The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw, Rosalinde; Mutsaers, Henricus A M; Toyohara, Takafumi; Abe, Takaaki; Jhawar, Sachin R.; Sweet, Douglas H.; Lowenstein, Jerome

doi:10.1016/j.semnephrol.2014.02.010

Cited by 137 publications

(132 citation statements)

References 166 publications

(164 reference statements)

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“…Active renal secretion appears to play an important role in the elimination of several uremic solutes, particularly for protein bound solutes. 4 Recent data suggest free water-soluble solutes could also interact with OAT1/3. 35,36 4.1.…”

Section: Discussionmentioning

confidence: 99%

“…7−9 Clinical data suggest that uremic solutes may modulate the activity of OAT1 and OAT3, thereby affecting renal clearance. 4 However, so far only a few studies have characterized the interactions between uremic solutes and OAT1 and OAT3. For example, hippuric acid, a canonical uremic solute, has been reported to inhibit the uptake of paminohippurate and penicillin G by OAT1 and OAT3, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

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One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

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“…In Oat1 knockout mice, some of these organic anions accumulate (61), although the mice do not appear ill and have normal life spans (14). Putative uremic toxins are also affected to varying degrees in Oat3 knockout mice and OATP4C1 transgenic rats (8,62,63). Uremic toxins interact with other SLC and ABC transporters as well.…”

Section: Uremic Toxinsmentioning

confidence: 99%

“…As discussed earlier, many of the putative uremic toxins, including indoxyl sulfate and kynurenine, are excellent substrates of OATs and other drug transporters, such as OATPs, and they accumulate in the knockout or transgenic models of these transporters. These substances may themselves be toxic to the tubule cell and may also contribute to the progression of CKD (8,(61)(62)(63)101).…”

Section: Aki and Ckdmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

227

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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“…These toxins are in large part handled by the proximal tubules [50] and, although traditional dialysis is able to remove small water-soluble toxins, the protein-bound solutes can only be removed through the biological processes inherent to PTEC [43,51]. Besides, dialysis is removing a part of the toxin population but is not replacing the kidney endocrine and metabolic physiological functions.…”

Section: The Need For a More Complete Rrt -The Bakmentioning

confidence: 99%

Development of an upscaled bioartificial kidney

Chevtchik¹

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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...

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The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Cited by 137 publications

References 166 publications

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Development of an upscaled bioartificial kidney

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