Nitric Oxide-Releasing Hemodialysis Catheter Lock Solutions

In an attempt to address the significant morbidity, mortality,and economic cost associated with tunneled dialysis catheter (TDC)dysfunction, we report the development of nitric oxide-releasing dialysiscatheter lock solutions. Catheter lock solutions with a range of NOpayloads and release kinetics were prepared using low-molecular-weight N-diazeniumdiolate nitric oxide donors. Nitric oxide releasedthrough the catheter surface as a dissolved gas was maintained attherapeutically relevant levels for at least 72 h, supporting clinicaltranslatability (interdialytic period). Slow, sustained NO releasefrom the catheter surface prevented bacterial adhesion in vitro by88.9 and 99.7% for Pseudomonas aeruginosa and Staphylococcus epidermidis, respectively,outperforming a burst NO-release profile. Furthermore, bacteria adheredto the catheter surface in vitro prior to lock solution use was reducedby 98.7 and 99.2% for P. aeruginosa and S. epidermidis, respectively,when using a slow releasing NO donor, demonstrating both preventativeand treatment potential. The adhesion of proteins to the cathetersurface, a process often preceding biofilm formation and thrombosis,was also lessened by 60-65% by sustained NO release. In vitrocytotoxicity of catheter extract solutions to mammalian cells wasminimal, supporting the non-toxic nature of the NO-releasing locksolutions. The use of the NO-releasing lock solution in an in vivoTDC porcine model demonstrated decreased infection and thrombosis,enhanced catheter functionality, and improved outcome (i.e., likelihoodof survival) as a result of catheter use.