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. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: Transl Res. 2016 Apr 30;179:24–37. doi: 10.1016/j.trsl.2016.04.007

Table 1.

Uremic toxins: source, mechanisms of injury and consequence

Toxin Source/ Mechanism of action Consequences Remarks
Ammonia and Urea Ammonia, the end product of protein
catabolism is converted to urea by
Ornithine -Urea cycle. Gut bacteria
expressing urease cleave urea into
ammonia and carbon dioxide (1).		 Epithelial cell injury by
increasing the pH of
surrounding
environment (2)		 Some ammonia is used
for microbial synthesis
of amino acids (3)
Creatinine, Guanidine
and Uric acid		 Up to 60% of creatinine is excreted
by routes other than urine in kidney
failure (4). Colonic bacteria degrade
creatinine in gut. Guanidine is
produced by creatinine metabolism
by Pseudomonas stutzeri (5).
Intestinal organisms can degrade
urate, generating allantoin, allantoic
acid, urea and ammonia (6)		 Guanidine
accumulation in CKD
(7) increases mortality
noticed in animal
studies (8)
Indoles:
Indoxyl sulphate (IS)		 Generated from metabolism of
tryptophan (9), cleared by proximal
tubules and increased in CKD (10,
11). Nephrotoxic via OAT mediated
uptake by proximal tubule cells,
activation of nuclear factor (NF)-Kb
and plasminogen activator inhibitor
type 1 (12–14)		 Increased expression of
genes related to
tubulointerstitial
fibrosis (15), aortic and
vascular calcification
(16–18), endothelial
cell damage (19, 20).
Lowers erythropoietin
production (21), bone
turnover (22)		 Transport is mediated
by organic anion
transporter 1 and 3
(OAT1, OAT3) (69–
71). Not effectively
removed by HD (23,
24)
Indole acetic acid (IAA) Produced by intestinal bacteria form
tryptophan.		 Glomerulosclerosis,
interstitial fibrosis (3),
oxidative stress (4)		 Partly removed by
hemodialysis (25–27)
Phenols:
Para (p) -Cresol		 Breakdown of tyrosine and
phenylalanine by intestinal bacteria		 Renal fibrosis,
oxidative stress,
increased inflammatory
cytokines (28), all-
cause mortality and
CVD . (29,
30)Inhibition of
endothelial
proliferation, increased
endothelial
permeability (20, 31)		 Uremic toxin excreted
by tubular secretion
through specific
transporters (32–34),
accumulates in CKD
(35)
Phenylacetylglutamine
(PAG)		 Microbe derived, accumulates in
uremia (36–38). Phenyl acetic acid, a
precursor of PAG is derived from
phenylalanine (39). Impairs
immunoregulation (40), increases
oxidative stress (41) and osteoblast
dysfunction (42)		 Tubular damage and
progression of CKD
(43) mediated by
Phenyl acetic acid
Hippurate Gut microbial-mammalian co
metabolite (44, 45). Causes anion gap
acidosis in CKD (46, 47)		 Interferes with
erythropoiesis and
platelet cyclooxygenase
activity (48). Possible
glucose intolerance.
Amines Polyamines Play regulatory role in cell function
and growth (49). Polyamine induced
cellular downregulation play a role in
lack of tissue responses to hormones
in uremia (50)		 Erythropoietin
inhibition, anemia of
CKD (51)
 Many polyamines are
generated by
microbiota from
precursor amino acids
D-amino Acids Bacterial production in the intestinal
tract		 Possible neurotoxicity
(52)		 Plasma levels increase
with declining kidney
function (53)
Trimethylamine N
Oxide (TMAO)		 Choline is catabolized by intestinal
microbiota to trimethylamine gas,
which is metabolized by liver to
TMAO.
Dietary carnitine is also a substrate
for gut flora to produce TMAO (54).
Promotes atherosclerosis by
promoting foam cell formation and
increasing scavenger receptors on
macrophage (54–56)		 Associated with higher
long term mortality
(54–56). Levels are
high in CKD (57).
Hydrogen sulfide (H2S) Generated by sulfate reducing
bacteria in colon. Inhibits
mitochondrial cytochrome-c oxidase
(58). Genotoxic, cytotoxic and
inflammatory (59). May decrease
inflammation and inhibiting renal
fibrosis (60).		 Can be cardio
protective (61).
 Levels reduced in
hemodialysis patients
(62)
Endotoxin Binds to lipopolysaccharide-binding
protein (LBP), forming a complex
that interacts with the MD-2 part of
the toll like receptor 4, anchored by
CD14 (100). This stimulates
production of inflammatory cytokines
(35, 41)		 Endotoxin translocation
causes inflammation in
CKD (54, 63), possible
role in progression of
atherosclerosis (64, 65)		 Soluble CD14
associates with
progression of
CKD,CVD and
mortality (66–68)

Reference List

1

WALSER M, BODENLOS LJ. Urea metabolism in man. J.Clin.Invest 1959;38:1617-1626.

2

Vaziri ND, Dure-Smith B, Miller R et al. Pathology of gastrointestinal tract in chronic hemodialysis patients: an autopsy study of 78 cases. Am.J.Gastroenterol. 1985;80(8):608-611.

3

Stewart GS, Smith CP. Urea nitrogen salvage mechanisms and their relevance to ruminants, non-ruminants and man. Nutr.Res.Rev. 2005;18(1):49-62.

4

Jones JD, Burnett PC. Creatinine metabolism in humans with decreased renal function: creatinine deficit. Clin.Chem. 1974;20(9):1204-1212.

5

Eyk HG, van, Vermaat RJ et al. The conversion of creatinine by creatininase of bacterial origin. Enzymologia. 1968;34(3):198-202.

6

Yokozawa T, Mo ZL, Oura H. Comparison of toxic effects of methylguanidine, guanidinosuccinic acid and creatinine in rats with adenine-induced chronic renal failure. Nephron 1989;51(3):388-392.

7

OLSEN NS, BASSETT JW. Blood levels of urea nitrogen, phenol, guanidine and creatinine in uremia. Am.J.Med. 1951;10(1):52-59.

8

OLSEN NS, BASSETT JW. Blood levels of urea nitrogen, phenol, guanidine and creatinine in uremia. Am.J.Med. 1951;10(1):52-59.

9

Cummings JH. Fermentation in the human large intestine: evidence and implications for health. Lancet 1983;1(8335):1206-1209.

10

Lin CJ, Chen HH, Pan CF et al. p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease. J.Clin.Lab Anal. 2011;25(3):191-197.

11

Wu IW, Hsu KH, Lee CC et al. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol.Dial.Transplant. 2011;26(3):938-947.

12

Lysaght MJ, Vonesh EF, Gotch F et al. The influence of dialysis treatment modality on the decline of remaining renal function. ASAIO Trans. 1991;37(4):598-604.

13

Motojima M, Hosokawa A, Yamato H et al. Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake. Br.J.Pharmacol. 2002;135(2):555-563.

14

Motojima M, Hosokawa A, Yamato H et al. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63(5):1671-1680.

15

Miyazaki T, Ise M, Seo H et al. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int.Suppl 1997;62:S15-S22.

16

Adijiang A, Higuchi Y, Nishijima F et al. Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats. Biochem.Biophys.Res.Commun. 2010;399(4):637-641.

17

Barreto FC, Barreto DV, Liabeuf S et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin.J.Am.Soc.Nephrol. 2009;4(10):1551-1558.

18

Yamamoto H, Tsuruoka S, Ioka T et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int. 2006;69(10):1780-1785.

19

Amabile N, Guerin AP, Leroyer A et al. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J.Am.Soc.Nephrol. 2005;16(11):3381-3388.

20

Dou L, Bertrand E, Cerini C et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 2004;65(2):442-451.

21

Chiang CK, Tanaka T, Inagi R et al. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest 2011;91(11):1564-1571.

22

Nii-Kono T, Iwasaki Y, Uchida M et al. Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. Kidney Int. 2007;71(8):738-743.

23

Niwa T, Takeda N, Tatematsu A et al. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin.Chem. 1988;34(11):2264-2267.

24

Martinez AW, Recht NS, Hostetter TH et al. Removal of P-cresol sulfate by hemodialysis. J.Am.Soc.Nephrol. 2005;16(11):3430-3436.

25

De SR, Dhondt A, Eloot S et al. Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-protein-bound and protein-bound uraemic solutes. Nephrol.Dial.Transplant. 2007;22(7):2006-2012.

26

Satoh M, Hayashi H, Watanabe M et al. Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure. Nephron Exp.Nephrol. 2003;95(3):e111-e118.

27

Dou L, Sallee M, Cerini C et al. The cardiovascular effect of the uremic solute indole-3 acetic acid. J.Am.Soc.Nephrol. 2015;26(4):876-887.

28

Watanabe H, Miyamoto Y, Honda D et al. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int. 2013;83(4):582-592.

29

Bammens B, Evenepoel P, Keuleers H et al. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int. 2006;69(6):1081-1087.

30

Liabeuf S, Barreto DV, Barreto FC et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol.Dial.Transplant. 2010;25(4):1183-1191.

31

Cerini C, Dou L, Anfosso F et al. P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb.Haemost. 2004;92(1):140-150.

32

Meijers BK, Evenepoel P. The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol.Dial.Transplant. 2011;26(3):759-761.

33

Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J.Ren Nutr. 2010;20(5 Suppl):S2-S6.

34

Mutsaers HA, Wilmer MJ, van den Heuvel LP et al. Basolateral transport of the uraemic toxin p-cresyl sulfate: role for organic anion transporters? Nephrol.Dial.Transplant. 2011;26(12):4149.

35

Poesen R, Viaene L, Verbeke K et al. Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD. Clin.J.Am.Soc.Nephrol. 2013;8(9):1508-1514.

36

Zimmerman L, Egestad B, Jornvall H et al. Identification and determination of phenylacetylglutamine, a major nitrogenous metabolite in plasma of uremic patients. Clin.Nephrol. 1989;32(3):124-128.

37

Smith EA, MacFarlane GT. Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine. Microb.Ecol. 1997;33(3):180-188.

38

Seakins JW. The determination of urinary phenylacetylglutamine as phenylacetic acid. Studies on its origin in normal subjects and children with cystic fibrosis. Clin.Chim.Acta 1971;35(1):121-131.

39

Yang D, Beylot M, Agarwal KC et al. Assay of the human liver citric acid cycle probe phenylacetylglutamine and of phenylacetate in plasma by gas chromatography-mass spectrometry. Anal.Biochem. 1993;212(1):277-282.

40

Schmidt S, Westhoff TH, Krauser P et al. The uraemic toxin phenylacetic acid impairs macrophage function. Nephrol.Dial.Transplant. 2008;23(11):3485-3493.

41

Schmidt S, Westhoff TH, Krauser P et al. The uraemic toxin phenylacetic acid increases the formation of reactive oxygen species in vascular smooth muscle cells. Nephrol.Dial.Transplant. 2008;23(1):65-71.

42

Yano S, Yamaguchi T, Kanazawa I et al. The uraemic toxin phenylacetic acid inhibits osteoblastic proliferation and differentiation: an implication for the pathogenesis of low turnover bone in chronic renal failure. Nephrol.Dial.Transplant. 2007;22(11):3160-3165.

43

Yang D, Beylot M, Agarwal KC et al. Assay of the human liver citric acid cycle probe phenylacetylglutamine and of phenylacetate in plasma by gas chromatography-mass spectrometry. Anal.Biochem. 1993;212(1):277-282.

44

Remer T, Manz F. Paleolithic diet, sweet potato eaters, and potential renal acid load. Am.J.Clin.Nutr. 2003;78(4):802-803.

45

Li M, Wang B, Zhang M et al. Symbiotic gut microbes modulate human metabolic phenotypes. Proc.Natl.Acad.Sci.U.S.A 2008;105(6):2117-2122.

46

Cathcart-Rake W, Porter R, Whittier F et al. Effect of diet on serum accumulation and renal excretion of aryl acids and secretory activity in normal and uremic man. Am.J.Clin.Nutr. 1975;28(10):1110-1115.

47

Mitch WE, Brusilow S. Benzoate-induced changes in glycine and urea metabolism in patients with chronic renal failure. J.Pharmacol.Exp.Ther. 1982;222(3):572-575.

48

Uremic toxins. Proceedings of the Ghent Symposium. October 3-4, 1986, Ghent, Belgium. Adv.Exp.Med.Biol. 1987;223:1-296.

49

Igarashi K, Ueda S, Yoshida K et al. Polyamines in renal failure. Amino.Acids 2006;31(4):477-483.

50

Campbell RA, Grettie DP, Bartos F et al. Uremic polyamine dysmetabolism. Proc.Clin.Dial.Transplant.Forum 1978;8:194-198.

51

Kushner D, Beckman B, Nguyen L et al. Polyamines in the anemia of end-stage renal disease. Kidney Int. 1991;39(4):725-732.

52

Oh MS, Phelps KR, Traube M et al. D-lactic acidosis in a man with the short-bowel syndrome. N.Engl.J.Med. 1979;301(5):249-252.

53

Bruckner H, Hausch M. Gas chromatographic characterization of free D-amino acids in the blood serum of patients with renal disorders and of healthy volunteers. J.Chromatogr. 1993;614(1):7-17.

54

Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat.Med. 2013;19(5):576-585.

55

Tang WH, Wang Z, Levison BS et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N.Engl.J.Med. 2013;368(17):1575-1584.

56

Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63.

57

Tang WH, Wang Z, Kennedy DJ et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ.Res. 2015;116(3):448-455.

58

Reiffenstein RJ, Hulbert WC, Roth SH. Toxicology of hydrogen sulfide. Annu.Rev.Pharmacol.Toxicol. 1992;32:109-134.

59

Aminzadeh MA, Vaziri ND. Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease. Nephrol.Dial.Transplant. 2012;27(2):498-504.

60

Song K, Wang F, Li Q et al. Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int. 2014;85(6):1318-1329.

61

Perna AF, Lanza D, Sepe I et al. Hydrogen sulfide, a toxic gas with cardiovascular properties in uremia: how harmful is it? Blood Purif. 2011;31(1-3):102-106.

62

Song K, Wang F, Li Q et al. Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int. 2014;85(6):1318-1329.

63

Freudenberg MA, Tchaptchet S, Keck S et al. Lipopolysaccharide sensing an important factor in the innate immune response to Gram-negative bacterial infections: benefits and hazards of LPS hypersensitivity. Immunobiology 2008;213(3-4):193-203.

64

Eggesbo JB, Hjermann I, Ovstebo R et al. LPS induced procoagulant activity and plasminogen activator activity in mononuclear cells from persons with high or low levels of HDL lipoprotein. Thromb.Res. 1995;77(5):441-452.

65

Reidy MA, Bowyer DE. Distortion of endothelial repair. The effect of hypercholesterolaemia on regeneration of aortic endothelium following injury by endotoxin. A scanning electron microscope study. Atherosclerosis 1978;29(4):459-466.

66

Raj DS, Carrero JJ, Shah VO et al. Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients. Am.J.Kidney Dis. 2009;54(6):1072-1080.

67

Raj DS, Shah VO, Rambod M et al. Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis. Am.J.Kidney Dis. 2009;54(6):1062-1071.

68

Poesen R, Ramezani A, Claes K et al. Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD. Clin.J.Am.Soc.Nephrol. 2015;10(9):1525-1533.