Disposition and clinical implications of protein-bound uremic toxins

Abstract

In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein-bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug-uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug-drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology.

Understanding Development of Malnutrition in Hemodialysis Patients: A Narrative Review

“…Incomplete clearance of uremic solutes and the generation of urea from both dialysis-induced tissue degradation and dietary proteins contribute to uremic solute accumulation [ 104 ]. Excessive uremic solute burden influences amino-acid and protein metabolism by inhibiting transamination activities of enzymes such as threonine dehydratase and alanine and aspartate transferases [ 104 ], impairing membrane transport [ 105 ], inhibiting protein binding [ 106 ], and promoting muscle wasting [ 104 ].…”

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

“…Recently, there has been renewed interest in the relative importance of renal tubular secretory capacity in the setting of declining renal function in the context of the handling of drugs and organic solutes, including uremic solutes and uremic toxins (2)(3)(4). Growing evidence suggests the residual renal secretory capacity -especially via the organic anion transport (OAT) system -may be particularly important in the setting of CKD (2)(3)(4)(5)(6)(7)(8). In fact, it is believed that residual function of the proximal tubule is likely to be central to the removal of compounds not generally cleared by hemodialysis, which include many of the protein-bound small-molecule uremic solutes and toxins (2,3,7,(9)(10)(11)(12)(13).…”

Role of Vitamin D in Maintaining Renal Epithelial Barrier Function in Uremic Conditions

“…In order to replicate the uremic conditions present in kidney patients, a specific mixture of eight known anionic uremic toxins ( Table 1 ), predominantly derived from endogenous metabolism pathways and food digestion in the gut [ 33 ], and corresponding approximately to the concentrations found in patients (1×), or higher (2.5×, 5× and 10×) ( Table 1 ), was used in the present study. It was prepared as a 100× concentrated mixture in a serum-free medium and subsequently diluted to desired concentrations.…”