Gut-Derived Uremic Retention Solutes in Patients With Moderate Chronic Kidney Disease and Healthy Adults
thesisposted on 16.08.2019, 16:29 by Gretchen N Wiese
Elevated levels of uremic retention solutes (URS), breakdown products of protein digestion, are associated with an increase in overall mortality, cardiovascular risk, and chronic kidney disease (CKD) progression. Increased levels of the URS Indoxyl sulfate (IS), p-cresol sulfate (PCS), and Trimethylamine N-oxide (TMAO) have been observed in patients with late stages of kidney disease (1-3). URS are formed via bacterial fermentation in the colon and are removed by urinary excretion, a task easily accomplished by healthy kidneys. However, in individuals with CKD, kidney function declines, resulting in decreased removal and subsequent accumulation of URS in the serum. However, few studies have evaluated URS in pre-dialysis CKD patients or have controlled for diet. Only one cross-sectional study evaluated levels of TMAO in both serum and urine of non-dialysis CKD patients compared with healthy adults (1), and no studies have examined all three of these URS while controlling dietary intake. Thus, in this secondary analysis, we aimed to determine serum and urine levels of IS, TMAO, and PCS in patients with moderate CKD compared with matched healthy adults who participated in a one-week controlled feeding study. Participants included patients with CKD (N=7) and healthy controls (N=7) matched for age, sex, and race. Participants consumed a diet controlled for macronutrients, fiber, phosphorus, calcium, potassium, and sodium for one week. Fasting serum and urine samples were collected at the end of the week. IS, PCS, and TMAO were quantified using LC-MS. Paired comparisons were used to determine differences between the groups and associations were examined with Pearson’s correlations. Results show that fasting serum URS were higher in CKD compared with controls (p<0.05). Urine URS tended to be higher in CKD patients, with IS reaching significance. Overall, kidney function (eGFR) was inversely related to each serum URS (p<0.05) and urine URS. However, when the relationship between eGFR and URS was evaluated within groups, strong inverse relationships only persisted in the CKD group. There were strong relationships among the serum and urine metabolites, and higher levels of serum URS corresponded with higher levels of the respective urine URS. When evaluated by group, these relationships remained strong in the CKD group, and slightly weakened in the control group. In conclusion, we have found that serum levels of URS are significantly elevated when compared with healthy adults even in early to moderate stages of CKD. Increased intestinal URS production via intestinal microbiome and altered liver function remain potential confounding variables in elevated serum URS levels over simply reduced excretion. Therapeutics, such as modified dietary protein intake or pre/pro/synbiotics, aimed at reducing URS production in the gut, may have the potential to reduce overall serum URS levels. Larger, longer studies evaluating diurnal serum URS and 24-hour urine URS excretion are needed to better understand URS retention and production in moderate chronic kidney disease patients.