uremic toxins (niwa/uremic toxins) || advanced glycation endproducts (ages)

19ADVANCED GLYCATIONENDPRODUCTS (AGEs)

NAILA RABBANI AND PAUL J. THORNALLEY

19.1 CHEMICAL STRUCTURE ANDMOLECULAR WEIGHT

Advanced glycation endproducts (AGEs), as applied to proteins and peptides, is a term

applied to a groupof amino acid derivatives formedbyglycation of amino acid residues

in proteins and peptides and also free amino acids, excluding early glycation adducts of

Schiff’s base and fructosamines. AGEs were originally defined as products formed

from the degradation of fructosamines, N-(1-deoxy-D-fructos-1-yl)-amino acid resi-

dues, usually Ne-(1-deoxy-D-fructos-1-yl)lysine (FL) residues. AGEs is a term now

used to describe these and other glycation adducts formed by other processes including

glycation of amino acid residues and free amino acids by dicarbonyl compounds,

glyoxal, methylglyoxal (MG), and 3-deoxyglucosone (3-DG).1

The structures of AGEs are given in Figure 19.1. Structures given are for AGE

residues with the ionization state of the side chains indicated at physiological pH. The

major quantitative AGEs found are arginine-derived hydroimidazolone AGEs, par-

ticularly MG-derived hydroimidazolone MG-H1. The major lysine-derived AGE is

Ne-(carboxymethyl)-lysine (CML), which is usually found at contents 5- to 10-fold

lower than MG-H1 in plasma protein. Pentosidine is a well-studied fluorescent AGEs

usually found at contents in plasma protein of 100- to 300-fold lower than MG-H1

residues. Hydroimidazolone AGEs exist as three structural isomers.2,3

WhenAGEs are formed from amino acid residues in proteins they are termed “AGE

residues.” AGE residues in AGE-modified proteins have also been called “protein-

bound AGEs.”4 This is an incorrect term as AGEs are formed from part of the protein

293

Uremic Toxins, Edited by Toshimitsu Niwa.� 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

and peptide structure rather than by a discrete AGE molecule binding to proteins and

peptides that this nomenclature implies.1 The same advanced glycation modifications

are found for free amino acids in tissues and body fluids. The metabolites are called

“AGE free adducts.”3 AGE free adducts are formed by cellular proteolysis of AGE-

modified proteins with contributions also from glycation of free amino acids and

absorption of digested AGE-modified proteins in food. Low-molecular-mass AGEs in

HN

NHC

NH

CO(CH2)3 NH

CH3H

N (CH2)4 CHNH

CO

CMC

S CH2CO2–HC

CO

NHCH2

GlucosepaneMODIC

Pentosidine (fluorophore)Argpyrimidine (fluorophore)

CHCO

NH

NHN

HN N(CH2)4

HCCO

NH(CH2)3

(f)

(e)

MOLDGOLD

HCCO

NHCHCO

NHN N (CH2)4(CH2)4 + CH

NH

COHC

NH

CON N (CH2)4

CH3

(CH2)4 +

DOLD

HCCO

NHCHN N (CH2)4(CH2)4

CH2 CO

NH

(CHOH)2CH2OH

+

NH2NH

NH2 CH2CO2–

CMA

+

NH HC CO

(CH2)4H +

N

NNNH (CH2)3 CH

NH

CO

HHO

HHOH

Vesperlysine A (LM-1)

+HC

CO

NH(CH2)3

N

NCH3

CH3

OHNH

(b)

G-H1 MG-H1

HCCO

NH

HN

NNH(CH2)3

H

H

OHC

CO

NH

HN

NNH

CH3

H

O

(CH2)3HN

NNH

CH2

H

O

HOCH2(CHOH)2

HCCO

NH(CH2)3

3DG-H1

(c)

CML

+

CEL

HCCO

NHNH2CH2CO2

–(CH2)4

Pyrraline

HCCO

NH(CH2)4 N

HOCH2

HO

(d)

CHHCCO

NHNH2(CH2)4

CO2–

CH3+

+

AGE residue

(a)

HCCO

NHR

+HC

CO2

NH3

R AGE free adduct

HCCO

NH(CH2)3

N

N

(CH2)4 CHNH

CO

HO

(CH2)4

NH HC CO

–

294 ADVANCED GLYCATION ENDPRODUCTS (AGEs)

plasma were initially thought to represent AGE-modified peptides5 but later mass

spectrometric analysis showed this was rather due to AGE free adducts.3

AGE residues are present in most proteins to a minor or minimal extent6 usually

less than 5% total protein having one AGE residue (except for long-lived proteins

modified by chemically stable AGEs).7–10 For plasma proteins, AGE residues are

present on proteins of all molecular weights: albumin and higher molecular weight

proteins and “middle molecule” proteins and peptides (500–60,000 g/mol). How-

ever, we found no preferential enrichment of AGE residues in middle molecules.8

AGE free adducts have molecular weights <500 g/mol and molecular diameters

1–3 nm and are therefore readily filtered in the glomeruli. They are expected to

readily traverse the vascular endothelium by paracellular flow except for non-

fenestrated blood capillaries with tight gap junctions (such as capillaries of the

brain and spinal cord).11 They have limited paracellular flow through the tight gap

junctions of the intestinal and renal tubular epithelium. AGE free adducts are amino

acid derivatives and hence are highly ionized. For other membrane permeability they

likely traverse by amino acid transporters or similar membrane transporter proteins.

19.2 METABOLISM AND BIOLOGY

AGEs are formed by glycation of cellular and extracellular proteins.3 The rate of

formation of AGE-modified proteins depends on the concentration of the protein

substrate, the concentration of the glycating agent, and the reactivity of the site with

the protein substrate toward glycation for AGE residues formation. Neighboring

FIGURE 19.1 Molecular structures of glycation adduct residues. (a) Generic structure of

AGE residues and AGE free adducts. R indicates the amino acid side chain. (b) Hydro-

imidazolones AGEs. G-H1: glyoxal-derived hydroimidazolone, Nd-(5-hydro-4-imidazolon-2-

yl)ornithine, MG-H1:MG-derived hydroimidazolone,Nd-(5-hydro-5-methyl-4-imidazolon-2-

yl)-ornithine, and 3-DG-derived hydroimidazolone: Nd-[5-(2,3,4-trihydroxybutyl)-5-hydro-4-

imidazolon-2-yl]ornithine. Only one isomer is shown but the three structural isomers are

usually summed together in estimations. (c) Monolysine adducts. CML: Ne-(carboxymethyl)-

lysine, CEL: Ne-(1-carboxyethyl)lysine, pyrraline: 6-2-(formyl-5-hydroxymethyl-pyrrol-1-

yl)-L-norleucine. (d) imidazolium and other crosslinks. GOLD: glyoxal-derived lysine

dimer, 1,3-di(Ne-lysino)imidazolium salt, MOLD: methylglyoxal-derived lysine dimer,

1,3-di(Ne-lysino)-4-methyl-imidazolium salt, and DOLD: 3-deoxyglucosone-derived lysine

dimer, 1,3-di(Ne-lysino)-4-(2,3,4-trihydroxybutyl)-imidazolium salt, MODIC: MG-derived

lysine-arginine dimer, N6-(2-{[(4S)-4-ammonio-5-oxido-5-oxopentyl]amino}-5-methyl-3,5-

dihydro-4H-imidazol-4-ylidene)-L-lysinate, glucosepane-6-[2-{[(4S)-4-ammonio-5-oxido-5-

oxopentyl]amino}-6,7-dihydroxy-6,7,8,8a-tetrahydroimidazo[4,5-b]-azepin-4(5H)-yl]-L-nor-

leucinate. (e) Fluorophores. Pentosidine, argpyrimidine and vesperlysine A (also known

as fluorophore LM-1). (f) Other structures. CMC: S-Carboxymethylcysteine, and CMA:

Nv-(carboxymethyl)-arginine. The peptide linkage is shown cut away for clarity. For the

corresponding free adducts at physiological pH, the N-terminal amino group is protonated,

NH3þ, and the C-terminal carbonyl is a carboxylate, CO2

� moiety. Ionization status is given

for the major solution form at pH 7.4.

J

METABOLISM AND BIOLOGY 295

group interactions within proteins activate particular residues for AGE formation

such that are “hotspots” for AGE formation.12 The steady-state concentration of

AGE residues measured in plasma protein depends on the rate of formation of AGE

residues, the rate of clearance of the protein from plasma, and rate of reversal or

repair of the AGE adduct.13 There is no known mechanism of repair of AGE residues

in plasma protein but hydroimidazolone AGEs have slow dynamic reversibility with

half-lives of 12–69 days2,3 such that if the precursor dicarbonyl concentration was

decreased, then the AGE content of even long-lived proteins would be expected to

decrease. The AGE content of plasma protein is therefore a marker of the balance

between the rate of AGE formation in the plasma compartment and the rate of plasma

clearance of the AGE-modified protein. Human serum albumin is a major component

of plasma protein. The synthesis and catabolism of albumin may decline in HD and

PD, and albumin catabolism may be consequently decreased.14 This may contribute

to increased AGE residue content of plasma protein in renal failure.

Glycationmay also affect leakage of protein through the glomerular filter. Albumin

glycated by glucose, FL-modified albumin, has increased molecular radius. With

angiotensin receptor blocker (ARB) therapy the glomerular filter pore size decreased

such that there was a preferential retention of FL-modified albumin in the plasma

compartment independent of glycemic status. This may also increase AGE-modified

albumin in the plasma by increased content of FL-modified albumin precursor.15

AGE-modified proteins formed in tissues and body fluids undergo cellular proteol-

ysis to form AGE free adducts. AGE free adducts are released into plasma and other

body fluids, and are excreted in urine (Fig. 19.2). They are the major form in which the

AGEs are excreted from the body.3 The rate of urinary excretion of AGE free adducts

reflect the total body exposure or flux of AGEs, with a contribution also coming from

AGE free adducts absorbed from digested proteins in food. The contribution to AGE

flux from food has been controversial.16,17 Many foodstuffs, particularly saccharide-

rich and thermally processed foodstuffs, are a rich source of AGEs.18 AGE residues in

foods are often in highly-damaged proteins, however, and are difficult to digest and

hence tend to have a low bioavailability.19 Feeding studies with animals of differing

intakes suggested that for the major quantitative AGEs, CML, and MG-H1, with

normal food intake therewas aminor contribution to total body exposure toAGEs from

food.10 This may vary, however, for different AGEs, those formed only at high

temperatures of cooking of foodstuffs, when absorbed from digested food may be

mainly sourced from the diet. For example, pyrraline is sourced mainly from food.20

The highest concentration of absorbed foodAGEs is expected in portal venous plasma.

We determined the concentration of AGEs in portal venous plasma of patients with

cirrhosis undergoing the transjugular intrahepatic portosystemic shunt (TIPS) proce-

dure. There was no evidence for increased AGE residues of plasma protein and AGE

free adducts in portal venous plasma, compared to peripheral venous plasma (although

some AGE residues and AGE free adducts were increased in cirrhosis). There were,

however, AGE-rich peptides with a content ofMG-H1 residues approximately 10-fold

higher than in plasma protein in portal venous plasma.21 AGEs from food are therefore

probably absorbed as both AGE free adducts and AGE-rich peptides; the latter appear

to be degraded efficiently after absorption. Since AGE free adducts have high renal


clearance and low plasma concentrations, AGEs absorbed from food are expected to

have low toxicity in subjects with normal renal function.

AGE free adducts filtered by the glomeruli are partly reabsorbed and have

characteristic renal clearances in healthy people (Tab. 19.1). In predialysis chronic

renal failure (CRF) there is a minor increase in AGE residue content of plasma

protein (up to twofold) and a two- to fivefold increase in plasma AGE free adducts

inversely linked to decrease in AGE free adduct. Indeed, in a study of patients with

progressive decline in glomerular filtration rate (GFR) we found an inverse increase

in AGE free adducts with relatively minor increase in AGE residue content of plasma

protein.22 In patients with end-stage renal disease, plasma AGE free adducts were

increased up to 18-fold on PD and up to 40-fold on HD whereas plasma protein AGE

residue content increased only two- to fourfold. AGE free adduct concentrations in

peritoneal dialysate increased over 2–12 h dwell time, exceeding the plasma levels

markedly. Plasma AGE free adducts equilibrated rapidly with dialysate of HD

patients, with both plasma and dialysate concentrations decreasing during a 4 h

dialysis session.8 It is AGE free adducts, therefore, that are readily filtered by the

normal functioning kidney and filtered through the peritoneal membrane in PD and

extracorporeal filter in HD. Some loss of AGE residue may also occur in PD and HD

associated with protein loss during the dialysis procedures.

FIGURE 19.2 Biodistribution scheme illustrating flows of formation and removal of AGE

residues with urinary excretion of AGE free adducts.

METABOLISM AND BIOLOGY 297

Insights into the role of the kidney in removing AGE-modified plasma proteins and

AGE free adducts came from studies of model acute renal failure. In bilateral

nephrectomized rats, a model acute loss of renal clearance, there were minor changes

in AGE residue content of plasma protein but profound increases in AGE free adducts,

CML23-fold,CEL12-fold,MOLD14-fold,G-H114-fold,MG-H18-fold, 3DG-H13-

fold, andpentosidine 5-fold at 72 h postsurgery. The accumulation ofAGE free adducts

was, therefore, similar to that expected for total loss of renal clearance.23 This indicates

that the kidney filters and removes AGE free adducts from circulation mainly rather

than AGE-modified proteins, although the kidney is expected to remove some AGE-

modified protein by uptake and proteolysis of protein by the tubular epithelium.24

Similarly in bilateral ureteral-ligated rats, a model of acute partial loss of renal

function, there were minor changes in AGE residue content of plasma protein but

also profound increases in AGE free adducts, 11-fold, CML 9-fold, CEL 7-fold,

MOLD6-fold, G-H1 9-fold, 3DG-H 3-fold, and pentosidine 2-fold at 72 h postsurgery.

These increases were, however, 25–77% lower than in bilateral nephrectomized rats.23

With bilateral ureteral ligation, the AGE free adducts were cleared from the plasma.

This provided in vivo evidence of intrarenal removal of AGE free adducts from the

circulation and concentration in the kidney. In contrast there is limited removal of

AGE-modified plasma proteins from circulation by the kidney.

In future studies of AGEs in renal failure, estimates of both AGE residues of

proteins and AGE free adducts in plasma, urine, and dialysate are key to character-

izing the disturbance in formation and metabolism of AGEs.

19.3 QUANTIFICATIONMETHOD

The measurement of choice to quantified AGEs is stable isotopic dilution analysis

using liquid chromatography with positive ion electrospray ionization tandem mass

spectrometric detection (LC/MS/MS).3 The concentrations of AGE free adducts in

plasma, urine, and dialysate are determined in sample ultrafiltrate. AGE residues in

proteins are determined in washed and delipidified plasma protein after exhaustive

enzymatic hydrolysis. Enzymatic hydrolysis of protein substrates is employed as

TABLE 19.1 Renal Clearances of Glycation Free Adducts (mL/min)

AGE free adduct Healthy subjects CRF PD

CML 74� 6 28� 4 42 (14–75)

CEL 85� 11 25� 5 9 (6–45)

G-H1 48� 6 15� 3 16� 2

MG-H1 41 (22–121) 10 (7–38) 17� 4

3DG-H 38 (25–92) 26� 7 16 (4–36)

MOLD 12� 3 15� 5 16� 5

Pentosidine 19� 3 22� 3 13 (4–27)

Data are mean�SD or median (minimum – maximum).

� Includes clearance in dialysate.8


several analytes are labile in conventional acid or base chemical hydrolysis of

proteins. The exhaustive enzymatic hydrolysis of proteins substrates involves a

cocktail of enzymes (pepsin, pronase E, prolidase, and aminopeptidase). The

protocol avoids oxidative degradation of protein adducts residues, and hence

artifactual formation of AGEs involves glycoxidation during enzymatic hydrolysis

by addition of the antioxidant thymol and incubation under argon.2,3 After an initial

step with pepsin under acidic conditions, antibiotics were included in the enzymatic

digest to prevent bacterial growth in the amino acid solution being produced.2 By

sterile filtration of the initial protein sample and reagents and use of a robotic sample

processor for sterile aliquot additions (e.g., Prep and Load platform, CTC Analytics,

Switzerland), the enzymatic hydrolysis may be fully automated performed under

aseptic conditions. These procedures give acceptable analytes stabilities and exhaus-

tive proteolysis that proceeds to near completion for proteins modified minimally by

AGEs. Correction of the analytes detected in enzymatic hydrolysates is made for

AGEs released by autohydrolysis of the proteolytic enzymes added. For the

LC/MS/MS, a graphitic stationary phase such as HypercarbTM columns (Thermo-

hypersil, USA) are used with column switching. This facilitates the retention and

sequential elution of analytes of diverse hydrophobicity and column washing.3 The

method was reported initially for 12 AGEs. Further analytes have been added since,

and chromatographic procedures have been further customized to complete data

collection of all analytes in a 35min run.

Analysis of exhaustive digests of protein gives the amounts of AGE residue

normalized to amount protein (pmol analyte per mg protein) or to corresponding

unmodified amino acid (mmol analyte per mol unmodified amino acid). Analysis of

analytes in ultrafiltrates of plasma, urine, or dialysate gives the concentrations of

AGE free adducts. Relating the plasma concentration of AGE free adduct to the total

amount of AGE free adduct excreted in urine and in dialysate where appropriate over

24 h gives the effective clearance.8

Stable isotopic dilution analysis with LC/MS/MS detection is the gold standard

reference technique for analysis of protein glycation, oxidation, and nitration free

adducts. The major restriction of access to this technique is the availability of

isotope-substituted standards for a comprehensive range of analytes since most are

not available commercially. The overwhelming advantage of this technique is that it

can provide a relatively comprehensive and quantitative analysis of AGE residues

and free adducts using a small amount of sample. With latest tandem mass

spectrometers analysis can be made with 5mg protein and 5mL of ultrafiltrate

and analyte sensitivities are low and sub fmol. Care then has to be taken to avoid

contamination with proteins from extraneous sources, such as fingerprints and dust.

19.4 PLASMA/SERUM LEVELS IN UREMIC PATIENTS AND HEALTHY

SUBJECTS

AGEmetabolism in healthy people and patients with renal failure is characterized by

measurement of AGE residue content of plasma protein, AGE free adducts in plasma

PLASMA/SERUM LEVELS IN UREMIC PATIENTS AND HEALTHY SUBJECTS 299

and dialysate, flux of excretion of AGE free adducts, and clearance of AGE free

adducts. Typical estimates by the LC/MS/MS technique of healthy people, patients

with predialysis mild CRF and patients with end-stage renal disease receiving

treatment with PD or HD are given in Tables 19.1–19.4. This showed that MG-

H1 residue is the AGE of highest content in plasma protein, MG-H1 free adducts

attains the highest level in plasma of HD patients and increases in flux by ninefold in

PD. CML has been determined by gas chromatography-mass spectrometry (GC/MS)

and similar estimates were obtained to those herein.25

19.5 TOXICITY AND CLINICAL RELEVANCE

Studies have been performed to assess the link of AGEs to mortality in renal failure.

High CML residue content of plasma protein in HD patients, determined by

immunoassay, was associated with increased mortality.26 In a similar study an

apparent contradictory finding was reported, high CML residue content of plasma

protein was linked to decreased mortality in HD patients.27 The CML estimates in

both studies were similar in magnitude to those of CML residues content of

plasma protein of HD patients determined by LC/MS/MS. There may have been

TABLE 19.2 Plasma Protein Content of AGE Residues in Renal Failure

AGE residue Healthy subjects CRF PD HD

CML (mmol/mol lys) 0.038� 0.010 0.094� 0.040 0.094� 0.053 0.140� 0.031

CEL (mmol/mol lys) 0.021� 0.010 0.048� 0.022 0.039� 0.019 0.045� 0.017

G-H1 (mmol/mol arg) 0.049� 0.015 0.066� 0.016 0.063� 0.015 0.056� 0.030

MG-H1 (mmol/mol arg) 0.67� 0.36 0.88� 0.20 1.34� 0.55 1.19� 0.15

3DG-H (mmol/mol arg) 0.37� 0.11 0.72� 0.29 0.71� 0.23 1.02� 0.54

MOLD (mmol/mol lys) 0.009� 0.007 0.017� 0.009 0.009� 0.004 0.012� 0.007

Pentosidine (mmol/mol lys) 0.010� 0.005 0.032� 0.019 0.022� 0.009 0.043� 0.021

Data are mean�SD.8

TABLE 19.3 Plasma AGE Free Adducts in Renal Failure (nM)

AGE Healthy subjects CRF PD HD

CML 19� 3 66� 13 111� 18 221� 11

CEL 35� 6 127� 24 336� 64 740� 75

G-H1 40� 7 159� 38 149� 23 256� 17

MG-H1 122� 23 573� 163 2236� 592 4824� 429

3DG-H 122� 15 208� 15 965� 195 1230� 234

MOLD 3.0� 0.7 2.3� 0.6 2.6� 0.6 9.5� 1.0

Pentosidine 0.9� 0.5 1.1� 0.5 5.1� 0.4 4.2� 0.6



confounding factors in these studies. In the study linking high CML with increased

mortality, the high CML group had received HD treatment for longer and had lower

residual renal function (RRF) than the low CML group. Both time on dialysis and

RRF are factors independently linked to high mortality risk in HD.28 In the study

linking low CML with increased mortality, the low CML group had decreased

plasma albumin and increased plasma C-reactive protein concentration compared to

the high CML group. Low plasma albumin and increased vascular inflammation are

factors independently linked to high mortality risk in HD.29

There have been no robust quantitative studies of the association of AGE free

adducts and mortality. As AGE free adducts are the form of AGE cleared from

plasma by renal function and dialysis, the levels of AGE free adducts will be

surrogate indicators of renal function and the quality of dialysis. Correction for RRF

and clearance will therefore be required. The flux of excretion of AGE free adducts

also gives an indication of increased exposure to AGEs.While therewas nomarkedly

change in predialysis mild CRF, the flux of some AGEs was increased markedly in

patients with PD receiving treatment with first generation, high glucose degradation

product (GDP) PD fluids. Measurement of the flux of AGE free adduct excretion may

be used as an indicator to work toward minimizing the increase in AGE exposure

from dicarbonyl GDPs in PD therapy.

The toxicity of AGEs is related to their modification and functional impairment of

proteins. While it now seems less likely that AGE-modified proteins in vivo bind to

specific cell surface receptors,30 the formation of AGE residues in functional

domains of proteins may have profound physiological consequences. The major

AGE quantitatively in vivo is methylglyoxal-derived hydroimidazolone (MG-H1).

Even for this it is unusual to find more that 5% of proteins modified by MG-H1

residues. This is often unlikely to have a significant impact on physiological

function. Toxicity arises, however, where the modified protein acquires a new

activity that is damaging physiologically. Examples of this are (i) AGE modification

of vascular type IV collagen in integrin binding sites leading to endothelial cell

detachment and anoikis with the sub-endothelium exposed and increased risk of

thrombosis,9 (ii) AGE modification of mitochondrial protein leading to leakage from

electron transport chains, increased reactive oxygen species formation, and oxidative

stress,31 and (iii) AGE modification of apolipoprotein B100 in low density

TABLE 19.4 Excretion of AGE Free Adducts in Renal Failure (mmol/24 h)

AGE Healthy subjects CRF PD

CML 2.1� 0.3 2.5� 0.3 4.7� 0.4

CEL 3.1� 0.4 5.1� 0.8 6.5� 0.7

G-H1 3.0� 0.4 2.8� 0.5 4.1� 0.7

MG-H1 6.6� 0.7 10.8� 2.1 58.5� 6.2

3DG-H 6.9� 0.7 8.1� 1.6 16.6� 2.0

MOLD 0.039� 0.005 0.029� 0.004 0.053� 0.008

Pentosidine 0.027� 0.002 0.038� 0.004 0.082� 0.002


TOXICITYAND CLINICAL RELEVANCE 301

lipoprotein (LDL) leading to formation of small, dense atherogenic LDL with

increased affinity for the arterial wall and atherosclerosis32 as recently reviewed.13

These and other key functional impairments by AGE formation likely contribute to

markedly increased risk of cardiovascular disease and premature mortality in renal

failure.

The most profound change in AGE metabolism in renal failure is the marked

accumulation of AGE free adducts in plasma in experimental and clinical uremia. It is

unknown if AGE free adducts have any intrinsic toxicity but there are surrogate

indicators of residual clearance and total AGE exposure and thereby may be linked to

RRF and protein damage in plasma and tissue compartments caused by AGE residues.

Their measurement would be a valuable clinical biomarker and adapting therapy to

minimize them may help improve clinical care of patients with renal failure.

19.6 THERAPEUTIC METHODS TO REMOVE THE TOXINS

The major form in which AGEs are removed from the body in treatment of renal

failure is removal of AGE free adducts by dialysis. Removal of AGE residues of

proteins can only be achieved with related protein loss. Clinical HD and PD protocols

may therefore be modified to improve clearance of AGE free adducts. Some

preliminary studies have been made to achieve this.33 As AGE free adducts are

removed from circulation by the kidney, preservation of RRF will also help to

achieve this. With effective clearance of AGE free adducts it would also be beneficial

to decrease the flux of AGE free adduct excretion indicating decreased total AGE

exposure. This may be achieved by decreased exposure to AGE precursors such as

dicarbonyls in PD fluids. Use of second and third generation dialysis fluids with

decreased GDP content may therefore decrease total AGE exposure for PD patients.

Other strategies to decrease dicarbonyl AGE precursors, high dose thiamine supple-

ments and Nrf2 activators, were described and discussed in Chapter 12.

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uremic toxins (niwa/uremic toxins) || advanced glycation endproducts (ages)

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