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

Abstract

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 [β 2 -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: uremic toxins; uremic toxicity; uremia; Chronic Kidney Disease; CKD; cardiovascular disease; inflammation; fibrosis; patho-physiology CKD; middle molecules; protein bound uremic solutes; water-soluble uremic solutes Key Contribution: This publication contains a comprehensive overview of the current knowledge on uremic toxicity, as well as an estimation of the degree of toxicity attributed to each individual toxin, and a classification according to the degree of known toxicity.

Kidney cachexia or protein‐energy wasting in chronic kidney disease: facts and numbers

“…In CKD, increased serum inflammatory cytokines predispose to the pathogenesis of PEW . Accumulating data also suggest that during CKD, specific accretion of uremic toxins may have a direct effect on inflammation stimulation and cytokines production . Therefore, inflammation contributes to PEW/cachexia in several ways, both by direct and indirect mechanisms of muscle proteolysis and by impinging upon and magnifying other causes of PEW in a vicious circle.…”

“…[36][37][38] Accumulating data also suggest that during CKD, specific accretion of uremic toxins may have a direct effect on inflammation stimulation and cytokines production. 39 Therefore, inflammation contributes to PEW/ cachexia in several ways, both by direct and indirect mechanisms of muscle proteolysis and by impinging upon and magnifying other causes of PEW in a vicious circle. Therefore, the rationale not to include inflammatory criteria in the PEW criteria might be reconsidered.…”

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration

“…1,[5][6][7][8][9][10] Most drugs are at least partly eliminated by nonrenal pathways in subjects with normal renal function. 7,10,11,20,21 The reduction of total clearance (CL) caused by a decline of renal clearance (CLr) and/or CLnr in CKD increases drug exposure and, more importantly, drug response. [11][12][13][14][15][16] Renal impairment can impact the concentrations of albumin and α1-acid glycoprotein, which may increase, reduce, or have no effect on the fraction of unbound drug in plasma (fu), and thus on CLnr.…”

A plea for more uremic toxin research in children with chronic kidney disease

“…As proposed by the European Uremic Toxin Workgroup (EUTox), uremic toxins can be subdivided into three major classes based on their physicochemical properties that affect their removal during dialysis: (1) small water-soluble compounds (< 500 Da; e.g., urea) that are easily removed by diffusion, (2) middle molecules (≥ 500 Da; e.g., β2-microglobulin) that are most efficiently removed using large pore dialyzer membranes and by adding convective transport (hemodiafiltration), and (3) protein-bound compounds (e.g., indoxyl sulfate) that most often have a low molecular weight but are poorly removed by dialysis due to their protein binding [5,7]. In experimental and clinical studies, many of these uremic toxins exert some degree of toxicity on one or more functional systems that contributes to the uremic syndrome and its complications [8]. In general, the cardiovascular, inflammatory, and fibrogenic system were most frequently affected by uremic toxins in experimental and clinical studies [8].…”

“…In experimental and clinical studies, many of these uremic toxins exert some degree of toxicity on one or more functional systems that contributes to the uremic syndrome and its complications [8]. In general, the cardiovascular, inflammatory, and fibrogenic system were most frequently affected by uremic toxins in experimental and clinical studies [8].…”