Stein G, Mahiout A, Schneider S, Matata BM, Borst S, Schaefer
K
Elimination of beta-2 microglobulin, AGE beta-2 microglobulin,
and AGE peptides from serum of ESRD patients during dialysis
Am Soc Nephrol
J Am Soc Nephrol (abstract)
(Sep) 7:1420 1996
Non-enzymatic reactions occur between ambient glucose or other sugars and
plasma/tissue proteins. If allowed to undergo a slow and complex series of
chemical rearrangements, irreversible formation of a heterogeneous family
of chemically reactive and biologically active advanced glycosylation
endproducts (AGE) occurs [1]. These modified proteins are capable of many
biological activities, promoting cytokine production, matrix expansion,
and vascular damage, and they have been implicated in accelerated
atherosclerosis.
Both diabetics and patients with renal failure have high concentrations of
AGE in tissue and plasma, due to impaired elimination. New findings
suggest that AGE modification of beta-2-microglobulin (beta-2M) is
implicated in
the pathogenesis of dialysis-related amyloidosis [2,3]. The implication of
AGE in these various disorders makes it imperative to attempt inhibition
of their formation via aminoguinidine or and increase in their removal via
renal replacement
therapies.
Circulating low-molecular-weight-AGE beta-2000-6000 Da), measured by
competitive AGE-ELISA [4] in diabetic patients receiving high-flux
hemodialysis (F80 and F60) were significantly lower (by 33%) than in
patients treated with conventional hemodialysis (C101) [5]. However,
LMW-AGE concentrations remained 3.5-6 fold above normal, whether
high-flux, conventional dialysis or continuous ambulatory peritoneal
dialysis was used. Of note, high-flux dialysis markedly reduced AGE
following a session, but levels returned to the pre-treatment range within
3 hours
[5].
Superflux F800S (Fresenius) is a newly developed, large surface area (2.4
m2) polysulfone membrane, with an altered fibre geometry and hydraulic
permeability. Modifications include a thinner membrane (30 um rather than
40 um) and an inner lumen of 150 um, causing a higher pressure
drop in the dialyzer resulting in increased ultrafiltration and higher
convective transport across the membrane of large sized molecules (<
30,000 Da), such as beta-2M (11,800 Da), beta-2M-AGE and other
AGE-peptides.
In this clinical study, diabetic patients (n=10) with ESRD, undergoing
dialysis with Superflux F800S, were compared to non-diabetics (n=10),
treated with the high-flux dialyzer F60S. Serum concentrations of AGE,
beta-2M and beta-2M-AGE were measured before and following dialysis, using
competitive
ELISA.
All measured proteins were reduced in both patient groups, however, a
significantly higher reduction was measured following treatment with the
Superflux F800S. The percentage decreases in serum AGE, beta-2M and
beta-2M-AGE
were 88%, 79% and 79% respectively, in the diabetic group treated with
Superflux F800S, whereas the percentage decreases were 78%, 66% and 53%
respectively, in the non-diabetic group treated with the F60S. After 6
months of dialysis with Superflux F800S, a reduction in the predialysis
serum concentration of AGE, beta-2M and beta-2M-AGE could be observed. The
percentage decreases in predialysis serum AGE, beta-2M and beta-2M-AGE were
33%,
18% and 55% respectively, in the diabetic group treated with Superflux
F800S, whereas in the non-diabetic group treated with the F60S,
predialysis serum AGE increased by 20%, beta-2M-AGE by 100%, while beta-2M
was
unchanged.
Comment: This prospective non-randomized study compared the
elimination of AGE, beta-2M and beta-2M-AGE in two groups of dialysis
patients.
The fundamental shortcoming of this study is that the authors did not
compare the same population (diabetics or non-diabetics) with the two
different membranes. This could have been easily accomplished in either a
randomised or cross-over study design. Further, the duration of each
treatment and frequency of dialysis in the two groups were not controlled
for. Hence, the provided data is observational.
While transport by diffusion is always size-dependent (small solutes
transported faster than large ones), convective mass transfer is
independent of particle size [6], relying on hydraulic permeability. A
modified fibre geometry and hydraulic permeability confer to the Superflux
F800S dialyzer higher solute convective transport of larger solutes such as
AGE, beta-2M and beta-2M-AGE, and may offer new therapeutic approaches for
the
removal of these molecules, especially in diabetics.
However, the authors failed to acknowledge other differences in membrane
characteristics. Indeed, although of different hydraulic permeability,
Superflux F800S (2.4 m2) was compared to a dialyzer (F60S) of half the
surface area (1.2 m2). Furthermore, protein loss as high as 20 gm in one
dialysis session has been reported with polysulfone dialyzers reprocessed
with bleach [7]. The authors did not measure urea kinetic modelling nor
report on the nutritional parameters of the patients and whether protein
losses were exacerbated by the use of F800S. Finally, in a cost effective
era, dialyzer reprocessing of Superflux F800S was not reported.
We can only speculate whether transmembrane passage of bacterial
contaminants through this highly permeable membrane increases with reuse,
since in vitro studies using reprocessed polysulfone dialyzers (F80B) have
shown significant passage of cytokine-inducing bacterial products
[8].
In conclusion, this new dialyzer seems to achieve favourable clearances of
AGE-related peptides, however, the effects of possible increased loss
of proteins and backfiltration during dialysis were not assessed.
Long-term studies are
awaited to assess for the prevention or treatment of dialysis-related
amyloidosis and overall survival.
REFERENCES
1. Vlassara H. Recent progress on the biologic and clinical significance
of advanced glycosylation products. J Lab Clin Med 1994;
124:19-30.
2. Niwa T, Miyazaki S, Katsuzaki T, Tatemichi N, Takei Y, Miyazaki T,
Morita T, Hirasawa Y. Immunohistochemical detection of advanced glycation
end products in dialysis-related amyloidosis. Kidney Int 1995;
48:771-778.
3. Miyata T, Maeda K. Pathogenesis of dialysis-related amyloidosis.
[Review]. Current Opinion in Nephrology & Hypertension 1995;
4:493-497.
4. Makita Z, Vlassara H, Cerami A, Bucala R. Immunochemical detection of
advanced glycosylation end products in vivo. J Biol Chem 1992;
267:5133-5138.
5. Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM,
Barth RH, Winston JA, Fuh H, Manogue KR, Cerami A, Vlassara H. Reactive
glycosylation endproducts in diabetic uraemia and treatment of renal
failure. Lancet 1994; 343:1519-1522.
6. Colton CK, Henderson LW, Ford CA, Lysaght MJ. Kinetics of
hemodiafiltration. I. In vitro transport characteristics of a hollow-fibre
blood ultrafilter. J Lab Clin Med 1975; 85:355-371.
7. Kaplan AA, Halley SE, Lapkin RA, Graeber CW. Dialysate protein losses
with bleach processed polysulfone dialyzers. Kidney Int 1995;
47:573-578.
8. Sundaram S, Barrett TW, Meyer KB, Perrella C, Cendoroglo MN, King AJ,
Pereira BJG. Transmembrane passage of cytokine-inducing bacterial products
across new and reprocessed polysulfone dialyzers. J Am Soc Nephrol
1996;7:2183-2191.
(Reviewed by: Bertrand L. Jaber, M.D. and Brian J. G. Pereira, M.D.,
D.M., Division of Nephrology, New England Medical Center, Tufts University
School of Medicine, Boston, Massachusetts.)
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Am Soc Nephrol
Basic hemodialysis :
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CRF by organ system :
Joint disease, beta-2 microglobulin