The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Seminars in Nephrology

Volumn 34, Issue 2, 2014, Pages 191-208

  Masereeuw, Rosalinde ^a   Mutsaers, Henricus A M ^a   Toyohara, Takafumi ^b,c   Abe, Takaaki ^c,d   Jhawar, Sachin ^e   Sweet, Douglas H ^f   Lowenstein, Jerome ^e  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^b KYOTO UNIVERSITY   (Japan)

^c TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^d TOHOKU UNIVERSITY   (Japan)

^e NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^f VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

Active tubular secretion; ATP binding cassette transporters; Organic anion transport; Organic anion transporting polypeptide 4C1; Organic cation transport; Residual renal function

Indexed keywords

ABC TRANSPORTER; AROMATIC HYDROCARBON RECEPTOR; BREAST CANCER RESISTANCE PROTEIN; DRUG METABOLIZING ENZYME; MULTIDRUG RESISTANCE PROTEIN; ORGANIC ANION TRANSPORTER 1; ORGANIC ANION TRANSPORTER 3; ORGANIC ANION TRANSPORTER H; UNCLASSIFIED DRUG; UREMIC RETENTION SOLUTE; UREMIC TOXIN; ORGANIC ANION TRANSPORTER; ORGANIC CATION TRANSPORTER; SLCO4C1 PROTEIN, HUMAN; TOXIN;

BIOACCUMULATION; CELL FATE; CELL FUNCTION; CHRONIC KIDNEY DISEASE; DRUG INTERACTION; DRUG TRAFFIC; GLOMERULUS; HUMAN; KIDNEY CLEARANCE; KIDNEY FUNCTION; KIDNEY PROXIMAL TUBULE; KIDNEY TUBULE EXCRETION; MITOCHONDRION; NONHUMAN; PRIORITY JOURNAL; REVIEW; UREMIA; URINARY EXCRETION; ANIMAL; CHRONIC KIDNEY FAILURE; KIDNEY TUBULE; METABOLISM; PHYSIOLOGY;

ANIMALS; HUMANS; KIDNEY GLOMERULUS; KIDNEY TUBULES; ORGANIC ANION TRANSPORTERS; ORGANIC CATION TRANSPORT PROTEINS; RENAL INSUFFICIENCY, CHRONIC; TOXINS, BIOLOGICAL; UREMIA;

EID: 84899083735     PISSN: 02709295     EISSN: 15584488     Source Type: Journal    
DOI: 10.1016/j.semnephrol.2014.02.010     Document Type: Review

References (168)

1. Kolff W.J., Higgins C.C. Dialysis in the treatment of uremia: artificial kidney. J Urol 1954, 72:1082-1094.
2. Atkins R.C., Leonard C.D., Scribner B.H. Management of chronic renal failure. Dis Mon 1971, March:1-38.
3. Go A.S., Chertow G.M., Fan D., McCulloch C.E., Hsu C.Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004, 351:1296-1305.
4. Eknoyan G., Beck G.J., Cheung A.K., Daugirdas J.T., Greene T., Kusek J.W., et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002, 347:2010-2019.
5. Smith H.W. The kidney: structure and function in health and disease 1951, Oxford University Press, New York.
6. Weiner D.E., Tighiouart H., Amin M.G., Stark P.C., MacLeod B., Griffith J.L., et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004, 15:1307-1315.
7. Wolfe R.A., Ashby V.B., Milford E.L., Ojo A.O., Ettenger R.E., Agodoa L.Y., et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999, 341:1725-1730.
8. Duranton F., Cohen G., De Smet R., Rodriguez M., Jankowski J., Vanholder R., et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 2012, 23:1258-1270.
9. Vanholder R., De S.R., Glorieux G., Argiles A., Baurmeister U., Brunet P., et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003, 63:1934-1943.
10. Smith HW. From fish to philosopher. Summit, NJ: CIBA Pharmaceutical Products, Inc; 1961.
11. Beyenbach K.W. Direct demonstration of fluid secretion by glomerular renal tubules in a marine teleost. Nature 1982, 299:54-56.
12. Heemskerk S., Peters J.G., Louisse J., Sagar S., Russel F.G., Masereeuw R. Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. J Biomed Biotechnol 2010, 2010:525180.
13. Giacomini K.M., Huang S.M., Tweedie D.J., Benet L.Z., Brouwer K.L., Chu X., et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010, 9:215-236.
14. Masereeuw R., Russel F.G. Therapeutic implications of renal anionic drug transporters. Pharmacol Ther 2010, 126:200-216.
15. Toyohara T., Suzuki T., Morimoto R., Akiyama Y., Souma T., Shiwaku H.O., et al. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. J Am Soc Nephrol 2009, 20:2546-2555.
16. Wang L., Sweet D.H. Renal organic anion transporters (SLC22 family): expression, regulation, roles in toxicity, and impact on injury and disease. AAPS J 2013, 15:53-69.
17. Hook J.B., Munro J.R. Specificity of the inhibitory effect of "uremic" serum on p-aminohippurate transport. Proc Soc Exp Biol Med 1968, 127:289-292.
18. White A.G. Uremic serum inhibition of renal paraaminohippurate transport. Proc Soc Exp Biol Med 1966, 123:309-310.
19. Boumendil-Podevin E.F., Podevin R.A., Richet G. Uricosuric agents in uremic sera. Identification of indoxyl sulfata and hippuric acid. J Clin Invest 1975, 55:1142-1152.
20. Niwa T., Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994, 124:96-104.
21. Sirich T.M., Meyer T.W., Gonduin B., Brunet P., Niwa T. Protein-bound molecules: a large family with a bad character. Semin Nephrol 2014, 34:106-117.
22. Sweet D.H. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol Appl Pharmacol 2005, 204:198-215.
23. VanWert A.L., Gionfriddo M.R., Sweet D.H. Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos 2010, 31:1-71.
24. Wikoff W.R., Nagle M.A., Kouznetsova V.L., Tsigelny I.F., Nigam S.K. Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J Proteome Res 2011, 10:2842-2851.
25. Naud J., Michaud J., Beauchemin S., Hebert M.J., Roger M., Lefrancois S., et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011, 39:1363-1369.
26. Monica Torres A., Mac Laughlin M., Muller A., Brandoni A., Anzai N., Endou H. Altered renal elimination of organic anions in rats with chronic renal failure. Biochim Biophys Acta 2005, 1740:29-37.
27. Kwon O., Hong S.M., Blouch K. Alteration in renal organic anion transporter 1 after ischemia/reperfusion in cadaveric renal allografts. J Histochem Cytochem 2007, 55:575-584.
28. Matsuzaki T., Watanabe H., Yoshitome K., Morisaki T., Hamada A., Nonoguchi H., et al. Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure. Kidney Int 2007, 71:539-547.
29. Schneider R., Sauvant C., Betz B., Otremba M., Fischer D., Holzinger H., et al. Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. Am J Physiol Renal Physiol 2007, 292:F1599-F1605.
30. Kwon O., Wang W.W., Miller S. Renal organic anion transporter 1 is maldistributed and diminishes in proximal tubule cells but increases in vasculature after ischemia and reperfusion. Am J Physiol Renal Physiol 2008, 295:F1807-F1816.
31. Niwa T., Ise M., Miyazaki T. Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am J Nephrol 1994, 14:207-212.
32. Taki K., Nakamura S., Miglinas M., Enomoto A., Niwa T. Accumulation of indoxyl sulfate in OAT1/3-positive tubular cells in kidneys of patients with chronic renal failure. J Ren Nutr 2006, 16:199-203.
33. Miyamoto Y., Watanabe H., Noguchi T., Kotani S., Nakajima M., Kadowaki D., et al. Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney. Nephrol Dial Transplant 2011, 26:2498-2502.
34. Mutsaers H.A., Wilmer M.J., van den Heuvel L.P., Hoenderop J.G., Masereeuw R. Basolateral transport of the uraemic toxin p-cresyl sulfate: role for organic anion transporters?. Nephrol Dial Transplant 2011, 26:4149.
35. Yamaguchi H., Sugie M., Okada M., Mikkaichi T., Toyohara T., Abe T., et al. Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1: estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1. Drug Metab Pharmacokinet 2010, 25:314-317.
36. Lowenstein J. The anglerfish and uremic toxins. FASEB J 2011, 25:1781-1785.
37. Farthing C.A., Sweet D.H. Expression and function of organic cation and anion transporters (SLC22 family) in the CNS. Curr Pharm Des 2013, (Epub ahead of print).
38. Gondouin B., Cerini C., Dou L., Sallee M., Duval-Sabatier A., Pletinck A., et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 2013, 84:733-744.
39. Yamamoto H., Tsuruoka S., Ioka T., Ando H., Ito C., Akimoto T., et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int 2006, 69:1780-1785.
40. Humes H.D., MacKay S.M., Funke A.J., Buffington D.A. Tissue engineering of a bioartificial renal tubule assist device: in vitro transport and metabolic characteristics. Kidney Int 1999, 55:2502-2514.
41. Humes H.D., Buffington D.A., MacKay S.M., Funke A.J., Weitzel W.F. Replacement of renal function in uremic animals with a tissue-engineered kidney. Nat Biotechnol 1999, 17:451-455.
42. Mikkaichi T., Suzuki T., Onogawa T., Tanemoto M., Mizutamari H., Okada M., et al. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A 2004, 101:3569-3574.
43. Hagenbuch B., Stieger B. The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 2013, 34:396-412.
44. Suzuki T., Toyohara T., Akiyama Y., Takeuchi Y., Mishima E., Suzuki C., et al. Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease. J Pharm Sci 2011, 100:3696-3707.
45. Sekine T., Cha S.H., Tsuda M., Apiwattanakul N., Nakajima N., Kanai Y., et al. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 1998, 429:179-182.
46. Anzai N., Kanai Y., Endou H. Organic anion transporter family: current knowledge. J Pharmacol Sci 2006, 100:411-426.
47. Abe T., Suzuki T., Unno M., Tokui T., Ito S. Thyroid hormone transporters: recent advances. Trends Endocrinol Metab 2002, 13:215-220.
48. Rubera I., Poujeol C., Bertin G., Hasseine L., Counillon L., Poujeol P., et al. Specific Cre/Lox recombination in the mouse proximal tubule. J Am Soc Nephrol 2004, 15:2050-2056.
49. Soga T., Ohashi Y., Ueno Y., Naraoka H., Tomita M., Nishioka T. Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res 2003, 2:488-494.
50. Toyohara T., Akiyama Y., Suzuki T., Takeuchi Y., Mishima E., Tanemoto M., et al. Metabolomic profiling of uremic solutes in CKD patients. Hypertens Res 2010, 33:944-952.
51. Saffran M., Prado J.L. Inhibition of aconitase by trans-aconitate. J Biol Chem 1949, 180:1301-1309.
52. Kielstein J.T., Zoccali C. Asymmetric dimethylarginine: a novel marker of risk and a potential target for therapy in chronic kidney disease. Curr Opin Nephrol Hypertens 2008, 17:609-615.
53. Marescau B., Nagels G., Possemiers I., De Broe M.E., Becaus I., Billiouw J.M., et al. Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism 1997, 46:1024-1031.
54. Vanholder R., Van Laecke S., Glorieux G. What is new in uremic toxicity?. Pediatr Nephrol 2008, 23:1211-1221.
55. Torremans A., Marescau B., Kranzlin B., Gretz N., Billiouw J.M., Vanholder R., et al. Biochemical validation of a rat model for polycystic kidney disease: comparison of guanidino compound profile with the human condition. Kidney Int 2006, 69:2003-2012.
56. Schepers E.S., Speer T., Leiper J., Fliser D., Kielstein J. The dimethylarginines ADMA and SDMA: the real water soluble small toxins?. Semin Nephrol 2014, 34:97-105.
57. Fujii-Kuriyama Y., Mimura J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem Biophys Res Commun 2005, 338:311-317.
58. Denison M.S., Nagy S.R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 2003, 43:309-334.
59. Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013, 34:413-435.
60. Ji L., Masuda S., Saito H., Inui K. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int 2002, 62:514-524.
61. Heemskerk S., Wouterse A.C., Russel F.G., Masereeuw R. Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia. Eur J Pharmacol 2008, 584:390-397.
62. Schophuizen C.M., Wilmer M.J., Jansen J., Gustavsson L., Hilgendorf C., Hoenderop J.G., et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013, 465:1701-1714.
63. Kimura N., Masuda S., Katsura T., Inui K. Transport of guanidine compounds by human organic cation transporters, hOCT1 and hOCT2. Biochem Pharmacol 2009, 77:1429-1436.
64. Winter T.N., Elmquist W.F., Fairbanks C.A. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm 2011, 8:133-142.
65. Song I.S., Lee do Y., Shin M.H., Kim H., Ahn Y.G., Park I., et al. Pharmacogenetics meets metabolomics: discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition. PLoS One 2012, 7:e36637.
66. Stone T.W., Stoy N., Darlington L.G. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 2013, 34:136-143.
67. Wikoff W.R., Anfora A.T., Liu J., Schultz P.G., Lesley S.A., Peters E.C., et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009, 106:3698-3703.
68. Meyer T.W., Hostetter T.H. Uremic solutes from colon microbes. Kidney Int 2012, 81:949-954.
69. Schefold J.C., Zeden J.P., Fotopoulou C., Von H.S., Pschowski R., Hasper D., et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant 2009, 24:1901-1908.
70. Ciarimboli G., Lancaster C.S., Schlatter E., Franke R.M., Sprowl J.A., Pavenstadt H., et al. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res 2012, 18:1101-1108.
71. Chambers J.C., Zhang W., Lord G.M., van der Harst P., Lawlor D.A., Sehmi J.S., et al. Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 2010, 42:373-375.
72. Boger C.A., Gorski M., Li M., Hoffmann M.M., Huang C., Yang Q., et al. Association of eGFR-related loci identified by GWAS with incident CKD and ESRD. PLoS Genet 2011, 7:e1002292.
73. Reznichenko A., Sinkeler S.J., Snieder H., vanden B.J., deBorst M.H., Damman J., et al. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol Genomics 2013, 45:201-209.
74. Eisner C., Faulhaber-Walter R., Wang Y., Leelahavanichkul A., Yuen P.S., Mizel D., et al. Major contribution of tubular secretion to creatinine clearance in mice. Kidney Int 2010, 77:519-526.
75. Vallon V., Eraly S.A., Rao S.R., Gerasimova M., Rose M., Nagle M., et al. A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am J Physiol Renal Physiol 2012, 302:F1293-F1299.
76. Gaowa A., Motohashi H., Katsura T., Inui K. Effects of metabolic acidosis on expression levels of renal drug transporters. Pharm Res 2011, 28:1023-1030.
77. Nies A.T., Koepsell H., Damme K., Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol 2011, 201:105-167.
78. Kajiwara M., Terada T., Ogasawara K., Iwano J., Katsura T., Fukatsu A., et al. Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. J Hum Genet 2009, 54:40-46.
79. Masereeuw R., Russel F.G. Regulatory pathways for ATP-binding cassette transport proteins in kidney proximal tubules. AAPS J 2012, 14:883-894.
80. Schinkel A.H., Jonker J.W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 2003, 55:3-29.
81. Sun H., Frassetto L., Benet L.Z. Effects of renal failure on drug transport and metabolism. Pharmacol Ther 2006, 109:1-11.
82. Deeley R.G., Westlake C., Cole S.P. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 2006, 86:849-899.
83. Russel F.G., Koenderink J.B., Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci 2008, 29:200-207.
84. Laouari D., Yang R., Veau C., Blanke I., Friedlander G. Two apical multidrug transporters, P-gp and MRP2, are differently altered in chronic renal failure. Am J Physiol Renal Physiol 2001, 280:F636-F645.
85. Robey R.W., Ierano C., Zhan Z., Bates S.E. The challenge of exploiting ABCG2 in the clinic. Curr Pharm Biotechnol 2011, 12:595-608.
86. Mutsaers H.A., van den Heuvel L.P., Ringens L.H., Dankers A.C., Russel F.G., Wetzels J.F., et al. Uremic toxins inhibit transport by breast cancer resistance protein and multidrug resistance protein 4 at clinically relevant concentrations. PloS One 2011, 6:e18438.
87. Dankers A.C., Mutsaers H.A., Dijkman H.B., van den Heuvel L.P., Hoenderop J.G., Sweep F.C., et al. Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Biochim Biophys Acta 2013, 1832:1715-1722.
88. Bobulescu I.A., Moe O.W. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis 2012, 19:358-371.
89. Wu W., Dnyanmote A.V., Nigam S.K. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. Mol Pharmacol 2011, 79:795-805.
90. Filiopoulos V., Hadjiyannakos D., Vlassopoulos D. New insights into uric acid effects on the progression and prognosis of chronic kidney disease. Ren Fail 2012, 34:510-520.
91. Jhawar S., Zavadil J., Lowenstein J. The molecular basis of the renal and vascular consequence of uremia [abstract]. J Am Soc Nephrol 2012, 23.
92. Kewley R.J., Whitelaw M.L., Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 2004, 36:189-204.
93. Opitz C.A., Litzenburger U.M., Sahm F., Ott M., Tritschler I., Trump S., et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011, 478:197-203.
94. DiNatale B.C., Murray I.A., Schroeder J.C., Flaveny C.A., Lahoti T.S., Laurenzana E.M., et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol Sci 2010, 115:89-97.
95. Watanabe I., Tatebe J., Namba S., Koizumi M., Yamazaki J., Morita T. Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. Circ J 2013, 77:224-230.
96. Hwang S.J., Hwang Y.J., Yun M.O., Kim J.H., Oh G.S., Park J.H. Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis. Toxicol Lett 2013, 220:109-117.
97. Schroeder J.C., Dinatale B.C., Murray I.A., Flaveny C.A., Liu Q., Laurenzana E.M., et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 2010, 49:393-400.
98. Esser C., Rannug A., Stockinger B. The aryl hydrocarbon receptor in immunity. Trends Immunol 2009, 30:447-454.
99. Bui L.C., Tomkiewicz C., Chevallier A., Pierre S., Bats A.S., Mota S., et al. Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity. Oncogene 2009, 28:3642-3651.
100. Trecherel E., Godin C., Louandre C., Benchitrit J., Poirot S., Maziere J.C., et al. Upregulation of BAD, a pro-apoptotic protein of the BCL2 family, in vascular smooth muscle cells exposed to uremic conditions. Biochem Biophys Res Commun 2012, 417:479-483.
101. Cohen G., Rudnicki M., Horl W.H. Uremic toxins modulate the spontaneous apoptotic cell death and essential functions of neutrophils. Kidney Int Suppl 2001, 78:S48-S52.
102. Kim S.H., Yu M.A., Ryu E.S., Jang Y.H., Kang D.H. Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. Lab Invest 2012, 92:488-498.
103. Koopman W.J., Willems P.H., Smeitink J.A. Monogenic mitochondrial disorders. N Engl J Med 2012, 366:1132-1141.
104. Mutsaers H.A., Wilmer M.J., Reijnders D., Jansen J., van den Broek P.H., Forkink M., et al. Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration. Biochim Biophys Acta 2013, 1832:142-150.
105. Owada S., Maeba T., Sugano Y., Hirayama A., Ueda A., Nagase S., et al. Spherical carbon adsorbent (AST-120) protects deterioration of renal function in chronic kidney disease rats through inhibition of reactive oxygen species production from mitochondria and reduction of serum lipid peroxidation. Nephron Exp Nephrol 2010, 115:e101-e111.
106. Dzurik R., Spustova V., Krivosikova Z., Gazdikova K. Hippurate participates in the correction of metabolic acidosis. Kidney Int Suppl 2001, 78:S278-S281.
107. Riegel W., Ulrich C., Sauernheimer S., Deppisch R.M., Kohler H. Hepatotoxic substance(s) removed by high-flux membranes enhances the positive acute phase response. Kidney Int Suppl 2001, 78:S308-S314.
108. Kitagawa A. Effects of cresols (o-, m-, and p-isomers) on the bioenergetic system in isolated rat liver mitochondria. Drug Chem Toxicol 2001, 24:39-47.
109. Dreisbach A.W. The influence of chronic renal failure on drug metabolism and transport. Clin Pharmacol Ther 2009, 86:553-556.
110. Gibson GG, Skett P. Pathways of drug metabolism. In: Introduction to drug metabolism. 2nd ed. London: Chapman & Hall, 1995.
111. Leblond F., Guevin C., Demers C., Pellerin I., Gascon-Barre M., Pichette V. Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 2001, 12:326-332.
112. Leblond F.A., Giroux L., Villeneuve J.P., Pichette V. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos 2000, 28:1317-1320.
113. Dowling T.C., Briglia A.E., Fink J.C., Hanes D.S., Light P.D., Stackiewicz L., et al. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther 2003, 73:427-434.
114. Dreisbach A.W., Japa S., Gebrekal A.B., Mowry S.E., Lertora J.J., Kamath B.L., et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther 2003, 73:475-477.
115. Turpeinen M., Koivuviita N., Tolonen A., Reponen P., Lundgren S., Miettunen J., et al. Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites. Br J Clin Pharmacol 2007, 64:165-173.
116. Molanaei H., Stenvinkel P., Qureshi A.R., Carrero J.J., Heimburger O., Lindholm B., et al. Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation. Eur J Clin Pharmacol 2012, 68:571-577.
117. Nolin T.D., Frye R.F., Le P., Sadr H., Naud J., Leblond F.A., et al. ESRD impairs nonrenal clearance of fexofenadine but not midazolam. J Am Soc Nephrol 2009, 20:2269-2276.
118. Michaud J., Nolin T.D., Naud J., Dani M., Lafrance J.P., Leblond F.A., et al. Effect of hemodialysis on hepatic cytochrome P450 functional expression. J Pharmacol Sci 2008, 108:157-163.
119. Nolin T.D., Appiah K., Kendrick S.A., Le P., McMonagle E., Himmelfarb J. Hemodialysis acutely improves hepatic CYP3A4 metabolic activity. J Am Soc Nephrol 2006, 17:2363-2367.
120. Sun H., Huang Y., Frassetto L., Benet L.Z. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos 2004, 32:1239-1246.
121. Tsujimoto M., Higuchi K., Shima D., Yokota H., Furukubo T., Izumi S., et al. Inhibitory effects of uraemic toxins 3-indoxyl sulfate and p-cresol on losartan metabolism in vitro. J Pharm Pharmacol 2010, 62:133-138.
122. Naud J., Michaud J., Beauchemin S., Hebert M.J., Roger M., Lefrancois S., et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011, 39:1363-1369.
123. Kim Y.G., Shin J.G., Shin S.G., Jang I.J., Kim S., Lee J.S., et al. Decreased acetylation of isoniazid in chronic renal failure. Clin Pharmacol Ther 1993, 54:612-620.
124. Howie M.B., Bourke E. Metabolism of p-aminobenzoic acid in the perfused livers of chronically uraemic rats. Clin Sci (Lond) 1979, 56:9-14.
125. Osborne R., Joel S., Grebenik K., Trew D., Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993, 54:158-167.
126. Bateman D.N., Gokal R., Dodd T.R., Blain P.G. The pharmacokinetics of single doses of metoclopramide in renal failure. Eur J Clin Pharmacol 1981, 19:437-441.
127. Simard E., Naud J., Michaud J., Leblond F.A., Bonnardeaux A., Guillemette C., et al. Downregulation of hepatic acetylation of drugs in chronic renal failure. J Am Soc Nephrol 2008, 19:1352-1359.
128. Shannon J.A. Renal tubular excretion. Physiol Rev 1939, 19:63-93.
129. Bowmer C.J., Lindup W.E. Decreased drug binding in uraemia: effect of indoxyl sulphate and other endogenous substances on the binding of drugs and dyes to human albumin. Biochem Pharmacol 1982, 31:319-323.
130. Wang A.Y., Lai K.N. The importance of residual renal function in dialysis patients. Kidney Int 2006, 69:1726-1732.
131. Marquez I.O., Tambra S., Luo F.Y., Li Y., Plummer N.S., Hostetter T.H., et al. Contribution of residual function to removal of protein-bound solutes in hemodialysis. Clin J Am Soc Nephrol 2011, 6:290-296.
132. Bargman J.M., Thorpe K.E., Churchill D.N. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001, 12:2158-2162.
133. Termorshuizen F., Dekker F.W., van Manen J.G., Korevaar J.C., Boeschoten E.W., Krediet R.T. Relative contribution of residual renal function and different measures of adequacy to survival in hemodialysis patients: an analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2. J Am Soc Nephrol 2004, 15:1061-1070.
134. Grantham J.J., Irwin R.L., Qualizza P.B., Tucker D.R., Whittier F.C. Fluid secretion in isolated proximal straight renal tubules. Effect of human uremic serum. J Clin Invest 1973, 52:2441-2450.
135. Evenepoel P., Meijers B.K., Bammens B.R., Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney Int Suppl 2009, 114:S12-S19.
136. Barreto F.C., Barreto D.V., Liabeuf S., Meert N., Glorieux G., Temmar M., et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009, 4:1551-1558.
137. Ahn S.Y., Nigam S.K. Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol Pharmacol 2009, 76:481-490.
138. Ahn S.Y., Jamshidi N., Mo M.L., Wu W., Eraly S.A., Dnyanmote A., et al. Linkage of organic anion transporter-1 to metabolic pathways through integrated "omics"-driven network and functional analysis. J Biol Chem 2011, 286:31522-31531.
139. Lowenstein J. Competition for organic anion transporters in chronic renal disease. Kidney Int 2012, 82:1033.
140. Kunin M., Holtzman E.J., Melnikov S., Dinour D. Urinary organic anion transporter protein profiles in AKI. Nephrol Dial Transplant 2012, 27:1387-1395.
141. Wang L., Sweet D.H. Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11). Biochem Pharmacol 2012, 84:1088-1095.
142. Deguchi T., Ohtsuki S., Otagiri M., Takanaga H., Asaba H., Mori S., et al. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int 2002, 61:1760-1768.
143. Motojima M., Hosokawa A., Yamato H., Muraki T., Yoshioka T. Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake. Br J Pharmacol 2002, 135:555-563.
144. Deguchi T., Kusuhara H., Takadate A., Endou H., Otagiri M., Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int 2004, 65:162-174.
145. Tahara H., Shono M., Kusuhara H., Kinoshita H., Fuse E., Takadate A., et al. Molecular cloning and functional analyses of OAT1 and OAT3 from cynomolgus monkey kidney. Pharm Res 2005, 22:647-660.
146. Deguchi T., Isozaki K., Yousuke K., Terasaki T., Otagiri M. Involvement of organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. J Neurochem 2006, 96:1051-1059.
147. Bahn A., Ljubojevic M., Lorenz H., Schultz C., Ghebremedhin E., Ugele B., et al. Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol 2005, 289:C1075-C1084.
148. Kaler G., Truong D.M., Khandelwal A., Nagle M., Eraly S.A., Swaan P.W., et al. Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members. J Biol Chem 2007, 282:23841-23853.
149. Schnabolk G.W., Gupta B., Mulgaonkar A., Kulkarni M., Sweet D.H. Organic anion transporter 6 (Slc22a20) specificity and Sertoli cell-specific expression provide new insight on potential endogenous roles. J Pharmacol Exp Ther 2010, 334:927-935.
150. Sugawara M., Mochizuki T., Takekuma Y., Miyazaki K. Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites. Biochim Biophys Acta 2005, 1714:85-92.
151. Cropp C.D., Komori T., Shima J.E., Urban T.J., Yee S.W., More S.S., et al. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol 2008, 73:1151-1158.
152. Whitley A.C., Sweet D.H., Walle T. The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1. Drug Metab Dispos 2005, 33:1097-1100.
153. Enomoto A., Takeda M., Taki K., Takayama F., Noshiro R., Niwa T., et al. Interactions of human organic anion as well as cation transporters with indoxyl sulfate. Eur J Pharmacol 2003, 466:13-20.
154. Enomoto A., Takeda M., Tojo A., Sekine T., Cha S.H., Khamdang S., et al. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol 2002, 13:1711-1720.
155. VanWert A.L., Sweet D.H. Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm Res 2008, 25:453-462.
156. Uwai Y., Honjo H., Iwamoto K. Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacol Res 2012, 65:254-260.
157. Hosoyamada M., Sekine T., Kanai Y., Endou H. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 1999, 276:F122-F128.
158. Ichida K., Hosoyamada M., Kimura H., Takeda M., Utsunomiya Y., Hosoya T., et al. Urate transport via human PAH transporter hOAT1 and its gene structure. Kidney Int 2003, 63:143-155.
159. Sato M., Mamada H., Anzai N., Shirasaka Y., Nakanishi T., Tamai I. Renal secretion of uric acid by organic anion transporter 2 (OAT2/SLC22A7) in human. Biol Pharm Bull 2010, 33:498-503.
160. Bakhiya A., Bahn A., Burckhardt G., Wolff N. Human organic anion transporter 3 (hOAT3) can operate as an exchanger and mediate secretory urate flux. Cell Physiol Biochem 2003, 13:249-256.
161. Hagos Y., Stein D., Ugele B., Burckhardt G., Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 2007, 18:430-439.
162. Bahn A., Hagos Y., Reuter S., Balen D., Brzica H., Krick W., et al. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J Biol Chem 2008, 283:16332-16341.
163. Anzai N., Miyazaki H., Noshiro R., Khamdang S., Chairoungdua A., Shin H.J., et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. J Biol Chem 2004, 279:45942-45950.
164. Iwanaga T., Kobayashi D., Hirayama M., Maeda T., Tamai I. Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos 2005, 33:1791-1795.
165. Enomoto A., Kimura H., Chairoungdua A., Shigeta Y., Jutabha P., Cha S.H., et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002, 417:447-452.
166. Hosoyamada M., Ichida K., Enomoto A., Hosoya T., Endou H. Function and localization of urate transporter 1 in mouse kidney. J Am Soc Nephrol 2004, 15:261-268.
167. Leal-Pinto E., Tao W., Rappaport J., Richardson M., Knorr B.A., Abramson R.G. Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem 1997, 272:617-625.
168. Meijers B.K., Bammens B., Verbeke K., Evenepoel P. A review of albumin binding in CKD. Am J Kidney Dis 2008, 51:839-850.