New therapeutic perspectives on protein-bound uremic toxins in chronic kidney disease

Abstract

The uremic syndrome is a complex mosaic of clinical alterations that may be attributable to one or more of these different solutes. Uremic symptoms in patients with chronic kidney disease are primarily a consequence of inadequate removal and subsequent accumulation of organic products normally metabolized or excreted by the kidney.

Keywords::

• AST-120
• chronic kidney disease
• indoxyl sulfate
• uremic toxins

The uremic syndrome is a complex mosaic of clinical alterations that may be attributable to one or more of these different solutes. Uremic symptoms in patients with chronic kidney disease (CKD) are primarily a consequence of inadequate removal and subsequent accumulation of organic products normally metabolized or excreted by the kidney [1]. Knowledge about the nature and kinetic behavior of the responsible compounds may help when new therapeutic options are considered in the future. Normally, healthy kidneys excrete a myriad of compounds. Uremic retention solutes accumulate in CKD patients, including patients with K/DOQI stage 5 disease or end-stage renal disease (ESRD) [2]. The retention of these solutes is directly or indirectly attributable to deficient renal clearance. These retained solutes are called uremic toxins when they contribute to the uremic syndrome. Accumulated uremic solutes are termed uremic toxins, if they are biologically active. The accumulation of uremic toxins is associated with negative effects on almost every organ system, though most notably on the cardiovascular (CV) system [1].

Considerable effort has gone into understanding the mechanisms responsible for such toxicity and to develop therapeutic interventions which can reduce the adverse effects of uremic toxins.

In the very elegant review paper on indoxyl sulfate (IS) and therapeutic approaches, Niwa presented the state of art on this interesting compound [3]. Owing to the fact that removal of only one substance does not influence or ameliorate uremic symptoms, therefore, combined approaches should be instituted to yield the best possible results.

Since he focused on the protein-bound uremic toxins, let the readers be also acquainted with other types of uremic toxins, their possible removal and clinical significance.

Protein-bound compounds

This is the area of the great interest for Niwa, an expert in this field. In his up-to- date review, he has described the search for these toxins. Using metabolomic analysis of comprehensive small-molecular metabolites with liquid chromatography/electrospray ionization-tandem mass spectrometry and principal component analysis, Kikuchi et al. [4] identified uremic toxins accumulated in the serum of CKD rats. They also demonstrated that IS was the first principal serum metabolite which differentiates CKD from normal, followed by phenyl sulfate, hippuric acid and p-cresyl sulfate (PCS).

Almost 20 years ago, Niwa was the first researcher to demonstrate the nephrotoxicity of IS [5].

A number of uremic toxins, including phenolic and indolic compounds, originate from protein fermentation in the large intestine following hydrolysis of polypeptide chains by proteases and peptidases. Phenols (e.g., phenylacetic acid, phenol, p-cresol) are generated during the partial breakdown of tyrosine and phenylalanine by intestinal facultative or obligate anaerobes. Most phenols produced in the colon are absorbed and detoxified by conjugation to sulfate compounds by the liver (e.g., p-cresol to PCS) [6]. Indoles are found in various plants and herbs, and some are also produced by the intestinal flora as the end-products of metabolism in the colon. Tryptophan breakdown leads to synthesis of indolic compounds, while decarboxylation of lysine and ornithine causes synthesis of simple amines. Indoles are absorbed and metabolized by the liver into the sulfate form (e.g., IS). IS is derived from dietary protein. A part of the protein-derived tryptophan is metabolized into indole by tryptophanase in intestinal bacteria such as Escherichia coli. Indole is then absorbed into the blood from the intestine and is metabolized to IS in the liver, while IS is normally excreted into urine. In uremia, however, the inadequate renal clearance of IS leads to its elevation; however, kinetic behavior appears to differ among the indoles. Simple amines can be either detoxified by monoamine and diamine oxidases in the liver or colonic mucosa or can be eliminated by the kidneys [6].

PCS and IS are prototypic protein-bound uremic toxin molecules. In addition, being biomarkers for kidney function, they are also involved in the progression of CKD [7]. They share several similarities as they are synthesized by intestinal flora [8] and are strongly bound to albumin at the Sudlow II site [9] and their level depends on kidney function and their removal is hampered during dialysis [10,11]. Moreover, as shown in the excellent paper by Niwa [3] and Meijers et al. [12], mortality risk factors are emerging in renal patients. This is of particular importance since uremic toxins have gained substantial interest in recent years due to their potential hazardous role in excessive mortality among ESRD patients [13] and due the fact that they can be considered as nontraditional risk factors in this population. Several in vitro data have suggested a pathophysiological role of the solute in some important aspects of the uremic syndrome. It has been shown that PCS and IS exert their toxic effects in vitro [14]. Moreover, Niwa showed us the role of IS in the progression of CKD starting from its nephrotoxicity, formation of reactive oxygen species in the kidney, by inducing an inflammatory reaction, with enhanced expression of profibrotic cytokines such as transforming growth factor-β1, then reduction of Klotho and induction of senescence in the kidney to the activation of renin-angiotensin-aldosterone system in the kidney. In the next paragraphs, he leads us through the journey of detrimental effect of IS on the CV system by inhibition endothelial proliferation and wound repair and stimulation of proliferation of vascular smooth muscle cells, promotion of aortic calcification and aortic wall thickening, impairment of endothelial progenitor cells leading to endothelial cell injury, and finally profibrotic, prohypertrophic and proinflammatory effects on cardiac fibroblasts and cardiomyocytes [3]. Recently, Baretto et al. [15] in the first clinical study demonstrated the association between IS and CV disease (CVD) in renal patients. In addition, Lin et al. [16] revealed that serum total IS in haemodialysis (HD) patients is significantly associated with CVD but not with all-cause mortality. They also demonstrated that in patient serum high total (> 24.3 mg/l) and free (> 1.4 mg/l) PCS seem to be good predictors of CV events in HD patients.

Coming from bench to bedside, Niwa [3] discussed the therapeutic strategies at the end of the review. In 1991, an oral sorbent AST-120 under the name of Kremezin® was introduced in the Japanese market as the first pharmaceutical drug in the world for the proactive treatment of CKD. It is an orally administered beaded porous activated carbon of high purity which strongly adsorbs dietary advanced glycation end-products and uremic toxins. It excretes the toxins out from the body through the feces. It also reduces serum level of IS by adsorbing indole in the intestine. Kremezin, discovered by the Japanese Kureha Corp., is currently available for therapeutic use in Japan and Korea for chronic renal failure. As of 1 April 2011, the marketing rights were transferred from Daiichi Sankyo to the Mitsubishi Tanabe which markets Kremezin Capsules 200 mg and Kremezin Fine Granules 2 g (the company Mitsubishi Tanabe acquired the exclusive rights to market and developed Kremezin in the United States and Europe in November 2006). The proven and potential benefits in clinical studies include: increased vasodilation, decreased IS levels in a dose-dependent way and decreased markers of oxidative stress following 24 weeks of treatment in CKD patients [17], a slower decline of estimated glomerular filtration rate (eGFR), later initiation of dialysis, and longer survival on dialysis in patients with nondiabetic kidney disease [18-22], delaying the progression of the diabetic kidney disease [23]. AST-120 might also reduce arterial stiffness and intima-media thickness (which are related to coronary artery disease) in nondiabetic patients before hemodialysis and decreases carotid artery intima-media thickness and pulse wave velocity (a measure of arterial stiffness) in patients with nondiabetic CKD treated for 24 months when compared with patients who did not receive this compound [24]. Improvement of symptoms and outcomes in patients with congestive heart failure and moderate CKD were reported after treatment with AST-120, in addition to conventional therapy for 24 months; the length of hospital stay and number of hospital admissions decreased significantly after treatment with AST-120 when compared with the 2-year period prior to initiation of therapy in those who required hospital admission; improvements in renal function indices, atrial natriuretic peptide, edema and cardiothoracic ratio were also observed [25].

Other therapeutic strategy proposed by Niwa [3] include oral administration of bifidobacteria in gastro-resistant capsules modifying intestinal flora to hemodialysis patients, which reduces serum levels of IS by correcting gastrointestinal flora [26]. In addition, diet may also affect serum levels of IS. Vegetarians with normal renal function had 58% lower IS excretion (reflecting generation) than among subjects on an unrestricted diet [27].

This may be the new avenue to slow the progression of CKD; however, the problem arises in hemodialyzed population. Because of their strong protein binding, their removal by classical dialysis is hampered, with removal of small water-soluble molecules being completely different [28]. It is, therefore, conceivable that alternative removal methods (e.g., adsorption or convective transport) should be developed before adequate elimination of these toxins can be obtained [29]. High-flux dialysis, compared to low-flux dialysis, has no beneficial effect on the removal of these toxins [28]. However, De Smet et al. [30] reported that super-flux triacetate membrane was superior to low-flux cellulose triacetate in regard to removal of IS. On the other hand, p-cresol is cleared better with high-flux hemodialysis, when compared to peritoneal dialysis [31]. Nevertheless, the plasma concentrations of protein-bound toxins is lower in patients on peritoneal dialysis compared with those on hemodialysis [31]; it seems that besides dietary protein intake or residual renal function, metabolism and/or intestinal handling may play a role. Among dialysis modalities, convective strategies were superior, that is, more efficient to diffusion with regard to removal [32-34]. By applying combined fractionated plasma separation and adsorption, removal of PCS could be markedly enhanced, by an artificial liver (Prometheus, Fresenius Medical Care) with a price of major coagulation disturbances [35]. Albumin dialysis, thus, offers proof that adsorption may become an additional asset in the removal of this type of compound, however, at a much higher cost with some drawbacks.

Summary

The uremic syndrome is a complex mosaic of clinical alterations that may be attributable to one or more of these different solutes. Uremic toxins are now considered as nontraditional risk factors for mortality, mainly CV one. Uremic solutes accumulate not only in the plasma but also in the cells, where most of the biological activity is exerted. Therefore, there is no single strategy for their removal. So far, the main strategy that has been used till date to decrease uremic solute concentration is dialysis. On the other hand, therapeutic intervention includes administration of drugs countering biological impact of uremic solutes and reaching a much larger population than with removal strategies such as AST-120. Potential and proven benefits of AST-120 include absorption of IS, and subsequent preservation of renal function a slower decline of eGFR, while patients started later on dialysis, and longer survivival r once dialysis was initiated, improvement of symptoms and out comes in patients with congestive heart failure and moderate CKD. However we should stress, this substance also absorbs p-cresol as well as other compounds. Preservation of residual renal function may also be an important matter to pursue additional removal of retention solutes. Residual renal function was better preserved after administering the sorbent AST-120 to patients with CKD, including diabetic nephropathy. However, as stressed by Niwa [5] ‘the long-term effects of AST-120 are still uncertain' and ‘further clinical studies are required to clarify the long-term effects of AST-120 on the progression of CKD and CVD'.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.