Wheeler DC. Cardiovascular disease in patients with chronic renal failure. Lancet. 1996;348(9043):1673–4.

CAS  Article  Google Scholar 

Sozio SM, Armstrong PA, Coresh J, Jaar BG, Fink NE, Plantinga LC, et al. Cerebrovascular disease incidence, characteristics, and outcomes in patients initiating dialysis: the choices for healthy outcomes in caring for ESRD (CHOICE) study. Am J Kidney Dis. 2009;54(3):468–77. https://doi.org/10.1053/j.ajkd.2009.01.261.

Article  PubMed  PubMed Central  Google Scholar 

•• Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339–52. https://doi.org/10.1016/S0140-6736(13)60595-4. An important paper that quantifies cardiovascular risk by severity of CKD.

Article  PubMed  Google Scholar 

Bowman B, Abdel-Rahman EM. Cardiovascular outcomes in dialysis patients: one size does not fit all. Eur Heart J. 2019;40(11):899–901. https://doi.org/10.1093/eurheartj/ehy544.

Article  PubMed  Google Scholar 

• Ku E, McCulloch CE, Ahearn P, Grimes BA, Mitsnefes MM. Trends in cardiovascular mortality among a cohort of children and young adults starting dialysis in 1995 to 2015. JAMA Netw Open. 2020;3(9):e2016197. https://doi.org/10.1001/jamanetworkopen.2020.16197. Secular trends of CVD mortality in dialysis patients.

Article  PubMed  PubMed Central  Google Scholar 

Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.

Article  Google Scholar 

• Ghoshal S, Freedman BI. Mechanisms of stroke in patients with chronic kidney disease. Am J Nephrol. 2019;50(4):229–39. https://doi.org/10.1159/000502446. A review of mechanisms of stroke in CKD.

Article  PubMed  Google Scholar 

Albakr RB, Bargman JM. A comparison of hemodialysis and peritoneal dialysis in patients with cardiovascular disease. Cardiol Clin. 2021;39(3):447–53. https://doi.org/10.1016/j.ccl.2021.04.013.

Article  PubMed  Google Scholar 

Loutradis C, Papadopoulos CE, Sarafidis P. Longer dialysis sessions improve cardiac systolic function by reducing myocardial stunning. J Card Fail. 2020;26(11):1026–7. https://doi.org/10.1016/j.cardfail.2020.06.001.

Article  PubMed  Google Scholar 

•• Sillesen H, Muntendam P, Adourian A, Entrekin R, Garcia M, Falk E et al. Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage Study. JACC Cardiovasc Imaging. 2012;5(7):681–9. S1936–878X(12)00397-X; https://doi.org/10.1016/j.jcmg.2012.03.013. An important study reporting that measurement of carotid plaque burden correlates highly with coronary calcium whereas IMT does not.

•• Baber U, Mehran R, Sartori S, Schoos MM, Sillesen H, Muntendam P et al. Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study. J Am Coll Cardiol. 2015;65(11):1065–74. https://doi.org/10.1016/j.jacc.2015.01.017. An important paper reporting that carotid plaque burden is as predictive of CVD as coronary calcium whereas IMT is not.

•• Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002;33(12):2916–22. The original description of the high CVD risk associated with high carotid plaque burden.

•• Spence JD, Hackam DG. Treating arteries instead of risk factors. a paradigm change in management of atherosclerosis. Stroke. 2010;41(6):1193–9. STROKEAHA.110.577973; https://doi.org/10.1161/STROKEAHA.110.577973. The original description of a process called “Treating Arteries” instead of merely treating risk factors to consensus targets.

•• Spence JD, Coates V, Li H, Tamayo A, Munoz C, Hackam DG et al. Effects of Intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol. 2010;67(2):180–6. The original description of marked reduction of CVD risk by “Treating arteries.”

•• Spence JD, Solo K. Resistant Atherosclerosis: The Need for Monitoring of Plaque Burden. Stroke. 2017;48(6):1624–9. https://doi.org/10.1161/STROKEAHA.117.017392. The original description of “Resistant Atherosclerosis.”

Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238–48. https://doi.org/10.1056/NEJMoa043545.

CAS  Article  PubMed  Google Scholar 

Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395–407. https://doi.org/10.1056/NEJMoa0810177.

CAS  Article  PubMed  Google Scholar 

•• Lim YJ, Sidor NA, Tonial NC, Che A, Urquhart BL. Uremic toxins in the progression of chronic kidney disease and cardiovascular disease: mechanisms and therapeutic targets. Toxins (Basel). 2021;13(2). https://doi.org/10.3390/toxins13020142. A review of uremic toxins, mechanisms, and therapeutic targets.

• Rader DJ, Ischiropoulos H. ‘Multipurpose oxidase’ in atherogenesis. Nat Med. 2007;13(10):1146–7. An important review of thiocyanate and oxidation in atherosclerosis.

• Nygård O, Nordehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230–6. Showed strong graded CVD risk with plasma total homocysteine.

•• Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018;273:91–7. https://doi.org/10.1016/j.atherosclerosis.2018.04.015. Plasma levels of the toxic metabolites of the intestinal microbiome are higher in patients with severe atherosclerosis despite low levels of traditional risk factors.

Poesen R, Claes K, Evenepoel P, de Loor H, Augustijns P, Kuypers D, et al. Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J Am Soc Nephrol. 2016;27(11):3479–87. https://doi.org/10.1681/ASN.2015121302.

CAS  Article  PubMed  PubMed Central  Google Scholar 

• Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180(5):862–77 e22. https://doi.org/10.1016/j.cell.2020.02.016. Phenylacetylglutamine affects platelet function by an adrenergic mechanism.

•• Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84. Plasma TMAO increased 2.5-fold the 3-year CVD risk in patients referred for coronary angiography.

Senthong V, Wang Z, Fan Y, Wu Y, Hazen SL, Tang WH. Trimethylamine N-oxide and mortality risk in patients with peripheral artery disease. J Am Heart Assoc. 2016;5(10). https://doi.org/10.1161/JAHA.116.004237.

• Pignanelli M, Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Urquhart BL et al. Moderate renal impairment and toxic metabolites produced by the intestinal microbiome: dietary implications. J Ren Nutr. 2019;29(1):55–64. https://doi.org/10.1053/j.jrn.2018.05.007. Even moderate renal impairment significantly increases plasma levels of the toxic metabolites of the intestinal microbiome.

•• Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116(3):448–55. CIRCRESAHA.116.305360 [pii]; https://doi.org/10.1161/CIRCRESAHA.116.305360. TMAO accelerates decline of renal function and increases mortality in CKD.

Spence JD, Urquhart BL, Bang H. Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine. Nephrol Dial Transplant. 2016;31(6):937–44. https://doi.org/10.1093/ndt/gfv380.

CAS  Article  PubMed  Google Scholar 

Spence JD, Urquhart BL, Bang H. Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine. Nephrol Dial Transplant. 2015. https://doi.org/10.1093/ndt/gfv380.

Article  PubMed  PubMed Central  Google Scholar 

•• Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant. 1997;12(8):1622–8. Patients with severe CKD have high plasma cyanide/thiocyanate.

•• 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. Am J Kidney Dis. 2010;55(6):1069–78. Methylcobalamin and folate significantly reduce tHcy and ADMA in dialysis patients.

Poesen R, Claes K, Evenepoel P, de Loor H, Augustijns P, Kuypers D, et al. Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J Am Soc Nephrol. 2016. https://doi.org/10.1681/ASN.2015121302.

Article  PubMed  PubMed Central  Google Scholar 

Poesen R, Evenepoel P, de Loor H, Kuypers D, Augustijns P, Meijers B. Metabolism, protein binding, and renal clearance of microbiota-derived p-cresol in patients with CKD. Clin J Am Soc Nephrol. 2016;11(7):1136–44. https://doi.org/10.2215/CJN.00160116.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Rossi M, Campbell K, Johnson D, Stanton T, Pascoe E, Hawley C, et al. Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: an observational study. Nutr Metab Cardiovasc Dis. 2014;24(9):1035–42. https://doi.org/10.1016/j.numecd.2014.04.006.

CAS  Article  PubMed  Google Scholar 

Lin CJ, Pan CF, Chuang CK, Sun FJ, Wang DJ, Chen HH, et al. P-cresyl sulfate is a valuable predictor of clinical outcomes in pre-ESRD patients. Biomed Res Int. 2014;2014:526932. https://doi.org/10.1155/2014/526932.

Article  PubMed  PubMed Central  Google Scholar 

Lin CJ, Wu V, Wu PC, Wu CJ. Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One. 2015;10(7):e0132589. https://doi.org/10.1371/journal.pone.0132589.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Lin CJ, Lin J, Pan CF, Chuang CK, Liu HL, Sun FJ, et al. Indoxyl sulfate, not P-cresyl sulfate, is associated with advanced glycation end products in patients on long-term hemodialysis. Kidney Blood Press Res. 2015;40(2):121–9. https://doi.org/10.1159/000368488.

CAS  Article  PubMed  Google Scholar 

Keys A. Mediterranean diet and public health: personal reflections. Am J Clin Nutr. 1995;61(6 Suppl):1321S-S1323.

CAS  Article  Google Scholar 

•• Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(3):229–41. The Mediterranean diet is better for insulin resistance and diabetes than a low-fat or low-carbohydrate diet.

CAS  Article  Google Scholar 

Spence JD. Reducing the risk of stroke in patients with impaired renal function: nutritional issues. J Stroke Cerebrovasc Dis. 2020;105376. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105376.

Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85. nm.3145 https://doi.org/10.1038/nm.3145.

Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63. nature09922 https://doi.org/10.1038/nature09922.

•• Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J. 2019;40(7):583–94. https://doi.org/10.1093/eurheartj/ehy799. Switching from red meat to white meat or a meatless diet markedly reduces TMAO levels within a month.

CAS  Article  PubMed  Google Scholar 

• Spence JD, Srichaikul KK, Jenkins DJA. Cardiovascular harm from egg yolk and meat: more than just cholesterol and saturated fat. J Am Heart Assoc. 2021;10(7):e017066. https://doi.org/10.1161/JAHA.120.017066. Meat and egg yolk not only increase CVD risk because of cholesterol and saturated fat but also increase plasma levels of toxic intestinal metabolites.

Article  PubMed  PubMed Central  Google Scholar 

Cailleux A, Subra JF, Riberi P, Tuchais E, Premel-Cabic A, Allain P. Cyanide and thiocyanate blood levels in patients with renal failure or respiratory disease. J Med. 1988;19(5–6):345–51.

CAS  PubMed  Google Scholar 

Hasuike Y, Nakanishi T, Moriguchi R, Otaki Y, Nanami M, Hama Y, et al. Accumulation of cyanide and thiocyanate in haemodialysis patients. Nephrol Dial Transplant. 2004;19(6):1474–9.

CAS  Article  Google Scholar 

•• 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. https://doi.org/10.1001/jama.2010.490. B vitamins containing 1000 mcg daily of cyanocobalamin doubled CVD risk in patients with diabetic nephropathy.

Spence JD, Eliasziw M, House AA. B-vitamin therapy for diabetic nephropathy: reply. JAMA. 2010;304(6):636–7.

CAS  Article  Google Scholar 

•• Xu X, Qin X, Li Y, Sun D, Wang J, Liang M et al. Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy of the China Stroke Primary Prevention Trial. JAMA Intern Med. 2016;176(10):1443–50. https://doi.org/10.1001/jamainternmed.2016.4687. Folic acid significantly reduced the risk of stroke among >20,000 hypertensive patients over 4.5 years.

• Spence JD, Hankey GJ. Problem in the recent American Heart Association guideline on secondary stroke prevention: B vitamins to lower homocysteine do prevent stroke. Stroke. 2022:101161STROKEAHA122038640. https://doi.org/10.1161/STROKEAHA.122.038640. B vitamins do reduce the risk of stroke, but we should be using methylcobalamin, not cyanocobalamin.

EFSA Panel on Dietetic Products N, Allergies. Scientific opinion on dietary reference values for cobalamin (vitamin B12). EFSA Journal. 2015;13(7):4150. https://doi.org/10.2903/j.efsa.2015.4150.

Zhang Y-F, Ning G. Mecobalamin. Expert Opin Investig Drugs. 2008;17(6):953–64. https://doi.org/10.1517/13543784.17.6.953.

Article  PubMed  Google Scholar 

Herrington W, Haynes R, Staplin N, Emberson J, Baigent C, Landray M. Evidence for the prevention and treatment of stroke in dialysis patients. Semin Dial. 2015;28(1):35–47. https://doi.org/10.1111/sdi.12281.

Article  PubMed  Google Scholar 

Shih DM, Zhu W, Schugar RC, Meng Y, Jia X, Miikeda A, et al. Genetic deficiency of flavin-containing monooxygenase 3 ( Fmo3) protects against thrombosis but has only a minor effect on plasma lipid levels-brief report. Arterioscler Thromb Vasc Biol. 2019;39(6):1045–54. https://doi.org/10.1161/ATVBAHA.119.312592.

CAS  Article