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Dng uremic toxins menyet elnasr
1. Uremic Toxins: An Update
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
4.
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
retention solutes 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
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. Relationship between plasma asymmetric dimethylarginine (ADMA) and intima-media thickness (IMT) .
90 HD patients
Relation between IMT and ADMA.
16. The Symmetric Dimethyl Arginine (SDMA)
Dose-response effect of ADMA and SDMA on intracellular
(A) TNF- and (B) IL-6 expression in monocytes.
Has long been considered inert .
Kielstein JTet al (2004) Circulation 109:172–177
18. • 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
19.
20. 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)
21. IS
PCS
PTCs, proximal tubular cells; RAAS, renin–angiotensin–aldosterone system, IS, indoxyl sulphate, PCS, p cresulsulphate
PCS and IS added to PTCs in vitro resulted in
increased RAAS system genes
Masson trichrome
24. 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
25. 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 Organs 25:411–420
Middle Mollecules
b2-microglobulin
31. 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-microglobulin concentrations plotted as a function of time after
starting the hemodialysis treatment.
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
32. Prospective, controlled, cross-over design.
12 patients underwent four treatments, two with the HCO dialyze
and two with the PF dialyzer, each in either a haemodialysis (HD
or haemodiafiltration (HDF) mode.
Amount of β 2 M recovered in dialysate
in mg/h
AGE molecules in dialysate.
33.
34. • 1846 patients undergoing thrice-weekly dialysis.
• Patients randomly to a standard or high dose of dialysis
and to a low-flux or high-flux dialyzer.
• The primary outcome, death from any cause.
35. The patients were stratified 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.
36. • 738 incident hemodialysis patients, stratified them by serum albumin
4 g/dl, and assigned them to either low-flux or high-flux membranes.
• No significant difference between high-flux and low-flux membranes.
Kaplan-Meier survival curves for the complete intention-to-treat population
38. 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.
40. 36 chronic dialysis patients followed for 13 months.
Group 1 patients BHD (Treatment A) for 6 months, and afterwards,
to Hv-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 to Treatment A for a further 6
months.
Pre-dialysis IS and Pcs free levels in hv-OL-HDF and BHD (time 0 and 6 months);
*p < 0.001. # p< 0.01.
41.
42. Predialysis b-2-microglobulin levels in patients treated with online
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 postdilution hemodiafiltration (n=358) or to continue
low-flux hemodialysis (n=356).
• After a mean 3.0 years of follow-up .
43. • 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 cardiovascular survival (B) among the treatment groups.
44. • A multicenter, open-label, randomized controlled trial .
• 906 chronic hemodialysis patients either to continue hemodialysis (n=450) or to switch to high-efficiency
postdilution OL-HDF (n=456).
• The mean follow-up 2.08 years .
46. FPAD
(Fractionated Plasma separation, Adsorption and Dialysis)
187% IS
127% PCS
compared to high flux dx
Brettschneider F et al Artif Organs 2013;37:409
Fractionated plasma separation and adsorption
47. • 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
48. Increasing plasma ionic strength by
infusion of hypertonic saline 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
59. Meta-analysis for pre-, pro-, and synbioic therapy on serum IS in the HD
population.
19 eligible studies- Five studies included 91 HD patients
60. Therapeutic Options
Adsorbent
40 B.C
Terra sigillata from sacred earth found on the Greek
island of Lemons is useful for multiple disorders including diseases of the
kidney .
Dioscorides
De Materia Medica
61. Koide K et al. Clin Eval 1987;15:527–64
AST-120
63. 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).
Evaluating Prevention of Progression in Chronic
Kidney Disease
68. Total and free IS levels were
significantly higher in non-transplant
patients with CKD than in transplant
At M1 an M12, total and free IS levels were
significantly lower than at T0.
131 Renal TX.
69.
70. Transepithelial clearance of indoxyl sulfate in the presence of human
serum albumin, and albumin-fluorescein isothiocyanate (FITC) handling in
bioengineered renal tubules.
71. A schematic representation of Microarray Hemostatic provider ( MOHP) and its
position in the extracorporeal blood circuit
quantitative microarray detector (QMD)
Hemostatsis oriented microarray column HOMC
72.
73. 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
74. • 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
75. • 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?
76. • 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?
