PROGRESS IN UREMIC TOXIN RESEARCH: Guanidino Compounds as Uremic (Neuro)Toxins

Abstract

Neurological and vascular impairment are important sources of morbidity in patients with renal failure. A portion of patients still suffers from uremic encephalopathy or other signs of nervous system impairment. Several reports demonstrate increased incidence of cardiac infarction and cerebrovascular accidents in chronic renal failure patients, even in those otherwise adequately dialyzed. Epileptic and cognitive symptoms are among the most typical manifestations of uremic encephalopathy. Several guanidino compounds (GCs) may play an important role in the etiology of uremic encephalopathy. Four GCs appeared to be substantially increased as well in serum, cerebrospinal fluid, and brain of uremic patients. These compounds, "uremic" GCs, are creatinine, guanidine (G), guanidinosuccinic acid (GSA), and methylguanidine. All four compounds are experimental convulsants in concentrations similar to those found in uremic brain. We described a possible mechanism for the contribution of GCs to uremic hyperexcitability, referring to the in vitro effects of uremic GCs on inhibitory and excitatory amino acid receptors. It was demonstrated that the excitatory effects of uremic GCs on the central nervous system can be explained by the activation of N-methyl-d-aspartate receptors by GSA, concomitant inhibition of gamma-aminobutyric acid type A receptors by uremic GCs, and other depolarizing effects. These effects might also indicate the putative contribution of uremic GCs to the etiology of uremic encephalopathy. In this article, we review the uremic GCs with particular attention to their neurotoxicity. We elaborate in detail on the mechanisms of action of the neurotoxic uremic GCs and summarize the kinetics of these toxins.

Cognitive Disorders and Dementia in CKD

“…79 DeDeyn et al reported that cerebrospinal fluid and brain levels of some guanidine compounds, such as creatinine, guanidine, guanidinosuccinic acid, and methylguanidine, are substantially elevated in uremic patients. 80 Interestingly, these high toxin concentrations (up to 10-fold higher in CKD patients than in controls) were found in brain regions that play a determinant role in cognition, such as the thalamus, the mammillary bodies, and the cerebral cortex. 80 It is well known that these uremic guanidine compounds are neuroexcitatory agents and have convulsant activity in animal studies.…”

“…80 Interestingly, these high toxin concentrations (up to 10-fold higher in CKD patients than in controls) were found in brain regions that play a determinant role in cognition, such as the thalamus, the mammillary bodies, and the cerebral cortex. 80 It is well known that these uremic guanidine compounds are neuroexcitatory agents and have convulsant activity in animal studies. 81 However, it is still not clear whether uremic toxins are directly responsible for cognitive impairment.…”

Liver Transplantation Prevents Progressive Neurological Impairment in Argininemia

“…Argininemia treatments that successfully lower arginine and guanidino compounds levels should prevent neurological symptoms, but although arginine plasmatic levels may normalize under conventional treatment, the arginine's catabolites can remain elevated (Marescau et al 1990), and some of these guanidino compounds are neurotoxic (De Deyn et al 2009;Hiramatzu, 2003). In both of our patients, arginine concentration decreased significantly under conventional treatment (but never normalized), and guanidine compounds were markedly elevated in plasma and urine.…”

Uremic Encephalopathy

“…Another possibility is that, together with urea, other uremic solutes antagonizing its toxic impact are retained (Lee et al, 1991). Finally, urea might be at the origin of other, more toxic moieties, such as some of the guanidines or carbamylation products (De Deyn et al, 2003;De Deyn et al, 2009;Stim et al, 1995;Vanholder & De Smet, 1999) .…”

“…Based on the results summarized above, a hypothetical mechanism for the action of uremic guanidino compounds on glutamatergic transmission in the central nervous system was proposed by De Deyn et al (De Deyn et al, 2009) (Fig. 2).…”