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Review
. 2017 Mar 23;9(4):114.
doi: 10.3390/toxins9040114.

Inflammatory Cytokines as Uremic Toxins: "Ni Son Todos Los Que Estan, Ni Estan Todos Los Que Son"

Esmeralda Castillo-Rodríguez  1 , Soledad Pizarro-Sánchez  2 , Ana B Sanz  3 , Adrian M Ramos  4 , Maria Dolores Sanchez-Niño  5 , Catalina Martin-Cleary  6 , Beatriz Fernandez-Fernandez  7 , Alberto Ortiz  8
Affiliations
Review

Inflammatory Cytokines as Uremic Toxins: "Ni Son Todos Los Que Estan, Ni Estan Todos Los Que Son"

Esmeralda Castillo-Rodríguez et al. Toxins (Basel). .

Abstract

Chronic kidney disease is among the fastest growing causes of death worldwide. An increased risk of all-cause and cardiovascular death is thought to depend on the accumulation of uremic toxins when glomerular filtration rate falls. In addition, the circulating levels of several markers of inflammation predict mortality in patients with chronic kidney disease. Indeed, a number of cytokines are listed in databases of uremic toxins and uremic retention solutes. They include inflammatory cytokines (IL-1β, IL-18, IL-6, TNFα), chemokines (IL-8), and adipokines (adiponectin, leptin and resistin), as well as anti-inflammatory cytokines (IL-10). We now critically review the cytokines that may be considered uremic toxins. We discuss the rationale to consider them uremic toxins (mechanisms underlying the increased serum levels and evidence supporting their contribution to CKD manifestations), identify gaps in knowledge, discuss potential therapeutic implications to be tested in clinical trials in order to make this knowledge useful for the practicing physician, and identify additional cytokines, cytokine receptors and chemokines that may fulfill the criteria to be considered uremic toxins, such as sIL-6R, sTNFR1, sTNFR2, IL-2, CXCL12, CX3CL1 and others. In addition, we suggest that IL-10, leptin, adiponectin and resistin should not be considered uremic toxins toxins based on insufficient or contradictory evidence of an association with adverse outcomes in humans or preclinical data not consistent with a causal association.

Keywords: adipokines; chemokines; chronic kidney disease; decoy receptor; inflammation; mortality; uremic toxins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Increased production versus decreased clearance of cytokines that are potential uremic toxins in CKD: practical consequences. Traditionally, increased levels of uremic toxins, such as cytokines, were considered to result from decrease renal clearance. However, there is evidence for increased production of certain uremic toxins, such as PTH or cytokines. The distinction may have therapeutic implications. (A) Healthy subject. A small amount of cytokines and soluble cytokine receptors are produced and cleared by the kidneys and other organs. Soluble decoy receptors will render cytokines inactive, while agonistic soluble receptors will allow transactivation of target cells not expressing the receptor in the cell membrane; (B) Inflammatory disease with normal renal function. Increased local production of cytokines and receptors in the inflamed tissue will lead to leukocyte infiltration and tissue injury (the red epithelial cell represents a damaged cell), as well as to increased circulating levels of cytokines and soluble receptors. Sterile inflammatory conditions are currently treated with anti-cytokine strategies; (C) Conventional view of uremic toxins, including cytokines, in CKD. Decreased kidney clearance will lead to higher circulating levels. This may be deleterious for the vasculature, but tissue levels are not expected to reach the values found in inflammatory conditions. However, the ultimate consequences of the high cytokine levels will depend on the levels of modifiers such as decoy and transactivating soluble receptors; (D) Current view of cytokines as uremic toxins. On top of the reduced renal clearance, there is an excessive production of cytokines and soluble receptors, leading to higher tissue cytokine concentrations and tissue injury. Both leukocytes and parenchymal cells secrete excess amounts of cytokines in response to the presence of other uremic toxins. The excess production of cytokines will render efforts at increasing cytokine clearance useless, as suggested by unchanged cytokine levels during dialysis despite clearance. These patients may benefit from exploring anti-cytokine strategies. In individual patients, the scenario presented in (C) or (D) may predominate, depending among other factors, on levels of uremic toxins that are known to promote cytokine secretion and are modulated by environmental factors or by diet and the gut microbiota, such as p-Cresyl sulphate.
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