Development of an upscaled bioartificial kidney

Abstract

Printed by Gildeprint, Enschede, the Netherlands, Cover design by Natalia Chevtchik and Felix Broens Front page: confocal microscopy image of conditionnaly imrtalized proximal tubule renal epithelial cells (ciPTEC) cultured on polymeric hollow fiber membranes (HFM) with DAPI staining of the nuclei and immunostaining for the tight junction protein ZO-1. The kidneys are composed of hundreds of thousands of filtration units called nephrons (see Figure 1). In the nephron, blood initially passes through the glomerulus where small and middle-size solutes and excess fluids are removed out of the blood by convection. This glomerular filtrate is then transferred to the proximal tubules, which are responsible for reabsorbing essential components of the pre-urine but also for additional removal of a great variety of solutes and wastes from the blood stream, among which, the protein-bound toxins. More details about kidney physiology are explained in chapter 2 of this thesis. DEVELOPMENT OF AN UPSCALED BIOARTIFICIAL KIDNEY Kidney diseaseMore than 10% of the worldwide population is estimated to present a more or less severe form of kidney disease [4][5][6] Chapter 1 4 Renal replacement therapiesThe most common treatment for CKD, ESRD and AKI patients is artificial kidney or dialysis, applied for 2.2 million patients worldwide [10]. This treatment only covers a fraction of the physiological renal function -mostly that of the glomerulus in the normal kidney -and its efficiency in waste removal is incomplete [11, 12]. Indeed, only small water-soluble molecules, inferior to 40 kDa, present in free fraction in the blood, can be eliminated [13] whereas most of the big size and protein bound toxins cannot be removed. Their accumulation is strongly linked to the fatal outcome of the hemodialysed population [14][15][16].These toxins are in large part handled by the proximal tubules in the healthy kidneys [13, 17]. Besides, dialysis is removing a part of the toxin population but is not replacing the kidney endocrine and metabolic physiological functions. The need for a more complete renal replacement therapyThere is a strong need for a device, extracorporeal or implantable, which could fully replace the kidney function. Such a device could be a hybrid combination of polymeric membranes and renal proximal tubule epithelial cells (PTEC), called the bioartificial kidney (BAK). The BAK is conceived to be used in combination with a classical hemofilter [18, 19]. In this way, there is a direct similitude with the natural kidney. First, the glomerular function is replaced by the classical hemodialysis for removal of small size water-soluble molecules.Second, the glomerular filtrate, which comes out of the hemodialysis module, can be processed by the PTEC of the BAK. The principle of application of the BAK is presented in Figure 2.The first BAK prototype was presented by Aebisher et al. in 1987 [21]. Since then, several other prototypes have been proposed by the groups of Humes, Zink and Saito [18,[22][23][24][25][26][27][28][29]. The first...