بسم ا الرحمن الرحيمبسم ا الرحمن الرحيمأفل ”” أنفسكم في أفل و أنفسكم في و

““تبصرونتبصرون صدق ا العظيمصدق ا العظيم

Uremic ToxinsUremic Toxins

The Known and The UnknownThe Known and The UnknownByBy

Ahmed M. Abd El WhabAhmed M. Abd El WhabAss. Lect. of Int. Med.Ass. Lect. of Int. Med.

Department 3Department 3

INTRODUCTION INTRODUCTION

The uremic syndromeThe uremic syndrome The deterioration of multiple biochemical and The deterioration of multiple biochemical and physiological functions in parallel with progressive physiological functions in parallel with progressive renal failure resulting in complex but variable renal failure resulting in complex but variable symptomatology .symptomatology .

Uremic retention solutes accumulate in the patient Uremic retention solutes accumulate in the patient with chronic kidney disease (CKD), including the with chronic kidney disease (CKD), including the patient with K/DOQI stage 5 disease or end-stage patient with K/DOQI stage 5 disease or end-stage renal disease (ESRD). renal disease (ESRD).

Uremic toxinsUremic toxins can be subdivided into three major can be subdivided into three major groups based upon their chemical and physical groups based upon their chemical and physical characteristics:characteristics:

1.1. Small, water-soluble, non-protein-bound Small, water-soluble, non-protein-bound compounds, such as compounds, such as ureaurea

2.2. Small, lipid-soluble and/or protein-bound Small, lipid-soluble and/or protein-bound compounds, such as compounds, such as the phenolsthe phenols

3.3. Larger so-called middle-molecules, such as Larger so-called middle-molecules, such as beta2-beta2-microglobulinmicroglobulin

A) SMALL WATER-SOLUBLE COMPOUNDSA) SMALL WATER-SOLUBLE COMPOUNDS

1) Urea1) Urea

Urea Urea inhibits Na-K-2Cl cotransport in human erythrocytesinhibits Na-K-2Cl cotransport in human erythrocytes.. Urea Urea inhibits macrophage-inducible nitric oxide synthesisinhibits macrophage-inducible nitric oxide synthesis Urea may Urea may provoke dialysis disequilibriumprovoke dialysis disequilibrium if the decrease in if the decrease in

plasma concentration of urea during dialysis occurs too plasma concentration of urea during dialysis occurs too rapidly. rapidly.

Urea is a precursorUrea is a precursor of some of the guanidines of some of the guanidines which induce which induce

biochemical alterations by themselves. biochemical alterations by themselves.

Increasing amounts of cyanateIncreasing amounts of cyanate are spontaneously transformed are spontaneously transformed from urea.from urea.

Marker of dialysis adequacy.Marker of dialysis adequacy. Thus, urea kinetic modeling is Thus, urea kinetic modeling is one of the principal tools to currently estimate and (if one of the principal tools to currently estimate and (if necessary) correct the dialysis dose. necessary) correct the dialysis dose.

However, high blood concentrations of urea may not However, high blood concentrations of urea may not necessarily correlate with poor outcome:necessarily correlate with poor outcome:

1.1. High serum concentrations of urea due to adequate protein High serum concentrations of urea due to adequate protein intake that are compensated by adequate removal may be intake that are compensated by adequate removal may be relatively harmless, as compared with high urea levels due to relatively harmless, as compared with high urea levels due to inadequate dialysis .inadequate dialysis .

2.2. Low urea levels related to low protein intake may negatively Low urea levels related to low protein intake may negatively correlate with prognosis .correlate with prognosis .

The dialytic removal of lipophilic protein-bound The dialytic removal of lipophilic protein-bound compounds, as well as that of several other water compounds, as well as that of several other water soluble compounds, is different from that of urea.soluble compounds, is different from that of urea.

Therefore, there should be a search for marker Therefore, there should be a search for marker molecules that are representative of large and/or lipid-molecules that are representative of large and/or lipid-soluble compounds soluble compounds ((B2-microglobulin).B2-microglobulin).

2) Guanidines2) Guanidines Inhibit neutrophil superoxide production .Inhibit neutrophil superoxide production .

Exert both pro- and anti-inflammatory effects upon Exert both pro- and anti-inflammatory effects upon leukocytes.leukocytes.

Induce seizures after systemic and/or cerebroventricular Induce seizures after systemic and/or cerebroventricular administration in animals.administration in animals.

Suppress the natural killer cell response.Suppress the natural killer cell response.

Cause structural damage to proteins which in turn reduces the Cause structural damage to proteins which in turn reduces the binding of homocysteine binding of homocysteine

Nitric oxide and guanidines Nitric oxide and guanidines

1.1. Nitric oxide (NO) synthesis is inhibited in patients with Nitric oxide (NO) synthesis is inhibited in patients with ESRD.ESRD.

2.2. Inhibitors include ADMA, SDMA, Inhibitors include ADMA, SDMA,

3.3. Asymmetric dimethylarginineAsymmetric dimethylarginine (ADMA), (ADMA), most specificmost specific. In the . In the brain, ADMA causes brain, ADMA causes vasoconstriction and inhibition of vasoconstriction and inhibition of acetylcholine-induced vasorelaxationacetylcholine-induced vasorelaxation. It has also been . It has also been implicated in the implicated in the development of hypertensiondevelopment of hypertension and adverse and adverse cardiovascular events . cardiovascular events .

4.4. Symmetric dimethylarginineSymmetric dimethylarginine (SDMA) (SDMA) was linked to an was linked to an increase in increase in reactive oxygen production.reactive oxygen production.

3) Oxalate 3) Oxalate

Among ESRD patients , serum oxalate concentrations are Among ESRD patients , serum oxalate concentrations are increased approximately increased approximately 40-fold40-fold, compared with healthy , compared with healthy controls . Secondary oxalosis in such patients is characterized controls . Secondary oxalosis in such patients is characterized by the deposition of calcium oxalate in multiple tissues.by the deposition of calcium oxalate in multiple tissues.

Currently, such findings may be seen among those with Currently, such findings may be seen among those with excessive intake of oxalate precursors and those with excessive intake of oxalate precursors and those with inflammatory bowel disease.inflammatory bowel disease.

In hemodialysis patients, pyridoxine at 800 mg/day causes a In hemodialysis patients, pyridoxine at 800 mg/day causes a decrease in oxalate concentration. However, such high doses decrease in oxalate concentration. However, such high doses of pyridoxine may induce gastrointestinal intolerance.of pyridoxine may induce gastrointestinal intolerance.

Dialytic removal of oxalate is similar to that of urea and, Dialytic removal of oxalate is similar to that of urea and, therefore, is relatively easy with any of the classic dialysis therefore, is relatively easy with any of the classic dialysis strategies.strategies.

4) Phosphorus4) Phosphorus A high serum concentration of phosphates is clearly related to A high serum concentration of phosphates is clearly related to

pruritus and hyperparathyroidism. Phosphorus excess also pruritus and hyperparathyroidism. Phosphorus excess also inhibits 1 alpha-hydroxylase and hence the production of inhibits 1 alpha-hydroxylase and hence the production of calcitriol. calcitriol.

Phosphorus retention causes intestinal dysfunction and Phosphorus retention causes intestinal dysfunction and proliferation of intestinal villi.proliferation of intestinal villi.

Blood phosphorus concentration is the result of protein Blood phosphorus concentration is the result of protein catabolism and protein intake as well as of the ingestion of catabolism and protein intake as well as of the ingestion of other dietary sources. Restriction of oral protein intake other dietary sources. Restriction of oral protein intake increases the risk of malnutrition which can be avoided by the increases the risk of malnutrition which can be avoided by the administration of oral phosphate binders (Sevelamer). administration of oral phosphate binders (Sevelamer).

One major effect related to hyperphosphatemia is the increase One major effect related to hyperphosphatemia is the increase in serum Ca x P product resulting in Ca deposition in the in serum Ca x P product resulting in Ca deposition in the tissues, especially the vessel wall. Application of calcium tissues, especially the vessel wall. Application of calcium containing intestinal phosphate binders may decrease P, but containing intestinal phosphate binders may decrease P, but this effect is counterbalanced by a rise in Ca and an this effect is counterbalanced by a rise in Ca and an unmodified Ca x P product.unmodified Ca x P product.

Dialytic removal of phosphate is unpredictable and often Dialytic removal of phosphate is unpredictable and often followed by impressive rebounds, which is due to the release followed by impressive rebounds, which is due to the release of intracellular phosphate stores. of intracellular phosphate stores.

Slower dialysis techniques may allow a better control of Slower dialysis techniques may allow a better control of phosphate levels.phosphate levels.

5) Metabolic acidosis5) Metabolic acidosis —Metabolic acidosis can —Metabolic acidosis can cause muscle wasting and bone mineral loss cause muscle wasting and bone mineral loss and, in children, impair growth.and, in children, impair growth.

6) Creatinine6) Creatinine — Although serum creatinine is a — Although serum creatinine is a marker for renal function, only limited data marker for renal function, only limited data suggest that this substance is associated with suggest that this substance is associated with adverse effects.adverse effects.

7) Polyamines 7) Polyamines — Polyamines, which are — Polyamines, which are measured at increased levels in uremia, may measured at increased levels in uremia, may contribute to anorexia, vomiting, and adverse contribute to anorexia, vomiting, and adverse central nervous system effects.central nervous system effects.

B) PROTEIN-BOUND COMPOUNDSB) PROTEIN-BOUND COMPOUNDS

1) P-cresol and p-cresylsulfate1) P-cresol and p-cresylsulfate —Because of their strong —Because of their strong protein binding, their removal by classical dialysis is protein binding, their removal by classical dialysis is hampered, therefore alternative removal methods (eg, hampered, therefore alternative removal methods (eg, adsorption or convective transport) should be developed adsorption or convective transport) should be developed before adequate elimination of these toxins can be obtained.before adequate elimination of these toxins can be obtained.

High-flux dialysis, compared to low-flux dialysis, has no High-flux dialysis, compared to low-flux dialysis, has no beneficial effect on the removal of these toxins. However, beneficial effect on the removal of these toxins. However, compared with peritoneal dialysis, p-cresol is cleared better compared with peritoneal dialysis, p-cresol is cleared better with high-flux hemodialysis.with high-flux hemodialysis.

P-cresol is an end-product of protein catabolism, produced by P-cresol is an end-product of protein catabolism, produced by intestinal bacteria that metabolize tyrosine and phenylalanine. intestinal bacteria that metabolize tyrosine and phenylalanine. Environmental sources of p-cresol are toluene, menthofuran Environmental sources of p-cresol are toluene, menthofuran (in several herbal medicines, flavoring agents) and cigarette (in several herbal medicines, flavoring agents) and cigarette smoke. smoke.

p-cresylsulfate stimulated baseline leukocyte activity, thereby p-cresylsulfate stimulated baseline leukocyte activity, thereby pointing to a pro-inflammatory effect, whereas the parent pointing to a pro-inflammatory effect, whereas the parent compound p-cresol essentially inhibits activated leukocyte compound p-cresol essentially inhibits activated leukocyte function and both may alter endothelial function.function and both may alter endothelial function.

By applying combined fractionated plasma separation and By applying combined fractionated plasma separation and adsorption, removal of p-cresol could be markedly enhanced, a adsorption, removal of p-cresol could be markedly enhanced, a strategy currently used as an artificial liver. Unfortunately, the strategy currently used as an artificial liver. Unfortunately, the approach applied in this study resulted in major coagulation approach applied in this study resulted in major coagulation disturbancesdisturbances. .

There are studies in animals suggesting that intestinal bacterial There are studies in animals suggesting that intestinal bacterial production and intestinal uptake of p-cresol can be altered. As production and intestinal uptake of p-cresol can be altered. As an example, prevention of the intestinal absorption of p-cresol an example, prevention of the intestinal absorption of p-cresol by administration of oral sorbents decreased its serum by administration of oral sorbents decreased its serum concentration.concentration.

2) Homocysteine 2) Homocysteine — (Hcy) is a sulphur-containing amino acid — (Hcy) is a sulphur-containing amino acid produced by the demethylation of methionine. produced by the demethylation of methionine.

Its retention with uremia results in the cellular accumulation of Its retention with uremia results in the cellular accumulation of S-adenosyl homocysteine (AdoHcy), an extremely toxic S-adenosyl homocysteine (AdoHcy), an extremely toxic compound that competes with S-adenosyl-methionine compound that competes with S-adenosyl-methionine (AdoMet) and inhibits methyltransferases. (AdoMet) and inhibits methyltransferases.

Hyperhomocysteinemia also disturbs gene expression . Hyperhomocysteinemia also disturbs gene expression . Guanidino compounds modify serum albumin in a way that Guanidino compounds modify serum albumin in a way that protein binding of homocysteine is decreased.protein binding of homocysteine is decreased.

Patients with chronic renal failure have total serum Hcy levels Patients with chronic renal failure have total serum Hcy levels two- to fourfold above those observed in normal individuals.two- to fourfold above those observed in normal individuals.

Hcy increases the proliferation of vascular smooth muscle Hcy increases the proliferation of vascular smooth muscle cells, one of the most prominent hallmarks of atherosclerosis. cells, one of the most prominent hallmarks of atherosclerosis. Hcy also disrupts several vessel wall-related anticoagulant Hcy also disrupts several vessel wall-related anticoagulant functions, resulting in enhanced thrombogenicityfunctions, resulting in enhanced thrombogenicity

Hcy levels can be moderately reduced by the administration of Hcy levels can be moderately reduced by the administration of folic acid, vitamin B6, and/or vitamin B12. To reduce Hcy, folic acid, vitamin B6, and/or vitamin B12. To reduce Hcy, patients with ESRD may require higher quantities of vitamins patients with ESRD may require higher quantities of vitamins than the nonuremic population.than the nonuremic population.

Dialytic removal of Hcy is thought to be hampered in a similar Dialytic removal of Hcy is thought to be hampered in a similar way as the other protein-bound uremic toxins. Dialysis with way as the other protein-bound uremic toxins. Dialysis with the extremely open ("super flux") dialysis membranes, the extremely open ("super flux") dialysis membranes, however, could decrease homocysteine concentrations, however, could decrease homocysteine concentrations, possibly due to a modification of metabolism, rather than to possibly due to a modification of metabolism, rather than to direct removal.direct removal.

3) Indoles 3) Indoles

Indoxyl sulfate is metabolized by the liver from indole, Indoxyl sulfate is metabolized by the liver from indole, which is produced by the intestinal flora as a metabolite of which is produced by the intestinal flora as a metabolite of tryptophan.tryptophan.

Indoxyl sulfate, which is secreted in the normal kidney by Indoxyl sulfate, which is secreted in the normal kidney by organic anion transporter 3, enhances drug toxicity by organic anion transporter 3, enhances drug toxicity by competition with acidic drugs at protein binding sites and competition with acidic drugs at protein binding sites and inhibits the active tubular secretion of these compounds as inhibits the active tubular secretion of these compounds as well as the deiodination of (T4).well as the deiodination of (T4).

Indoxyl sulfate may cause a faster progression of glomerular Indoxyl sulfate may cause a faster progression of glomerular sclerosis and renal failure by inducing free radical sclerosis and renal failure by inducing free radical production, and upregulation of plasminogen activator production, and upregulation of plasminogen activator inhibitor-1 (PAI-1) expression . inhibitor-1 (PAI-1) expression .

Indoxyl sulfate may play a role in inhibiting endothelial cell Indoxyl sulfate may play a role in inhibiting endothelial cell proliferation and repair.proliferation and repair.

It has been suggested that indoxyl sulfate plays a role in aortic It has been suggested that indoxyl sulfate plays a role in aortic calcification and elements of bone dysfunction, such as calcification and elements of bone dysfunction, such as osteoblast dysfunction.osteoblast dysfunction.

Removal of protein-bound indoles is hampered during Removal of protein-bound indoles is hampered during dialysis, superflux membrane was superior to low flux one. In dialysis, superflux membrane was superior to low flux one. In a group of CKD patients not yet on dialysis, the adsorbent a group of CKD patients not yet on dialysis, the adsorbent AST-120 (Kremezin R) actively decreased indoxyl sulfate in a AST-120 (Kremezin R) actively decreased indoxyl sulfate in a dose dependent way.dose dependent way.

Oral administration of bifidobacteria (probiotic) in gastro-Oral administration of bifidobacteria (probiotic) in gastro-resistant capsules modifying intestinal flora to hemodialysis resistant capsules modifying intestinal flora to hemodialysis patients reduces serum levels of indoxyl sulfate by correcting patients reduces serum levels of indoxyl sulfate by correcting gastrointestinal flora.gastrointestinal flora.

4) Furanpropionic acid (FPA)4) Furanpropionic acid (FPA) A major inhibitor of drug protein binding, causes a decrease in A major inhibitor of drug protein binding, causes a decrease in

renal excretion of various drugs, metabolites, and renal excretion of various drugs, metabolites, and endogenously produced organic acids.endogenously produced organic acids.

FPA also inhibits hepatic glutathione-S-transferase, FPA also inhibits hepatic glutathione-S-transferase, deiodination of T4.deiodination of T4.

There is a correlation between neurologic abnormalities and There is a correlation between neurologic abnormalities and the plasma concentration FPA . the plasma concentration FPA .

Since FPA is virtually 100 percent protein-bound, its removal Since FPA is virtually 100 percent protein-bound, its removal by hemodialysis strategies is virtually nonexistent. FPA levels by hemodialysis strategies is virtually nonexistent. FPA levels can be lowered substantially only with peritoneal dialysis.can be lowered substantially only with peritoneal dialysis.

C) MIDDLE MOLECULESC) MIDDLE MOLECULES

Middle molecules, arbitrarily defined as those of a molecular Middle molecules, arbitrarily defined as those of a molecular weight (MW) in excess of 500 D.weight (MW) in excess of 500 D.

Chromatographic fractions of uremic ultrafiltrate with a MW Chromatographic fractions of uremic ultrafiltrate with a MW between 1 and 5 kD inhibit appetite and suppress food intake between 1 and 5 kD inhibit appetite and suppress food intake in animals.in animals.

A 500 to 2000 D subfraction of uremic serum inhibits A 500 to 2000 D subfraction of uremic serum inhibits apolipoprotein (apo) A-I secretion.apolipoprotein (apo) A-I secretion.

A compound of MW between 750 and 900 D inhibits A compound of MW between 750 and 900 D inhibits osteoblast mitogenesis.osteoblast mitogenesis.

By now, more than 20 compounds have been By now, more than 20 compounds have been identified that conform to the strict definition of identified that conform to the strict definition of middle molecules. Several of those have biological middle molecules. Several of those have biological effects, especially a pro-inflammatory impact.effects, especially a pro-inflammatory impact.

Dialysis membranes with a capacity to remove Dialysis membranes with a capacity to remove middle molecules (high flux membranes) have been middle molecules (high flux membranes) have been related to lower morbidity and mortality. related to lower morbidity and mortality.

1) Beta2-microglobulin1) Beta2-microglobulin — — (ß2M) (ß2M)

(MW of approximately 12,000 D) is a component of the major (MW of approximately 12,000 D) is a component of the major histocompatibility antigen. histocompatibility antigen.

Dialysis-related amyloid, which can be observed in patients being Dialysis-related amyloid, which can be observed in patients being maintained on long-term dialysis, is to a large extent composed of maintained on long-term dialysis, is to a large extent composed of ß2M. ß2M.

AGE-modified ß2M has been identified in amyloid of hemodialyzed AGE-modified ß2M has been identified in amyloid of hemodialyzed patients ; it also enhances monocytic migration and cytokine secretion patients ; it also enhances monocytic migration and cytokine secretion , suggesting that foci containing AGE-ß2M may initiate inflammatory , suggesting that foci containing AGE-ß2M may initiate inflammatory response, leading to bone/joint destruction.response, leading to bone/joint destruction.

Serum ß2M levels may be lower in peritoneal dialysis (PD) patients Serum ß2M levels may be lower in peritoneal dialysis (PD) patients than in hemodialysis patients. This may be due to a better than in hemodialysis patients. This may be due to a better conservation of endogenous residual renal function with PD, since PD conservation of endogenous residual renal function with PD, since PD alone poorly clears ß2-microglobulin.alone poorly clears ß2-microglobulin.

In prospective studies, a progressive decline of predialysis In prospective studies, a progressive decline of predialysis ß2M-levels has frequently been demonstrated in patients ß2M-levels has frequently been demonstrated in patients dialyzed with membranes with a larger pore size.dialyzed with membranes with a larger pore size.

Because ß2M is only removed by dialyzers with large pore Because ß2M is only removed by dialyzers with large pore size, it may be representative of other large molecules in its size, it may be representative of other large molecules in its kinetic behavior. Apart from its role in amyloidosis, the kinetic behavior. Apart from its role in amyloidosis, the biological impact of ß2M seems minor.biological impact of ß2M seems minor.

Each 10 mg/L increase in predialysis level being associated Each 10 mg/L increase in predialysis level being associated with an 11 percent increase for all-cause mortality (propably with an 11 percent increase for all-cause mortality (propably due to infection).due to infection).

2) Parathyroid hormone2) Parathyroid hormone MW of approximately 9000 D, its increase in concentration MW of approximately 9000 D, its increase in concentration

during ESRD is attributable to enhanced glandular secretion, during ESRD is attributable to enhanced glandular secretion, rather than to decreased removal by the kidneys. Excess PTH rather than to decreased removal by the kidneys. Excess PTH gives rise to an increase in intracellular calcium, resulting in gives rise to an increase in intracellular calcium, resulting in disturbances in the function of virtually every organ system.disturbances in the function of virtually every organ system.

A downregulation of PTH/PTHrP receptor mRNA expression A downregulation of PTH/PTHrP receptor mRNA expression is observed in the liver, kidney, and heart with advanced is observed in the liver, kidney, and heart with advanced chronic renal failure, thereby blunting the cellular response to chronic renal failure, thereby blunting the cellular response to excess PTH and creating resistance to PTH.excess PTH and creating resistance to PTH.

The increased PTH concentration in uremia is the result of a The increased PTH concentration in uremia is the result of a number of compensatory homeostatic mechanisms; phosphate number of compensatory homeostatic mechanisms; phosphate retention, decreased production of calcitriol and hypocalcemia.retention, decreased production of calcitriol and hypocalcemia.

3) Advanced glycosylation end products3) Advanced glycosylation end products

(MW 2000 to 6000 D), among the postulated (MW 2000 to 6000 D), among the postulated structures for AGE are imidazolone, pyrrole structures for AGE are imidazolone, pyrrole aldehyde.aldehyde.

The increased accumulation of AGE is not the result The increased accumulation of AGE is not the result of enhanced glucose levels or reduced removal of of enhanced glucose levels or reduced removal of modified proteins by glomerular filtration. modified proteins by glomerular filtration.

With uremia, it is more likely due to increased With uremia, it is more likely due to increased concentrations of small carbonyl precursors. Thus, concentrations of small carbonyl precursors. Thus, uremia can be described as a status of increased uremia can be described as a status of increased carbonyl stress, resulting from increased oxidation or carbonyl stress, resulting from increased oxidation or decreased detoxification of these carbonyl decreased detoxification of these carbonyl compounds.compounds.

AGE products affect multiple processes. These compounds:AGE products affect multiple processes. These compounds:

1.1. Cause an inflammatory reaction in monocytes by the induction of IL-6, Cause an inflammatory reaction in monocytes by the induction of IL-6, TNF-alpha, and interferon-gamma.TNF-alpha, and interferon-gamma.

2.2. Modify ß2M, which (as previously mentioned) may play an important Modify ß2M, which (as previously mentioned) may play an important role in the formation of dialysis-related amyloid.role in the formation of dialysis-related amyloid.

3.3. React with and chemically inactivate nitric oxide (NO), a potent React with and chemically inactivate nitric oxide (NO), a potent endothelium-derived vasodilator, antiaggregant, and antiproliferative endothelium-derived vasodilator, antiaggregant, and antiproliferative factor.factor.

4.4. Induce oxidative protein modification.Induce oxidative protein modification.

5.5. In addition to renal failure, AGE products are also retained in diabetes In addition to renal failure, AGE products are also retained in diabetes mellitus and aging, settings in which they have been implicated in tissue mellitus and aging, settings in which they have been implicated in tissue damage and functional disturbances. Specific receptors for AGE damage and functional disturbances. Specific receptors for AGE products have also been identified (RAGE), with their expression being products have also been identified (RAGE), with their expression being enhanced during moderate uremia enhanced during moderate uremia

5) Leptin5) Leptin, a 16 kD plasma protein that suppresses appetite is , a 16 kD plasma protein that suppresses appetite is retained in renal failure. The increase in serum leptin levels is retained in renal failure. The increase in serum leptin levels is almost entirely due to a rise in free (non-protein-bound) almost entirely due to a rise in free (non-protein-bound) concentration ; it has been suggested to play a role in the concentration ; it has been suggested to play a role in the decreased appetite of uremic patients. decreased appetite of uremic patients.

6) The dinucleoside polyphosphates6) The dinucleoside polyphosphates (MW1000 Dalton), and (MW1000 Dalton), and are protein-bound. are protein-bound. The diadenosine polyphosphatesThe diadenosine polyphosphates induce induce proliferation of smooth muscle cells. proliferation of smooth muscle cells. Uridine adenosine Uridine adenosine tetraphosphate tetraphosphate is a strong vasoconstrictor, which is released by is a strong vasoconstrictor, which is released by endothelin.endothelin.

7) Others7) Others: Complement factor D, adrenomedullin, atrial : Complement factor D, adrenomedullin, atrial natriuretic peptide (ANP), ghrelin, resistin, immunoglobulin natriuretic peptide (ANP), ghrelin, resistin, immunoglobulin light chains, neuropeptide Y, and various cytokines.light chains, neuropeptide Y, and various cytokines.

GENERAL REMOVAL STRATEGIESGENERAL REMOVAL STRATEGIES

Conventional hemodialysis and peritoneal dialysis. Conventional hemodialysis and peritoneal dialysis.

However, dialysis is nonspecific and also removes However, dialysis is nonspecific and also removes essential compounds. In addition, lipophilic essential compounds. In addition, lipophilic compounds, which may be responsible at least in part compounds, which may be responsible at least in part for functional alterations in uremia, are inadequately for functional alterations in uremia, are inadequately removed by current dialysis strategies.removed by current dialysis strategies.

With maintenance hemodialysis, treatment with high With maintenance hemodialysis, treatment with high flux membranes was suggested to provide superior flux membranes was suggested to provide superior removal of middle molecules, possibly resulting in removal of middle molecules, possibly resulting in improved survival.improved survival.

Adding convection by increasing ultrafiltration and Adding convection by increasing ultrafiltration and equivoluminous substitution with sterile saline or ultrapure equivoluminous substitution with sterile saline or ultrapure dialysate (hemodiafiltration), further adds to middle molecule dialysate (hemodiafiltration), further adds to middle molecule removal.removal.

Lower morbidity and mortality are observed in patients Lower morbidity and mortality are observed in patients submitted to long dialysis sessions.submitted to long dialysis sessions.

Compounds may be cleared more efficiently with continuous Compounds may be cleared more efficiently with continuous or long-lasting low efficiency strategies, because removal is or long-lasting low efficiency strategies, because removal is more gradual.more gradual.

Optimal removal for each type of molecule may be obtained Optimal removal for each type of molecule may be obtained with a different type of extracorporeal treatment, eg, by using with a different type of extracorporeal treatment, eg, by using large pore membranes and/or dialyzers or devices with a high large pore membranes and/or dialyzers or devices with a high adsorptive capacity for some or several of the uremic toxins. adsorptive capacity for some or several of the uremic toxins.

Removal is also influenced by intestinal intake and Removal is also influenced by intestinal intake and preservation of renal function:preservation of renal function:

1.1. Intestinal uptake can be reduced by influencing dietary Intestinal uptake can be reduced by influencing dietary uptake, or by oral administration of absorbents.uptake, or by oral administration of absorbents.

2.2. Preservation of residual renal function may also be an Preservation of residual renal function may also be an important manner to pursue additional removal of retention important manner to pursue additional removal of retention solutes.solutes.

Finally, it should be considered that in uremia, not only Finally, it should be considered that in uremia, not only strategies decreasing solute concentration are important, but strategies decreasing solute concentration are important, but interventions countering their biological impact also play a interventions countering their biological impact also play a role. role.