# Nanotechnology, Nanomedicine, and the Kidney
## 2 Kidney  
One of the main factors influencing the pharmacokinetics of drugs and therapeutic materials is the clearance rate from the body. After their absorption, nanoparticles enter the systemic circulation, diffuse and interact with the body, and are eventually cleared by the reticuloendothelial system (RES) or the kidney. In this review, we will focus on the kidney's influence, as renal excretion is one of the most critical factors involved in the excretion of nanomedicines. For more information regarding the optimization of nanodrug pharmacokinetics, we recommend the review by [PERSON] and [PERSON] [14].  
The kidneys receive 1 to 1.2 L of blood per minute, that is 20-25% of the cardiac output. Each kidney contains an average of one million nephrons, the basic functional unit of the kidney. Each nephron consists of the renal corpuscle, or glomerulus, the proximal, and distal tubules. Blood is transported via the renal vasculature to the glomeruli, where the primary filtrate is passed through fenestrated capillaries into the Bowman's capsule, which  
Figure 1: Causes of End-Stage Kidney Disease in the United States in 2016. Data based on patients of all ages (n = 726,331) [16].  
encloses the glomerulus and collects the filtrate. The filtrate is then transported to the proximal and distal renal tubules where nutrients, water, and ions are reabsorbed and waste products secreted.  
From the lumen of the capillary to the inside of the Bowman's capsule, the glomerulus contains four structures that act as filters: the glycocalyx, the endothelium, the glomerular basement membrane (GBM), and the podocytes. The glycocalyx is a negatively charged layer of glycoproteins and glycolipids that protects the underlying endothelial cells and prevents large protein leakage. The endothelial layer is a fenestrated endothelium with large pores of 70-90 nm in diameter. The endothelial cells repose on the negatively charged GBM with pores of 2-8 nm. Its role is to prevent the filtration of large proteins and cellular components from the blood. The last filtration barrier is composed of the podocytes that sit on the urine side of the GBM. Organized as a monolayer, their interdigitating foot processes form the filtration slit sized 4 to 11 nm. Overall, the four layers create a charge- and size-selective filtration barrier with a glomerular functional barrier's (GFB) pore size of 4.5-5 nm [17].  
Size, shape, and charge of nanoparticles must be considered when designing nanomedicine, as they will decide between renal clearance and accumulation. For example, a positively charged nanomedicine may cross more efficiently the filtration through a negatively charged GBM and podocytes than neutral or negatively charged compounds. An overview of the potential interaction of NP with the kidney is shown in Figure 2.  
Figure 2: Nanoparticle interactions in the Nephron. Sites of interaction and potential uptake of NPs that are subject to extraction or used to target the kidney. NPs enter the kidney via the renal artery and are transported to the afferent arteriole (1). Depending on particle characteristics, NPs remain in the blood stream or are subjected to renal filtration from the blood in the glomerular capillaries (2). NPs can be designed so that renal structures, such as the glycocalyx (3), endothelial cells, or the glomerular basement membrane (4), can function in selecting NPs for filtration. After filtration, NPs can interact with podocytes in the Bowman’s lumen (5). NPs in the filtrate are then transported to the proximal tubule, where they interact with proximal epithelial cells (6) and are potentially reabsorbed. Pro-drug NPs can be activated in the lysosome of proximal tubular cells (7). NPs not selected for renal filtration can interact with the renal tubular comparted after being transported from the efferent arteriole to the peritubular network (8).