Intravenous N-Acetylcysteine During Haemodialysis Reduces the Plasma Concentration of Homocysteine in Patients With End-Stage Renal Disease

Mochammad Thaha; Mohammad Yogiantoro; Yasuhiko Tomino

Disclosures

Clin Drug Invest. 2006;26(4):195-202. 

In This Article

Abstract and Introduction

Abstract

Background: Hyperhomocysteinaemia is an independent cardiovascular risk factor in patients with renal disease. The current study aimed to determine the effect of intravenous N-acetylcysteine on plasma homocysteine levels when administered during haemodialysis in patients with end-stage renal failure.
Patients and Methods: Sixty patients with end-stage renal failure were randomised to receive a 4-hour intravenous infusion of N-acetylcysteine or placebo during a 4-hour haemodialysis session. Plasma homocysteine levels were measured before and after haemodialysis. Haemodynamic parameters, including pulse pressure, were also measured.
Results: After haemodialysis in the placebo treatment group, plasma homocysteine was reduced by 23.7% from the pre-dialysis level, whereas patients treated with N-acetylcysteine exhibited an 88.3% decrease (p < 0.001). Reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure (p = 0.001). A 10% decrease in plasma homocysteine concentration was associated with a 1.45mm Hg decrease in pulse pressure.
Conclusions: Intravenous administration of N-acetylcysteine during haemodialysis normalises plasma homocysteine concentration, and this is associated with improved pulse pressure in patients with end-stage renal failure. Intravenous administration of N-acetylcysteine during haemodialysis may be a promising approach to help reduce cardiovascular risk in this vulnerable group of patients.

Introduction

Homocysteine is a sulphur amino acid intermediate of the methionine pathway.[1] Hyperhomocysteinaemia, which is extremely prevalent in patients with chronic renal disease,[2] is recognised as an independent cardiovascular risk factor in these patients.[3,4,5,6] The incidence of hyperhomocysteinaemia ranges between about 5% and 7% in the general population, but exceeds 85% in patients with chronic renal disease.[7] Chronic renal disease patients have a markedly higher risk of cardiovascular disease-related death than the general population, and traditional cardiac risk factors may not be able to account for this high mortality rate.[8,9]

The normal kidney plays a major role in plasma amino acid clearance and metabolism, and patients with renal disease increasingly tend to exhibit hyperhomocysteinaemia as renal function declines.[1] It has been suggested that, in patients with chronic renal disease, hyperhomocysteinaemia seems to involve reduced clearance of plasma homocysteine, which could be attributable to defective renal clearance and/or extrarenal clearance and metabolism.[10] Folic acid administration is the principal treatment modality for hyperhomocysteinaemia, but supraphysiological doses of folic acid in patients with end-stage renal disease generally result in only a partial response and are not able to normalise homocysteine levels in haemodialysis patients with uraemia.[11,12,13,14] Both folic acid-dependent and -independent defects in metabolic homocysteine clearance have been suggested in patients with end-stage renal disease.[12] Efforts to resolve the precise pathological mechanisms underlying the hyper- homocysteinaemic state will advance the search for effective homocysteine-lowering therapies in patients with renal disease.[1]

N-Acetylcysteine is a sulphur-containing amino acid, chronic oral administration of which in a placebo-controlled trial has been shown to reduce composite cardiovascular endpoints in patients with end-stage renal failure undergoing haemodialysis.[15]N-Acetylcysteine is able to reduce levels of plasma total homocysteine when administered orally or intravenously to healthy individuals.[16,17,18] Furthermore, in a randomised, placebo-controlled crossover study of 20 patients with end-stage renal disease, Scholze and colleagues found that intravenous administration of N-acetylcysteine during a haemodialysis session in patients with end-stage renal failure normalised plasma homocysteine concentration.[19]

We have conducted a randomised, placebo-controlled, parallel-designed trial that primarily aimed to determine the effect of intravenous N-acetylcysteine on plasma homocysteine levels when administered during a haemodialysis session in patients with end-stage renal disease. Our trial was conducted in order to extend the existing small body of research investigating changes in plasma homocysteine levels after intravenous administration of N-acetylcysteine in patients undergoing haemodialysis.

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