PROGRESS IN UREMIC TOXIN RESEARCH: Hyperhomocysteinemia in Uremia—A Red Flag in a Disrupted Circuit

Abstract

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function.

SuperTAG Methylation-specific Digital Karyotyping Reveals Uremia-induced Epigenetic Dysregulation of Atherosclerosis-Related Genes

“…2 Of note, patients on dialysis display aberrations in global DNA methylation, 11,13 to which several features of the unphysiological uremic milieu, such as inflammation, 13 hyperhomocysteinemia, 10,11 oxidative stress, 16 and dyslipidemia, 14,15 may contribute. Against this background, it has been speculated that disturbed DNA methylation in CKD may affect atherosclerosisrelated genes with consequently higher susceptibility for vascular complications, [3][4][5][6][7][8] although information on site-specific regulation of these genes in CKD is virtually missing so far.…”

“…Following the postulate that uremia induces dysregulation of both atherosclerosis-protective genes and atherosclerosis-susceptible genes, [3][4][5][6][7][8] we finally analyzed whether the 1089 differentially methylated genes between patients on HD and controls can be directly linked to cardiovascular disease. Using the Genetic Association Database (accessible from the National Institutes of Health; http://geneticassociationdb.nih.gov/), we tested these genes for association with cardiovascular disease, as well as for immune/infection diseases, given that inflammation plays a central role in the pathogenesis of atherosclerosis.…”

“…Based on our pathophysiological understanding of SAH as the direct inhibitor of methylation reactions, its measurement as a biomarker for epigenetic dysregulation in cardiovascular disease seems to be more meaningful than measuring its derivate homocysteine. 42,43 Interestingly, all trials aiming at lowering homocysteine for primary or secondary prevention of cardiovascular disease used folate, vitamin B 6 , and/or vitamin B 12 , all of which efficiently lower plasma homocysteine levels, but unfortunately do not affect SAH levels. 44 Furthermore, in patients with CKD, SAH accumulates more compared with homocysteine because the kidneys are the major site of SAH disposal in humans.…”

Advantages of New Hemodialysis Membranes and Equipment

“…Next to the middle molecules, the comprehensive review on uremic toxicity mentioned above also devoted attention to the protein-bound solutes homocysteine [46], indoxyl sulfate [47,48], and p- cresylsulfate [47] as well as to protein-bound solutes in general [47]. Of note, several of the middle molecules are protein bound as well (leptin, the cytokines, the advanced glycation end products, the dinucleoside polyphosphates).…”

Hydrogen Sulfide, a Toxic Gas with Cardiovascular Properties in Uremia: How Harmful Is It?

“…More reliable biomarkers for predicting cardiovascular risk in CKD patients are under investigation. Thiol metabolites, such as homocysteine, cysteine, and S-adenosylhomocysteine, are increased in CKD patients, reaching their highest levels in hemodialysis patients [28]. Homocysteine and cysteine, or their direct derivatives, are utilized as substrates by the key enzymes involved in H 2 S biosynthesis, namely, CBS, CSE, and MST.…”