A host of compounds are retained in the body of uremic patients, as a consequence of progressive renal failure. Hundreds of compounds have been reported to be retention solutes and many have been proven to have adverse biological activity, and recognized as uremic toxins. The major mechanistic overview considered to contribute to uremic toxin overload implicates glucotoxicity, lipotoxicity, hexosamine, increased polyol pathway activity and the accumulation of advanced glycation end-products (AGEs). Until recently, the gastrointestinal tract (GIT) and its associated micro-biometabolome was a neglected factor in chronic disease development. A systematic underestimation has been to undervalue the contribution of GIT dysbiosis (a gut barrier-associated abnormality) whereby low-level pro-inflammatory processes contribute to chronic kidney disease (CKD) development. Gut dysbiosis provides a plausible clue to the origin of systemic uremic toxin loads encountered in clinical practice and may explain the increasing occurrence of CKD. In this review, we further expand a hypothesis that posits that environmentally triggered and maintained microbiome perturbations drive GIT dysbiosis with resultant uremia. These subtle adaptation responses by the GIT microbiome can be significantly influenced by probiotics with specific metabolic properties, thereby reducing uremic toxins in the gut. The benefit translates to a useful clinical treatment approach for patients diagnosed with CKD. Furthermore, the role of reactive oxygen species (ROS) in different anatomical locales is highlighted as a positive process. Production of ROS in the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which acts as an essential second messenger required for normal cellular homeostasis and physiological function. Whilst this critical review has focused on end-stage CKD (type 5), our aim was to build a plausible hypothesis for the administration of probiotics with or without prebiotics for the early treatment of kidney disease. We postulate that targeting healthy ROS production in the gut with probiotics may be more beneficial than any systemic antioxidant therapy (that is proposed to nullify ROS) for the prevention of kidney disease progression. The study and understanding of health-promoting probiotic bacteria is in its infancy; it is complex and intellectually and experimentally challenging.