causes of death were shown in Supplementary Table 2. The cardiovascular mortality and all-cause mortality rates were 4.81% and 23.32%, respectively. The prevalence of cardiovascular death was 5.77%, 5.46%, and 3.29%, and all-cause death was 26.50%, 23.56%, and 21.94% in the low, intermediate and high stool frequency categories, respectively. Participants with hard, normal and loose stool consistency showed cardiovascular mortality rates of 6.52%, 4.65% and 4.75% and all-cause mortality rates of 32.58%, 22.09% and 24.64%, respectively (Table 3).
Table 3.
Cardiovascular and all-cause mortality according to stool frequency and consistency.
| Cardiovascular mortality |
All-cause mortality |
Follow-up time (month) | |||
|---|---|---|---|---|---|
| Events, n/N (Unweighted) | % (SE) | Events, n/N (Unweighted) | % (SE) | Mean ± SE | |
| Overall | 144/2460 | 4.81 (0.51) | 669/2460 | 23.32 (0.82) | 87.47 ± 0.98 |
| Stool Frequencya | |||||
| Low | 16/206 | 5.77 (1.37) | 69/206 | 26.50 (3.67) | 80.99 ± 2.31 |
| Intermediate | 97/1428 | 5.46 (0.62) | 409/1428 | 23.56 (1.02) | 87.49 ± 1.21 |
| High | 31/826 | 3.29 (0.68) | 191/826 | 21.94 (1.64) | 89.27 ± 1.40 |
| Stool Consistencyb | |||||
| Hard | 13/191 | 6.52 (2.40) | 69/191 | 32.58 (4.05) | 82.96 ± 2.45 |
| Normal | 105/1796 | 4.65 (0.56) | 477/1796 | 22.09 (1.19) | 88.69 ± 1.13 |
| Loose | 26/473 | 4.75 (1.06) | 123/473 | 24.64 (2.18) | 84.18 ± 1.70 |
Stool frequency per week was categorized into low (3 or fewer bowel movements), intermediate (4 to 10 bowel movements) and high (more than 10 bowel movements).
Stool consistency was categorized into hard stools (types 1 and 2), normal stools (types 3 and 4) and loose stools (types 5, 6 and 7) according to the Bristol Stool Form Scale.
3.3. Stool frequency and mortality
The Kaplan-Meier analysis with the adjustment of covariates demonstrated that participants with low stool frequency showed the highest risk of cardiovascular mortality (Figure 1, A) and all-cause mortality (Figure 1, B) compared with other categories. Compared with participants with intermediate stool frequency, those reporting 3 or fewer BMs per week showed an 83% increased risk of cardiovascular mortality (HR = 1.83, 95% CI: 1.06, 3.17) and a 71% increased risk of all-cause mortality (HR = 1.71, 95% CI: 1.20, 2.43). We also observed a positive association between high stool frequency (more than 10 bowel movements per week) and all-cause mortality (HR = 1.21, 95% CI: 1.01, 1.45). In addition, high stool frequency was negatively associated with cardiovascular mortality; however, this relationship did not reach statistical significance (HR = 0.80, 95% CI: 0.55, 1.18) (Table 4).
Figure 1.
Kaplan-Meier survival curves (fully adjusted) of cardiovascular mortality (A) and all-cause mortality (B) according to stool frequency.
Table 4.
Hazard ratios (95% CIs) of cardiovascular and all-cause mortality by stool frequency and consistency.
| Cardiovascular mortality | All-cause mortality | |
|---|---|---|
| HRa (95% CIb) | HRa (95% CIb) | |
| Stool Frequencyc | ||
| Low | 1.83 (1.06, 3.17) | 1.71 (1.20, 2.43) |
| Intermediate | 1.00 (Reference) | 1.00 (Reference) |
| High | 0.80 (0.55, 1.18) | 1.21 (1.01, 1.45) |
| Stool Consistencyd | ||
| Hard | 2.05 (0.92, 4.55) | 2.00 (1.48, 2.70) |
| Normal | 1.00 (Reference) | 1.00 (Reference) |
| Loose | 1.19 (0.66, 2.14) | 1.20 (0.90, 1.59) |
All results were calculated using sampling weights and adjusted for age, race, education level, family income-poverty ratio, body mass index, triglycerides, hemoglobin A1c, eGFR, smoking, hypertension and diabetes status.
HR: Hazard ratio;.
95% CI: 95% confidence interval;.
Stool frequency per week was categorized into low (3 or fewer bowel movements), intermediate (4 to 10 bowel movements) and high (more than 10 bowel movements).
Stool consistency was categorized into hard stools (types 1 and 2), normal stools (types 3 and 4) and loose stools (types 5, 6 and 7) according to the Bristol Stool Form Scale.
3.4. Stool consistency and mortality
In Kaplan-Meier survival analysis, the risks for cardiovascular (Figure 2A) and all-cause death (Figure 2B) were highest among CKD patients reporting hard stool. Participants with loose stool consistency also showed poorer survival than those with normal stools. The results from Cox proportional hazard regression analysis are shown in Table 3 for cardiovascular and all-cause mortality. Participants reporting hard stools had a significantly higher risk of all-cause mortality (HR= 2.00, 95% CI: 1.48, 2.70) than those reporting normal consistency. Hard stools were also associated with higher cardiovascular mortality (HR= 2.05, 95% CI: 0.92, 4.55), but the association was not statistically significant. Loose stools increased the hazards of cardiovascular mortality (HR = 1.19, 95% CI: 0.66, 2.14) and all-cause mortality (HR = 1.20, 95% CI: 0.90, 1.59); however, these associations did not meet the level of statistical significance.
Figure 2.
Kaplan-Meier survival curves (fully adjusted) of cardiovascular mortality (A) and all-cause mortality (B) according to stool consistency.
4. Discussion
This study evaluated the relationship between bowel habits and mortality among CKD adults. In our prospective cohort enrolled 2460 patients, we found low stool frequency was significantly associated with increased both cardiovascular and all-cause mortality in CKD patients. Hard stools were also positively associated with a higher risk of all-cause mortality. Our findings underscore the importance of healthy bowel habits for CKD patients, which may reduce all-cause and cardiovascular mortality.
Constipation is generally considered a benign, self-limiting or curable disease, but its chronic and multiple symptoms could negatively affect the quality of life of patients and even lead to some life-threatening diseases [16,17]. Approximately 30% of the general population may have constipation problems, mostly in the elderly and women [18]. Yamamoto et al. found that functional constipation was mainly observed in females, people with a low BMI, and elderly individuals (60–69 years old) in Japan [19]. Several surveys in Europe reported a prevalence of constipation of approximately 20% in adults and 22% in the elderly [20–22]. It has been reported that patients with CKD, especially those in advanced stages, have a higher prevalence of constipation than the general population [23–25]. Numerous studies have focused on the prevalence of constipation in ESRD patients who are treated with peritoneal dialysis (PD) or hemodialysis (HD). Some found that patients receiving HD were more likely to have constipation than those receiving PD [24–26], but a survey that enrolled 5161 dialysis patients (1507 PD and 3804 HD) came to the opposite conclusion [6]. It is worth noting that there is little evidence for the prevalence of constipation in patients with non-dialysis CKD.
To the best of our knowledge, this is the first study to investigate the association between bowel habits and mortality in CKD patients. The relationship of bowel habits with several other diseases has been reported before. It has been reported that constipation could be a good predictor of cardiovascular disease both in postmenopausal and menopausal females [27,28]. An investigation in Japan found that the risk of overall cardiovascular mortality was significantly higher in the 1 time/2-3 days and ≤1 time/4 days groups versus participants in the ≥1 time/day group [29]. In a large observational study in America, higher morbidity of cerebral ischemic stroke and coronary artery disease was associated with constipation as well [7]. Sundbøll et al. suggested that defecation problems were especially associated with a higher risk of ischemic stroke and venous thromboembolism [30]. Furthermore, another similar study of people with normal renal function found that people with constipation had a greater probability of declining eGFR, progression to CKD and even ESRD [8]. In China, a large-scale survey reported that BMs >1 time/day patients had an increased risk of ischemic heart disease (IHD), heart failure, chronic obstructive pulmonary disease, type 2 diabetes mellitus and CKD compared with those in the once a day group. They also found that <3 times/week patients were associated with a higher risk of IHD, major coronary events, ischemic stroke, and CKD [31] However, Ma et al. found no relevance of bowel problems (1 time/5 days) with the risk of cardiovascular events and mortality in US women [32]. Our study focused on patients with CKD and concluded that low stool frequency and hard stool consistency were independently associated with an increased risk of mortality in individuals with CKD, indicating the negative effects of unhealthy bowel habits.
The exact mechanism of constipation in CKD patients is complex and may result from gut dysbiosis, lifestyle, medicine use and so on. Several studies have proven that the intestinal flora of constipated non-CKD patients is marked by a relative reduction in obligate anaerobe (Bifidobacterium genera, Lactobacillus, etc.) and a simultaneous increase in pathogenic microorganisms (Enterobacteriaceae family, etc.) [33,34]. Meanwhile, the concept of the gut-kidney axis is increasingly being accepted. Uremic toxins, such as indoxyl sulfate (IS), trimethylamine-N-oxide (TMAO), and p-cresyl sulfate (PCS), could accumulate in the body, thus inducing oxidative stress and proinflammatory responses [35,36], which may also be related to the pathogenesis of illnesses [37,38]. Additionally, the decrease in saccharolytic leads to the reduction of butyrate and other short-chain fatty acids, which may cause the impairment of the intestinal epithelial barrier [39]. Prior research has demonstrated that the gut microbiota plays a role in the development of cardiovascular disease through a meta-organismal pathway. This pathway involves the gut microbiota-dependent production of trimethylamine and the host hepatic flavin monooxygenase 3-dependent formation of TMAO, a gut-derived uremic toxin which has been mechanistically associated with atherosclerosis and has a strong correlation with cardiovascular disease risks [39,40]. In the CKD population, TMAO is a uremic toxin, and its accumulation is associated with a poor prognosis [35,36]. Elevated blood pressure (BP) is also common in constipation patients. Constipation usually contributes to straining at stool, which is related to the surge of BP [41]. In addition, chronic constipated patients may have psychological stress, which might increase BP as well [42]. It has been reported that the risk of cardiovascular disease doubles when systolic BP increases by 20 mmHg, and manifestations may include acute heart failure due to increased load, heart rupture, and ventricular tachycardia/ventricular fibrillation [41].
Many medications may also lead to constipation, such as 5-hydroxytryptamine receptor blockers, antihypertensive drugs, anticholinergic agents, opioids, antidepressants, anticonvulsants and chemotherapy agents [18]. Since patients with CKD often have some complications, it is difficult to reduce drugs. Previous studies have concluded that high morbidity of hyperkalemia was associated with increasing mortality in CKD population [43]. To avoid hyperkalemia, a low-fiber diet is recommended. Several studies have reported a relationship between low fiber intake and difficult defecation in general population [18]. However, Voderholzer et al. found that dietary fiber supplementation was only effective in some specific kinds of constipation [44]. Hence, the relationship between a low-fiber diet and constipation is not yet clear. Moreover, fiber intake has been shown to reduce cardiovascular and cancer mortality [45]. On the other hand, an investigation revealed that low physical activity is linked to constipation [18]. As the number of defecations decreases, stool stays in the intestine for longer, and the intestine absorbs more water, making it more likely to produce hard stools. All these changes were considered important potential factors of renal functional decline, cardiovascular events and death [46], which may explain what we found in our study.
Our study has several strengths. First, our study was based on data from NHANES with a large sample and a relatively long follow-up. The analysis was conducted considering the appropriate sample weights to make our results more representative. We also adjusted for confounding factors to ensure that our results were reliable. However, limitations cannot be ignored. Although we tried to adjust some potential confounders, we could not eliminate the effects of other possible confounding factors, for example, the use of diuretics and renal replacement therapy including hemodialysis and peritoneal dialysis, fiber intake, physical activity, comorbidities including coronary artery disease, stroke, heart failure, and medications associated with constipation may affect the relationship of constipation and prognosis did not included in our multivariable Cox models as well. For physical activity, since our study included different NHANES cycles, which measure physical activity differently. We think it is unproper to combine physical activity assessed by different methods in our analysis. Thus, we did not include physical activity as a confounding factor. Bowel habits in our study were obtained from patients’ self-statement, and recall bias was inevitable. In addition, the participants in our study are all from the same country and may be ethnically homogenous, which cannot reflect a global or multiethnic group, thus limiting our capacity to extend our findings to the general population or other ethnic groups.
In conclusion, low stool frequency and hard stools increase the risk of mortality among CKD patients. Management of healthy bowel habits for CKD patients may improve their prognosis.
Supplementary Material
Acknowledgement
None.
Funding Statement
None.
Ethics approval and consent to participate
Not applicable.
Authors’ contributions
MH: Data analysis, Writing-Original draft; GD: Conceptualization, Writing-Reviewing and Editing; YY: Methodology; JZ: Methodology. All authors contributed to the article and approved the final version.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Clinical trials registry
Not applicable.
Data availability statement
All data analyzed during this study are available at www.cdc.gov/nchs/nhanes/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data analyzed during this study are available at www.cdc.gov/nchs/nhanes/.