Journal of Renal Nutrition
Volume 18, Issue 1 , Pages 2-6, January 2008

Uremic Toxins: What Are They? An Integrated Overview of Pathobiology and Classification

  • Richard J. Glassock, MD, MACP

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Richard J. Glassock, MD, MACP, 8 Bethany, Laguna Niguel, CA 92677.

Department of Internal Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Article Outline

Toxic substances, known as uremic toxins, accumulate in body fluids during the course of progressive, chronic kidney disease. This article will briefly summarize current views on the definition, physico-chemical characteristics, pathobiological mechanisms for generation and retention, and cellular pathophysiology of uremic toxins. In addition, this article will attempt to integrate these disparate phenomena into a systems biology approach as to how such toxins lead to the diverse clinical manifestations so characteristic of the uremic state.

 

THE ACCUMULATION OF TOXIC substances in the body-fluid compartments during the course of progressive, chronic kidney disease (CKD) is responsible for many of the clinical consequences of the condition known as uremia (literally, “urine in the blood”). These “uremic toxins” exhibit a broad array of physicochemical characteristics, mechanisms of generation, and patho-biological actions at the cellular and molecular levels. A precise knowledge of these features of uremic toxins would be very useful in the design of strategies for their removal (by dialysis) and in the prevention or inhibition of their undesirable effects on tissues and organs. Because of the diversity in the structure and actions of uremic toxins, it is beneficial to possess a comprehensive classification, based on fundamental chemical and biological principles.1 It is the purpose of this brief presentation to summarize the current approach to the pathobiology and classification of uremic toxins, emphasizing their chemical diversity, patho-biological generation, and effects on cellular and organ function.

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Definitions and Guiding Principles 

To understand uremic toxins, it is necessary to have a definition of uremia itself. Bergstrom and Furst provided a very succinct definition of uremia: “a toxic syndrome caused by severe glomerular deficiency associated with disturbances in tubular and endocrine functions of the kidney. It is characterized by the retention of toxic metabolites, associated with changes in the volume and composition of the body fluids and an excess or deficiency or various hormones.”2 This definition embraces uremia as a syndrome resulting from the accumulation of toxic substances in body fluids consequent to a failure of renal excretion, as well as from hormonal surfeits and deficiencies. It does not fully embrace the concept that excessive endogenous production or the impaired degradation of nonhormonal toxic metabolites can also participate in the generation of the uremic milieu, but it does include the possibility that states of deficiency are responsible for the elements of uremic syndrome.

Uremic toxins cannot be defined simply as substances present in the body fluids of individuals suffering from uremic syndrome. A connection between the toxic substance and one or more of the patho-biological or clinical features of the uremic syndrome must be firmly demonstrated.

To establish this connection requires the fulfillment of a form of Koch's postulates, as modified by Massry in 1977.3 The Massry/Koch requirements for the identification of an “authentic” uremic toxin are:

(1)The toxin must be chemically identified and characterized.

(2)Quantitative analysis of the toxin in biological fluids should be possible.

(3)The level of the toxin in biological fluids must be elevated in uremia.

(4)A relationship between the level of the toxin in biological fluids and one or more of the manifestations of uremia must be present.

(5)A reduction in the level of the toxin in biological fluids must result in the amelioration of the uremic manifestation.

(6)Administration of the toxin to achieve levels similar to those observed in uremia must reproduce the uremic manifestation in otherwise normal animals or man (in vitro demonstration of cellular toxicity alone is insufficient to fulfill this criterion).

In addition to these six criteria a seventh should be added, i.e., a plausible patho-biological mechanism should be demonstrated to explain the linkage between the toxin and the uremic manifestation.

The Massry/Koch postulates lead to a more narrow definition of uremic toxins than encompassed by the definition of uremia by Bergstrom and Furst.2 Certain hormonal/vitamin/substance/enzyme-deficiency states (e.g., 1,25 dihydroxy vitamin D, erythropoietin, selenium, zinc, carnitine, or paraoxonase) develop inexorably in uremia and definitely contribute to many manifestations of uremia. Thus uremia, as defined by Bergstrom and Furst,2 cannot be directly equated with uremic toxicity. The mechanisms underlying the generation of uremic toxins may also vary widely. In its broadest sense, the cellular pathogenesis of uremia toxicity can be explained by a direct toxic interference of normal cellular processes leading to disturbed function or premature cellular death, or by an indirect interference with normal cellular mechanics because of deficiency states. Specific uremic toxins can also exhibit a broad range of “tropisms” for an array of cell types or fundamental biological pathways.

The clinical manifestations of uremia are manifold. More than 75 individual clinical symptoms or signs have been described in uremia, associated with disturbances in all organ systems of the body.4

The ability of an individual toxin to induce or elaborate a manifestation is influenced by a number of factors, as listed in Table 1. These factors are dominated by the appearance rate of the toxin (synthesis, degradation, and renal and nonrenal elimination), body-fluid and intracellular distribution, and the existence of constitutive or induced inhibitors (or promoters) of the toxin action.

Table 1. Factors Influencing the Toxicity of Substances Accumulating in Uremia
1. Rapidity of changes in levels of biological fluids
2. Fluctuations in levels over time (time-averaged versus peak levels)
3. Penetration into sites of action
4. Intrinsic toxicity versus dependence of metabolism to more (or less) toxic compounds
5. Distribution in body fluids (protein-binding, lipophilicity, and hydrophilicity)
6. Presence and activity of naturally occurring inhibitors or promoters
7. Rate of metabolism at active sites

Thus, descriptions of the pleomorphic behavior of uremic toxins need to take into account many facets, including physiochemical characteristics and patho-biological actions.

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Physicochemical Characteristics 

The physicochemical characteristics of uremic toxins may be classified according to their chemical nature (inorganic or organic), molecular mass/volume (small, “middle,” or large), or their distribution in body fluids (hydrophilic [water-soluble], lipophilic, or bound to plasma proteins1). A useful and widely accepted categorization is based on molecular weight and plasma protein-binding characteristics.1 In this scheme, uremic toxins are divided into four nonoverlapping categories, i.e., (1) water-soluble, low molecular weight (<500 Da), and nonprotein-bound; (2) water-soluble, low molecular weight (<500 Da), and protein-bound; (3) “middle” molecular weight (>500 Da and <12,000 Da); and (4) high molecular weight (>12,000 Da). According to the above definitions, inorganic substances qualifying as uremic toxins would include H2O, Na+, K+, H+, Mg++, PO4−−−, Ca++, SO4 , and trace metals such as Al, Cr, Si, and Pb. The organic compounds associated with uremia are numerous and diverse. More than 90 individual organic chemical entities have been described in association with uremia, but relatively few have fulfilled all of the Massry/Koch postulates. In a comprehensive review of the literature from 1966 to 2002, Vanholder et al. and the European Uremic Toxin Work Group (EuTox) identified 90 organic compounds reportedly associated with uremia, 68 with a molecular weight <500 Da (23 of which were protein-bound), 10 compounds with a molecular weight >500 Da and <12,000 Da, and 12 with a molecular weight >12,000 Da.1 The plasma concentrations of these compounds found in uremia vary from a few nanograms to grams per liter. Although many of these potential uremic toxins have elevated plasma concentrations because of impaired renal excretion, many are associated with increased synthesis or impaired degradation compared with normal subjects. Among the low molecular weight compounds, derivatives of guanidine, arginine, amino acids, and phenols, and some nonenzymatic glycation intermediates, are commonly represented. Urea is often used as a “surrogate” low molecular weight uremic toxin, although its intrinsic toxicity is limited to extremely high concentrations. However, through the spontaneous production of isocyanate from urea, a carbamylation effect (e.g., on hemoglobin, albumin, or low-density lipoprotein) may promote its toxicity indirectly. Protein-binding of some of these low molecular weight toxins is an important phenomenon, because it will influence removal by dialysis, space of distribution, and penetration into intracellular sites. Indoxyl sulfate, p-cresyl sulfate, deoxyglucosone (derived from fructose), pentosidine, homocysteine, and asymmetric dimethylarginine are important protein-bound, low molecular weight, potential uremic toxins.1, 5, 6, 7 Asymmetric dimethylarginine (ADMA) appears to accumulate in uremia more as a consequence of disturbed metabolism than as a result of impaired renal excretion.7 Uric acid and other purine nucleotide derivatives are also emerging as important low molecular weight uremic toxins.8, 9

“Middle” molecular weight compounds have assumed a key role in the understanding of uremia since the seminal observations of Babb et al. and the elucidation of the “middle molecule hypothesis” in 1972.10 Vanholder et al. identified 10 such middle molecules (molecular weight >500 Da and <12,000 Da) in their survey of the literature in 2002.1 These “middle” molecules are commonly glucuronide conjugates, small peptides, carbohydrate derivatives, advanced glycosylation/glycol-oxidation products (AGEP/AOP), peptide hormones, and metabolites (parathyroid hormone and atrial natriuretic peptide). These compounds may be highly reactive and may induce the synthesis of other compounds which may also have toxic properties. The characterization of these “middle” molecules is critical to an understanding of uremia and its treatment, because they may be removed differentially by dialysis modality (membrane characteristics and duration of treatment session). The high molecular weight potential uremic toxins (>12,000 Da), of which about 12 were identified in the survey of Vanholder et al.,1 are less well-characterized and include cytokines and chemokines (interleukin-6 and tumor necrosis factor), immunoglobulin light chains, leptin, complement factors, carbamylated proteins or lipoproteins, advanced glycation or oxidation products (AGEP and AOP), and inhibitor proteins (granulocyte-inhibitor protein, chemotaxis-inhibiting peptide, and degranulating-inhibitor protein). The compartmentalization of these uremic toxins in biological fluids, based on their physicochemcal characteristics, creates special requirements and unique kinetic behaviors when their removal by extracorporeal (hemodialysis and hemofiltration) or intracorporeal (peritoneal dialysis) means are under consideration.

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Patho-Biological Mechanisms of Generation 

The uremic toxins mentioned above can accumulate in body fluids through a number of categories or types of mechanisms. Type I represents accumulation in body fluids of toxic substances normally produced endogenously by metabolic processes, largely as a result of reduced renal excretory capacity (e.g., urea). Type II involves a surfeit of toxic substances in body fluids as a result of excess endogenous production or impaired degradation (or both), but not because of reduced renal excretory capacity (e.g., parathyroid hormone of ADMA). Type III involves the accumulation of toxic substances in biological fluids from exogenous sources by virtue of reduced renal excretory capacity, often combined with continued dietary consumption (e.g., aluminum). A special type of pathobiology (type IV) is a deficiency or reduced activity of substances normally produced endogenously as a result of decreased synthesis, enhanced degradation, or biological inhibition. Combinations of more than one patho-biological process are possible. For example, urea is a uremic toxin which arises because of a combination of type I and type III processes: excessive accumulation because of impaired renal excretion, and continued production because of exogenous (dietary) consumption of protein as a precursor of urea.

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Systems Biology 

In recent years, a new concept has emerged, to the effect that uremia is strongly associated with a state of “chronic inflammation,” manifested by an increase in “positive” acute-phase reactant proteins (such as C-reactive protein, interleukin-6, fibrinogen, ferritin, and serum amyloid A protein) and a reduction in “negative” acute-phase reactant proteins (albumin, transferrin, and prealbumin).11 The proposed origins of this inflammatory state include: (1) an imbalance between proinflammatory and anti-inflammatory factors; (2) underlying organ-based chronic inflammation (occult infection, e.g., periodontal disease, infected vascular access, or vulnerable atherosclerotic plaques, and kidney inflammation associated with basic disease); and (3) exposure to inflammatory promoters (endotoxin-contaminated dialysate and bio-incompatible membranes). No doubt, in individual patients, multiple factors explain the presence of an inflammatory state. Certain candidate uremic toxins, such as uric acid or ADMA, may be potent promoters of inflammation, and inflammation in turn can lead to the generation of uremic toxins, such as advanced oxidation products via the generation and inadequate scavenging of toxic oxygen radicals.

The “toxicity” of ADMA is also emerging as a new concept in the biology of uremic toxicity.7, 12 This methylated amino acid is highly protein-bound, and its concentration in plasma is elevated in uremia. The elevation is predominantly caused by the inhibition of its major kidney-derived metabolizing enzyme (dimethylarginine dimethylaminodydrolase-1, or DDAH-1), rather than by markedly decreased renal excretion. Asymmetric dimethylarginin is a potent inhibitor of endothelial cell nitric oxide synthase (NOS).12, 13 Impaired NOS and nitric oxide production by endothelial cells may lead to vasoconstriction, elevated blood pressure, and vascular damage. Oxidative stress associated with uremia may also impair the effectiveness of DDAH-1, and may establish a link between endothelial cell dysfunction and inflammation in uremia. Moreover, DNA methylation and repair may be adversely affected by putative uremic toxins.14

Thus, the biology of uremic toxicity should be viewed as a complex, dynamic, interacting system of effector, promoter, and inhibitory molecules occurring in a situation of reduced renal excretory capacity, impaired defensive ability, and superimposed deficiency states. The cumulative adverse effects on cellular and organ system function will depend on the balance of these factors.

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Clinical Manifestations 

The clinical manifestations of uremic toxicity are broad and diverse. As described previously, every organ system in the body can be affected. Each individual uremic toxin may have its own unique profile of “tropisms,” i.e., each toxin may have a preferential action on only one system (monotropic), or may act on only a few systems (oligotropic). Most of the uremic toxins studied so far have effects on multiple systems (pleiotropic), perhaps by interference with very fundamental common pathways of cellular behavior (nitric oxide synthesis, DNA methylation and repair, or defense against oxidative stress), as exemplified by parathyroid hormone, uric acid, and other derivatives of purine nucleotides and ADMA. Elucidation of the “tropic” behavior of individual toxins is an important element in their full characterization.

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Conclusion 

An exposition of uremic toxicity requires an integrative analysis of the physicochemical properties of putative toxins (molecular size and protein binding), an understanding of the patho-biological processes responsible for their formation and accumulation, and a mechanistic view of how they alter fundamental cellular behavior. An explanation of how individual or groups of toxins lead to clinical manifestations requires a consideration of tropism (monotropic, oligotropic, and pleiotropic toxins). This “three-dimensional” integration allows for a better understanding of the complexity and potential for mapping of the important elements of uremic toxicity, in a fashion somewhat analogous to the development of the periodic table of the elements by Mendeleev in 1869.15 In this scenario, each individual putative toxin would be assigned a unique descriptor encompassing physicochemical characteristics, patho-biological type of generation, and “tropism” behavior. The long-term viewpoint underlying this classification involves the development of better and more rational methods of treatment, including the ablation of organ sources of putative toxins, the reduction of exogenous sources of toxic precursors, a reduction in the absorption of and an enhancement of the extrarenal removal of toxins, supplementation for the replacement of deficiencies, extracorporeal removal, the suppression of toxic effects at the cellular level, and the replacement of renal tissue or its products. In this scheme, the dialytic therapy of uremic toxicity is but one small part of the overall picture.

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References 

  1. Vanholder R, De Smet R, Glorieux G, et al. Review on uremic toxins. Classification, concentration and inter-individual variability. Kidney Int. 2003;63:1934–1943
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PII: S1051-2276(07)00221-X

doi:10.1053/j.jrn.2007.10.003

Journal of Renal Nutrition
Volume 18, Issue 1 , Pages 2-6, January 2008

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