Uremic Toxins and the Elusive Middle Molecules

Schoots, A.C.; Mikkers, F.E.P.; Cramers, C.A.M.G.; Smet, Rita De; Ringoir, S

doi:10.1159/000183269

Cited by 53 publications

(17 citation statements)

References 10 publications

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“…Which factors in the plasma of regularly dialyzed patients are responsible for these findings remain to be investigated. "Middle molecules" with a molecular weight between 500 and 2,000 d, 68 such as aromatic and indolic organic acids like hippuric acid and phenolic acid, 69 are difficult to remove from and therefore tend to accumulate in hemodialysis patients. 70 The list of urerriic toxins that possibly inhibit platelet function should at least include these metabolites.…”

Section: -50mentioning

confidence: 99%

Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma.

Zwaginga¹,

Ijsseldijk²,

Groot³

et al. 1991

Arterioscler Thromb

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Uremia is associated with bleeding diathesis. Platelet adhesion to the subendothelium is inhibited by a factor in uremic plasma that may play a role in the disturbed hemostasis of uremic patients. In the formation of the hemostatic plug, platelet adherence is followed by stimulus-induced platelet aggregation and reinforcement by thrombin-generated fibrin. To study these processes in uremic blood, a newly developed thrombosis model was used. Perfusates anticoagulated with low-molecular-weight heparin were circulated over a matrix of stimulated cultured endothelial cells. By stimulation of the endothelial cells, tissue factor was synthesized and deposited in the matrix. When this tissue factor rich-matrix was exposed to flowing blood, local thrombin was formed via activation of the extrinsic coagulation pathway. With this system, platelet adhesion, thrombin-dependent platelet activation, and fibrin formation can all be studied at the same surface. In addition to an adhesion defect, decreased aggregate formation was also found in uremic perfusates. Normal platelets in uremic plasma showed similar results, which indicates that a factor in uremic plasma caused this adhesion and aggregation defect. Platelet aggregation in the system was dependent on endogeneously formed thrombin. Fibrinopeptide A generation, however, was normal in uremic perfusates; therefore, uremic plasma has a normal capacity to form thrombin. Resuspension of washed uremic platelets in control plasma did not reverse the aggregation defect in perfusions. In contrast, aggregometer studies with isolated uremic platelets could not detect an abnormal response to threshold concentrations of exogenous thrombin. Thus, uremic toxin (s) cause defective aggregate formation in flow, but not necessarily in the aggregometer. This apparent discrepancy may be due to the higher shear forces in the flow system, which may prevent aggregate formation that is allowed in the aggregometer. Another explanation, that uremic platelets are less responsive to locally formed thrombin than they are to exogenously added thrombin, seems less likely. [Arteriosclerosis and Thrombosis 1991;ll:733-744)

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Section: -50mentioning

confidence: 99%

Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma.

Zwaginga¹,

Ijsseldijk²,

Groot³

et al. 1991

Arterioscler Thromb

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“…Uremic syndrome resembles a systemic intoxication, therefore, the search for putative uremic toxins has been the subject of intensive investigation. Three major groups of solutes accumulate in the blood of the affected patients: low molecular weight compounds (<500 Da) [1], "middle molecules" (MM) ranging from 500 to 5000 Da [1][2][3][4], and large molecules (>5000 Da) [1,[5][6][7]. Small molecules accumulate in uremic blood as free water-soluble substances (e.g.…”

Section: Introductionmentioning

confidence: 99%

Search for peptidic “middle molecules” in uremic sera: isolation and chemical identification of fibrinogen fragments

Kaplan

Cojocaru

Unsworth

et al. 2003

Journal of Chromatography B

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“…Another major advantage of fast atom bom bardment mass spectrometry is the wide scanning range for the molecular ion peak (m/z 50-2,000) which certainly covers the expected molecular weight range of middlemolecular uremic toxins. Our technique is certainly supe- rior to the conventional gel filtration chromatographic technique used by many investigators to study uremic toxins, because the separation efficiency of gel filtration is relatively poor, and several low molecular weight com pounds tend to elute in the middle-molecular mass region [26].…”

Section: Resultsmentioning

confidence: 99%

Fast Atom Bombardment Mass Spectrometric Determination of the Molecular Weight Range of Uremic Compounds that Displace Phenytoin from Protein Binding: Absence of Midmolecular Uremic Toxins

Dasgupta

Malik

1994

Am J Nephrol

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Uremic compounds are known to displace phenytoin from protein binding, resulting in a higher concentration of the pharmacologically active free fraction of phenytoin. The true chemical identities and molecular weight range of all these compounds are still unknown. We demonstrated that indoxyl sulfate and hippuric acid, which are found at high concentrations in uremic patients, can only partially explain the elevated free phenytoin concentration. Other known uremic compounds, guanidine, methylguanidine, and guanidinosuccinic acid, do not displace phenytoin from the protein-binding sites. Uremic compounds from sera of patients on maintenance hemodialysis were removed using activated charcoal. These compounds were then backextracted from activated charcoal using methanol and analyzed by fast atom bombardment mass spectroscopy. Mass spectra of uremic sera showed no peak over m/z 450, indicating that midmolecular uremic toxins are not involved in displacing phenytoin from protein binding. We also observed additional peaks in the mass spectrum of uremic compounds when compared with the normal serum extract, indicating the presence of several endogeneous compounds in uremic sera, as expected.

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Uremic Toxins and the Elusive Middle Molecules

Cited by 53 publications

References 10 publications

Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma.

Defects in platelet adhesion and aggregate formation in uremic bleeding disorder can be attributed to factors in plasma.

Search for peptidic “middle molecules” in uremic sera: isolation and chemical identification of fibrinogen fragments

Fast Atom Bombardment Mass Spectrometric Determination of the Molecular Weight Range of Uremic Compounds that Displace Phenytoin from Protein Binding: Absence of Midmolecular Uremic Toxins

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