Hyperhomocysteinemia occurs in renal failure and may increase the risk for cardiovascular disease, possibly by damaging the endothelium. Folic acid and betaine are required in two separate homocysteine conversion pathways and may therefore lower plasma homocysteine.
Objective
To study the therapeutic role of betaine and the effect on endothelial function of long-term homocysteine-Iowering therapy with folic acid, in peritoneal dialysis (PO) patients.
Patients and Design
Thirty PO patients were randomized to a 12-week treatment with 5 mg folic acid and 4 g betaine daily, or to 5 mg folic acid alone daily. They were then rerandomized to treatment with 1 or 5 mg folic acid daily for 40 weeks.
Measurements
At baseline and after 52 weeks, endothelial function was assessed by determination of endothelium-dependent vasodilatation and biochemical markers.
Results
Plasma total homocysteine (tHcy) was elevated at baseline: 42.6 (5.8) μmol/L. Only 1 patient (3%) had a normal plasma homocysteine (i.e., ≤ 15 μmol/L) before therapy. Normalization of plasma homocysteine occurred in 39% of the patients at 12 weeks. Betaine had no additional homocysteine-Iowering effect. Plasma tHcy levels were similar during treatment with 1 or 5 mg folic acid daily. Endothelial function was impaired at baseline and had not improved after 52 weeks of treatment.
Conclusions
Peritoneal dialysis patients have hyperhomocysteinemia, which can be normalized with folic acid alone in about 40% of patients. Betaine does not further lower plasma homocysteine. A maintenance dose of 1 or 5 mg folic acid daily results in equivalent plasma homocysteine levels. Long-term reduction in plasma homocysteine did not result in improvement of endothelial function as assessed by our methods.
Excerpts from the USRDS 1996 annual data report.Am J Kidney Dis1996; 28: S79–102.
2.
RaineA.E.G., MargreiterR., BrunnerF.P., EhrichJ.H.H., GeerlingsW., LandaisP.Report on management of renal failure in Europe, XXII, 1991.Nephrol Dial Transplant1992; 7: 7–35.
3.
BeckerB.N., HimmelfarbJ., HenrichW.L., HakimR.M.Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors.J Am Soc Nephrol1997; 8: 475–86.
4.
BousheyC.J., BeresfordS.A.A., OmennG.S., MotulskyA.G.A quantitative assessment of plasma homocysteine as a risk factor for vascular disease.JAMA1995; 274: 1049–57.
5.
GrahamI.M., DalyL.E., Ref sumH.M., RobinsonK., BrattströmL.E., UelandP.M.Plasma homocysteine as a risk factor for vascular disease.JAMA1997; 277: 1775–81.
6.
BostomA.G., SheminD., VerhoefP., NadeauM.R., JacquesP.F., SelhubJ.Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients.Arterioscler Thromb Vasc Biol1997; 17: 2554–8.
7.
MoustaphaA., NasoA., NahlawiM., GuptaA., ArheartK.L., JacobsenD.W.Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease.Circulation1998; 97: 138–41.
8.
ArnadottirM., HultbergB., Nilsson-EhleP., ThysellH.The effect of reduced glomerular filtration rate on plasma homocysteine concentration.Scand J Clin Lab Invest1996; 56: 41–6.
9.
ChauveauP., ChadefauxB., CoudéM., AupetitJ., HannedoucheT., KamounP.Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients.Kidney Int1993; 43(Suppl 41): S72–7.
10.
JanssenMJFM, Van GuldenerC., De JongG.M.T., Van Den BergM., StehouwerC.D.A., DonkerA.J.M.Folic acid treatment of hyperhomocysteinemia in dialysis patients.Miner Electrolyte Metab1996; 22: 110–14.
11.
RobinsonK., GuptaA., DennisV., ArheartK., ChaudharyD., GreenR.Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in endstage renal disease and is closely linked to plasma folate and pyridoxine concentrations.Circulation1996; 94: 2743–8.
12.
BlundellG., JonesB.G., RoseF.A., TudballN.Homocysteine mediated endothelial cell toxicity and its amelioration.Atherosclerosis1996; 122: 163–72.
13.
LentzS.R., SobeyC.G., PiegorsD.J., BhopatkarM.Y., FaraciF.M., MalinowM.R.Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.J Clin Invest1996; 98: 24–9.
14.
TawakolA., OmlandT., GerhardM., WuJ.T., CreagerM.A.Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.Circulation1997; 95: 1119–21.
15.
RossR.The pathogenesis of atherosclerosis: A perspective for the 1990s.Nature1993; 362: 801–9.
16.
Van GuldenerC., LambertJ., JanssenMJFM, DonkerA.J.M., StehouwerC.D.A.Endothelium-dependent vasodilatation and distensibility of large arteries in chronic haemodialysis patients.Nephrol Dial Transplant1997; 12(Suppl 2): 14–18.
17.
GrisJ.C., BrangerB., VécinaF., AI SabadaniB., FourcadeJ., SchvedJ.F.Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients.Kidney Int1994; 46: 807–13.
18.
TakagiM., WadaH., MukaiK., KihiraH., YanoS., MinamikawaK.Increased vascular endothelial cell markers in patients with chronic renal failure on maintenance haemodialysis.Blood Coagul Fibrinolysis1994; 5: 713–17.
19.
ArnadottirM., BrattströmL., SimonsenO., ThysellH., HultbergB., AnderssonA.The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients.Clin Nephrol1993; 40: 236–40.
20.
BostomA.G., SheminD., LapaneK.L., HumeA.L., YoburnD., NadeauM.R.High dose B-vitamin treatment of hyperhomocysteinemia in dialysis patients.Kidney Int1996; 49: 147–52.
21.
WilckenD.E.L., GuptaV.J., BettsA.K.Homocysteine in the plasma of renal transplant recipients: Effects of cofactors for methionine metabolism.Clin Sci1981; 61: 743–9.
22.
BostomA.G., SheminD., NadeauM.R., ShihV, StablerS.P., AllenR.H.Short term betaine therapy fails to lower elevated fasting total plasma homocysteine concentrations in hemodialysis patients maintained on chronic folic acid supplementation.Atherosclerosis1995; 113: 129–32.
23.
StampferM.J., MalinowM.R., WillettW.C., NewcomerL.M., UpsonB., UllmannD.A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.JAMA1992; 268: 877–81.
24.
PerryI.J., RefsumH., MorrisR.W., EbrahimS.B., UelandP.M., ShaperA.G.Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.Lancet1995; 346: 1395–8.
25.
UbbinkJ.B., VermaakW.J.H., BissbortS.Rapid high- performance liquid chromatographic assay for total homocysteine levels in human serum.J Chromatogr1991; 565: 441–6.
26.
Van Den BergM., FrankenD.G., BoersG.H.J., BlomH.J., JakobsC., StehouwerC.D.A.Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia.J Vasc Surg1994; 20: 933–40.
27.
CelermajerD.S., SorensenK.E., GoochV.M., SpiegelhalterD.J., MillerO.I., SullivanI.D.Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.Lancet1992; 340: 1111–15.
28.
LambertJ., AarsenM., DonkerA.J.M., StehouwerC.D.A.Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol1996; 16: 705–11.
29.
AndersonT.J., UehataA., GerhardM.D., MeredithI.T., KnabS., DelagrangeD.Close relation of endothelial function in the human coronary an d peripheral circulations.J Am Coll Cardiol1995; 26: 1235–41.
30.
IwashimaY., SatoT., WatanabeK., OoshimaE., HiraishiS., IshiiH.Elevation of plasma thrombomodulin level in diabetic patients with early diabetic nephropathy.Diabetes1990; 39: 983–8.
31.
StehouwerC.D.A., NautaJ.J.P., ZeldenrustG.C., HackengW.H.L., DonkerA.J.M., Den OttolanderG.J.H.Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus.Lancet1992; 340: 319–23.
32.
ThompsonS.G., KienastJ., PykeS.D.M., HavercateF., Van De LooJ.C.W.Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.N Engl J Med1995; 332: 635–41.
33.
HamstenA., WalldiusG., SzamosiA., BlombäckM., De FaireU., DahlénG.Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction.Lancet1987; ii: 3–9.
34.
OmlandT., LieR.T., AakvaagA., AarslandT., DicksteinK.Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction.Circulation1994; 89: 1573–9.
35.
BelchJ.J.F., ShawJ.W., KirkG., McLarenM., RobbR., MapleC.The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty.Circulation1997; 95: 2027–31.
36.
HoeksA.P.G., BrandsP.J., SmeetsF.A.M., RenemanR.S.Assessment of the distensibility of superficial arteries.Ultrasound Med Biol1990; 16: 121–8.
37.
Van GuldenerC., JanssenMJFM, LambertJ., Ter WeeP.M., JakobsC., DonkerA.J.M.No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinaemia in haemodialysis patients.Nephrol Dial Transplant1998; 13: 106–12.
38.
Fö dingerM., MannhalterC., WölflG., PabingerI., MullerE., SchmidR.Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteine mi a in hemodialysis patients.Kidney Int1997; 52: 517–23.
39.
BostomA.G., SheminD., LapaneK.L., NadeauM.R., SutherlandP., ChanJ.Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients.Atherosclerosis1996; 123: 193–202.
40.
Van GuldenerC., JanssenMJFM, LambertJ., SteynM., DonkerA.J.M., StehouwerC.D.A.Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients.Nephrol Dial Transplant (in press).
41.
StroesE.S., KoomansH.A., De BruinT.W., RabelinkT.J.Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.Lancet1995; 346: 467–71.
42.
O'DriscollG., GreenD., TaylorR.R.Simvastatin, an HMG- coenzyme A reductase inhibitor, improves endothelial function within 1 month.Circulation1997; 95: 1126–31.
