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Intervenciones para reducir los niveles plasmáticos de homocisteína en pacientes bajo diálisis

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References

Referencias de los estudios incluidos en esta revisión

ASFAST 2004 {published data only}

McGrath B, Zoungas S, McNeil J, Branley P, Kerr P, ASFAST Investigators. The atherosclerosis and folic acid supplementation trial in CRF (ASFAST): rationale, design and baseline results [abstract no: 65]. Nephrology 2002;7(Suppl 3):A17. [CENTRAL: CN‐00856590]CENTRAL
McGrath B, Zoungas S, McNeil J, Kerr PG. The atherosclerosis and folic acid supplementation trial in CRF (ASFAST): rationale, design and baseline results [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):228A. [CENTRAL: CN‐00446685]CENTRAL
Polkinghorne K, Kerr PG, Muske C, McGrath BP, Zoungas S, The ASFAST Investigators. The effect of lowering homocysteine on haemodialysis vascular access outcomes: the ASFAST randomised placebo controlled trial [abstract no: SU‐FC110]. Journal of the American Society of Nephrology 2007;18(Abstracts):92A. [CENTRAL: CN‐00716085]CENTRAL
Zoungas S, Branley P, Kerr PG, Ristevski S, Muske C, Demos L, et al. Atherosclerosis and folic acid supplementation trial in chronic renal failure: baseline results. Nephrology 2004;9(3):130‐41. [MEDLINE: 15189174]CENTRAL
Zoungas S, Cameron JD, Kerr PG, Wolfe R, Muske C, McNeil JJ, et al. Association of carotid intima‐medial thickness and indices of arterial stiffness with cardiovascular disease outcomes in CKD. American Journal of Kidney Diseases 2007;50(4):622‐30. [MEDLINE: 17900462]CENTRAL
Zoungas S, Kerr P, Lui M, Teede H, McNeil J, McGrath B, et al. Chronic kidney disease, cardiovascular events and the effect of diabetes: post hoc analyses from ASFAST [abstract no: 128]. Nephrology 2008;13(Suppl 3):A133. CENTRAL
Zoungas S, Lui M, Kerr PG, Teede HJ, McNeil JJ, McGrath BP, et al. Advanced chronic kidney disease, cardiovascular events and the effect of diabetes: data from the Atherosclerosis and Folic Acid Supplementation Trial. Internal Medicine Journal 2011;41(12):825‐32. [MEDLINE: 20298505]CENTRAL
Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, et al. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. Journal of the American College of Cardiology 2006;47(6):1108‐16. [MEDLINE: 16545638]CENTRAL

Heinz 2009 {published data only}

Heinz J, Dierkes J, Domrose U, Neumann KH, Luley C. Influence of a supplementation with vitamins on morbidity and mortality of ESRD patients: a multi‐center randomly designed double blinded intervention trial; Prismavit ‐ prospective intervention study from Magdeburg with vitamins [abstract]. XIV Lipid Meeting; 2003 Dec 5‐7; Leipzig, Germany. 2003:89. [CENTRAL: CN‐00740532]CENTRAL
Heinz J, Domrose U, Luley C, Westphal S, Kropf S, Neumann KH, et al. Influence of a supplementation with vitamins on cardiovascular morbidity and mortality in patients with end‐stage renal disease: design and baseline data of a randomized clinical trial. Clinical Nephrology 2009;71(3):363‐5. [MEDLINE: 19281755]CENTRAL
Heinz J, Kropf S, Domrose U, Westphal S, Borucki K, Luley C, et al. B vitamins and the risk of total mortality and cardiovascular disease in end‐stage renal disease: results of a randomized controlled trial. Circulation 2010;121(12):1432‐8. [MEDLINE: 20231532]CENTRAL

HOST Study 2004 {published data only}

Brady CB, Gaziano JM, Cxypoliski RA, Guarino PD, Kaufman JS, Warren SR, et al. Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study. American Journal of Kidney Diseases 2009;54(3):440‐9. [MEDLINE: 19628319]CENTRAL
Jamison R, Hartigan P, Gaziano M, Kaufman J, Goldfarb DS, Warren S, et al. High plasma homocysteine (Hcy) and cardiovascular (CV) disease in end stage (ESRD) and advanced chronic (ACKD) kidney disease. The VA Coop. study program homocysteine study (HOST) progress report [abstract no: PUB272]. Journal of the American Society of Nephrology 2003;14(Nov):832A. [CENTRAL: CN‐00550589]CENTRAL
Jamison RL, Hartigan P, Gaziano JM, Fortmann SP, Goldfarb DS, Haroldson JA, et al. Design and statistical issues in the homocysteinemia in kidney and end stage renal disease (HOST) study. Clinical Trials 2004;1(5):451‐60. [MEDLINE: 16279283]CENTRAL
Jamison RL, Hartigan P, Gaziano M, Kaufman J, Goldfarb DS, Warren S, et al. Cardiovascular disease in patients with advanced chronic kidney disease (ACKD) and hyperhomocysteinemia. The VA Coop. Studies Program Homocysteine Study (HOST) [abstract no: F‐PO300]. Journal of the American Society of Nephrology 2004;15(Oct):132A. [CENTRAL: CN‐00550590]CENTRAL
Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino P, et al. Homocysteine lowering effect on mortality and vascular disease in advanced chronic kidney disease and end stage renal disease [abstract no: M‐FC‐041]. 4th World Congress of Nephrology.19th International Congress of the International Society of Nephrology (ISN); 2007 Apr 21‐25; Rio de Janeiro, Brazil. 2007:211. CENTRAL
Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end‐stage renal disease: a randomized controlled trial.[Erratum appears in JAMA. 2008 Jul 9;300(2):170]. JAMA 2007;298(10):1163‐70. [MEDLINE: 17848650]CENTRAL
Jamison RL, Shih MC, Humphries DE, Guarino PD, Kaufman JS, Goldfarb DS, et al. Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD: a prospective study. American Journal of Kidney Diseases 2009;53(5):779‐89. [MEDLINE: 19272686]CENTRAL
Jovanovich A, Chonchol M, Cheung AK, Kaufman JS, Greene T, Roberts WL, et al. Racial differences in markers of mineral metabolism in advanced chronic kidney disease. Clinical Journal of the American Society of Nephrology: CJASN 2012;7(4):640‐7. [MEDLINE: 22383748]CENTRAL
Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, et al. Associations of plasma 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D concentrations with death and progression to maintenance dialysis in patients with advanced kidney disease. American Journal of Kidney Diseases 2012;60(4):567‐75. [MEDLINE: 22621970]CENTRAL
Kendrick JB, Cheung AK, Kaufman JS, Greene T, Roberts W, Smits G, et al. Fibroblast growth factor‐23 and progression to dialysis in patients with advanced kidney disease [abstract no: F‐PO1879]. Journal of the American Society of Nephrology 2009;20:542A. [CENTRAL: CN‐00740513]CENTRAL
Kendrick JB, Cheung AK, Kaufman JS, Greene T, Roberts W, Smits G, et al. Fibroblast growth factor‐23 and the risk of death and cardiovascular events among patients with chronic kidney disease [abstract no: F‐PO1873]. Journal of the American Society of Nephrology 2009;20:540A. [CENTRAL: CN‐00740525]CENTRAL
Kendrick JB, Cheung AK, Kaufman JS, Greene T, Roberts W, Smits G, et al. Higher intact parathyroid hormone levels are not associated with all‐cause mortality or cardiovascular events in patients with advanced kidney disease [abstract no: F‐PO1902]. Journal of the American Society of Nephrology 2009;20:547A. [CENTRAL: CN‐00740514]CENTRAL
Kendrick JB, Cheung AK, Kaufman JS, Greene T, Roberts W, Smits G, et al. Low serum levels of 1,25‐dihydroxyvitamin D, not 25‐hydroxyvitamin D, is associated with all‐cause mortality in chronic kidney disease [abstract no: TH‐PO656]. Journal of the American Society of Nephrology 2009;20:265A. [CENTRAL: CN‐00740559]CENTRAL
Kendrick JB, Cheung AK, Kaufman JS, Greene T, Roberts W, Smits G, et al. Low serum levels of 1,25‐dihydroxyvitamin D, not 25‐hydroxyvitamin D, is associated with progression to dialysis in patients with advanced kidney disease [abstract no: TH‐PO647]. Journal of the American Society of Nephrology 2009;20:263A. [CENTRAL: CN‐00740517]CENTRAL
Montford JR, Chonchol M, Cheung AK, Kaufman JS, Greene T, Roberts WL, et al. Low body mass index and dyslipidemia in dialysis patients linked to elevated plasma fibroblast growth factor 23. American Journal of Nephrology 2013;37(3):183‐90. [MEDLINE: 23428834]CENTRAL
Rafeq Z, Roh JD, Guarino P, Kaufman J, Joseph J. Adverse myocardial effects of B‐vitamin therapy in subjects with chronic kidney disease and hyperhomocysteinaemia. Nutrition Metabolism & Cardiovascular Diseases 2013 Sep;23(9):836‐42. [MEDLINE: 22902185]CENTRAL

Righetti 2003 {published data only}

Righetti M. Homocysteine‐lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Clinical Chemistry & Laboratory Medicine 2007;45(12):1586‐9. [MEDLINE: 17937606]CENTRAL
Righetti M, Ferrario GM, Milani S, Serbelloni P, La Rosa L, Uccellini M, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Medical Science Monitor 2003;9(4):19‐24. [MEDLINE: 12709680]CENTRAL
Righetti M, Ferrario GM, Milani S, Serbelloni P, La Rosa L, Uccellini M, et al. Long‐term effects of oral folic acid therapy on homocysteinemia and vascular disease in haemodialysis patients [abstract no: T237]. Nephrology Dialysis Transplantation 2002;17(Suppl 1):255. [CENTRAL: CN‐00509435]CENTRAL
Righetti M, Serbelloni P, Milani S, Ferrario G. Homocysteine‐lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purification 2006;24(4):379‐86. [MEDLINE: 16755160]CENTRAL

Vianna 2007 {published data only}

Vianna AC, Mocelin AJ, Matsuo T, Morais‐Filho D, Largura A, Delfino VA, et al. Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Hemodialysis International 2007;11(2):210‐6. [MEDLINE: 17403173]CENTRAL

Wrone 2004 {published data only}

Wrone E, Hornberger J, Zehnder J, McCann L, Coplon N, Fortmann S. Randomized trial of folic acid for homocysteine reduction in end‐stage renal disease [abstract]. American Journal of Kidney Diseases 2002;39(4):A34. [CENTRAL: CN‐00403143]CENTRAL
Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end‐stage renal disease. Journal of the American Society of Nephrology 2004;15(2):420‐6. [MEDLINE: 14747389]CENTRAL

Referencias de los estudios excluidos de esta revisión

Ali 2003 {published data only}

Ali Z, Idham C, Effendi I. The effect of n‐acetylcysteine on homocysteine level in chronic hemodialysis patients: randomized control trial [abstract]. Nephrology 2003;8(Suppl 3):A62. [CENTRAL: CN‐00671778]CENTRAL

Alvares Delfino 2007 {published data only}

Alvares Delfino V, de Andrade Vianna AC, Mocelin AJ, Barbosa DS, Mise RA, Matsuo T. Folic acid therapy reduces plasma homocysteine levels and improves plasma antioxidant capacity in hemodialysis patients. Nutrition 2007;23(3):242‐7. [MEDLINE: 17321110]CENTRAL

Anderson 2006 {published data only}

Anderson TJ, Sun YH, Hubacek J, Hyndman ME, Verma S, Shewchuk L, et al. Effects of folinic acid on forearm blood flow in patients with end‐stage renal disease. Nephrology Dialysis Transplantation 2006;21(7):1927‐33. [MEDLINE: 16520350]CENTRAL

Ardalan 2003 {published data only}

Ardalan MR, Etemadi J, Mortazavi M, Majidi J. Hyperhomocysteinaemia therapy in haemodialysis patients with combination of Vitamin B6, B12 and folic acid [abstract no: W467]. Nephrology Dialysis Transplantation 2003;18(4):696. [CENTRAL: CN‐00716091]CENTRAL

Ardalan 2003a {published data only}

Ardalan MR, Mortazavi M, Etemadi J. Hyperhomocysteinemia and its therapy in renal transplant recipients with combination of: Vit B6, Vit B12 and folic acid [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):509‐10. [CENTRAL: CN‐00444217]CENTRAL

Armada 2003 {published data only}

Armada E, Perez C, Otero A, Esteban J, Camba M, Gayoso P, et al. Neither folic nor folinic acid normalize homocysteine levels in hemodialysis patients. Clinical Nephrology 2003;60(3):168‐75. [MEDLINE: 14524579]CENTRAL

Arnadottir 2003 {published data only}

Arnadottir M, Hultberg B. The effect of vitamin B12 on total plasma homocysteine concentration in folate‐replete hemodialysis patients. Clinical Nephrology 2003;59(3):186‐9. [MEDLINE: 12653261]CENTRAL

ATIC Study 2005 {published data only}

Nanayakkara PW, Kiefte‐De Jong JC, Stehouwer CD, van Ittersum FJ, Olthof MR, Kok RM, et al. Association between global leukocyte DNA methylation, renal function, carotid intima‐media thickness and plasma homocysteine in patients with stage 2‐4 chronic kidney disease. Nephrology Dialysis Transplantation 2008;23(8):2586‐92. [MEDLINE: 18287179]CENTRAL
Nanayakkara PW, Kiefte‐de Jong JC, ter Wee PM, Stehouwer CD, van Ittersum FJ, Olthof MR, et al. Randomized placebo‐controlled trial assessing a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on plasma asymmetric dimethylarginine concentration in mild to moderate CKD. American Journal of Kidney Diseases 2009;53(1):41‐50. [MEDLINE: 18786751]CENTRAL
Nanayakkara PW, Teerlink T, Stehouwer CD, Allajar D, Spijkerman A, Schalkwijk C, et al. Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima‐media thickness and plasma soluble vascular cell adhesion molecule‐1 (sVCAM‐1) concentration in patients with mild‐to‐moderate renal failure. Kidney International 2005;68(5):2230‐6. [MEDLINE: 16221223]CENTRAL
Nanayakkara PW, van Guldener C, ter Wee PM, Scheffer PG, van Ittersum FJ, Twisk JW, et al. Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid intima‐media thickness, endothelial function, and renal function in patients with mild to moderate chronic kidney disease: results from the Anti‐Oxidant Therapy in Chronic Renal Insufficiency (ATIC) Study. Archives of Internal Medicine 2007;167(12):1262‐70. [MEDLINE: 17592099]CENTRAL
Nanayakkara PW, van Guldener C, van Ittersum F, Stehouwer CD, ter Wee PM. Effect of an oxidative‐stress‐reducing strategy on carotid intima‐media thickness, endothelial function and renal function in patients with mild‐to‐moderate chronic kidney disease [abstract no: F‐PO145]. Journal of the American Society of Nephrology 2006;17(Abstracts):367A. [CENTRAL: CN‐00602094]CENTRAL
Nanayakkara PW, van Ittersum FJ, Fouque D, Charrie A, Stehouwer CD, ter Wee PM. Plasma adiponectin is inversely associated with renal function in patients with Stage 3 and 4 chronic kidney disease [abstract no: F‐PO146]. Journal of the American Society of Nephrology 2006;17(Abstracts):367A. [CENTRAL: CN‐00602093]CENTRAL
Thijs A, Nanayakkara PW, ter Wee PM, Huijgens PC, van Guldener C, Stehouwer CD. Mild‐to‐moderate renal impairment is associated with platelet activation: a cross‐sectional study. Clinical Nephrology 2008;70(4):325‐31. [MEDLINE: 18826858]CENTRAL
Veringa SJ, Nanayakkara PW, van Ittersum FJ, Vegting IL, van Guldener C, Smulders YM, et al. Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility in patients with mild‐to‐moderate chronic kidney disease. Clinical Nephrology 2012;78(4):263‐72. [MEDLINE: 22981031]CENTRAL

Azadibakhsh 2007 {published data only}

Azadibakhsh N, Hosseini RS, Atabak S, Nateghiyan N, Golestan B, Rad AH. Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients. Saudi Journal of Kidney Diseases & Transplantation 2009;20(5):779‐88. [MEDLINE: 19736473]CENTRAL
Azadibakhsh N, Hosseini RS, Atabak S, Nateghiyan N, Golestan B, Rad AH. The effect of folate and vitamin B12 supplementation on homocysteine concentrations: a study in hemodialysis patients. Tehran University Medical Journal 2007;65(8):49‐56. [CENTRAL: CN‐00796293]CENTRAL

Beavers 2008 {published data only}

Beavers KM, Beavers DP, Bowden RG, Wilson RL, Gentile M. Effect of over‐the‐counter fish‐oil administration on plasma Lp(a) levels in an end‐stage renal disease population. Journal of Renal Nutrition 2009;19(6):443‐9. [MEDLINE: 19748798]CENTRAL
Beavers KM, Beavers DP, Bowden RG, Wilson RL, Gentile M. Omega‐3 fatty acid supplementation and total homocysteine levels in end‐stage renal disease patients. Nephrology 2008;13(4):284‐8. [MEDLINE: 18331436]CENTRAL

Bennett‐Richards 2002 {published data only}

Bennett‐Richards K, Kattenhorn M, Donald A, Oakley G, Varghese Z, Rees L, et al. Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?. Circulation 2002;105(15):1810‐5. [MEDLINE: 11956124]CENTRAL
Bennett‐Richards K, Taylor M, Oakley G, Varghese Z, Deanfield J, Rees L. Does oral folic acid lower total homocystine levels and improve endothelial function in children with CRF? [abstract]. Pediatric Nephrology 2001;16(8):C167. [CENTRAL: CN‐00444396]CENTRAL

Bostom 1996 {published data only}

Bostom AG, Shemin D, Lapane KL, Hume AL, Yoburn D, Nadeau MR, et al. High dose‐B‐vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney International 1996;49(1):147‐52. [MEDLINE: 8770960]CENTRAL

Bostom 2000 {published data only}

Bostom AG, Shemin D, Bagley P, Massy ZA, Zanabli A, Christopher K, et al. Controlled comparison of L‐5‐methyltetrahydrofolate versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.[Erratum appears in Circulation 2000 Aug 1;102(5):598]. Circulation 2000;101(24):2829‐32. [MEDLINE: 10859289]CENTRAL
Bostom AG, Shemin D, Bagley P, Massy ZA, Zanabli A, Spiegel P, et al. Reduced folates are an expensive treatment for hyperhomocysteinemia in hemodialysis patients with no greater efficacy than folic acid: results of a controlled comparison study [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):257A. [CENTRAL: CN‐00550713]CENTRAL
Bostom AG, Shemin D, Gohh RY, Beaulieu AJ, Bagley P, Massy ZA, et al. Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients. Kidney International ‐ Supplement 2001;59(Suppl 78):S246‐52. [MEDLINE: 11169020]CENTRAL
Bostom AG, Shemin D, Gohh RY, Beaulieu AJ, Jacques PF, Dworkin L, et al. Treatment of mild hyperhomocysteinemia in renal transplant recipients versus hemodialysis patients. Transplantation 2000;69(10):2128‐31. [MEDLINE: 10852611]CENTRAL

Branley 2000 {published data only}

Branley P, D'Intini V, Thomson N, Fraenkel M, McNeil JJ. Randomised placebo controlled clinical trial of supplementary folic acid in CRF [abstract]. Nephrology 2000;5(3):A79. [CENTRAL: CN‐00400364]CENTRAL

Brensing 2002 {published data only}

Brensing KA, Kaschell D, Hages M, Lutjohann D, Sigit J, Pietrizik K, et al. Improved hyperhomocysteinemia in hemodialysed ESRD‐patients by intravenous folate or folinic acid: a randomized controlled trial [abstract no: O100]. Nephrology Dialysis Transplantation 2002;17(Suppl 1):30. [CENTRAL: CN‐00509104]CENTRAL

Brensing 2003 {published data only}

Brensing KA, Hages M, Raab P, Pietrzik K, von Bergmann K, Frotscher U, et al. Vitamin B12 and folic‐acid as intravenous high‐dose vitamin therapy for hyperhomocysteinemia in hemodialysed ESRD‐patients: data of a prospective randomized controlled study [abstract no: SU‐PO1048]. Journal of the American Society of Nephrology 2003;14(Nov):766A. [CENTRAL: CN‐00644257]CENTRAL

Chang 2007 {published data only}

Chang TY, Chou KJ, Tseng CF, Chung HM, Fang HC, Hung YM, et al. Effects of folic acid and vitamin B complex on serum C‐reactive protein and albumin levels in stable hemodialysis patients. Current Medical Research & Opinion 2007;23(8):1879‐86. [MEDLINE: 17605895]CENTRAL

Chiu 2009 {published data only}

Chiu YW, Chang JM, Hwang SJ, Tsai JC, Chen HC. Pharmacological dose of vitamin B12 is as effective as low‐dose folinic acid in correcting hyperhomocysteinemia of hemodialysis patients. Renal Failure 2009;31(4):278‐83. [MEDLINE: 19462276]CENTRAL

Cianciolo 2008 {published data only}

Cianciolo G, La Manna G, Coli L, Donati G, D'Addio F, Persici E, et al. 5‐methyltetrahydrofolate administration is associated with prolonged survival and reduced inflammation in ESRD patients. American Journal of Nephrology 2008;28(6):941‐8. [MEDLINE: 18587236]CENTRAL

Cutler 2009 {published data only}

Cutler MJ, Urquhart BL, Freeman DJ, Spence JD, House AA. Mesna for the treatment of hyperhomocysteinemia in hemodialysis patients. Blood Purification 2009;27(3):306‐10. [MEDLINE: 19270449]CENTRAL

De Angelis 2007 {published data only}

De Angelis S, Noce A, Dessi M, Pastore A, Scaccia F, Trombetta M, et al. Hyperhomocysteinemia and alternate vitamin supplementation [Iperomocisteinemia nei pazienti uremici: effetti della supplementazione alternata di acido folico e vitamina B 12]. Giornale Italiano di Nefrologia 2007;24(1):51‐5. [MEDLINE: 17342693]CENTRAL
Dessi M, Di Giovamberardino G, Pieri M, Noce A, Zenobi R, Di Daniele N, et al. Influence of dialysis techniques and alternate vitamin supplementation on homocysteine levels in patients with known MTHFR genotypes. Clinical & Experimental Nephrology 2015;19(1):140‐5. [MEDLINE: 24652221]CENTRAL

Del Pozo 2005 {published data only}

Del Pozo C, Alvarez L, Lopez‐Menchero R, Torregrosa I, Sanchez L, Albero MD. Optimization of a therapy schedule with folinic acid to treat hyperhomocysteinemia in patients on hemodialysis [abstract no: SP261]. Nephrology Dialysis Transplantation 2005;20(Suppl 5):v106. [CENTRAL: CN‐00671828]CENTRAL

De Vecchi 2001 {published data only}

De Vecchi AF, Patrosso C, Novembrino C, Finazzi S, Colucci P, De Franceschi M, et al. Folate supplementation in peritoneal dialysis patients with normal erythrocyte folate: effect on plasma homocysteine. Nephron 2001;89(3):297‐302. [MEDLINE: 11598393]CENTRAL

De Vriese 2003 {published data only}

De Vriese AS, Langlois M, Bernard D, Geerolf I, Stevens L, Boelaert JR, et al. Effect of dialyser membrane pore size on plasma homocysteine levels in haemodialysis patients. Nephrology Dialysis Transplantation 2003;18(12):2596‐600. [MEDLINE: 14605283]CENTRAL

Dierkes 1999 {published data only}

Dierkes J, Domrose U, Ambrosch A, Bosselmann HP, Neumann KH, Luley C. Response of hyperhomocysteinemia to folic acid supplementation in patients with end‐stage renal disease. Clinical Nephrology 1999;51(2):108‐15. [MEDLINE: 10069646]CENTRAL

Dierkes 2001 {published data only}

Dierkes J, Domrose U, Bosselmann KP, Neumann KH, Luley C. Homocysteine lowering effect of different multivitamin preparations in patients with end‐stage renal disease. Journal of Renal Nutrition 2001;11(2):67‐72. [MEDLINE: 11295026]CENTRAL

DIVINe Study 2010 {published data only}

House AA, Ehasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, et al. Vitamin therapy for homocysteine accelerates loss of renal function in diabetic kidney disease [abstract no: SA‐FC343]. Journal of the American Society of Nephrology 2009;20:80A. [CENTRAL: CN‐00740523]CENTRAL
House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, et al. Effect of B‐vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 2010;303(16):1603‐9. [MEDLINE: 20424250]CENTRAL

Dobronravov 2008 {published data only}

Dobronravov V, Ardebili M, Golubev R, Galkina O, Nabokow A, Kliem V, et al. The effect of IV administration of sodium 2,3‐dimercaptopropane‐1‐sulfonate (DMPS) and 8‐week high‐dosed IV vitamin B therapy on total plasma homocysteine (tHcy) in patients undergoing chronic hemodialysis (HD) [abstract no: PUB584]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):943A. [CENTRAL: CN‐00758243]CENTRAL

Ducloux 2002 {published data only}

Ducloux D, Aboubakr A, Motte G, Toubin G, Fournier V, Chalopin JM, et al. Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12. Nephrology Dialysis Transplantation 2002;17(5):865‐70. [MEDLINE: 11981075]CENTRAL
Ducloux D, Aboubakr A, Motte G, Toubin G, Fournier V, Chalopin JM, et al. Hyperhomocysteinemia therapy in hemodialysis (HD) patients: folinic versus folic acid in combination with vitamin B6 and B12 [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):354A‐5A. [CENTRAL: CN‐00445156]CENTRAL

Elian 2002 {published data only}

Elian KM, Hoffer LJ. Hydroxocobalamin reduces hyperhomocysteinemia in end‐stage renal disease. Metabolism: Clinical & Experimental 2002;51(7):881‐6. [MEDLINE: 12077735]CENTRAL

Friedman 2003 {published data only}

Friedman AN, Bostom AG, Laliberty P, Selhub J, Shemin D. The effect of N‐acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study. American Journal of Kidney Diseases 2003;41(2):442‐6. [MEDLINE: 12552508]CENTRAL

Galli 2003 {published data only}

Galli F, Benedetti S, Buoncristiani U, Piroddi M, Conte C, Canestrari F, et al. The effect of PMMA‐based protein‐leaking dialyzers on plasma homocysteine levels. Kidney International 2003;64(2):748‐55. [MEDLINE: 12846775]CENTRAL
Galli F, Benedetti S, Floridi A, Canestrari F, Piroddi M, Buoncristiani E, et al. Glycoxidation and inflammatory markers in patients on treatment with PMMA‐based protein‐leaking dialyzers. Kidney International 2005;67(2):750‐9. [MEDLINE: 15673326]CENTRAL

Gonin 2003 {published data only}

Gonin JM, Nguyen H, Gonin R, Sarna A, Michels A, Masri‐Imad F, et al. Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. Journal of Nephrology 2003;16(4):522‐34. [MEDLINE: 14696754]CENTRAL
Gonin JM, Sarna A, Loya A, Gonin R, Chassaing C, Wainer I, et al. A double‐blind, controlled study of folate and vitamin therapy for hyperhomocysteinemia in hemodialysis [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):269A. [CENTRAL: CN‐00755224]CENTRAL

Gonin 2003a {published data only}

Gonin J, Nguyen H, Michels A, Santos A, Gonin R, Cary D, et al. Evaluation of folinic acid and serine in hyperhomocysteinemia in ESRD: a prospective placebo‐controlled randomized study [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):356A. [CENTRAL: CN‐00445513]CENTRAL
Gonin JM, Nguyen H, Gonin R, Sarna A, Michels A, Masri‐Imad F, et al. Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. Journal of Nephrology 2003;16(4):522‐34. [MEDLINE: 14696754]CENTRAL

Hauser 2001 {published data only}

Hagen W, Hauser A, Rehak PH, Buchmayer H, Fodinger M, Horl WH, et al. Comparison of intravenous folinic acid with intravenous folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients. A randomized, double blinded trial [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):148A. [CENTRAL: CN‐00583332]CENTRAL
Hagen W, Kletzmayr J, Fodinger M, Hauser AC, Horl WH, Sunder‐Plassmann G. Effect of intravenous folic acid or folinic acid therapy on mean arterial pressure and pulse pressure in hemodialysis patients [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):483A. [CENTRAL: CN‐00583333]CENTRAL
Hauser AC, Hagen W, Rehak PH, Buchmayer H, Fodinger M, Papagiannopoulos M, et al. Efficacy of folinic versus folic acid for the correction of hyperhomocysteinemia in hemodialysis patients. American Journal of Kidney Diseases 2001;37(4):758‐65. [MEDLINE: 11273876]CENTRAL

Henning 2001 {published data only}

Henning BF, Zidek W, Riezler R, Graefe U, Tepel M. Homocyst(e)ine metabolism in hemodialysis patients treated with vitamins B6, B12 and folate. Research in Experimental Medicine 2001;200(3):155‐68. [MEDLINE: 11426667]CENTRAL

Hoffer 2005 {published data only}

Hoffer LJ, Saboohi F, Golden M, Barre PE. Cobalamin dose regimen for maximum homocysteine reduction in end‐stage renal disease. Metabolism: Clinical & Experimental 2005;54(6):835‐40. [MEDLINE: 15931623]CENTRAL

Hoffer 2005a {published data only}

Hoffer LJ, Djahangirian O, Bourgouin PE, Eid J, Saboohi F. Comparative effects of hydroxocobalamin and cyanocobalamin on plasma homocysteine concentrations in end‐stage renal disease. Metabolism: Clinical & Experimental 2005;54(10):1362‐7. [MEDLINE: 16154437]CENTRAL

HOPE‐2 Study 2006 {published data only}

Lonn E, Held C, Arnold JM, Probstfield J, McQueen M, Micks M, et al. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high‐risk patients: the Heart Outcomes Prevention Evaluation (HOPE)‐2 trial. Canadian Journal of Cardiology 2006;22(1):47‐53. [MEDLINE: 16450017]CENTRAL
Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease.[erratum appears in N Engl J Med. 2006 Aug 17;355(7):746]. New England Journal of Medicine 2006;354(15):1567‐77. [MEDLINE: 16531613]CENTRAL
Mann JF, Sheridan P, McQueen MJ, Held C, Arnold JM, Fodor G, et al. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease‐‐results of the renal Hope‐2 study. Nephrology Dialysis Transplantation 2008;23(2):645‐53. [MEDLINE: 18003666]CENTRAL
Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E, Heart Outcomes Prevention Evaluation (HOPE‐2). Homocysteine‐lowering therapy and risk for venous thromboembolism: a randomized trial.[Summary for patients in Ann Intern Med. 2007 Jun 5;146(11):I22; PMID: 17470823]. Annals of Internal Medicine 2007;146(11):761‐7. [MEDLINE: 17470822]CENTRAL
Righetti M. Hopeful for a second HOPE‐2 post hoc analysis. Nephrology Dialysis Transplantation 2008;23(7):2428‐9. [MEDLINE: 18403437]CENTRAL
Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteine‐lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 2009;40(4):1365‐72. [MEDLINE: 19228852]CENTRAL
Sawka AM, Ray JG, Yi Q, Josse RG, Lonn E. Randomized clinical trial of homocysteine level lowering therapy and fractures. Archives of Internal Medicine 2007;167(19):2136‐9. [MEDLINE: 17954810]CENTRAL

House 1999 {published data only}

House A, Freeman D. Larger intradialytic effect of high flux vs low flux polysulfone on homocysteine levels, but not on lipids or apo AI/CIII ratio [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):209A. [CENTRAL: CN‐00445778]CENTRAL
House AA, Donnelly JG. Effect of multivitamins on plasma homocysteine and folate levels in patients on hemodialysis. ASAIO Journal 1999;45(1):94‐7. [MEDLINE: 9952016]CENTRAL
House AA, Donnelly JG. Impact of methylenetetrahydrofolate reductase (MTHFR) genotype on folate status and homocysteine (hcy) in hemodialysis patients [abstract]. Journal of the American Society of Nephrology 1999;10(Program & Abstracts):168A. [CENTRAL: CN‐00756935]CENTRAL
House AA, Wells GA, Donnelly JG, Nadler SP, Hebert PC. Effect of high flux vs low flux hemodialysis on homocysteine, lipoprotein(a) and lipid profiles: a prospective randomized trial [abstract]. Journal of the American Society of Nephrology 1998;9(Program & Abstracts):211A. [CENTRAL: CN‐00401331]CENTRAL
House AA, Wells GA, Donnelly JG, Nadler SP, Hebert PC. Randomized trial of high‐flux vs low‐flux haemodialysis: effects on homocysteine and lipids. Nephrology Dialysis Transplantation 2000;15(7):1029‐34. [MEDLINE: 10862642]CENTRAL

House 2004 {published data only}

House AA, Eliasziw M, Urquhart BL, Freeman DJ, Spence JD. Dimercaptosuccinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients: a placebo‐controlled, double‐blind, randomized trial. American Journal of Kidney Diseases 2004;44(4):689‐94. [MEDLINE: 15384020]CENTRAL

Imani 2009 {published data only}

Imani H, Tabibi H, Atabak S, Rahmani L, Ahmadinejad M, Hedayati M. Effects of soy consumption on oxidative stress, blood homocysteine, coagulation factors, and phosphorus in peritoneal dialysis patients. Journal of Renal Nutrition 2009;19(5):389‐95. [MEDLINE: 19577483]CENTRAL
Tabibi H, Imani H, Hedayati M, Atabak S, Rahmani L. Effects of soy consumption on serum lipids and apoproteins in peritoneal dialysis patients: a randomized controlled trial. Peritoneal Dialysis International 2010;30(6):611‐8. [MEDLINE: 20378840]CENTRAL

Isbel 2003 {published data only}

Isbel NM, Reiger K, Hayley CM, Campbell SB, Burke J, Bofinger A, et al. Vitamin B12 is effective in the treatment of hyperhomocysteinaemia in patients with ESRD [abstract no: 58]. Nephrology 2003;8(Suppl 3):A69. [CENTRAL: CN‐00758625]CENTRAL

ISRCTN22151635 {published data only}

ISRCTN22151635. Assessment of the lipid lowering agents on plasma homocysteine concentration and renal function. controlled‐trials.com/ISRCTN22151635 (accessed 4 February 2016). CENTRAL

Jara 2001 {published data only}

Jara A, Morales M. Intravenous folinic acid versus oral folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):357A. [CENTRAL: CN‐00445900]CENTRAL

Kazory 2008 {published data only}

Kazory A, Kribs M, Fournier V, Motte G, Guy C, Devillard N, et al. Homocysteine lowering effect of adsorptive dialysis membranes: a multicenter, randomized, open study [abstract no: 118]. American Journal of Kidney Diseases 2008;51(4):A57. [CENTRAL: CN‐00756882]CENTRAL

Klemm 2004 {published data only}

Klemm A, Franke C, Busch M, Muller A, Franke S, Lang D, et al. Influence of hemodialysis membrane permeability on serum levels of advanced glycation end products (AGEs) and homocysteine metabolites. Clinical Nephrology 2004;61(3):191‐7. [MEDLINE: 15077870]CENTRAL

Kooshki 2011 {published data only}

Kooshki A, Taleban FA, Tabibi H, Hedayati M. Effects of marine omega‐3 fatty acids on serum systemic and vascular inflammation markers and oxidative stress in hemodialysis patients. Annals of Nutrition & Metabolism 2011;58(3):197‐202. [MEDLINE: 21757893]CENTRAL
Kooshki A, Taleban FA, Tabibi H, Hedayati M. Effects of omega‐3 fatty acids on serum lipids, lipoprotein (a), and hematologic factors in hemodialysis patients. Renal Failure 2011;33(9):892‐8. [MEDLINE: 21859401]CENTRAL

Koyama 2002 {published data only}

Koyama K, Usami T, Takeuchi O, Morozumi K, Kimura G. Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high‐dose folic acid supplementation. Nephrology Dialysis Transplantation 2002;17(5):916‐22. [MEDLINE: 11981084]CENTRAL

Koyama 2010 {published data only}

Koyama K, Ito A, Ichikawa T, Miura T, Ono M. Short term regimen of homocysteine‐lowering therapy reduces serum concentration of asymmetric dimethylarginine in patients on chronic hemodialysis [abstract no: SaP317]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi339. [CENTRAL: CN‐00671829]CENTRAL
Koyama K, Ito A, Yamamoto J, Nishio T, Ichikawa T. Co‐administration of methylcobalamin and folic acid normalizes hyperhomocysteinemia and reduces arterial stiffness in hemodialsyis patients [abstract no: PUB074]. Journal of the American Society of Nephrology 2005;16:798A. [CENTRAL: CN‐00676039]CENTRAL
Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y, et al. Randomized controlled trial of the effect of short‐term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long‐term hemodialysis. American Journal of Kidney Diseases 2010;55(6):1069‐78. [MEDLINE: 20430500]CENTRAL

Kuhlmann 2004 {published data only}

Kuhlmann MK, Obeid R, Herrmann W. Normalization of plasma homocystein (Hcy) levels in hyperhomocysteinemic hemodialysis patients by intravenous dosage of vitamins B6, B12 and folic acid. [abstract no SA‐PO345]. Journal of the American Society of Nephrology 2004;15(Oct):377A. [CENTRAL: CN‐00757352]CENTRAL

Kumar 2007b {published data only}

Kumar R, Vincent L, Perkins NJ, Tobe SW. Impact of folic acid on homocysteine levels in haemodialysis patients, a randomized double blinded placebo controlled cross over trial [abstract no: SA‐PO788]. Journal of the American Society of Nephrology 2007;18(Abstracts Issue):516A. [CENTRAL: CN‐00716086]CENTRAL

Kuo 2001a {published data only}

Kuo HT, Tsai JC, Chen LN, Chen HC, Guh JY, Hwang SJ, et al. Intravenous methylcobalamin further improves hyperhomocysteinemia in hemodialysis patients under maintenance folic acid therapy: role of methyletetrahydrofolate reductase (mthfr) genotype [abstract]. Nephrology Dialysis Transplantation 2001;16(6):A87. [CN‐00509297]CENTRAL

LANDMARK Study 2006 {published data only}

Isbel N, Rakhit D, Armstrong K, Leano R, Hawley C, Campbell S, et al. Rapid progression of myocardial ischaemia in patients with chronic kidney disease is not altered by risk factor modification [abstract no: PS107]. Nephrology 2005;10(Suppl 3):A408. [CENTRAL: CN‐00583922]CENTRAL
Isbel NM, Haluska B, Johnson DW, Beller E, Hawley C, Marwick TH. Increased targeting of cardiovascular risk factors in patients with chronic kidney disease does not improve atheroma burden or cardiovascular function. American Heart Journal 2006;151(3):745‐53. [MEDLINE: 16504645]CENTRAL
Isbel NM, Reiger K, Hawley CM, Campbell SB, Haluska B, Short L, et al. Aggressive intervention in traditional cardiovascular risk factors in patients with chronic renal failure does not improve atheroma burden, cardiovascular function or outcome [abstract]. Nephrology 2004;9(Suppl 1):A1‐2. [CENTRAL: CN‐00509247]CENTRAL
Johnson DW, Armstrong K, Campbell SB, Mudge DW, Hawley CM, Coombes JS, et al. Metabolic syndrome in severe chronic kidney disease: Prevalence, predictors, prognostic significance and effects of risk factor modification. Nephrology 2007;12(4):391‐8. [MEDLINE: 17635756]CENTRAL
Rakhit DJ, Marwick TH, Armstrong KA, Johnson DW, Leano R, Isbel NM. Effect of aggressive risk factor modification on cardiac events and myocardial ischaemia in patients with chronic kidney disease. Heart 2006;92(10):1402‐8. [MEDLINE: 16606867]CENTRAL

Libetta 2004 {published data only}

Libetta C, Corbetta R, Zucchi M, Gori E, Villa G, Bezoari G, et al. Treatment of hyperhomocysteinemia in hemodialysis patients reduce progressive atherosclerosis: a long‐term controlled study [abstract no: SA‐PO343]. Journal of the American Society of Nephrology 2004;15(Oct):376A‐7A. [CENTRAL: CN‐00626028]CENTRAL
Libetta C, Corbetta R, Zucchi M, Gori E, Villa G, Sepe V, et al. Long‐term treatment of hyperhomocysteinemia prevents carotid artery atherosclerosis in haemodialysed patients [abstract]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:4. [CENTRAL: CN‐00604353]CENTRAL
Libetta C, Villa G, Gori E, Zucchi M, Pisacco P, Bezoari G, et al. Vitamins supplementation effectiveness on hyperhomocysteinemia in hemodialyzed patients: a two‐year single‐blind randomized study [abstract no: SA‐PO344]. Journal of the American Society of Nephrology 2004;15(Oct):377A. [CENTRAL: CN‐00626027]CENTRAL
Libetta C, Villa G, Gori E, Zucchi M, Sepe V, Pisacco P, et al. Effect of folate or folate plus vitamins B6 and B12 on hyperhomocysteinemia in hemodialyzed patients: a 2‐year controlled randomized study [abstract]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:126. [CENTRAL: CN‐00636150]CENTRAL

Madsen 2011 {published data only}

Madsen T, Christensen JH, Toft E, Aardestrup I, Lundbye‐Christensen S, Schmidt EB. Effect of intravenous omega‐3 fatty acid infusion and hemodialysis on fatty acid composition of free fatty acids and phospholipids in patients with end‐stage renal disease. Jpen: Journal of Parenteral & Enteral Nutrition 2011;35(1):97‐106. [MEDLINE: 21224436]CENTRAL

Manns 2001 {published data only}

Hyndman ME, Manns BJ, Snyder FF, Bridge PJ, Scott‐Douglas NW, Fung E, et al. Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic acid in end‐stage renal disease: a link with glycine metabolism and possible explanation of hyperhomocysteinemia in end‐stage renal disease. Metabolism: Clinical & Experimental 2003;52(2):168‐72. [MEDLINE: 12601627]CENTRAL
Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, et al. Oral vitamin B(12) and high‐dose folic acid in hemodialysis patients with hyper‐homocyst(e)inemia. Kidney International 2001;59(3):1103‐9. [MEDLINE: 11231366]CENTRAL

Mazdeh 2005 {published data only}

Abolghasemi R, Mazdeh MM, Khatami M, Lessan‐Pezeshki M, Ahmadi F, Seifi S, et al. Hyperhomocysteinemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12 [abstract no: MP318]. Nephrology Dialysis Transplantation 2005;20(Suppl 5):v307. CENTRAL
Mazdeh MM, Abolghasemi R, Khatami M, Lessan‐Pezeshki M, Ahmadi F, Seifi S, et al. Hyperhomocysteinemia therapy in hemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12 [abstract no: W‐PO40014]. Nephrology 2005;10(Suppl 1):A283. [CENTRAL: CN‐00756890]CENTRAL

McGregor 2000a {published data only}

McGregor D, Shand B, Lynn K. A controlled trial of the effect of folate supplements on homocysteine, lipids and hemorheology in end‐stage renal disease. Nephron 2000;85(3):215‐20. [MEDLINE: 10867536]CENTRAL

Mudge 2005 {published data only}

Mudge D, Rogers R, Hollett P, Law B, Reiger K, Petrie JJP, et al. Plasma homocysteine levels with standard high flux haemodialysis compared with FX class dialysers [abstract]. Nephrology 2004;9(Suppl 1):A16. [CENTRAL: CN‐00509369]CENTRAL
Mudge DW, Rogers R, Hollett P, Law B, Reiger K, Petrie JJ, et al. Randomized trial of FX high flux vs standard high flux dialysis for homocysteine clearance. Nephrology Dialysis Transplantation 2005;20(10):2178‐85. [MEDLINE: 16030045]CENTRAL

Mueller 2001 {published data only}

Mueller T, Mueller N, Moser R, Stief T, Celle D, Pietrizk K. Reduced folates have an anti‐inflammatory effect in hemodialysis patients [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):700. [CENTRAL: CN‐00446856]CENTRAL
Mueller TF, Mueller N, Moser R, Stief T, Nau H, Lange H, et al. Effect of folate therapy on the inflammatory burden in hemodialysis patients [abstract no: SA‐FC185]. Journal of the American Society of Nephrology 2002;13(September, Program & Abstracts):38A. [CENTRAL: CN‐00446855]CENTRAL
Mueller TF, Mueller N, Moser R, Stief T, Ziegler A, Nau H, et al. Effect of oral substitution of reduced folates on homocysteine, neopterin, and lipid levels in patients treated with hemodialysis [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):360A‐1A. [CENTRAL: CN‐00756385]CENTRAL

Muller 2001 {published data only}

Muller A, Busch M, Stein G, Hein GE, Funfstuck R. L‐methionine loading test for the prediction of increased total homocysteine levels due to long term l‐methionine treatment [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):734A. [CENTRAL: CN‐00757145]CENTRAL

Nakamura 2003 {published data only}

Nakamura T, Hirayama H, Tajiri M, Saionji K, Hata A. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism influences the efficacy of folic acid (FA) and vitamin B12 (B12) on hyperhomocyteinemia in hemodialysis (HD) patients [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):699‐700. [CENTRAL: CN‐00446896]CENTRAL

Nakhoul 2004 {published data only}

Nakhoul F, Abassi Z, Plawner M, Khankin E, Ramadan R, Lanir N, et al. Comparative study of response to treatment with supraphysiologic doses of B‐vitamins in hyperhomocysteinemic hemodialysis patients. Israel Medical Association Journal ‐ Imaj 2004;6(4):213‐7. [MEDLINE: 15115259]CENTRAL
Plawner M, Nakhoul F, Khankin E, Laneer N, Brenner B, Green J. Folic acid and varying doses of B‐vitamines in the treatment of hyperhomocystinemia in hemodialysis patients [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):295A. [CENTRAL: CN‐00644331]CENTRAL

Nascimento 2010 {published data only}

Nascimento MM, Suliman ME, Anderstam B, Silva MM, Hayashi S, Pecoits‐Filho R, et al. Effect of N‐acetylcysteine supplementation on inflammatory and oxidative stress markers in peritoneal dialysis patients: a randomized placebo controlled study [abstract no: F‐PO769]. Journal of the American Society of Nephrology 2007;18(Abstracts):270A. [CENTRAL: CN‐00756376]CENTRAL
Nascimento MM, Suliman ME, Silva M, Chinaglia T, Marchioro J, Hayashi SY, et al. Effect of oral N‐acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo‐controlled study. Peritoneal Dialysis International 2010;30(3):336‐42. [MEDLINE: 20190028]CENTRAL

OPACH Study 2006 {published data only}

Harving F, Svensson M, Flyvbjerg A, Schmidt EB, Jorgensen KA, Eriksen HH, et al. n‐3 polyunsaturated fatty acids and adiponectin in patients with end‐stage renal disease. Clinical Nephrology 2015;83(5):279‐85. [MEDLINE: 25816805]CENTRAL
Kirkegaard E, Svensson M, Strandhave C, Schmidt EB, Jorgensen KA, Christensen JH. Marine n‐3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients. British Journal of Nutrition 2012;107(6):903‐9. [MEDLINE: 21791142]CENTRAL
Rasmussen LE, Svensson M, Jorgensen KA, Schmidt EB, Christensen JH. The content of docosahexaenoic acid in serum phospholipid is inversely correlated with plasma homocysteine levels in patients with end‐stage renal disease. Nutrition Research 2010;30(8):535‐40. [MEDLINE: 20851307]CENTRAL
Svensson M, Christensen JH, Jorgensen KA, Schmidt EB. Omacor as secondary prevention against cardiovascular disease in patients undergoing chronic hemodialysis: a randomised, placebo controlled intervention study [abstract no: F‐PO606]. Journal of the American Society of Nephrology 2005;16:466A. [CENTRAL: CN‐00583663]CENTRAL
Svensson M, Frobert O, Schmidt EB, Jorgensen KA, Simonsen U, Christensen JH. The effect of n‐3 fatty acids on levels of methylarginines in patients with end‐stage renal disease. Journal of Nephrology 2010;23(4):459‐64. [MEDLINE: 20349405]CENTRAL
Svensson M, Schmidt EB, Jorgensen KA, Christensen JH. The effect of n‐3 fatty acids on heart rate variability in patients treated with chronic hemodialysis. Journal of Renal Nutrition 2007;17(4):243‐9. [MEDLINE: 17586422]CENTRAL
Svensson M, Schmidt EB, Jorgensen KA, Christensen JH. The effect of n‐3 fatty acids on lipids and lipoproteins in patients treated with chronic haemodialysis: a randomized placebo‐controlled intervention study. Nephrology Dialysis Transplantation 2008;23(9):2918‐24. [MEDLINE: 18436564]CENTRAL
Svensson M, Schmidt EB, Jorgensen KA, Christensen JH, OPACH Study Group. N‐3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: A randomized, placebo‐controlled intervention trial. Clinical Journal of the American Society of Nephrology: CJASN 2006;1(4):780‐6. [MEDLINE: 17699287]CENTRAL

Ossareh 2009 {published data only}

Ossareh S, Shayan‐Moghaddam H, Salimi A, Asgari M, Farrokhi F. Different doses of oral folic acid for homocysteine‐lowering therapy in patients on hemodialysis: a randomized controlled trial.[Erratum appears in Iran J Kidney Dis. 2010 Jan;4(1):88 Note: Salimi, Ashraf [added]; Asgari, Mojgan [added]]. Iranian Journal of Kidney Diseases 2009;3(4):227‐33. [MEDLINE: 19841527]CENTRAL

Pakfetrat 2013 {published data only}

Pakfetrat M, Shahroodi JR, Zolgadr AA, Larie HA, Nikoo MH, Malekmakan L. Effects of zinc supplement on plasma homocysteine level in end‐stage renal disease patients: a double‐blind randomized clinical trial. Biological Trace Element Research 2013;153(1‐3):11‐5. [MEDLINE: 23475369]CENTRAL

Pastore 2006 {published data only}

Pastore A, De Angelis S, Casciani S, Ruggia R, Di Giovamberardino G, Noce A, et al. Effects of folic acid before and after vitamin B12 on plasma homocysteine concentrations in hemodialysis patients with known MTHFR genotypes. Clinical Chemistry 2006;52(1):145‐8. [MEDLINE: 16391331]CENTRAL

Peng 2005 {published data only}

Peng L, Liu Q. A prospective, randomized, placebo‐controlled study to evaluate the effect of combined treatment of folic acid and intravenous B‐complex vitamins on hyperhomocysteinemia in hemodialysis patients [abstract no: W‐PO40032]. Nephrology 2005;10(Suppl 1):A288. [CENTRAL: CN‐00671827]CENTRAL

Polkinghorne 2003 {published data only}

Polkinghorne KR, Zoungas S, Branley P, Villanueva E, McNeil JJ, Atkins RC, et al. A randomised placebo controlled trial of intramuscular vitamin B12 (hydroxyocobalamin) for the treatment of hyperhomocysteinemia in haemodialysis patients [abstract]. Kongres Nasional VIII Annual Meeting Perhimpunan Nefrologi Indonesia; 2002 Oct; Surabaya, Indonesia. 2002:2.5. [CENTRAL: CN‐00447252]CENTRAL
Polkinghorne KR, Zoungas S, Branley P, Villanueva E, McNeil JJ, Atkins RC, et al. A randomized placebo controlled trial of intramuscular vitamin B12 (hydroxyocobalamin) for the treatment of hyperhomocysteinemia in haemodialysis patients [abstract no: SU‐FC267]. Journal of the American Society of Nephrology 2002;13(September, Program & Abstracts):55A. [CENTRAL: CN‐00447251]CENTRAL
Polkinghorne KR, Zoungas S, Branley P, Villanueva E, McNeil JJ, Atkins RC, et al. Randomized, placebo‐controlled trial of intramuscular vitamin B12 for the treatment of hyperhomocysteinaemia in dialysis patients. Internal Medicine Journal 2003;33(11):489‐94. [MEDLINE: 14656250]CENTRAL
Polkinghorne KR, Zoungas S, Branley P, Villnueva E, McNeil J, Atkins RC, et al. A randomised placebo controlled trial of intramuscular vitamin B12 (hydroxyocobalamin) for the treatment of hyperhomocysteinemia in haemodialysis patients [abstract]. Nephrology 2002;7(Suppl 3):A68. CENTRAL

Poulia 2011 {published data only}

Poulia KA, Panagiotakos DB, Tourlede E, Rezou A, Stamatiadis D, Boletis J, et al. Omega‐3 fatty acids supplementation does not affect serum lipids in chronic hemodialysis patients. Journal of Renal Nutrition 2011;21(6):479‐84. [MEDLINE: 21439849]CENTRAL

Sanchez Alvarez 2005 {published data only}

Sanchez Alvarez JE, Perez Tamajon L, Hernandez D, Alvarez Gonzalez A, Delgado P, Lorenzo V. Efficacy and safety of two vitamin supplement regimens on homocysteine levels in hemodialysis patients. Prospective, randomized clinical trial. Nefrologia 2005;25(3):288‐96. [MEDLINE: 16053010]CENTRAL
Sanchez JE, Molina E, De La Vega MJ, Hernandez D, Perez L, Garcia R, et al. Sustained effect of two vitamin supplement regimens on hyperhomocysteinemia in maintenance hemodialysis (MHD) patients [abstract no: F‐PO773]. Journal of the American Society of Nephrology 2003;14(Nov):231A. [CENTRAL: CN‐00583425]CENTRAL

Scholze 2004 {published data only}

Scholze A, Rinder C, Beige J, Riezler R, Zidek W, Tepel M. Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end‐stage renal failure. Circulation 2004;109(3):369‐74. [MEDLINE: 14732754]CENTRAL
Scholze A, Rinder C, Beige J, Riezler R, Zidek W, Tepel M. Reduced plasma homocysteine concentration and improved pulse pressure in hemodialysis patients with acetylcysteine [abstract]. 41st Congress. European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004:127. [CENTRAL: CN‐00509467]CENTRAL

Seo 2003 {published data only}

Seo MD, Yoon S, Jeong JC, Choi SS, Kim SY, Son I, et al. Effects of folic acid treatment on homocysteine levels and echocardiographic findings in ESRD [abstract no: SA‐PO900]. Journal of the American Society of Nephrology 2003;14(Nov):497A. [CN‐00756462]CENTRAL

Sepe 1999 {published data only}

Sepe V, Patrucco G, Santagostine A, Bolis V, Caminiti R, Cecere P, et al. Hyperhomocysteinemia [HHcy] is not associated with elevated platelet annexin V [plt a‐v] expression in maintenance haemodialysis [HD] patients [abstract]. Nephrology Dialysis Transplantation 1999;14(9):A192. [CENTRAL: CN‐00485810]CENTRAL

Shemin 2001 {published data only}

Shemin D, Bostom AG, Selhub J. Treatment of hyperhomocysteinemia in end‐stage renal disease. American Journal of Kidney Diseases 2001;38(4 Suppl 1):S91‐4. [MEDLINE: 11576930]CENTRAL

Signorelli 2006 {published data only}

Signorelli SS, Fatuzzo P, Rapisarda F, Neri S, Ferrante M, Oliveri CG, et al. A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L‐carnitine in patients with peripheral arterial disease requiring haemodialysis. Drugs & Aging 2006;23(3):263‐70. [MEDLINE: 16608381]CENTRAL
Signorelli SS, Fatuzzo P, Rapisarda F, Neri S, Ferrante M, Oliveri CG, et al. Propionyl‐L‐carnitine therapy: effects on endothelin‐1 and homocysteine levels in patients with peripheral arterial disease and end‐stage renal disease. Kidney & Blood Pressure Research 2006;29(2):100‐7. [MEDLINE: 16809937]CENTRAL

Skoutakis 1975 {published data only}

Skoutakis VA, Acchiardo SR, Meyer MC, Hatch FE. Folic acid dosage for chronic hemodialysis patients. Clinical Pharmacology & Therapeutics 1975;18(2):200‐4. [MEDLINE: 1098832]CENTRAL

Stavrianaki 2002 {published data only}

Stavrianaki D, Bagiatoudi G, Salpigidis K, Sarris E, Siakotos M. Treatment efficacy of folic or folinic acid in lowering total plasma homocysteine levels in patients on hemodialysis [abstract]. Nephrology Dialysis Transplantation 2002;17(Suppl 12):256. [CENTRAL: CN‐00758491]CENTRAL

Tamadon 2011 {published data only}

Tamadon MR, Jamshidi L, Soliemani A, Ghorbani R, Malek F, Malek M. Effect of different doses of folic acid on serum homocysteine level in patients on hemodialysis. Iranian Journal of Kidney Diseases 2011;5(2):93‐6. [MEDLINE: 21368386]CENTRAL

Tayyebi‐Khosroshahi 2010 {published data only}

Tayyebi‐Khosroshahi H, Houshyar J, Tabrizi A, Vatankhah AM, Razzagi ZN, Dehghan‐Hesari R. Effect of omega‐3 fatty acid on oxidative stress in patients on hemodialysis. Iranian Journal of Kidney Diseases 2010;4(4):322‐6. [MEDLINE: 20852375]CENTRAL

Tepel 2003 {published data only}

Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end‐stage renal failure: a randomized, controlled trial. Circulation 2003;107(7):992‐5. [MEDLINE: 12600912]CENTRAL

Thaha 2006 {published data only}

Thaha M, Widodo, Yogiantoro M, Tomino Y. Reduction of pulse pressure by intravenous N‐acetylcyseine administration in chronic hemodialysis patients [abstract no: 1620]. Nephrology 2006;11(Suppl 2):A33. [CENTRAL: CN‐00653775]CENTRAL
Thaha M, Yogiantoro M, Tomino Y. Intravenous N‐acetylcysteine during haemodialysis reduces the plasma concentration of homocysteine in patients with end‐stage renal disease. Clinical Drug Investigation 2006;26(4):195‐202. [MEDLINE: 17163251]CENTRAL
Thaha M, Yogiantoro M, Tomino Y. Intravenous N‐acetylcysteine during haemodialysis reduces the plasma concentration of homocysteine in patients with end‐stage renal disease [abstract no: 1560]. Nephrology 2006;11(Suppl 2):A18. CENTRAL

Thaha 2008 {published data only}

Thaha M, Widodo B, Pranawa M, Yogiantoro HM, Tomino Y. Intravenous N‐acetylcysteine during hemodialysis reduces homocysteine and asymmetric dimethylarginine in ESRD patients: a randomized double blind controlled trial [abstract no: 1159]. Nephrology 2007;12(Suppl 2):A40. [CENTRAL: CN‐00740521]CENTRAL
Thaha M, Widodo, Pranawa W, Yogiantoro M, Tomino Y. Intravenous N‐acetylcysteine during hemodialysis reduces asymmetric dimethylarginine level in end‐stage renal disease patients. Clinical Nephrology 2008;69(1):24‐32. [MEDLINE: 18226399]CENTRAL

Thaha 2009 {published data only}

Thaha M, Mohani CI, Yogiantoro HM, Tomino Y. Oral n‐acetyl cysteine to treat non‐diabetic chronic kidney disease stage 1‐4 with albuminuria [abstract no: SA‐PO2242]. Journal of the American Society of Nephrology 2009;20:622A. [CENTRAL: CN‐00740560]CENTRAL

Thambyrajah 2000 {published data only}

Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?. Circulation 2000;102(8):871‐5. [MEDLINE: 10952955]CENTRAL
Thambyrajah J, Landray MJ, Townend JN, Wheeler DC. Folic acid decreases plasma homocysteine but does not improve endothelial function in chronic renal failure [abstract]. Journal of the American Society of Nephrology 2000;11(Sept):372A. [CENTRAL: CN‐00583252]CENTRAL

Tobe 1999 {published data only}

Tobe SW, Helmers K, Naimark DMJ, Perkins N, Baker B. Impact on homocysteine levels of folic acid and adherance in haemodialysis patients. A randomized double blind placebo cross over trial [abstract no: A1332]. Journal of the American Society of Nephrology 2000;11(Sept):253A. [CENTRAL: CN‐00583286]CENTRAL
Tobe SW, Naimark DN, Helmers KF, Perkins NJ, Baker B. Plasma homocysteine (hcy) levels in patients on chronic haemodialysis are inversely correlated with folate and B12 levels [abstract]. Journal of the American Society of Nephrology 1999;10(Program & Abstracts):306A. [CENTRAL: CN‐00583285]CENTRAL

Tochihara 2008 {published data only}

Tochihara Y, Whiting MJ, Barbara JA, Mangoni AA. Effects of pre‐ vs. intra‐dialysis folic acid on arterial wave reflections and endothelial function in patients with end‐stage renal disease. British Journal of Clinical Pharmacology 2008;66(5):717‐22. [MEDLINE: 18754845]CENTRAL

Treleaven 2001 {published data only}

Treleaven D, Gough J, Lonn E, Strickland D, Kitching A, Churchill D, et al. High dose folic acid in hemodialysis patients results in frequent side effects without improvement in plasma homocysteine levels [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):365A. [CENTRAL: CN‐00583283]CENTRAL

Tremblay 2000 {published data only}

Tremblay R, Bonnardeaux A, Geadah D, Busque L, Lebrun M, Ouimet D, et al. Hyperhomocysteinemia in hemodialysis patients: effects of 12‐month supplementation with hydrosoluble vitamins. Kidney International 2000;58(2):851‐8. [MEDLINE: 10916110]CENTRAL

Trimarchi 2002 {published data only}

Trimarchi H, Schiel A, Freixas E, Diaz M. Randomized trial of methylcobalamin and folate effects on homocysteine in hemodialysis patients. Nephron 2002;91(1):58‐63. [MEDLINE: 12021520]CENTRAL

Tungkasereerak 2006 {published data only}

Tungkasereerak P, Chaiyasoot W, Taruangsri P, Leowattana W, Vasuvattakul S, Vareesangthip K, et al. Can folate and vitamin B supplementation reduce total homocysteine levels and atherosclerosis in hemodialysis patients? [abstract no: SA‐PO472]. Journal of the American Society of Nephrology 2004;15(Oct):406A. [CENTRAL: CN‐00583721]CENTRAL
Tungkasereerak P, Ong‐ajyooth L, Chaiyasoot W, Ong‐ajyooth S, Leowattana W, Vasuvattakul S, et al. Effect of short‐term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients. Journal of the Medical Association of Thailand 2006;89(8):1187‐93. [MEDLINE: 17048428]CENTRAL

Urquhart 2008 {published data only}

Urquhart BL, Freeman DJ, Cutler MJ, Mainra R, Spence JD, House AA. Mesna for treatment of hyperhomocysteinemia in hemodialysis patients: a placebo‐controlled, double‐blind, randomized trial. Clinical Journal of the American Society of Nephrology: CJASN 2008;3(4):1041‐7. [MEDLINE: 18337551]CENTRAL

van Guldener 1998 {published data only}

van Guldener C, Janssen M, Lambert J, ter Wee P, Donker A, Stehonwer C. Treatment of hyperhomocysteinaemia with folic acid does not ameliorate endothelial function in chronic haemodialysis patients [abstract]. Nephrology Dialysis Transplantation 1997;12(9):A114. [CENTRAL: CN‐00261358]CENTRAL
van Guldener C, Janssen MJ, Lambert J, ter Wee PM, Donker AJ, Stehouwer CD. Folic acid treatment of hyperhomocysteinemia in peritoneal dialysis patients does not ameliorate endothelial function [abstract]. Journal of the American Society of Nephrology 1997;8(Program & Abstracts):274A. [CENTRAL: CN‐00448137]CENTRAL
van Guldener C, Janssen MJ, Lambert J, ter Wee PM, Donker AJ, Stehouwer CD. Folic acid treatment of hyperhomocysteinemia in peritoneal dialysis patients: no change in endothelial function after long‐term therapy. Peritoneal Dialysis International 1998;18(3):282‐9. [MEDLINE: 9663892]CENTRAL
van Guldener C, Janssen MJ, Lambert J, ter Wee PM, Jakobs C, Donker AJ, et al. No change in impaired endothelial function after long‐term folic acid therapy of hyperhomocysteinaemia in haemodialysis patients. Nephrology Dialysis Transplantation 1998;13(1):106‐12. [MEDLINE: 9481724]CENTRAL
van Guldener C, Janssen MJ, Stehouwer CD, Ter Wee PM, Donker AJ. Treatment of hyperhomocysteinemia in chronic dialysis patients with folic acid and betaine [abstract no: A1266]. Journal of the American Society of Nephrology 1996;7(9):1502. [CENTRAL: CN‐00758506]CENTRAL
van Guldener C, Janssen MJ, Stehouwer CD, ter Wee PM, Donker AJ. Folic acid and betaine in the treatment of hyperhomocysteinaemia in haemodialysis patients [abstract]. Netherlands Journal of Medicine 1996;48(5):A67. [CENTRAL: CN‐00416837]CENTRAL
van Guldener C, Janssen MJ, de Meer K, Donker AJ, Stehouwer CD. Effect of folic acid and betaine on fasting and postmethionine‐loading plasma homocysteine and methionine levels in chronic haemodialysis patients. Journal of Internal Medicine 1999;245(2):175‐83. [MEDLINE: 10081520]CENTRAL
van Guldener C, Lambert J, ter Wee PM, Donker AJ, Stehouwer CD. Carotid artery stiffness in patients with end‐stage renal disease: no effect of long‐term homocysteine‐lowering therapy. Clinical Nephrology 2000;53(1):33‐41. [MEDLINE: 10661480]CENTRAL

Van Tellingen 2001 {published data only}

Van Tellingen A, Grooteman MP, Bartels PC, Van Limbeek J, Van Guldener C, Wee PM, et al. Long‐term reduction of plasma homocysteine levels by super‐flux dialyzers in hemodialysis patients. Kidney International 2001;59(1):342‐7. [MEDLINE: 11135089]CENTRAL

VIENNA Study 2000 {published data only}

Sunder‐Plassmann G, Fodinger M, Buchmayer H, Papagiannopoulos M, Wojcik J, Kletzmayr J, et al. Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study. Journal of the American Society of Nephrology 2000;11(6):1106‐16. [MEDLINE: 10820175]CENTRAL
Sunder‐Plassmann G, Fodinger M, Buchmayer H, Wolfl G, Papagiannoupoulos M, Wojzik J, et al. High dose folic acid therapy in hemodialysis (HD) patients. The Vienna multicenter study [abstract]. Journal of the American Society of Nephrology 1999;10(Program & Abstracts):269A. [CENTRAL: CN‐00756862]CENTRAL

Vrentzos 2001 {published data only}

Vrentzos G, Ganotakis E, Vardakis K, Maliaraki N, Stratigis S, Stilianou K, et al. Effect of vitamin B12 supplementation in serum total homocysteine and folate in patients with end‐stage renal failure [abstract]. Atherosclerosis Supplements 2001;2(2):107. [CENTRAL: CN‐00671820]CENTRAL

Vychytil 2003 {published data only}

Vychytil A, Fodinger M, Pleiner J, Mullner M, Konner P, Skoupy S, et al. Acute effect of amino acid peritoneal dialysis solution on vascular function. American Journal of Clinical Nutrition 2003;78(5):1039‐45. [MEDLINE: 14594793]CENTRAL
Vychytil A, Fodinger M, Pleiner J, Mullner M, Wolzt M, Sunder‐Plassmann G. Acute effect of amino acid peritoneal dialysis (PD) solution on vascular function ‐ no association with HCY [abstract]. Journal of Inherited Metabolic Disease 2003;26(Suppl 1):94. [CENTRAL: CN‐00677763]CENTRAL
Vychytil A, Foedinger M, Pleiner J, Muellner M, Konner P, Skoupy S, et al. Acute effect of amino acid peritoneal dialysis solution on vascular function [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):215. CENTRAL
Vychytil A, Foedinger M, Pleiner J, Muellner M, Konner P, Skoupy S, et al. Acute effect of amino acid peritoneal dialysis solution on vascular function. [abstract no: SU‐PO935]. Journal of the American Society of Nephrology 2003;14(Nov):741A. CENTRAL

Westphal 2001 {published data only}

Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001;358(9275):39‐40. [MEDLINE: 11454380]CENTRAL

Yango 2001 {published data only}

Ghandour H, Bagley PJ, Shemin D, Hsu N, Jacques PF, Dworkin L, et al. Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L‐folinic or folic acid. Kidney International 2002;62(6):2246‐9. [MEDLINE: 12427152]CENTRAL
Yango A, Shemin D, Hsu N, Jacques PF, Dworkin L, Selhub J, et al. Rapid communication: L‐folinic acid versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients. Kidney International 2001;59(1):324‐7. [MEDLINE: 11135086]CENTRAL

Zeman 2006 {published data only}

Zeman M, Zak A, Vecka M, Tvrzicka E, Pisarikova A, Stankova B. N‐3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin‐fibrate combination. Journal of Nutritional Biochemistry 2006;17(6):379‐84. [MEDLINE: 16214329]CENTRAL

Zuo 2001 {published data only}

Zuo L, Wang M, Feng L, Wei H, Wang H. Can high dose of folic acid normalize fast total plama homocysteine (thcy) level in maintenance hemodialysis patients? [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):421A. [CENTRAL: CN‐00689429]CENTRAL

Referencias de los estudios en espera de evaluación

NCT00004495 {published data only}

Wilcox CS. Randomized study of folic acid therapy for hyperhomocysteinemia in patients with end stage renal disease receiving hemodialysis. clinicaltrials.gov/ct2/show/NCT00004495 (accessed 18 February 2014). CENTRAL

Soleimani 2011 {published data only}

Soleimani A, Usefzadeh M, Mianehsaz E, Foroozanfard F, Nikoueinejad H, Moraveji SA, et al. Comparison of oral folic acid and folinic acid on blood homocysteine level of patients on hemodialysis. Iranian Journal of Kidney Diseases 2011;5(1):45‐9. [MEDLINE: 21189434]CENTRAL

Tayebi‐Khosroshahi 2013 {published data only}

Tayebi‐Khosroshahi H, Dehgan R, Habibi AB, Safaian A, Panahi F, Estakhri R, et al. Effect of omega‐3 supplementation on serum level of homocysteine in hemodialysis patients. Iranian Journal of Kidney Diseases 2013;7(6):479‐84. [MEDLINE: 24241095]CENTRAL

Andreucci 2004

Andreucci VE, Fissell RB, Bragg‐Gresham JL, Ethier J, Greenwood R, Pauly M, et al. Dialysis Outcomes and Practice Patterns Study (DOPPS) data on medications in hemodialysis patients. American Journal of Kidney Diseases 2004;44(5 Suppl 2):61‐7. [MEDLINE: 15486876]

Aucella 2005

Aucella F, Margaglione M, Grandone E, Vigilante M, Gatta G, Forcella M, et al. The C677T methylenetetrahydrofolate reductase gene mutation does not influence cardiovascular risk in the dialysis population: results of a multicentre prospective study. Nephrology Dialysis Transplantation 2005;20(2):382‐6. [MEDLINE: 15618240]

Baigent 2000

Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000;356(9224):147‐52. [MEDLINE: 10963260]

Bostom 1999

Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. Journal of the American Society of Nephrology 1999;10(4):891‐900. [MEDLINE: 10203375]

Chauveau 1993

Chauveau P, Chadefaux B, Coude M, Aupetit J, Hannedouche T, Kamoun P, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney International ‐ Supplement 1993;41:S72‐7. [MEDLINE: 8320950]

de Jager 2009

de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 2009;302(16):1782‐9. [MEDLINE: 19861670]

Ducloux 2006

Ducloux D, Klein A, Kazory A, Devillard N, Chalopin JM. Impact of malnutrition‐inflammation on the association between homocysteine and mortality. Kidney International 2006;69(2):331‐5. [MEDLINE: 16408123]

Egger 1997

Egger M, Davey‐Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple graphical test. BMJ 1997;315(7109):629‐34. [MEDLINE: 9310563]

Eikelboom 1999

Eikelboom JW, Lonn E, Genest J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Annals of Internal Medicine 1999;131(5):363‐75. [MEDLINE: 10475890]

Foley 1998

Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. Journal of the American Society of Nephrology 1998;9(12 Suppl):S16‐23. [MEDLINE: 11443763]

Freidman 2001

Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH. The kidney and homocysteine metabolism. Journal of the American Society of Nephrology 2001;12(10):2181‐9. [MEDLINE: 11562419]

Go 2004

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.[Erratum appears in N Engl J Med. 2008;18(4):4]. New England Journal of Medicine 2004;351(13):1296‐305. [MEDLINE: 15385656]

Gonin 2005

Gonin JM. Folic acid supplementation to prevent adverse events in individuals with chronic kidney disease and end stage renal disease. Current Opinion in Nephrology & Hypertension 2005;14(3):277‐81. [MEDLINE: 15821423]

Haynes 2012

Haynes R, Clarke R. Homocysteine, the kidney, and vascular disease. BMJ 2012;344:e3925. [MEDLINE: 22695904]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [MEDLINE: 12958120]

Higgins 2011

Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

HSC 2002

Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta‐analysis. JAMA 2002;288(16):2015‐22. [MEDLINE: 12387654]

Huang 2012

Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D. Meta‐analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all‐cause mortality. Clinical Nutrition 2012;31(4):448‐54. [MEDLINE: 22652362]

Jardine 2012

Jardine MJ, Kang A, Zoungas S, Navaneethan SD, Ninomiya T, Nigwekar SU, et al. The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta‐analysis. BMJ 2012;344:e3533. [MEDLINE: 22695899]

K/DOQI 2005

K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. American Journal of Kidney Diseases 2005;45(4 Suppl 3):S1‐153. [MEDLINE: 15806502]

Kalantar‐Zadeh 2004

Kalantar‐Zadeh K, Block G, Humphreys MH, McAllister CJ, Kopple JD. A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients. Journal of the American Society of Nephrology 2004;15(2):442‐53. [MEDLINE: 14747392]

Kalantar‐Zadeh 2005

Kalantar‐Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Horwich TB. Survival advantages of obesity in dialysis patients. American Journal of Clinical Nutrition 2005;81(3):543‐54. [MEDLINE: 15755821]

Kanbay 2010

Kanbay M, Afsar B, Gusbeth‐Tatomir P, Covic A. Arterial stiffness in dialysis patients: where are we now?. International Urology & Nephrology 2010;42(3):741‐52. [MEDLINE: 19924558]

Klerk 2002

Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, et al. MTHFR 677C‐‐>T polymorphism and risk of coronary heart disease: a meta‐analysis. JAMA 2002;288(16):2023‐31. [MEDLINE: 12387655]

McDonald 2007

McDonald S, Excell L, Livingston B. ANZDATA Registry 2007 Report. Chapter 3 Deaths. www.anzdata.org.au/anzdata/AnzdataReport/30thReport/Ch03Deaths.pdf2007; Vol. (accessed 19 January 2016).

Menon 2006

Menon V, Sarnak MJ, Greene T, Wang X, Pereira AA, Beck GJ, et al. Relationship between homocysteine and mortality in chronic kidney disease. Circulation 2006;113(12):1572‐7. [MEDLINE: 16549639]

Moustapha 1998

Moustapha A, Naso A, Nahlawi M, Gupta A, Arheart KL, Jacobsen DW, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end‐stage renal disease.[Erratum appears in Circulation 1998 Feb 24;97(7):711]. Circulation 1998;97(2):138‐41. [MEDLINE: 9445164]

Pan 2012

Pan Y, Guo LL, Cai LL, Zhu XJ, Shu JL, Liu XL, et al. Homocysteine‐lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta‐analysis of randomised, controlled trials. British Journal of Nutrition 2012;108(3):400‐7. [MEDLINE: 22244447]

Robinson 1996

Robinson K, Gupta A, Dennis V, Arheart K, Chaudhary D, Green R, et al. Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end‐stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation 1996;94(11):2743‐8. [MEDLINE: 8941098]

Suliman 2007

Suliman ME, Lindholm B, Bárány P, Qureshi AR, Stenvinkel P. Homocysteine‐lowering is not a primary target for cardiovascular disease prevention in chronic kidney disease patients. Seminars in Dialysis 2007;20(6):523‐9. [MEDLINE: 17991198]

USRDS 2007

U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of End‐Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007. www.usrds.org/atlas07.aspx(accessed January 2016).

van Guldener 2006

van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine‐lowering?. Nephrology Dialysis Transplantation 2006;21(5):1161‐6. [MEDLINE: 16490741]

VITATOPS 2010

VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double‐blind, parallel, placebo‐controlled trial. Lancet Neurology 2010;9(9):855‐65. [MEDLINE: 20688574]

Wald 2002

Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta‐analysis. BMJ 2002;325(7374):1202. [MEDLINE: 1244653]

Weiner 2004

Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all‐cause mortality: a pooled analysis of community‐based studies. Journal of the American Society of Nephrology 2004;15(5):1307‐15. [MEDLINE: 15100371]

Wrone 2001

Wrone EM, Zehnder JL, Hornberger JM, McCann LM, Coplon NS, Fortmann SP. An MTHFR variant, homocysteine, and cardiovascular comorbidity in renal disease. Kidney International 2001;60(3):1106‐13. [MEDLINE: 11532106]

Yang 2012

Yang J, Hu X, Zhang Q, Cao H, Wang J, Liu B. Homocysteine level and risk of fracture: A meta‐analysis and systematic review. Bone 2012;51(3):376‐82. [MEDLINE: 22749888]

Zoccali 2010

Zoccali C, Jager KJ. Hyperhomocysteinemia: a renal and cardiovascular risk factor?. Nature Reviews Nephrology 2010;6(12):695‐6. [MEDLINE: 21109767]

Referencias de otras versiones publicadas de esta revisión

Nigwekar 2009

Nigwekar SU, Cass A, Gallagher MP, Jardine MJ, Kang A, Kulshrestha S, et al. Interventions for lowering plasma homocysteine levels in dialysis patients. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD004683.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

ASFAST 2004

Methods

  • Study design: parallel RCT

  • Study duration: 30 June 1998 to 31 December 2000, median follow‐up 3.6 years

  • Completeness of follow‐up‐specific information regarding dialysis population not available; however, overall 4 patients of 315 were lost to follow‐up

  • Withdrawal of consent‐specific information regarding dialysis population not available; however, overall 32 patients of 315 withdrew consent

Participants

  • Setting: 5 outpatient dialysis units

  • Country: Australia and New Zealand

  • Relevant health status: CKD of any cause, SCr ≥ 0.40 mmol/L and awaiting commencement of dialysis or on CAPD, intermittent PD or HD

  • Number: treatment group (136); control group (131)

  • Mean age ± SD (years) (specific information regarding dialysis population not available): treatment group (56 ± 13); control group (56 ± 14)

  • Sex (male) (specific information regarding dialysis population not available): treatment group (73%); control group (62%)

  • Exclusion criteria: inability to obtain informed consent; inability to comply with study protocol; planned early living‐related transplantation; presence of a life threatening disease such as cancer; state of high cell turnover such as inflammatory bowel disease; ongoing treatment with methotrexate; phenytoin, or trimethoprim‐sulphamethoxazole; recent return to dialysis after transplantation and still on immunosuppression; cobalamin deficiency without replacement; previous bilateral carotid artery surgery or carotid artery stenosis > 75% on screening

Interventions

Treatment group

  • Folic acid

  • 15 mg oral daily for median duration of 3.6 years

Control group

  • Identical appearing placebo daily for median duration of 3.6 year

 Co‐interventions

  •  None

Outcomes

  • Change in rate of progression of mean maximum carotid artery intimal media thickness, composite of MI, stroke, and death from cardiovascular cause

  • All fatal and nonfatal cardiovascular events including MI, stroke, unstable angina, revascularisation, and peripheral vascular disease

Notes

  • Funding source: National Health and Medical Research Council of Australia and National Heart Foundation of New Zealand

  • Study authors were contacted and additional information obtained

  • Other: mandatory folic acid fortification was not present in Australia and New Zealand at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

RCT with random sequence generation

Allocation concealment (selection bias)

Low risk

Study medication dispensed in identical containers with neither study staff nor participant aware of treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind RCT

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All clinical end points were subject to an independent adjudication process by an endpoint monitoring committee. Carotid intimal‐medial thickness measurements were performed in the same study laboratory in each major city centre and a single reference laboratory performed all image analyses.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data on mortality and morbidity available for 99% of participants; data analysed per intention to treat

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other bias

Heinz 2009

Methods

  • Study design: parallel RCT

  • Study duration: July 2002 to July 2008, median follow‐up 2.1 years

  • Completeness of follow‐up: of 650 patients, 107 received transplant, 75 withdrew from participation, and 18 discontinued treatment because of change in dialysis centre

  • Withdrawal of consent: 75 withdrew from participation

Participants

  • Setting: 33 outpatient dialysis units

  • Country: Germany

  • Relevant health status: ESKD treated for at least one month by HD

  • Number: treatment group (327); control group (323)

  • Mean age ± SD (years): treatment group (61 ± 13); control group (61 ± 13)

  • Sex (male): treatment group (58%); control group (59%)

  • Exclusion criteria: acute coronary events within 6 weeks before randomisation; active malignant tumour; pregnancy; lactation; addiction to drugs or alcohol

Interventions

Treatment group

  • 5 mg folic acid, 50 µg B12, 20 mg B6 orally after each HD session for a median follow‐up of 2.1 years

  • Taken under nurse supervision

Control group

  • 0.2 mg folic acid, 4 µg B12, 1 mg B6 orally after each HD session for a median follow‐up of 2.1 years

  • Taken under nurse supervision

 Co‐interventions

  • None

Outcomes

  • Total mortality

  • Occurrence of first fatal or nonfatal cardiovascular event (MI, unstable angina, coronary vascularisation procedure, sudden cardiac death, stroke, peripheral artery disease, PE, and thromboses). Shunt thromboses were not regarded as an end point

Notes

  • Funding source: School of Medicine of Otto‐von‐Guericke University Magdeburg; Roche diagnostics, Mannheim, Germany and Fresenius Medical Care, Bad Homburg, Germany

  • Study authors contacted for additional information but no additional information was obtained

  • Other: mandatory folic acid fortification was not present in Germany at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

RCT but sequence generation unclear

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind RCT

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Mortality data available on all patients

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other bias

HOST Study 2004

Methods

  • Study design: parallel RCT

  • Study duration: recruitment from September 2001 to October 2003, median follow‐up 3.2 years

  • Completeness of follow‐up: specific information regarding dialysis population not available; however, of 2056 randomised patients, 169 withdrew from regular telephone follow‐up but continued to allow medical record review, and 66 withdrew consent from follow‐up contacts and medical record review

  • Withdrawal of consent: specific information regarding dialysis population not available; however, of 2056 randomised patients, 66 withdrew consent from follow‐up contacts and medical record review

Participants

  • Setting: 36 participating outpatient VA medical centres

  • Country: USA

  • Relevant health status: ESKD on maintenance HD or PD, or with an estimated CrCl ≤ 30 mL/min and plasma homocysteine level ≥ 15 µmol/L. For this review only patients with ESKD were included

  • Number: treatment group (372); control group (379)

  • Mean age ± SD (years) (specific information regarding dialysis population not available): treatment group (65 ± 12); control group (66 ± 12)

  • Sex (male) (specific information regarding dialysis population not available): treatment group (98%); control group (98%)

  • Exclusion criteria: age < 21 years; expected life span < 6 months; pregnancy; metastatic cancer; end‐stage liver disease; treatment with methotrexate; other antifolate medication or anticonvulsants; unreliable or likely noncompliant participation in another long‐term RCT or unwilling or unable to give informed consent

Interventions

Treatment group

  • 40 mg folic acid, 100 mg vitamin B6, 2 mg vitamin B12 daily for a median follow‐up of 3.2 years

Control group

  • Identical: appearing placebo daily for a median follow‐up of 3.2 years

Co‐interventions

  • Participants in both groups were permitted to take additional vitamins containing no more than 1 mg of folate if prescribed by their physicians as part of their routine medical care

Outcomes

  • Time to death from any cause

  • Time to MI, stroke, amputation of all or part of a lower extremity, and a composite of these three plus all‐cause mortality

Notes

  • Funding source: Co‐operative Studies program, Department of Veterans Affairs Office of Research and Development. Abbott Laboratories donated the homocysteine analytic kits. The VA Palo Alto Health Care System received payment from Pam‐Lab for performing chemical analyses, including the salary of a research technician and for supplies

  • Study authors contacted for additional information but no additional information was obtained

  • Mandatory folic acid fortification was present in the USA at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random permuted block design of varying block size

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind RCT

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

For primary outcome all patients were counted. For secondary outcome analyses, 32 ESKD patients (from 751) were censored due to study withdrawal

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other bias

Righetti 2003

Methods

  • Study design: parallel RCT

  • Study duration: January 2001 to December 2003, median follow‐up 2.4 years

  • Completeness of follow‐up: of 114 patients, none were lost to follow‐up

  • Withdrawal of consent: none withdrew from participation

Participants

  • Setting: outpatient single centre study

  • Country: Italy

  • Relevant health status: ESKD treated for at least 4 months by HD

  • Number: treatment group (37); control group (51)

  • Mean age ± SD (years): treatment group (63.9 ± 1.6); control group (65.1 ± 1.9)

  • Sex (male): treatment group (65%); control group (49%)

  • Exclusion criteria: treatment with theophylline, oestrogens or anti‐epileptic medications

Interventions

Treatment group

  • 5 mg folic acid orally daily (every other day if serum folic acid > 16.8 ng/mL) along with an oral vitamin B complex (thiamine 250 mg, pyridoxine 250 mg and cyanocobalamin 500 mg every other day) for a median follow‐up of 871 days

Control group

  • Identical appearing placebo for a median follow‐up of 871 days

 Co‐interventions

  • None

Outcomes

  • Composite cardiovascular endpoint (typical history of angina with abnormal myocardial scintigraphy or coronarography, fatal and nonfatal MI, symptomatic extracranial carotid stenosis resulting in carotid endarterectomy, fatal and nonfatal stroke and sudden cardiac arrest)

Notes

  • Funding source: not provided

  • Study authors contacted for additional information but no additional information was obtained

  • Mandatory folic acid fortification was not present in Italy at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Independent person performed randomisation using a box containing blind numbers

Allocation concealment (selection bias)

Low risk

Independent person performed randomisation using a box containing blind numbers

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open RCT

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data complete

Selective reporting (reporting bias)

Unclear risk

Composite outcome reported

Other bias

High risk

No wash out period for group A, significant differences in baseline variables

Vianna 2007

Methods

  • Study design: parallel RCT

  • Study duration: April 2003 to March 2005, follow‐up 2 years

  • Completeness of follow‐up: no patients were lost to follow‐up. All patients were alive and examined at 6 months; between 6 and 24 months, 15 patients were transplanted and 53 died

  • Withdrawal of consent: 75 withdrew from participation

Participants

  • Setting: single centre outpatient study

  • Country: Brazil

  • Relevant health status: ESKD patients who were stable on HD 3 times/week for at least 4 months

  • Number: treatment group (93); control group (93)

  • Mean age ± SD (years): treatment group (49.3 ± 13.5); control group (47.6 ± 12.3)

  • Sex (male): treatment group (60%); control group (58%)

  • Exclusion criteria: a potential kidney transplant from a living donor in the next three months; class IV heart failure; unstable angina; indication for coronary revascularisation; recent cerebrovascular accident; cancer; and ongoing hospitalisation

Interventions

Treatment group

  • Oral folic acid 10 mg 3 times/week after dialysis sessions for 2 years

  • Under nurse supervision

Control group

  • Identical appearing placebo after dialysis sessions for 2 years

  • Under nurse supervision

 Co‐interventions

  • None

Outcomes

  • Primary end point was a composite of new major cardiovascular events, including death from cardiovascular causes, nonfatal MI, cardiac arrhythmias, angina, heart failure, and cerebral vascular accident

  • Secondary end point was the evaluation of the IMT of the common carotid arteries

Notes

  • Funding source: grant from Araucaria Foundation, a Parana State Government Agency

  • Study authors contacted for additional information but no additional information was obtained

  • Mandatory folic acid fortification was not present in Brazil at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blind RCT with participants and personnel blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinded fashion interpretation of secondary outcomes mentioned

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No patient lost to follow‐up

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other bias

Wrone 2004

Methods

  • Study design: parallel RCT

  • Study duration: March 1998 to May 1999

  • Completeness of follow‐up: patients terminated study interventions for the following reasons: death (189), received kidney transplant (58), moved away (37), and return of kidney function (2). There was no differential dropout among the treatment arms. Eight patients discontinued study medication due to side effects, which included nausea, abdominal discomfort, “hunger and weight gain”

  • Withdrawal of consent: 8 patients discontinued study medication due to side effects, which included nausea, abdominal discomfort, “hunger and weight gain.” The side effects were equally distributed among the treatment arms

Participants

  • Setting: 10 affiliated non‐profit outpatient dialysis facilities

  • Country: USA

  • Relevant health status: patients undergoing HD or PD

  • Number: treatment group 1 (176); treatment group 2 (166); control group (168)

  • Mean age ± SD (years): treatment group 1(59.8 ± 15.4), treatment group 2 (59.5 ± 15.4); control group (61.3 ± 14.6)

  • Sex (male): treatment group 1 (51.1%); treatment group 2 (48.9%), control group (50%)

  • Exclusion criteria: patients undergoing intradialytic parenteral nutrition; anticipating a living‐related kidney transplant; receiving an anti‐seizure medication; residing in an institution; terminally ill

Interventions

Treatment group 1

  • Renal multivitamin containing 5 mg of folic acid orally once daily for a median follow‐up of 2 years

Treatment group 2

  • Renal multivitamin containing 15 mg of folic acid orally once daily for a median follow‐up of 2 years

Control group

  • Renal multivitamin containing 1 mg folic acid orally once daily for a median follow‐up of 2 years

Co‐interventions

  • All capsules contained: 12.5 mg pyridoxine, 6 μg cobalamin, 60 mg ascorbic acid, 1.5 mg thiamine, 20 mg niacinamide, 10 mg pantothenic acid, and 0.3 mg biotin

Outcomes

  • Cardiovascular events (coronary artery intervention, MI, stroke, transient ischaemic attack, carotid endarterectomy, limb amputation) and mortality

  • Vascular access thrombosis (among those with AV fistulae)

Notes

  • Funding source: Study multivitamins were provided by R&D Laboratories, Inc., Marina del Rey, CA. This donor did not contribute to study design, data collection, analysis, interpretation of the data, or the decision to approve the manuscript

  • Study authors contacted for additional information but no additional information was obtained

  • Mandatory folic acid fortification was present in United States at the time of this study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Low risk

Randomisation codes were kept in a separate, locked file

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

To maintain double‐blind status, neither the person performing the randomisation nor the person preparing study medication for distribution to clinical coordinators had direct contact with participants. Patients, clinicians, and study staff with patient contact did not have access to any information that could identify treatment arm

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

18 patients of 588 did not receive intervention and were not analysed

Selective reporting (reporting bias)

Low risk

All relevant outcomes reported

Other bias

Low risk

The study appears to be free of other bias

AV ‐ arteriovenous; CAPD ‐ continuous ambulatory peritoneal dialysis; CKD ‐ chronic kidney disease; CrCl ‐ creatinine clearance; ESKD ‐ end‐stage kidney disease; HD ‐ haemodialysis; IMT ‐ intima‐media wall thickness; MI ‐ myocardial infarction; PD ‐ peritoneal dialysis; PE ‐ pulmonary embolism; RCT ‐ randomised controlled trial; SCr ‐ serum creatinine; SD ‐ standard deviation

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ali 2003

Intervention's primary action is not homocysteine lowering

Alvares Delfino 2007

< 100 patient‐years

Anderson 2006

< 100 patient‐years

Ardalan 2003

< 100 patient‐years

Ardalan 2003a

Kidney transplant not dialysis patients

Armada 2003

< 100 patient‐years

Arnadottir 2003

< 100 patient‐years

ATIC Study 2005

Multiple interventions and < 100 patient‐years

Azadibakhsh 2007

< 100 patient‐years

Beavers 2008

Not homocysteine lowering

Bennett‐Richards 2002

Cross‐over or sequential design

Bostom 1996

< 100 patient‐years

Bostom 2000

< 100 patient‐years

Branley 2000

< 100 patient‐years

Brensing 2002

< 100 patient‐years

Brensing 2003

< 100 patient‐years

Chang 2007

< 100 patient‐years

Chiu 2009

< 100 patient‐years

Cianciolo 2008

Compares different formulations

Cutler 2009

< 100 patient‐years

De Angelis 2007

< 100 patient‐years

De Vecchi 2001

< 100 patient‐years

De Vriese 2003

Sequential or cross‐over design

Del Pozo 2005

< 100 patient‐years

Dierkes 1999

< 100 patient‐years

Dierkes 2001

< 100 patient‐years

DIVINe Study 2010

Population: diabetic nephropathy

Dobronravov 2008

< 100 patient‐years

Ducloux 2002

< 100 patient‐years

Elian 2002

< 100 patient‐years

Friedman 2003

< 100 patient‐years

Galli 2003

< 100 patient‐years

Gonin 2003

< 100 patient‐years

Gonin 2003a

< 100 patient‐years

Hauser 2001

< 100 patient‐years

Henning 2001

< 100 patient‐years

Hoffer 2005

< 100 patient‐years

Hoffer 2005a

< 100 patient‐years

HOPE‐2 Study 2006

Population: CKD

House 1999

< 100 patient‐years

House 2004

Not folic acid‐based homocysteine lowering

Imani 2009

Not folic acid‐based homocysteine lowering

Isbel 2003

< 100 patient‐years

ISRCTN22151635

Not folic acid‐based homocysteine lowering

Jara 2001

< 100 patient‐years

Kazory 2008

Not folic acid‐based homocysteine lowering

Klemm 2004

Not proven homocysteine lowering treatment

Kooshki 2011

< 100 patient‐years

Koyama 2002

< 100 patient‐years

Koyama 2010

< 100 patient‐years

Kuhlmann 2004

< 100 patient‐years

Kumar 2007b

Cross‐over study

Kuo 2001a

< 100 patient‐years

LANDMARK Study 2006

Multiple interventions

Libetta 2004

< 100 patient‐years

Madsen 2011

Primary mechanism is not homocysteine lowering

Manns 2001

< 100 patient‐years

Mazdeh 2005

< 100 patient‐years

McGregor 2000a

< 100 patient‐years

Mudge 2005

< 100 patient‐years

Mueller 2001

< 100 patient‐years

Muller 2001

< 100 patient‐years

Nakamura 2003

Not an intervention study

Nakhoul 2004

< 100 patient‐years

Nascimento 2010

No pre‐specified outcome data

OPACH Study 2006

Intervention with other effects other than homocysteine lowering

Ossareh 2009

< 100 patient‐years

Pakfetrat 2013

< 100 patient‐years

Pastore 2006

< 100 patient‐years

Peng 2005

< 100 patient‐years

Polkinghorne 2003

< 100 patient‐years

Poulia 2011

< 100 patient‐years

Sanchez Alvarez 2005

< 100 patient‐years

Scholze 2004

N‐acetylcysteine study: intervention with multiple other effects other than homocysteine lowering

Seo 2003

< 100 patient‐years

Sepe 1999

< 100 patient‐years

Shemin 2001

Review article

Signorelli 2006

Intervention with no proven effects on homocysteine lowering

Skoutakis 1975

Not homocysteine lowering study

Stavrianaki 2002

< 100 patient‐years

Tamadon 2011

< 100 patient‐years

Tayyebi‐Khosroshahi 2010

Primary mechanism is not homocysteine lowering

Tepel 2003

N‐acetylcysteine study: intervention with multiple other effects other than homocysteine lowering

Thaha 2006

< 100 patient‐years

Thaha 2008

< 100 patient‐years

Thaha 2009

Cross‐over study

Thambyrajah 2000

< 100 patient‐years

Tobe 1999

< 100 patient‐years

Tochihara 2008

No pre‐specified outcomes

Treleaven 2001

No pre‐specified outcomes

Tremblay 2000

< 100 patient‐years

Trimarchi 2002

< 100 patient‐years

Tungkasereerak 2006

< 100 patient‐years

Urquhart 2008

< 100 patient‐years

van Guldener 1998

No pre‐specified outcomes

Van Tellingen 2001

No pre‐specified outcomes

VIENNA Study 2000

No pre‐specified outcomes

Vrentzos 2001

No pre‐specified outcomes

Vychytil 2003

< 100 patient‐years

Westphal 2001

Intervention with multiple effects in addition to homocysteine lowering

Yango 2001

< 100 patient‐years

Zeman 2006

< 100 patient‐years

Zuo 2001

< 100 patient‐years

CKD ‐ chronic kidney disease

Characteristics of studies awaiting assessment [ordered by study ID]

NCT00004495

Methods

This is an RCT. Patients are stratified according to pre‐study homocysteine levels (above or below average). Patients are randomised to receive placebo or one of two doses of oral folic acid, with or without pyridoxine and cyanocobalamin.

Arm I: Patients receive oral placebo daily.

Arm II: Patients receive oral pyridoxine, cyanocobalamin, and oral placebo daily.

Arm III: Patients receive oral pyridoxine, cyanocobalamin, and folic acid daily.

Arm IV: Patients receive oral pyridoxine and cyanocobalamin plus a higher dose of folic acid daily.

Arm V: Patients receive oral placebo and oral folic acid daily.

Arm VI: Patients receive oral placebo and higher dose folic acid daily.

Treatment continues for 8 weeks

Participants

Ages eligible for study:  21 to 89 years

Genders eligible for study:  both

Accepts healthy volunteers:  no

Entry criteria

Disease characteristics: diagnosis of ESKD requiring regular HD treatment 3 times weekly; baseline predialysis total homocysteine concentration in plasma greater than 16 µmol/L; no prior or concurrent pernicious anaemia; no blood smear examination showing unexplained macrocytosis

Prior/concurrent therapy

Chemotherapy: no concurrent chemotherapy for cancer

Other: no concurrent levodopa or carbidopa; no concurrent penicillamine or trimethoprim‐sulphonamide combination; no concurrent antiviral therapy No concurrent anticonvulsants

Patient characteristics

Hematopoietic: HCT at least 25%

Other: not pregnant or nursing Negative pregnancy test; fertile patients must use effective contraception; no Parkinson's disease; no convulsions or epilepsy requiring treatment; no lactose intolerance or allergy to milk products; no history of allergic sensitization following administration of folic acid, pyridoxine (vitamin B6), or cyanocobalamin (vitamin B12); no vitamin B12 concentration below lower limit of normal (150 pmol/L); no untreated hypothyroidism or psoriasis

Interventions

Patients are randomised to receive placebo or one of two doses of oral folic acid, with or without pyridoxine and cyanocobalamin

Arm I: Patients receive oral placebo daily

Arm II: Patients receive oral pyridoxine, cyanocobalamin, and oral placebo daily

Arm III: Patients receive oral pyridoxine, cyanocobalamin, and folic acid daily

Arm IV: Patients receive oral pyridoxine and cyanocobalamin plus a higher dose of folic acid daily

Arm V: Patients receive oral placebo and oral folic acid daily

Arm VI: Patients receive oral placebo and higher dose folic acid daily

Treatment continues for 8 weeks 

Outcomes

Objectives

I. Compare the efficacy of two doses of folic acid in normalizing plasma total homocysteine concentration in patients with ESKD receiving regular HD therapy resulting in hyperhomocysteinaemia

II. Determine the requirement of co‐supplementation with extra pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) daily in these patients

III. Assess the safety and tolerability of this therapy in these patients

Notes

 

Soleimani 2011

Methods

Participants

Interventions

Outcomes

Notes

Tayebi‐Khosroshahi 2013

Methods

Participants

Interventions

Outcomes

Notes

ESKD ‐ end‐stage kidney disease; HCT ‐ haematocrit; HD ‐ haemodialysis

Data and analyses

Open in table viewer
Comparison 1. Primary outcome

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality Show forest plot

4

1186

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.70, 1.22]

Analysis 1.1

Comparison 1 Primary outcome, Outcome 1 Cardiovascular mortality.

Comparison 1 Primary outcome, Outcome 1 Cardiovascular mortality.

Open in table viewer
Comparison 2. Secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

6

2447

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.89, 1.11]

Analysis 2.1

Comparison 2 Secondary outcomes, Outcome 1 All‐cause mortality.

Comparison 2 Secondary outcomes, Outcome 1 All‐cause mortality.

2 Myocardial infarction (fatal and non fatal) Show forest plot

4

1510

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.66, 1.62]

Analysis 2.2

Comparison 2 Secondary outcomes, Outcome 2 Myocardial infarction (fatal and non fatal).

Comparison 2 Secondary outcomes, Outcome 2 Myocardial infarction (fatal and non fatal).

3 Coronary revascularisation Show forest plot

2

1160

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.22, 3.14]

Analysis 2.3

Comparison 2 Secondary outcomes, Outcome 3 Coronary revascularisation.

Comparison 2 Secondary outcomes, Outcome 3 Coronary revascularisation.

4 Stroke Show forest plot

4

1510

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.57, 1.40]

Analysis 2.4

Comparison 2 Secondary outcomes, Outcome 4 Stroke.

Comparison 2 Secondary outcomes, Outcome 4 Stroke.

5 Deep venous thrombosis and pulmonary embolism Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

Analysis 2.5

Comparison 2 Secondary outcomes, Outcome 5 Deep venous thrombosis and pulmonary embolism.

Comparison 2 Secondary outcomes, Outcome 5 Deep venous thrombosis and pulmonary embolism.

6 Thrombosis of dialysis access Show forest plot

2

1261

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.88, 1.14]

Analysis 2.6

Comparison 2 Secondary outcomes, Outcome 6 Thrombosis of dialysis access.

Comparison 2 Secondary outcomes, Outcome 6 Thrombosis of dialysis access.

7 Adverse events Show forest plot

3

1248

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.51, 2.47]

Analysis 2.7

Comparison 2 Secondary outcomes, Outcome 7 Adverse events.

Comparison 2 Secondary outcomes, Outcome 7 Adverse events.

Flow diagram showing study selection
Figures and Tables -
Figure 1

Flow diagram showing study selection

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Funnel plot of comparison: 2 Secondary outcomes, outcome: 2.1 all‐cause mortality
Figures and Tables -
Figure 4

Funnel plot of comparison: 2 Secondary outcomes, outcome: 2.1 all‐cause mortality

Comparison 1 Primary outcome, Outcome 1 Cardiovascular mortality.
Figures and Tables -
Analysis 1.1

Comparison 1 Primary outcome, Outcome 1 Cardiovascular mortality.

Comparison 2 Secondary outcomes, Outcome 1 All‐cause mortality.
Figures and Tables -
Analysis 2.1

Comparison 2 Secondary outcomes, Outcome 1 All‐cause mortality.

Comparison 2 Secondary outcomes, Outcome 2 Myocardial infarction (fatal and non fatal).
Figures and Tables -
Analysis 2.2

Comparison 2 Secondary outcomes, Outcome 2 Myocardial infarction (fatal and non fatal).

Comparison 2 Secondary outcomes, Outcome 3 Coronary revascularisation.
Figures and Tables -
Analysis 2.3

Comparison 2 Secondary outcomes, Outcome 3 Coronary revascularisation.

Comparison 2 Secondary outcomes, Outcome 4 Stroke.
Figures and Tables -
Analysis 2.4

Comparison 2 Secondary outcomes, Outcome 4 Stroke.

Comparison 2 Secondary outcomes, Outcome 5 Deep venous thrombosis and pulmonary embolism.
Figures and Tables -
Analysis 2.5

Comparison 2 Secondary outcomes, Outcome 5 Deep venous thrombosis and pulmonary embolism.

Comparison 2 Secondary outcomes, Outcome 6 Thrombosis of dialysis access.
Figures and Tables -
Analysis 2.6

Comparison 2 Secondary outcomes, Outcome 6 Thrombosis of dialysis access.

Comparison 2 Secondary outcomes, Outcome 7 Adverse events.
Figures and Tables -
Analysis 2.7

Comparison 2 Secondary outcomes, Outcome 7 Adverse events.

Comparison 1. Primary outcome

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality Show forest plot

4

1186

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.70, 1.22]

Figures and Tables -
Comparison 1. Primary outcome
Comparison 2. Secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

6

2447

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.89, 1.11]

2 Myocardial infarction (fatal and non fatal) Show forest plot

4

1510

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.66, 1.62]

3 Coronary revascularisation Show forest plot

2

1160

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.22, 3.14]

4 Stroke Show forest plot

4

1510

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.57, 1.40]

5 Deep venous thrombosis and pulmonary embolism Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

6 Thrombosis of dialysis access Show forest plot

2

1261

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.88, 1.14]

7 Adverse events Show forest plot

3

1248

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.51, 2.47]

Figures and Tables -
Comparison 2. Secondary outcomes