Table 2.

Classification, levels in ESKD, and methods of measurement of large middle molecules (n=28)

Molecule (Alternative Names)GroupSize, kDUsual Biologic FunctionPossible Adverse Effects in Excess or UremiaRelative Increase in Dialysis or Advanced CKDCommercially Available Test System and Manufacturer
IL-18Cytokine18Proinflammatory; induction of TH1 response and IFN-γ productionProatherogenic; increased amyloid-β productionApproximately twofold higherELISA
IL-6Cytokine21–28Diverse proinflammatory actions; neutrophil attraction; monocyte and T cell recruitment; induction of feverProatherogenic; sarcopenia and wasting; anorexiaTwo- to fivefold higherELISA (Invitrogen)
IL-1βCytokine17.5Proinflammatory; upregulation of IL-6 and systemic inflammationProatherogenic; contributes to systemic inflammationApproximately twofold higherELISA (R&D Systems)
IL-10Cytokine18Anti-inflammatory actions; downregulation of macrophage activity and proinflammatory cytokine productionDiminished anti-infectious immune function (may have beneficial effects on CVS disease) ∼1.5-Fold higherELISA
TNF-αCytokine17Upregulation of immune response, induction of feverEnhanced protein catabolism, anorexia, and muscle protein breakdownFour- to fivefold higherELISA (R&D Systems)
AdiponectinAdipokine30Modulates glucose regulation and fatty acid oxidationUnknownTwo- to threefold higherELISA (R&D Systems)
Visfatin (Nicotinamide phosphoribosyltransferase)Adipokine52Intracellularly involved in NAD biosynthesis; extracellularly stimulates angiogenesis and endothelial cell proliferationProinflammatory cytokine effects; angiogenic effects, promotion of vascular smooth muscle cell proliferationThree- to sixfold higherELISA (R&D Systems)
LeptinAdipokine16Regulates appetite and body energy storesPossible contribution to anorexia and protein-energy wastingThree- to fourfold higherRIA
Retinol binding protein 4Adipokine21.2Delivers retinol from liver to peripheral tissuesInhibition of leukocyte chemotaxis and functionThree- to fourfold higherELISA (R&D Systems)
Soluble TNF receptor 2 (p55)Immune-mediated protein17Binds to and limits TNF-α activityMay increase circulating TNF-α t1/2 to prolong cytotoxic effectsThree- to tenfold fold higher
κ-Ig light chainsImmune-mediated protein22.5UnknownInhibit leukocyte chemotaxis, apoptosis, and functionTwo- to 16-fold higherNephelometric (Binding Site)
Complement factor D (C3 proactivator convertase)Immune-mediated protein24Component of alternative complement pathway; humoral defenseOveractivity of complement systemFour- to 17-fold higherELISA (R&D Systems)
Soluble TNF receptor 1 (p75)Immune-mediated protein27–30Binds to and limits TNF-α activityMay increase circulating TNF-α t1/2 to prolong cytotoxic effectsThree- to tenfold higher
α1-Acid glycoprotein (Orosomucoid)Immune-mediated protein35–44Anti-inflammatory acute-phase protein; suppresses local leukocyte activity and promotes immunosuppressive macrophage differentiationInhibition of leukocyte migration, contribution to secondary immunodeficiency <1.5-Fold higherNephelometric (Siemens Healthcare)
Pentraxin-3Immune-mediated protein40Opsonization and complement activation; modulates macrophage activityProthrombotic actions in endothelial cells; impaired NO productionTwo- to sevenfold higherELISA (R&D Systems)
YKL-40 (Chitinase-3–like protein 1)Immune-mediated protein40Regulates local inflammatory markers; other functions unclearContribution to upregulation of local tissue inflammation and fibrosisTwo- to fivefold higherELISA (Quidel)
λ-Ig light chainsImmune-mediated protein45UnknownInhibit leukocyte chemotaxis, apoptosis, and functionTwo- to 18-fold higherNephelometric (Binding Site)
Vascular endothelial growth factor (Vascular permeability factor)Growth factor34Promotes endothelial cell proliferation, migration, and differentiation; involved in cardiac adaptation to hypoxia and stretchInvolved in cardiomyopathy and left ventricular dysfunctionApproximately twofold higherELISA (Thermo Fisher)
Fibroblast growth factor 2 (Basic fibroblast growth factor)Growth factor18Angiogenic growth factor; stimulates neovascularization; upregulates inflammatory cytokines andchemokinesCardiac hypertrophy; contribution to local inflammationELISA (Thermo Fisher)
Fibroblast growth factor 23Growth factor32Regulates phosphate homeostasis via effects on the sodium/phosphate cotransporter and kidney hydroxylation of vitamin DCardiac hypertrophy >200-Fold higherELISA (R&D Systems)
ProlactinHormone23Primary role in mammary cell proliferation and reproductive function; diverse roles in immunomodulation etc.Amplification of inflammatory cytokine response (IL-12 and TNF-α); increased CVS eventsTwo- to fourfold higherELISA (R&D Systems)
Clara cell protein (CC16)Protein15.8Phospholipase-A2-inhibitor; immunosuppressive role in respiratory tractUnknownApproximately 30-fold higher
α1-MicroglobulinProtein33Inhibitor of heme and neutrophil-induced oxidative damage; immunomodulatory functionsInhibition of leukocyte migration, chemotaxis, and IL-2 secretionApproximately ninefold higherELISA (Abcam Nephelometric–Siemens Healthcare)
β-Trace protein (l-prostaglandin D2 synthase)Protein26Catalyzes isomerization of precursor prostanoids to active formsObservationally associated with atherosclerotic plaque >35-Fold higherNephelometric (Siemens Healthcare)
MyoglobinProtein17Oxygen carrier in muscle tissueIncreased oxidative stressThreefoldRIA
Hyaluronic acid (Hyaluronan)Glycosa-minoglycanVariableFormation of endothelial glycocalyx; structural role in extracellular matrixSmall species proinflammatory; innate immune system triggers; promotes endothelial dysfunction and damageFive- to 16-fold higherELISA (Echelon Biosciences)
Advanced glycosylation end productsOther<1–70UnknownAdverse structural effects; interactions with RAGETwo- to 20-fold higherELISA (Cell Biolabs)
  • CVS, cardiovascular system; NO, nitric oxide; RAGE, receptor for advanced glycosylation end product.