Enhanced protein-bound uremic toxin clearance by a membrane-drug-dendrimer synergic system

Challenges in effectively removing protein-bound uremic toxins (PBUTs), are a significant concern for patients with end stage renal disease (ESRD) undergoing hemodialysis (HD). Conventional 4-hour HD treatments rely on the transport of small and middle molecules through the semipermeable membranes of the hemodialyzer, moving from the blood side to the dialysate compartment. PBUTs, however, circulate bound to human serum albumin (HSA), forming large toxin-protein complexes that cannot cross these membranes. In recent years, the use of pharmaceutical drugs with competitive binding properties has emerged as a promising solution. A 2019 clinical trial demonstrated the potential of enhancing indoxyl sulfate (IS) removal - a key PBUT - by injecting 800 mg of ibuprofen (IBU) over 19 min during the initial phase of HD. Although this increased IS clearance by 2.4-fold, the effect diminished rapidly, returning to pre-infusion levels between 60 and 240 min. Additionally, residual IBU was detected in patients, raising safety concerns and highlighting the unsustainability of this approach. In response, we developed a method for the slow, controlled release of lower doses of IBU throughout the entire HD session using polymeric nanocarriers known for their high drug-loading capacity and controlled release properties. A lab-scale extracorporeal blood circulation circuit was constructed, where IBU (<8 mg) was gradually released into the blood plasma line using fourth-generation polyurea dendrimers (IBU@PUREG4). The concentration of free IS was monitored over a 4-hour period, and a membrane module that retains HSA while permeating unbound IS was positioned downstream from the IBU@PUREG4 release site. Our results showed a 3.7-fold increase in the unbound IS concentration in blood plasma and a 3.8-fold increase in IS clearance, validating the displacement effect of controlled low-dose IBU release. This innovative approach not only improves the efficiency of PBUT removal but also reduces the risk of excessive accumulation of competitive binders, such as IBU, in patients undergoing regular HD, making it a safer long-term solution for ESRD management.