Fig. 2.

Renal filtration and accumulation of nanoparticles. (1) NPs are typically administered IV. Alternative routes include intraperitoneal administration and phagocytosis by macrophages, which subsequently migrate to foci of inflammation [43] and administration of NP labelled mesenchymal stem cells for theranostics [44,45]. (2) Renal clearable NPs must pass through the glomerular filtration membrane (GFM), comprising the capillary endothelial layer with 70–90 nm fenestrations, the thick GBM with 2–8 nm pores and the podocyte layer with 4–11 nm filtration slits. Each layer of the GFM is negatively charged; cationic NPs are therefore much more efficiently cleared by the kidney than anionic and neutral NPs. Filtration is strongly size dependant: large NPs > 90–100 nm do not pass through the GFM significantly whilst small NPs < 6 nm are freely filtered. Very small (< 1 nm) NPs exhibit reduced renal clearance due to interactions with the endothelial glycocalyx [46]. Some intermediate size NPs (e.g. PEG-coated AuNPs < 100 nm) pass through the endothelial layer and accumulate in the mesangium, with potential for glomerular targeting [47]. The dependency of filtration on size and charge is further complicated by their interaction with NP shape and flexibility and the potential for some NPs to partially or completely disassemble to cross the GFM [48]. Renal disease causes increased GFM permeability (due to various factors including podocyte injury and reduced endothelial integrity) potentially allowing increased NP filtration and renal accumulation. (3) Renal-clearable NPs accumulate in urine in the tubules. Their precise interactions are not fully understood but several pathways for their endocytosis and accumulation within tubular epithelial cells have been identified, including megalin-, caveolae- and clathrin-mediated endocytosis [49-51]. Renal-clearable NPs may also be captured by the microvilli (e.g. glutathione-coated AuNPs), saturating the brush border before being eliminated in the urine [52]. (4) Non-renal-clearable NPs rarely reach the tubules; however, endocytosis of organic NPs 400 nm in diameter by the peritubular capillary endothelium has been studied, allowing selective accumulation in the proximal tubules for up to 7 days [53].