Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Abstract

In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β₂-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.

Keywords: CKD; Chronic Kidney Disease; cardiovascular disease; fibrosis; inflammation; middle molecules; patho-physiology CKD; protein bound uremic solutes; uremia; uremic toxicity; uremic toxins; water-soluble uremic solutes.

Figure 1

Number of publications per year of appearance included in the reference list of this article.

Figure 2

Number of toxins within a group affecting specific systems (left—panels (A,C,E)) and number of systems affected by each individual toxin (right, panels (B,D,F). Small water-soluble compounds (above, panels (A,B)), protein bound compounds (middle—panels (C,D) and middle molecules (below—panels (E,F)). The systems and solutes are ranked clockwise from 12 h on, in proportion to the number involved, the largest numbers coming first. Abbreviations—CVD: cardiovascular disease; CKD-MBD: chronic kidney disease-metabolic bone disease; PEW: protein energy wasting; ADMA: Asymmetric Dimethylarginine; TMA: Trimethylamine; DMA: Dimethylamine; TMAO: Trimethylamine-N-Oxide; carbam comp: carbamylated compounds; SDMA: Symmetric Dimethylarginine; MMA: Monomethylamine; 2PY: N-Methyl-2-Pyridone-carboxamide; PAG: Phenylacetylglutamine; AGEs: Advanced Glycation End Products, p-OH hippurate: p-hydroxyhippurate; AOPPs: Advanced Oxidation protein Products; CMPF: Carboxy Methyl Propyl Furanpropionic Acid; o-OH hippurate: o-hydroxyhippurate; β2M: β₂-microglobulin; PTX-3: pentraxin-3; IL-1β: Interleukin-1β; IL-6: interleukin-6; FGF-23: Fibroblast Growth Factor-23; L & L: lipids and lipoproteins; CFBa: Complement Factor Ba; IL-10: Interleukin-10; PTH: Parathyroid Hormone; RBP: Retinol Binding Protein; CFD: Complement Factor D; IL-18: Interleukin-18; TNF-α: Tumor Necrosis Factor-α; IgLC: Immunoglobulin Light Chains; Met-Enkephalin: Methionine-Enkephalin; MCSF: Macrophage Colony Stimulating Factor; ANP: Atrial Natriuretic¨Peptide.; * polyamines, carbamylated compounds, AGEs, AOPPs, kynurenines, Immunoglobulin Light Chains and lipids and lipoproteins (modified) considered as one group; ** guanidines considered as one group with the exception of ADMA and SDMA ; *** modified—post-translational.