Uremic toxins prof. alaa sabry

1. Uremic Toxins: Identification and Clinical Implication
By
Alaa Sabry., MD, FACP
Mansoura University,Egypt

2. Focus Of The Presentation
➢1-Current classification of Uremic
Toxins .
➢2-The effects of some of the probably
most important Uremic Toxins .
➢3-Provide an overview on therapeutic
approaches .

3. “
.”
“The uremic syndrome is characterized by the retention of
various solutes that would normally be excreted by the
kidneys.
JASN, 2012

5. • Treatment of uremia by hemodialysis has
become widespread over the last 40 years
and has improved substantially over that
time.
• However, people treated with this modality
continue to suffer from multiple disabilities.
• Retention of organic solutes, especially those
poorly removed by hemodialysis, likely
contributes to these disabilities.
Introduction

6. ➢ The set of signs and symptoms still present in people
receiving dialysis currently defined as adequate .
➢ “Patients who would have died from uremia but
survive because of dialysis suffer from a previously
non-existent life-threatening disease .
➢ This syndrome likely has complex origins.
➢ Retained organic solutes that are poorly removed by
dialysis.
Residual Syndrome

7. ➢Components of the residual syndrome
substantially diminish the quality independent
of the length of life.
➢Even if achievable, a few months of extra life
may mean little to a person encumbered by
multiple disabilities, especially if improved life
expectancy were obtained at the cost of more
hours of hemodialysis treatment.
Introduction

8. ➢ In 1999 Vanholder’s group, launched the European Uremic Toxins
(EUTox) Work Group .
➢ In 2003, the European Uremic Toxin (EUTox) Work Group classified 90
retentionsolutes which had been quantified at that time .
➢ In 2012 This list has been extended with an additional 56 solutes.
➢ At present, there are 152 solutes listed in the EUTox database (and
certainly an increase in this number in the following years can be
expected.
http://www.nephro- leipzig.de/eutoxdb/index.php

10. Classifications
≥500

11. Number of publicationson indoxylsulfate
v

12. Specific Uremic Toxins

13. ➢Our current marker of dialysis adequacy, has
been long considered to be inert but recent
data may suggest a toxic effect
➢
A-The small water-soluble compounds
Urea (60D)

14. ➢Metabolites of L-arginine that have long been
known for their neurotoxic effects.
➢There are three types :
➢ Monomethyl arginine (MMA).
➢Symmetric Dimethylarginine (SDMA).
➢Asymmetric Dimethylarginine (ADMA).
➢The distribution volume of the former is
significantly greater, which results in a decrease in
removal efficiency by dialysis procedures.
Vallence et al. 1992
A)Small water-soluble compounds
2- Guanidines

15. Relationshipbetweenplasma asymmetric dimethylarginine (ADMA) and intima-media thickness (IMT) .
90 HD patients
Relation between IMT and ADMA.

16. The Symmetric Dimethyl Arginine (SDMA)
Dose-responseeffect of ADMA and SDMA on intracellular
(A) TNF- and (B) IL-6 expressionin monocytes.
➢Has long been considered inert .
Kielstein JTet al (2004) Circulation 109:172–177

17. B-Protein-bound uremic toxins

19. • This molecule originates
Indoxyl sulfate
➢ A low-MW (213.21 Da)
derivated from dietary
protein.
➢ tryptophan is metabolized
into indole by
tryptophanase in intestinal
bacteria.
➢ Indole is absorbed into the
blood from the intestine,
and is metabolized to
indoxyl sulfate in the liver.
➢ Indoxyl sulfate is normally
excreted into urine (50-70
mg/day ) in healthy
persons
Para-cresol (p-cresol) and p-cresyl sulfate
(PCS)
MW: 108 Da) linked to
serum proteins .
➢tyrosine and
phenylalanine
metabolism by bacterial
microbiota
fermentation in the
large intestine.
➢p-Cresyl sulfate is
poorly removed by
hemodialysis because
its clearance is limited
by protein binding.
Meijers BK, et al. Am J Kidney Dis 2009;54:891-901

20. • Inhibit endothelial cell proliferation and wound repair
(Dou L et al, Kidney Int; 65:442, 2004)
• Shedding of endothelial cells (Faure V et al, JTH 2005;4:566)
• Endothelial dysfunction (Peng Y-S et al, J Cell Biochem 2012;113:
1034)
• Renal and Myocardial fibrosis (Lekawanvijit S et al, Eur Heart J
2010;14:1771)
• Insulin resistance (Koppe L et al, J Am Soc Nephrol. 2013;24:88)
• Progression of CKD and mortality .
Wu IW, Hsu KH, et al (2011)Nephrol Dial Transpl 26:938–947
Indoxyl sulphate causes
Cardiovascular and Diseases

21. Meert N et al Nephrol. Dial. Transplant. 2012;27:2388-2396PCG= p-cresylglucuronide; PCS=p-cresylsulphate
2-Para-cresol (p-cresol) and p-cresyl sulfate (PCS)

22. IS
PCS
PTCs, proximaltubular cells; RAAS, renin–angiotensin–aldosteronesystem, IS, indoxylsulphate, PCS, p cresulsulphate
PCS and IS added to PTCs in vitro resulted in
increased RAAS system genes
Masson trichrome

23. Real-time PCR
Immunofluorescencestaining

24. Clinical Outcomes Data

25. Para-cresol (p-cresol) and p-cresyl
sulfate (PCS)
Barreto FC et al Clin J Am Soc Nephrol 2009;4:1551–1558
Shorter renal survival with higher
levels of IS and PCS

26. • Formed by non-enzymatic glycosylation reactions with sugars, lipids and
nucleic acids.
• The exogenous forms come from diet when foods are processed at high
temperature.
• Endogenous transformation results from exposure to high glucose levels
such as in diabetic patients, from aging, and from uremia.
Semba RD, et al. J Gerontol A Biol Sci Med Sci 2010;65:963-75.91,92
• There are more than 20 AGE compounds
• Main pathway of elimination from the body is through the urine, or
through dialysis in case of renal function replacement.
• Alhamdani MS.Et al. Perit Dial Int 2007;27:86-9.
Advanced glycation end products (AGEs)

27. ➢Adequate marker of :
Severity of peripheral vascular disease.
Arterial stiffness in the general population and bone
remodeling
Wilson AMet al (2007) .Circulation 116: 1396–1403
Saijo Y, et al (2005) Hypertens Res 28:505–511
➢Although the distribution volume of b2-
microglobulin is 3–4 times smaller than that of
urea, the shift from the extra-plasmatic to the
plasmatic compartment is decreased almost 20-
fold, hampering removal .
Stiller S, et al.(2002)Int J Artif Organs25:411–420
Middle Mollecules
b2-macroglobulin
(molecular weight of 11,000)

28. Survival

29. Therapeutic Strategies

30. Protein
intake
Putrefaction Absorption
Tissue
uptake
Tissue
damage
↓Protein diet
Manipulate
colonic flora
Prevent
absorption
Removal
from blood
Antidote

31. Dialytic Removal
High Flux HD

32. Back To The Basics

34. Middle Molecules
Options for Increasing
Extracorporeal Removal

35. 11 stable anuric HD patients underwent two
bicarbonate HD sessions (~4 and ~8 h) in a
random sequence, at least 1 week apart.
Reduction ratios (RRs) at different time points during the 4- and 8-h
dialysis sessions for middle molecule β2M.
Plasma b2-microglobulinconcentrations plotted as a function of time after
starting the hemodialysistreatment.
TSR (8 h vs 4 h) were for β2M 39.2% (P < 0.005).
• Crossover study of 10 chronic
hemodialysis patients .
• Either low-flux cellulose
acetate or high-flux cellulose

36. Prospective, controlled, cross-over design.
12 patients underwent four treatments, two with the HCO dialyzer and tw
with the PF dialyzer, each in either a haemodialysis (HD)
haemodiafiltration (HDF) mode.
Amount of β 2 M recoveredin dialysate
in mg/h
AGE molecules in dialysate.

37. • High cut off hemodialysis
(HCO-HD) uses a dialyzer
membrane that provides
significant clearance of
molecules up to a molecular
weight (MW) of albumin
(65 kDa) from blood. The
characteristics of the
dialyzer are distinct from
high-flux HD (HF-HD) and
protein-permeable HD (PP-
HD), which remove
molecules up to a MW of 20
and 25 kDa.

39. • 1846 patients undergoing thrice-weekly dialysis.
• Patients randomly to a standard or high dose of dialysis
and to a low-fluxor high-flux dialyzer.
• The primary outcome, death fromany cause.

40. The patients werestratified into
a short-duration group and a long-duration group, on the basis
of the mean duration of dialysis of 3.7 yr before
randomization.

41. • 738 incident hemodialysispatients, stratified themby serumalbumin
4 g/dl, and assignedthemtoeither low-flux or high-flux membranes.
• Nosignificant difference betweenhigh-flux and low-flux membranes.
Kaplan-Meiersurvival curves for the complete intention-to-treatpopulation

42. Peritoneal dialysis

43. Daily removal of urea nitrogen (ureaN), indican, and PCS in the two groups of PD
patients as compared with hemodialysis (HD) patients and normal individuals.

44. Protein bound
Options for Increasing
Extracorporeal Removal

45. Nine patients
Two experimental dialysis treatments 1 week
apart. ( larger dilaysersand Qd 800 ml/min )
Options for Increasing Extracorporeal Removal
Impact of increasing KOA and QD

46. Impact of increasingdialysis time on removal of solutes into the dialysate while
maintainingtotal blood and dialysate volume, as well as dialyzer surfacearea the same for
the entire session.
Eloot S, et al. Kidney Int. 2008;73:765-770.
Options for Increasing Extracorporeal Removal
Impact of increasing dialysis time

47. Convective strategies (hemofiltration
or hemodiafiltration)

48. 36 chronic dialysis patients followed for 13 months.
Group1 patients BHD (TreatmentA) for 6 months, and afterwards,
toHv-OL-HDF for a further 6 months (Treatment B).
Group 2 patients were treated with Treatment BH for 6 months, and
afterwards, they were transferred toTreatmentA for a further 6 months.
Pre-dialysisIS and Pcs free levels in hv-OL-HDF and BHD (time 0 and 6 months);
*p < 0.001. # p< 0.01.

50. Predialysis b-2-microglobulin levels in patients treated withonline
hemodiafiltration
and low-flux hemodialysis
The incidence of both all-cause mortality and cardiovascular
events was not affected by treatment assignment. Survival
curves for time to death from any cause
• 714 patients
• online postdilutionhemodiafiltration(n=358) or to continue
low-fluxhemodialysis(n=356).
• Aftera mean 3.0 years of follow-up.

51. • PRC trial
• 782 randomly assigned them in a 1:1 ratio to either
postdilution OL-HDF or high-flux HD.
• The follow up period was 2 years.
Overall(A) and cardiovascularsurvival (B) among the treatment groups.

52. • A multicenter, open-label, randomizedcontrolledtrial .
• 906 chronic hemodialysis patients either to continue hemodialysis (n=450) or toswitch to high-efficiency
postdilution OL-HDF (n=456).
• The meanfollow-up2.08 years .

53. Adsorption

54. FPAD
(Fractionated Plasma separation, Adsorption and Dialysis)
187% IS
127% PCS
comparedto high flux dx
Brettschneider F et al Artif Organs 2013;37:409
Fractionated plasma separation and adsorption

55. • Magnetic beads containing sorbents were brought into
contact with blood spiked with digoxin and interleukin 1,
after which the beads were recaptured magnetically for
regeneration and reuse .
Magnetic beads containing sorbents

56. Increasing plasma ionic strength by infusionof
hypertonicsaline solution;
Changing Physical Conditions
Within the Dialyzer
• Has the potential to enhance
diffusive removal of protein-
bound solutes by increasing
their free fraction.
• Modifying osmotic conditions
within the dialyzer:
• Increasing the ionic strength
of the environment
surrounding protein-bound
solutes .
• Hypertonic saline solution,
may reduce the electrostatic
interaction between the
solute and protein

57. A-Non- Dialytic removal
Gut role
Adsorption
Tubular excretion

59. Humans are Supra-organisms

60. > 1012/ml bacteria separated by 10
μm over a surface area of 200 m2

61. Intestinal epithelial Barrier in CKDLeaky Gut In CKD

62. An Revolutionary Perspectives

63. Bad Relationship

64. Good Relationship???

65. Interventions With Potential Impact on the Intestine as a Source of Uremic
Toxins

67. The social networkbetween diet, gut microbiotaand kidney in CKD

68. Koide K et al. Clin Eval 1987;15:527–64
AST-120

69. Prospective clinical trials

70. Primary and secondary efficacy end points from the EPPIC trials
Multinational, Randomizemd ,Double blinded, placebo controlled studies.
2035 adults, Moderate to severe kidney disease ( s.cr 2-5mg/dl),
Primary End point: Initiation of dialysis, kidney Tx, doubling of S.Cr).
EvaluatingPreventionof Progression in Chronic
Kidney Disease

71. EPPIC trials(EPPICUSA)

72. Organic Anion Transporters
(OATs)

73. Organic Anion Transporters
(OATs)
SLCO4C1

74. Kidney Transplantation

75. Total and free IS levels were
significantlyhigher in non-transplant
patients with CKD than in transplant
At M1 an M12, total and free IS levels were
significantlylower than at T0.
131 Renal TX.

77. Bioengineered Kidney

78. Transepithelialclearance of indoxyl sulfate in the presence of human serum albumin,
and albumin-fluorescein isothiocyanate(FITC) handling in bioengineered renal
tubules.

79. A schematic representation of MicroarrayHemostaticprovider ( MOHP) and its
position in the extracorporealblood circuit
quantitative microarray detector (QMD)
Hemostatsis orientedmicroarray column HOMC

81. Knowing is not enough, we must apply.
Willing is not enough, we must do.
Johann Wolfgang von Goethe
28 August 1749 – 22 March 1832
Conclusion

82. • Not much, but certainly we have ended the
beginning of the quest for knowledge.
• Conventional renal replacement therapies
cannot remove many biologically significant
retention solutes
• Accumulation is they key word … we’ve got
to give more “GFR” back

83. • One cannot know (that one gives more GFR) what
one cannot measure (dose of dialysis).
• However kinetic models of the dose of dialysis based
on (KT/V)urea have to be drastically modified.
• The non-toxic “stuff” we measure (SCr/Urea)
increases far less than the toxic “stuff” we do not
routinely measure .
• The molecular analysis of what goes down the drain
points out that no matter how much (KT/V)UREA we
give there will be bigger bad guys that stay behind.
What can we do?

84. • The best way of giving GFR back is a transplant .
• If the organ shortage could be solved, then the
precise nature of the uremic toxins can be left
unexplored.
• It is unlikely that we can achieve this goal any
time soon for all our patients so we’ve got to
improve our dialysis Tx.
What can we do?

88. Prebiotic

89. Meta-analysis for pre-, pro-, and synbioic therapy on serum IS in the HD
population.
19 eligible studies- Five studies included 91 HD patients

90. A randomized, double–blind,
placebo–controlled, crossover trial of synbiotic therapy over
6 weeks (4-week washout).
37 Predialysis individualsrandomized
Treatment effect of synbioticson serum uremic