Chronic kidney disease (CKD) may alter the homeostatic relationship between human hosts and their intestinal tract microbial inhabitants (i.e., the gut microbiota) due to the enhanced delivery of urea to the gut microbiota, alterations in diet, and the decrease in urinary excretion of small molecules produced by the gut microbiota. As a result, both the composition of the gut microbiota and its metabolite byproducts may be altered in patients with CKD. We propose a set of inter-related specific aims to examine the association between CKD, gut microbiota and the fecal metabolome, the plasma metabolome, and the development of clinical outcomes using a longitudinal prospective cohort within the Chronic Renal Insufficiency Cohort (CRIC) Study. In addition, we propose a small interventional study to eradicate and then re-populate the gut microbiota among an additional population of CKD patients to identify gut-derived byproducts that accumulate in the systemic circulation. The results of our study will provide new insights into interventions, such as modulation of diet, that may alter the metabolome of the gut microbiota to help prevent and/or treat diseases associated with the development of CKD.