The kidney and uremic toxin removal: glomerulus or tubule?
Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes.
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: roos.masereeuw@radboudumc.nl.
Rosalinde
R
Masereeuw
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Henricus A M
HA
Mutsaers
Department of Cell Growth and Differentiation, Center for induced Pluripotent Stem Cell Research and Application, Kyoto University, Kyoto, Japan; Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University, Graduate School of Medicine, Sendai, Japan.
Takafumi
T
Toyohara
Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University, Graduate School of Medicine, Sendai, Japan; Division of Medical Science, Tohoku University, Graduate School of Biomedical Engineering, Sendai, Japan; Department of Clinical Biology and Hormonal Regulation, Tohoku University, Graduate School of Medicine, Sendai, Japan.
Takaaki
T
Abe
Department of Medicine, New York University Medical Center, New York, NY.
Sachin
S
Jhawar
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA.
Douglas H
DH
Sweet
Department of Medicine, New York University Medical Center, New York, NY.
Jerome
J
Lowenstein
D000818:Animals; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism*
D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C484530:SLCO4C1 protein, human; D014118:Toxins, Biological
ATP binding cassette transporters; Active tubular secretion; organic anion transport; organic anion transporting polypeptide 4C1; organic cation transport; residual renal function