A new formula is proposed to express the excess burden of cardiovascular risk faced by hemodialysis patients as a function of various inherent, acquired and potentially modifiable factors. The proposed equation CVRHD = CVRB X f(([CKD+HD]/[HDtech+Dr])+X) includes the terms: CVRHD (cardiovascular risk in hemodialysis patients); CVRB (baseline cardiovascular risk); CKD (risk associated with chronic kidney disease); HD (risks associated with the process of hemodialysis); HDtech (benefits of new hemodialysis technologies); Dr (benefits of drug therapies) and X (unknown or putative factors influencing cardiovascular morbidity).
We review the various factors included in this proposed formula, touching upon the epidemiology, pathophysiology and therapeutic implications, including possible strategies to modify risk. As is apparent from the formula, CKD and HD in particular act as risk multipliers in augmenting or amplifying the baseline cardiovascular risk, while new hemodialysis technologies may provide an opportunity for “cardioprotective dialysis.” Drug treatment may serve to mitigate some of the risk unique to this population.
GotchF.A., PanlilioF., SergeyevaO.A kinetic model of inorganic phosphorus mass balance in hemodialysis therapy. Blood Purif2003; 21: 51–7.
2.
GotchF.A., SargentJ.A.A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int1985; 28: 526–34.
3.
GotchF., KotankoP., HandelmanG., LevinN.A kinetic model of calcium mass balance during dialysis therapy. Blood Purif2007; 25: 139–49.
4.
YusufS., HawkenS., OunpuuS.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet2004; 364: 937–52.
5.
CulletonB.F., HemmelgarnB.Inadequate treatment of cardiovascular disease and cardiovascular disease risk factors in dialysis patients: a commentary. Semin Dial2004; 17: 342–5.
6.
WangT.J., GonaP., LarsonM.G.Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med2006; 355: 2631–9.
7.
BlankenbergS., McQueenM.J., SmiejaM.Comparative impact of multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation2006; 114: 201–8.
8.
RidkerP.M., RifaiN., RoseL.Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med2002; 347: 1557–65.
9.
LiuzzoG., BiasucciL.M., GallimoreJ.R.The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med1994; 331: 417–24.
10.
ParikhS.V., de LemosJ.A.Biomarkers in cardiovascular disease: integrating pathophysiology into clinical practice. Am J Med Sci2006; 332: 186–97.
11.
RattazziM., PuatoM., FagginE.New markers of accelerated atherosclerosis in end-stage renal disease. J Nephrol2003; 16: 11–20.
12.
StenvinkelP.Inflammation in end-stage renal disease: the hidden enemy. Nephrology (Carlton)2006; 11: 36–41.
13.
VermaS., KuliszewskiM.A., LiS.H.C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation2004; 109: 2058–67.
14.
D'AiutoF., ParkarM., NibaliL.Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am Heart J2006; 151: 977–84.
15.
IshaniA., GranditsG.A., GrimmR.H.Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial. J Am Soc Nephrol2006; 17: 1444–52.
16.
GargA.X., ClarkW.F., HaynesR.B., HouseA.A.Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I. Kidney Int2002; 61: 1486–94.
17.
GoA.S., ChertowG.M., FanD.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med2004; 351: 1296–1305.
18.
TonelliM., WiebeN., CulletonB.Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol2006; 17: 2034–47.
19.
UrquhartB.L., HouseA.A.Assessing plasma total homocysteine in patients with end-stage renal disease. Perit Dial Int2007; 27: 476–88.
20.
BlockG.A., KlassenP.S., LazarusJ.M.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol2004; 15: 2208–18.
21.
BostomA.G., KronenbergF., JacquesP.F.Proteinuria and plasma total homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true glomerular filtration rate. Atherosclerosis2001; 159: 219–23.
22.
BuschM., FrankeS., MullerA.Potential cardiovascular risk factors in chronic kidney disease: AGEs, total homocysteine and metabolites, and the C-reactive protein. Kidney Int2004; 66: 338–47.
23.
PiferT.B., McCulloughK.P., PortF.K.Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS. Kidney Int2002; 62: 2238–45.
24.
LevinA., ThompsonC.R., EthierJ.Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis1999; 34: 125–34.
25.
MeyerT.W., HostetterT.H.Uremia. N Engl J Med2007; 357: 1316–25.
26.
FoleyR.N., ParfreyP.S., SarnakM.J.Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis1998; 32(Suppl 3): S112–9.
27.
FortJ.Chronic renal failure: a cardiovascular risk factor. Kidney Int Suppl2005; 68: S25–9.
28.
SchiffrinE.L., LipmanM.L., MannJ.F.Chronic kidney disease: effects on the cardiovascular system. Circulation2007; 116: 85–97.
29.
BologaR.M., LevineD.M., ParkerT.S.Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis1998; 32: 107–14.
30.
WrattenM.L., GalarisD., TettaC., SevanianA.Evolution of oxidative stress and inflammation during hemodialysis and their contribution to cardiovascular disease. Antioxid Redox Signal2002; 4: 935–44.
PanichiV., MaggioreU., TaccolaD.Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol Dial Transplant2004; 19: 1154–60.
33.
PozzoniP., Del VecchioL., PontorieroG.Long-term outcome in hemodialysis: morbidity and mortality. J Nephrol2004; 17(Suppl 8): S87–95.
34.
ZoccaliC., MallamaciF., TripepiG.Traditional and emerging cardiovascular risk factors in end-stage renal disease. Kidney Int Suppl2003; 85: S105–10.
35.
StenvinkelP., BaranyP., HeimburgerO.Mortality, mal-nutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?Kidney Int Suppl2002; 61: S103–8.
36.
ZimmermannJ., HerrlingerS., PruyA.Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int1999; 55: 648–58.
37.
MovilliE., FelicianiA., CameriniC.A high calcium-phosphate product is associated with high C-reactive protein concentrations in hemodialysis patients. Nephron Clin Pract2005; 101: c161–7.
38.
YeunJ.Y., LevineR.A., MantadilokV., KaysenG.A.C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis2000; 35: 469–76.
39.
AnandS.S., RazakF., YiQ.C-reactive protein as a screening test for cardiovascular risk in a multiethnic population. Arterioscler Thromb Vasc Biol2004; 24: 1509–15.
40.
StenvinkelP.Inflammatory and atherosclerotic interactions in the depleted uremic patient. Blood Purif2001; 19: 53–61.
41.
SchindlerR., BeckW., DeppischR.Short bacterial DNA fragments: detection in dialysate and induction of cytokines. J Am Soc Nephrol2004; 15: 3207–14.
42.
CazzavillanS., RatanaratR., SegalaC.Inflammation and subclinical infection in chronic kidney disease: a molecular approach. Blood Purif2007; 25: 69–76.
43.
DaugirdasJ.T.Pathophysiology of dialysis hypotension: an update. Am J Kidney Dis2001; 38(Suppl 4): S11–7.
44.
SchreiberM.J.Setting the stage. Am J Kidney Dis2001; 38(Suppl 4): S1–10.
45.
RoccoM.V., BurkartJ.M.Prevalence of missed treatments and early sign-offs in hemodialysis patients. J Am Soc Nephrol1993; 4: 1178–83.
YetkinE., IleriM., TandoganI.Increased QT interval dispersion after hemodialysis: role of peridialytic electrolyte gradients. Angiology2000; 51: 499–504.
48.
MacRaeJ.M.Vascular access and cardiac disease: is there a relationship?Curr Opin Nephrol Hypertens2006; 15: 577–82.
49.
MacRaeJ.M., PandeyaS., HumenD.P.Arteriovenous fistula-associated high-output cardiac failure: a review of mechanisms. Am J Kidney Dis2004; 43: e17–22.
50.
EknoyanG., BeckG.J., CheungA.K.Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med2002; 347: 2010–19.
51.
PupimL.B., HimmelfarbJ., McMonagleE.Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress. Kidney Int2004; 65: 2371–9.
52.
StenvinkelP., WangK., QureshiA.R.Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin. Kidney Int2005; 67: 2383–92.
53.
MacleodA.M., CampbellM., CodyJ.D.Cellulose, modified cellulose and synthetic membranes in the haemodialysis of patients with end-stage renal disease. Cochrane Database Syst Rev2005; 3: CD003234.
54.
HouseA.A., WellsG.A., DonnellyJ.G.Randomized trial of high-flux vs low-flux haemodialysis: effects on homocysteine and lipids. Nephrol Dial Transplant2000; 15: 1029–34.
55.
ChauveauP., NguyenH., CombeC.Dialyzer membrane permeability and survival in hemodialysis patients. Am J Kidney Dis2005; 45: 565–71.
56.
GerdemannA., WagnerZ., SolfA.Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality. Nephrol Dial Transplant2002; 17: 1045–9.
57.
AltieriP., SorbaG.B., BolascoP.G.On-line predilution hemofiltration versus ultrapure high-flux hemodialysis: a multicenter prospective study in 23 patients. Sardinian Collaborative Study Group of On-Line Hemofiltration. Blood Purif1997; 15: 169–81.
VaslakiL., MajorL., BertaK.On-line haemodiafiltration versus haemodialysis: stable haematocrit with less erythropoietin and improvement of other relevant blood parameters. Blood Purif2006; 24: 163–73.
60.
CanaudB., MorenaM., Leray-MoraguesH.Overview of clinical studies in hemodiafiltration: what do we need now?Hemodial Int2006; 10(Suppl 1): S5–12.
61.
BasileC., GiordanoR., VernaglioneL.Efficacy and safety of haemodialysis treatment with the Hemocontrol bio-feedback system: a prospective medium-term study. Nephrol Dial Transplant2001; 16: 328–34.
62.
SantoroA., ManciniE., BasileC.Blood volume controlled hemodialysis in hypotension-prone patients: a randomized, multicenter controlled trial. Kidney Int2002; 62: 1034–45.
63.
DézielC., BouchardJ., ZellwegerM., MadoreF.Impact of Hemocontrol on hypertension, nursing interventions, and quality of life: a randomized, controlled trial. Clin J Am Soc Nephrol2007; 2: 661–8.
64.
WannerC., KraneV., MarzW.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med2005; 353: 238–48.
65.
LocatelliF., PisoniR.L., CombeC.Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant2004; 19: 121–32.
66.
SinghA.K., SzczechL., TangK.L.Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med2006; 355: 2085–98.
67.
DruekeT.B., LocatelliF., ClyneN.Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med2006; 355: 2071–84.
68.
TonelliM., WiebeN., CulletonB.Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant2007; 22: 2856–66.
69.
SukiW.N., ZabanehR., CangianoJ.L.Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int2007; 72: 1130–7.
70.
JamisonR.L., HartiganP., KaufmanJ.S.Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA2007; 298: 1163–70.
71.
WroneE.M., HornbergerJ.M., ZehnderJ.L.Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol2004; 15: 420–6.
72.
UrquhartB.L., FreemanD.J., SpenceJ.D., HouseA.A.The effect of mesna on plasma total homocysteine concentration in hemodialysis patients. Am J Kidney Dis2007; 49: 109–117.
73.
GarsideR., PittM., AndersonR.The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation. Health Technol Assess2007; 11: iii, xi–xiii, 1-167.
74.
ChertowG.M., PupimL.B., BlockG.A.Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. Clin J Am Soc Nephrol2007; 2: 898–905.
75.
WesterweelP.E., HoeferI.E., BlankestijnP.J.End-stage renal disease causes an imbalance between endothelial and smooth muscle progenitor cells. Am J Physiol Renal Physiol2007; 292: F1132–40.
