Therapy of Hyperhomocysteinemia in Chronic Kidney Disease

doi:10.1016/j.semnephrol.2005.06.006

Seminars in Nephrology

Volume 26, Issue 1, January 2006, Pages 24-27

https://doi.org/10.1016/j.semnephrol.2005.06.006 Get rights and content

Recent published evidence suggests that the correction of the multiple remethylation pathway abnormalities in chronic kidney disease (CKD), beyond folate-related disturbances, enhanced removal of uremic toxins and/or homocysteine (Hcy), and maneuvers aimed to displace Hcy from protein-binding sites, may represent valuable strategies to normalize total Hcy concentrations in CKD patients. The relevance of decreasing Hcy levels for cardiovascular disease in CKD patients should be shown definitively by the results of ongoing randomized trials.

Section snippets

Hcy-Decreasing Strategies in CKD Patients

Folic acid therapy in CKD patients has been shown to reduce, albeit not to normalize, plasma total Hcy concentrations, particularly in dialysis patients.¹ The relative resistance to folate action in CKD patients could explain why the correction of total Hcy concentrations generally remains partial.⁶ Indeed, routine minimal folic acid supplementation of less than 1 mg daily, in contrast to what usually is observed in the population at large, does not have any effect on plasma total Hcy

Hcy-Decreasing Strategies and CVD

The impact of Hcy-decreasing strategies on the risk for CVD in CKD patients has not yet been evaluated extensively. An acute decrease of total Hcy concentrations by N-acetylcysteine supplementation during the dialysis session has been shown to improve pulse pressure and endothelial function in hemodialysis patients.²² However, N-acetylcysteine may exert other effects (eg, via its antioxidant capacity), which could explain the endothelial actions independently of decreasing the total Hcy

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Cited by (5)

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension
2016, Pharmacological Research
Citation Excerpt :
In a recent review article, Perna and Ingrosso have creditably discussed this topic in more details with up-to-date information which are mostly based on clinical findings in patients with renal insufficiency [94]. Besides this, it has also been reported that the correction of multiple remethylation abnormalities with various other drugs in CKD patients, which are not related to folic acid supplementation, removes homocysteine from protein binding sites [97]. This information could add invaluable strategies to decrease homocysteine levels in CKD patients independent of folic acid remethylation-pathway.
Over the past several years, hydrogen sulfide (H₂S) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. H₂S is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to H₂S biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on H₂S regulation and function, genetic factors, and more recently epigenetics, also have a vital role in H₂S regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of H₂S throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how H₂S physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure.
Therapy of Hyperhomocysteinemia in Hemodialysis Patients: Effects of Folates and N-Acetylcysteine
2012, Journal of Renal Nutrition
Uremia represents a state where hyperhomocysteinemia is resistant to folate therapy, thus undermining intervention trials’ efficacy. N-acetylcysteine (NAC), an antioxidant, in addition to folates (5-methyltetrahydrofolate, MTHF), was tested in a population of hemodialysis patients.
The study is an open, parallel, intervention study.
Ambulatory chronic hemodialysis patients.
Clinically stable chronic hemodialysis patients, on hemodialysis since more than 3 months, undergoing a folate washout. Control group on standard therapy (n = 50).
One group was treated with intravenous MTHF (MTHF group, n = 48). A second group was represented by patients treated with MTHF, and, during the course of 10 hemodialysis sessions, NAC was administered intravenous (MTHF + NAC group, n = 47).
Plasma homocysteine measured before and after dialysis at the first and the last treatment.
At the end of the study, there was a significant decrease in predialysis plasma homocysteine levels in the MTHF group and MTHF + NAC group, compared with the control group, but no significant difference between the MTHF group and MTHF + NAC group. A significant decrease in postdialysis plasma homocysteine levels in MTHF + NAC group (10.27 ± 0.94 μmol/L, 95% confidence interval: 8.37-12.17) compared with the MTHF group (16.23 ± 0.83, 95% confidence interval: 14.55-17.90) was present. In the MTHF + NAC group, 64% of patients reached a postdialysis homocysteine level <12 μmol/L, compared with 19% in the MTHF group and 16% in the control group.
NAC therapy induces a significant additional decrease in homocysteine removal during dialysis. The advantage is limited to the time of administration.
Hyperhomocysteinemia in Chronic Renal Failure: Alternative Therapeutic Strategies
2012, Journal of Renal Nutrition
Chronic renal failure and uremia represent states wherein high blood levels of homocysteine, a cardiovascular risk factor, are largely resistant to folate therapy. Indeed, normalization of homocysteine levels through vitamin administration is rarely achieved in this population, and this fact could explain, among other causes, the negative results of intervention trials designed to lower cardiovascular risk. Dialysis itself lowers homocysteine levels, albeit transitorily. N-acetylcysteine therapy could induce an additional decrease in homocysteine removal during dialysis, thus representing an alternative approach in the attempt to lower cardiovascular risk in these patients.
Altered folate receptor 2 expression in uraemic patients on haemodialysis: Implications for folate resistance
2013, Nephrology Dialysis Transplantation
Sustained activation of N-methyl-D-aspartate receptors in podoctyes leads to oxidative stress, mobilization of transient receptor potential canonical 6 channels, nuclear factor of activated T cells activation, and apoptotic cell death
2012, Molecular Pharmacology

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Therapy of Hyperhomocysteinemia in Chronic Kidney Disease

Section snippets

Hcy-Decreasing Strategies in CKD Patients

Hcy-Decreasing Strategies and CVD

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Kidney Int

Kidney Int Suppl

Kidney Int

Metabolism

Kidney Int

Am J Kidney Dis

Adv Enzyme Regul

Kidney Int

Am J Transplant

Importance of homocysteine, lipoprotein (a) and non-classical cardiovascular risk factors (fibrinogen and advanced glycation end-products) for atherogenesis in uraemic patients

Nephrol Dial Transplant

Homocysteine and risk of ischemic heart disease and strokeA meta-analysis

JAMA