The authors have declared that no competing interests exist.
Conceived and designed the experiments: JS PE. Performed the experiments: LV. Analyzed the data: LT LV. Contributed reagents/materials/analysis tools: YJ YPL YG LT. Wrote the paper: LV LT BM KC JS PE.
Indoxyl sulfate and
Information on clinical determinants and heritability of indoxyl sulfate and
Serum levels of indoxyl sulfate and
Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.
The heritability of indoxyl sulfate and
The human intestinal tract is colonized by hundreds of trillions of microbes, which collectively possess hundreds of times as many genes as coded for by the human genome. The combined genetic potential of the endogenous flora is referred to as the ‘microbiome’
It is increasingly recognized that the microbiome may affect health and disease of the host, e.g. by modulating the immune system, by harvesting energy from the breakdown of otherwise difficult to digest plant glycans, by synthesizing vitamins, by metabolizing xenobiotics or by exposing the host to potentially toxic metabolites
Indoxyl sulfate and
In vitro and ex vivo data show that indoxyl sulfate and
Altogether, these data support the hypothesis that indoxyl sulfate and
To our knowledge, information on the clinical determinants and heritability of indoxyl sulfate and
From August 1985 until November 1990, a random sample of the households living in a geographically defined area of Northern Belgium was invited, with the goal of recruiting equal numbers of participants in each of six subgroups defined by sex and age (20–39, 40–59, and ≥60 years) that would go through repeated examination cycles. The study population included 2,310 subjects. The participation rate among the subjects contacted was 66.1%. The random subsample for the present analysis included 818 subjects invited for a follow-up examination. Our study sample included 112 unrelated subjects and 661 subjects from 80 complex pedigrees with a median size of 5 individuals (range: 2 to 38) and encompassing 1 (n = 18 pedigrees), 2 (n = 45) or 3 (n = 17) generations. In 44 of these participants we did not have serum available for analysis. In addition, indoxyl sulfate and
Subjects were fasted for at least 6 hours. Trained nurses measured blood pressure and anthropometric characteristics. They administered a questionnaire to collect information about each subject's medical history, smoking and drinking habits, and intake of medications. Each participant's office blood pressure was the average of five consecutive readings. Elevated blood pressure was a systolic blood pressure above 140 mmHg and/or 90 mmHg diastolic or use of antihypertensive drug treatment. Body mass index (BMI) was weight in kilograms divided by the square of height in metres. Myocardial infarctions, stroke, transient ischemic attack, coronary bypass surgery, percutaneous angioplasty and peripheral arterial disease were enclosed in the evaluation of cardiovascular complications. Blood glucose, total, HDL and LDL cholesterol, triglycerides, and serum creatinine were also measured in all subjects by routine laboratory methods. Glomerular filtration rate was estimated using the Cockcroft-Gault formula and the creatinine clearance was calculated form 24 hour urinary collections. Serum total indoxyl sulfate and
Unfortunately, individual dietary data are missing in the present cohort. According to a recent national nutritional survey, the mean total energy intake in Belgium for adults between 19–59 years is 2578 and 1680 kcal/day for respectively male and female individuals. Protein, carbohydrate and fat intake is as follows: 16%, 38% and 46%. Data on dietary fiber intake in this survey are lacking, but fruit and vegetable intake, overall, is considered too low as in most Western countries
Statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC, USA). A p-value of less than 0.05 was considered to be statistically significant. Continuous data are presented as mean ± standard deviation and categorical data as frequencies and percentages. Comparison between subjects according to quartiles of indoxyl sulfate or
Characteristics of the participants are summarized in
The vertical line is the limit of quantification.
The dots indicate the geometric means of indoxyl sulfate (IndS) and p-cresyl sulfate (PCS) in decades of age (<30 years, 30–39 years, 40–49 years, 50–59 years, 60–69 years and ≥70 years). The numbers above the horizontal axis are the number of subjects in the various age classes. The curves are calculated from a regression model with log IndS and log PCS as dependent variables and age and age-squared as independent variables. For IndS the P-values of the linear and squared terms were 0.035 and 0.0024 respectively. The corresponding P-values for PCS were 0.070 and 0.004.
Indoxyl Sulfate, µmol/L | |||||
Characteristics | <2.39 (n = 197) | 2.39–3.149 (n = 192) | 3.150–4.275 (n = 192) | >4.275 (n = 192) | |
Characteristic n (%) | |||||
Men | 100 (50.8) | 86 (44.8) | 88 (45.8) | 110 (57.3) | 0.206 |
Hypertension | 67 (33.8) | 77 (40.1) | 77 (40.1) | 97 (50.1) | 0.01 |
Antihypertensive drug intake | 33 (16.8) | 43 (22.4) | 51 (26.6) | 68 (35.4) | <0.0001 |
Diabetes mellitus | 4 (2.0) | 6 (3.1) | 5 (2.6) | 12 (6.3) | 0.044 |
Current smokers | 55 (27.9) | 44 (22.9) | 32 (16.7) | 26 (13.5) | 0.0002 |
Current drinkers | 156 (79.2) | 127 (66.1) | 118 (61.5) | 132 (68.8) | 0.014 |
History of CV disease | 14 (7.1) | 18 (9.4) | 16 (8.3) | 24 (12.5) | 0.106 |
Age-adjusted characteristics | |||||
Body mass index, kg/m2 | 26.2(0.30) | 26.5(0.31) | 26.6(0.30) | 26.8(0.31) | 0.507 |
Systolic blood pressure, mmHg | 129.7(1.04) | 127.7(1.04) | 128.4(1.04) | 132.0(1.05) | 0.023 |
Diastolic blood pressure, mmHg | 80.1(0.64) | 78.9(0.65) | 79.6(0.65) | 81.1(0.65) | 0.104 |
Serum cholesterol, mmol/L | 5.2(0.066) | 5.2(0.066) | 5.2(0.066) | 5.4(0.067) | 0.170 |
Triglycerides, mmol/L | 1.7(0.076) | 1.8(076) | 1.8(076) | 2.2(077) | <0.0001 |
Serum creatinine, µmol/L | 82.4(1.11) | 81.6(1.11) | 82.8(1.11) | 90.3(1.12) | <0.0001 |
Measured creatinine clearance, ml/sec/1.73m2 | 1.7(0.041) | 1.7(0.041) | 1.8(0.041) | 1.7(0.041) | 0.852 |
Calculated creatinine clearance, ml/min/1.73m2 | 93.6(1.63) | 94.9(1.64) | 94.5(1.64) | 90.9(1.65) | 0.304 |
P-value for trend across the quartiles is given. Values are mean (SD) or number of participants (%) as appropriate.
P-Cresyl Sulfate, µmol/L | |||||
Characteristics | <7.36 (n = 188) | 7.36–13.02 (n = 188) | 13.03–21.43 (n = 187) | >21.43 (n = 188) | |
Characteristics n (%) | |||||
Men | 101 (53.7) | 91 (48.4) | 92 (49.2) | 91 (48.4) | 0.35 |
Hypertension | 72 (38.6) | 61 (32.3) | 84 (44.9) | 89 (47.3) | 0.08 |
Antihypertensive drug intake | 40 (21.3) | 30 (16.0) | 56 (29.9) | 60 (31.9) | 0.0012 |
Diabetes mellitus | 6 (3.2) | 2 (1.1) | 9 (4.8) | 7 (3.7) | 0.35 |
Current smokers | 44 (23.4) | 48 (25.5) | 37 (19.8) | 23 (12.2) | 0.0029 |
Current drinkers | 135 (71.8) | 138 (73.4) | 135 (72.2) | 109 (58.0) | 0.0048 |
History of CV disease | 16 (8.5) | 17 (9.0) | 13 (7.0) | 25 (13.3) | 0.20 |
Age-adjusted characteristics | |||||
Body mass index, kg/m2 | 26.6 (0.31) | 26.5 (0.31) | 26.6 (0.31) | 26.3 (0.32) | 0.749 |
Systolic blood pressure, mmHg | 131.0 (1.07) | 128.4 (1.07) | 128.7 (1.06) | 129.5 (1.09) | 0.317 |
Diastolic blood pressure, mmHg | 80.4 (0.67) | 79.7 (0.66) | 80.2 (0.66) | 79.5 (0.68) | 0.775 |
Serum cholesterol, mmol/L | 5.2 (0.068) | 5.2 (0.067) | 5.3 (0.067) | 5.3 (0.069) | 0.960 |
Triglycerides, mmol/L | 1.9 (0.079) | 1.8 (078) | 1.8 (078) | 1.9 (080) | 0.877 |
Serum creatinine, µmol/L | 82.9 (1.16) | 82.7 (1.15) | 83.6 (1.15) | 88.3 (1.18) | 0.0019 |
Measured creatinine clearance, ml/min/1.73m2 | 1.78 (0.041) | 1.71 (0.041) | 1.78 (0.041) | 1.63 (0.042) | 0.041 |
Calculated creatinine clearance, ml/min/1.73m2 | 96.7 (1.66) | 94.4 (1.65) | 94.1 (1.65) | 88.5 (1.68) | 0.0062 |
The P-value for trend across the quartiles is given. Values are mean±SD or number of participants (%) as appropriate.
Current smokers had significantly lower levels of both indoxyl sulfate and
Log Indoxyl sulfate | Log |
|
773 | 751 | |
0.054 | 0.046 | |
0.153 | 0.069 | |
Intercept | 0.268±0.0782*** | 0.916±0.247*** |
Male sex | 0.0302±0.0152 |
0.0945±0.0387 |
Age, years | −0.00461±0.00225 |
−0.0128±0.00605 |
Age squared, years2 | 0.000056±0.000022 |
0.000195±0.000061** |
Current smoking | −0.0379±0.0159 |
NS |
Current alcohol intake | −0.0337±0.0146 |
NS |
Conventional systolic blood pressure | NS | −0.00289±0.00119 |
Log triglycerides, mmol/L | 0.120±0.0310*** | NS |
Serum creatinine, µmol/L | 0.00344±0.000475 |
0.0527±0.0126 |
*P<0.05; **P<0.01; ***P<0.001;
First a stepwise regression model not taking into account family relationships was used to select the covariables. Then, a mixed model with family included as a random effect and the covariables selected in the previous step entered as fixed effects was used to calculate parameter estimates. The following variables were offered to the stepwise regression model: sex, age (linear and squared term), systolic and diastolic blood pressure, history of cardiovascular disease, antihypertensive drug intake, current smoking and alcohol intake, body mass index, diabetes mellitus, serum total cholesterol, triglycerides, serum creatinine and calculated creatinine clearance.
Indoxyl sulfate (h2 = 0.16) as well as
Unadjusted | Age-adjusted | Fully adjusted |
||||
h2 | P | h2 | P | h2 | P | |
Indoxyl sulfate | 0.20±0.085 | 0.011 | 0.20±0.084 | 0.010 | 0.16±0.080 | 0.023 |
p-Cresyl sulfate | 0.22±0.085 | 0.005 | 0.23±0.087 | 0.004 | 0.24±0.119 | 0.024 |
Values are proportions ± standard error. Indoxyl sulfate and
h2, heritability.
Adjusted for sex, age (linear and squared term), triglycerides, current smoking status, measured creatinine clearance and history of cardiovascular complications.
The present study aimed to evaluate clinical determinants and heritability of indoxyl sulfate and
Serum levels of indoxyl sulfate and
The dependence of the serum concentrations of indoxyl sulfate and
The association between the serum concentrations of indoxyl sulfate and
Serum concentrations of indoxyl sulfate and
Smoking and alcohol consumption were associated with lower indoxyl sulfate levels and
Whether the independent and direct association between indoxyl sulfate and serum triglycerides reflects OAT lipotoxicity
Serum levels of indoxyl sulfate and
Literature data indicate that host genetics may influence the composition of the microbiota, e.g. by influencing the environmental conditions of the habitat, such as length of the intestine and transit time
The results of the present study must be interpreted within the context of its limitations and strengths. The cross-sectional design precludes conclusions regarding causality of determinants of serum indoxyl sulfate and
In summary, using a targeted approach, we demonstrated that the co-metabolites indoxyl sulfate and
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