It has been known for a long time that chronic kidney disease(CKD) is associated with dyslipidemia, but the full extent ofabnormalities has been appreciated only recently, because routinelaboratory tests fail to disclose the entire spectrum of lipidabnormalities. Lipids, particularly HDL cholesterol, are predictiveof cardiovascular events, but a paradoxic inverse relation betweencholesterol concentration and cardiovascular death has beennoted in uremic patients. This currently is thought to be explainedby the confounding effect of microinflammation and possiblycalcification, but this is not definitely proved. Several retrospectiveanalyses that included patients with mild or moderate CKD documentedbenefit from lowering of cholesterol by statins. In contrast,the Die Deutsche Diabetes Dialyse (4D) study and a small Scandinavianstudy failed to show a benefit from lowering of cholesterolby statins in ESRD. Pathomechanistically, it is possible thatnonclassical pathomechanisms override statin-sensitive mechanismsas also suggested by the observation that statins fail to reducecarotid intima-media thickening. Although, experimentally, exposureto lipids (particularly oxidized lipids) aggravates progression,data on the effect of statins on progression in patients withCKD are not definite. The most likely explanation is that theimpact of numerous confounders obscures their effect on progression.The increase in urinary protein excretion of patients who aretreated with statins had been a cause of concern, but the underlyingmechanism (i.e. interference with proximal tubular reabsorptionof protein) meanwhile has been well documented.
Since the days of Richard Bright, it has been known that inpatients with advanced renal disease, the serum is "milky,"pointing to the presence of hyperlipidemia. More recently, interestin hyperlipidemia of renal disease has been raised by the considerationthat the known abnormalities in the lipid spectrum of renalpatients might predispose to accelerated atherosclerosis (1).Indeed, the Seattle Group found excess death from coronary heartdisease in a large proportion of the first cohort of patientswho had been started on hemodialysis in Seattle (2).
The magnitude of lipid changes is not disclosed fully by routinelaboratory chemistry, which usually shows normal total and LDLcholesterol, low HDL cholesterol, and high triglycerides. Asshown in Table 1, more sophisticated analysis shows strikingabnormalities: Increased VLDL; remnants and intermediate-densitylipoproteins (3); prolonged persistence of postprandial chylomicronremnants (4); accumulation of small dense LDL; modificationof apolipoproteins by glycation, oxidation, and carbamoylation(5); increased lipoprotein(a) [Lp(a)] (6); and accumulationof noncardioprotective acute-phase HDL (7,8). An interestingproposal was made by Shoji et al. (9), who showed that intermediate-densitylipoproteins were an independent risk factor for aortic atherosclerosis.They also proposed calculation of non-HDL cholesterol (the sumof LDL and VLDL cholesterol). The latter is particularly elevatedin renal failure (10).
In a prospective study, Degoulet et al. (11) made the unexpected—andat first counterintuitive—observation that in dialysispatients, low cholesterol concentrations were associated withhigh mortality. This key observation meanwhile was confirmedin numerous studies (12,13). In a cohort of 823 patients whowere admitted for dialysis, Liu et al. (13) found in the overallcohort that an increased serum cholesterol was associated witha decreased risk for all-cause mortality, whereas in the absenceof inflammation/malnutrition (22% of the cohort with serum albumin>3.6 mg/dl, C-reactive protein <10 mg/L, and IL-6 <3.09pg/ml), an increment in baseline serum cholesterol was associatedwith increased mortality, as it is in the general population.This study demonstrates that the predictive value of cholesterolis confounded by concomitant inflammation.
Another controversial issue in the past had been the clinicalimplications of the changes in Lp(a) concentration. Lp(a) iscorrelated positively with higher cardiovascular risk in thegeneral population (14) but strongly dependent of the genotypeand the concomitant isoproteins of apolipoprotein(a) [apo(a)].Individuals with low molecular weight isoforms have the highestserum Lp(a) concentrations. In renal patients, the average Lp(a)concentration is particularly increased, but the absolute serumconcentration of Lp(a) is less predictive than the isoform itself.The prognosis is particularly adverse in patients with the lowmolecular weight apo(a) isoform compared with the high molecularweight isoform (15).
Evidence for Accelerated Atherosclerosis in Chronic Kidney Disease
Cross-sectional studies documented the high prevalence of carotidartery atherosclerosis and of atherosclerotic peripheral arterydisease (16). Autopsy studies showed an excessive prevalenceof advanced coronary atherosclerosis (17), and this has beenconfirmed by coronary angiography (18) and electron beam computedtomography (19). Coronary calcification is regarded as an indexof coronary atherosclerosis. Although in renal patients calcificationmay not be a specific expression of coronary atherosclerosis(and partially reflect media sclerosis as well), longitudinalstudies showed accelerated calcification of the coronaries comparedwith that in nonrenal control subjects (19,20), and this wastrue even in early renal disease (21).
In the first description of coronary artery disease of dialyzedpatients (2), the authors postulated that in uremic patients,atherogenesis was accelerated. Indeed, several groups showedaccelerated aortic atherosclerosis in the experimental modelof the apoE knockout mouse with reduced renal function (22–24).This is seen even with minor reduction of renal function (e.g.,uninephrectomy [22]) and responds to administration of angiotensinreceptor blockers (25).
It had been known for a long time that in diverse models ofrenal damage, high-lipid diets or other maneuvers to inducehyperlipidemia aggravate glomerulosclerosis and progressiverenal dysfunction (26–28). Oxidized lipids are particularlyinjurious in this context (29,30). Although various parametersof dyslipidemia predict accelerated progression in humans (31),a beneficial effect of statins on progression has not been documentedbeyond doubt. In several studies and meta-analyses that examinedthe effect of lipid lowering by statins, a trend for slowerprogression was seen (32), but this finding has not been consistentand significant (33). The most likely explanation is that inrenal patients, the adverse effect of dyslipidemia (and thebenefit from its reversal), which has been documented clearlyin animal experiments, is confounded and overridden by factorsthat are difficult to control fully even in prospective studies(e.g., BP, proteinuria). In populations with cardiovasculardisease, a recent meta-analysis showed that statin therapy seemsto reduce proteinuria modestly and results in a small reductionin the rate of kidney function loss (34).
Effect of Statins on Cardiovascular Disease in Patients with Chronic Kidney Disease
In large, prospective statin trials, post hoc analysis of theproportion of the included patients who had impaired renal function(mainly stages 2 and 3 chronic kidney disease [CKD], e.g., inthe Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT] [35] orCholesterol and Recurrent Events [CARE] study [36]), suggesteda benefit. In the CARE study, this depended on baseline GFRand was seen primarily in the small group of patients with aGFR of <40 ml/min (37).
A similar observation had also been made in patients who receiveda transplant in the Assessment of Lescol in Renal Transplantation(ALERT) study. There was a tendency for fluvastatin to reducecardiovascular death (38), including patients with reduced renalfunction. In a long-term open follow-up observation, the reductionof cardiovascular events became statistically significant (39).
These studies left unresolved the issue of whether statins loweredsignificantly cardiovascular death in patients with stages 4and 5 CKD. This possibility was not a priori certain. Fahtiet al. (40) drastically lowered LDL cholesterol by atorvastatinin patients with advanced CKD as well as in nonrenal patientswith coronary artery disease. As shown in Table 2, this maneuverreduced the maximum intima-media thickness in nonrenal patientswith coronary artery disease but failed to affect this indexin patients with CKD.
Table 2. Intensive lipid-lowering effect on carotid intima-media thickness: Comparison of renal and nonrenal patients (39)a
To resolve this issue, in the prospective Die Deutsche DiabetesDialyse (4D) study, 1255 patients who had type 2 diabetes andhad been on hemodialysis for <2 yr were randomly assignedto receive placebo or 20 mg/d atorvastatin (41). In the verumgroup, LDL cholesterol decreased by 42% from 125 to 72 mg/dlcompared with essentially no change (–1.2%) from 121 mg/dlat baseline in the placebo group during the 4-yr observationperiod. These values correspond to what LaRosa et al. (42) hadachieved in his widely known Treating to New Targets (TNT) study,which documented impressive reduction of cardiovascular endpoints. Although LDL cholesterol was lowered equally effectivelyin the 4D study, there was a minor trend at best for an improvedoutcome with respect to the primary composite end point (cardiacdeath, fatal myocardial infarction, stroke), which failed toreach statistical significance, however. This finding is infull agreement with a recent small Scandinavian study that foundsignificant lowering of cardiovascular end points in patientswith pre–end-stage CKD but no effect whatsoever with thesame dose of atorvastatin in the patients who were on hemodialysis(43).
The reasons for this unexpected failure to reduce the primaryend point despite substantial lowering of LDL cholesterol areunresolved. It might be due to the operation of alternativepathomechanisms such as inflammation or calcification (44),which might override the deleterious effect of dyslipidemia.Certainly cardiovascular death in these patients was due primarilyto noncoronary (or nonischemic) causes. For this reason, thepower of the study in retrospect was inadequate. Another possibilityto consider is that patients who would have been particularlysusceptible to statin treatment may have died before reachingESRD, because a major proportion of renal patients die fromcardiovascular causes before reaching ESRD (45). In this context,it is of note (Table 3) that the major cause of death was suddendeath and congestive heart failure, in good agreement with dataof other studies and the US Renal Data System (www.usrds.org).Indeed, death from confirmed coronary artery disease was loweredby 19% per mmol lowering of cholesterol even in the 4D study,but patients who died from coronary heart disease composed only9% of the patients who died. We shall have to wait for ongoingstudies such as the Study of Heart and Renal Protection (SHARP)(46) and Heart and Renal Protection (HARP) Study (47,48) tobe able to make evidence-based recommendations for the treatmentof dyslipidemic patients who are in terminal renal failure.
The cardiovascular risk is excessive in patients with even minorrenal dysfunction (49–51). However, at this stage of CKD,classical cardiovascular risk factors have an impact that issimilar to what is seen in nonrenal patients (48). Therefore,at that stage of CKD, the same rationale applies as in the similarhigh-risk population of diabetes (52): in our opinion, the highcardiovascular risk justifies the use of statins as if it weresecondary intervention (as in patients with a history of coronaryheart disease) and not primary intervention.
The current data do not support the general use of statins inpatients who are on dialysis. In the 4D study, at best, a delayedtrend of a reduction of the primary cardiovascular end pointwas observed (albeit much less pronounced compared with patientswithout renal disease and statistically NS). In retrospect,the study was underpowered to evaluate specifically coronarydeath. In our opinion, in dialysis patients with documentedcoronary heart disease, the use of statins can be justified,although the benefit is not yet proved, because the adverseeffect profile of the statin was not altered in renal failure;adverse effects indeed were extremely low with no cases of rhabdomyolysisand no excess frequency of creatine kinase elevation.
Bagdade J, Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man.
J Lab Clin Med 87
: 38
–48, 1976[Medline]
Lindner A, Charra B, Sherrard DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis.
N Engl J Med 290
: 697
–701, 1974[Medline]
Attman PO, Knight-Gibson C, Tavella M, Samuelsson O, Alaupovic P: The compositional abnormalities of lipoproteins in diabetic renal failure.
Nephrol Dial Transplant 13
: 2833
–2841, 1998[Abstract/Free Full Text]
Weintraub M, Burstein A, Rassin T, Liron M, Ringel Y, Cabili S, Blum M, Peer G, Iaina A: Severe defect in clearing postprandial chylomicron remnants in dialysis patients.
Kidney Int 42
: 1247
–1252, 1992[Medline]
Galle J, Wanner C: Modification of lipoproteins in uremia: Oxidation, glycation and carbamoylation.
Miner Electrolyte Metab 25
: 263
–268, 1999[CrossRef][Medline]
Kronenberg F, Kuen E, Ritz E, Junker R, Konig P, Kraatz G, Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Reigler P, Schwenger V, Von Eckardstein A: Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
J Am Soc Nephrol 11
: 105
–115, 2000[Abstract/Free Full Text]
Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS, de Beer FC: Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition.
J Biol Chem 261
: 9644
–9651, 1986[Abstract/Free Full Text]
Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Hama S, Hough G, Bachini E, Grijalva VR, Wagner AC, Shaposhnik Z, Fogelman AM: The double jeopardy of HDL.
Ann Med 37
: 173
–178, 2005[CrossRef][Medline]
Shoji T, Nishizawa Y, Kawagishi T, Kawasaki K, Taniwaki H, Tabata T, Inoue T, Morii H: Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients.
J Am Soc Nephrol 9
: 1277
–1284, 1998[Abstract]
Nishizawa Y, Shoji T, Kakiya R, Tsujimoto Y, Tabata T, Ishimura E, Nakatani T, Miki T, Inaba M: Non-high-density lipoprotein cholesterol (non-HDL-C) as a predictor of cardiovascular mortality in patients with end-stage renal disease.
Kidney Int Suppl 84
: S117
–S120, 2003[CrossRef][Medline]
Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P, Jacobs C: Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study.
Nephron 31
: 103
–110, 1982[Medline]
Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities.
Am J Kidney Dis 15
: 458
–482, 1990[Medline]
Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, Tracy RP, Powe NR, Klag MJ: Association between cholesterol level and mortality in dialysis patients: Role of inflammation and malnutrition.
JAMA 291
: 451
–459, 2004[Abstract/Free Full Text]
Kronenberg F, Steinmetz A, Kostner GM, Dieplinger H: Lipoprotein(a) in health and disease.
Crit Rev Clin Lab Sci 33
: 495
–543, 1996[Medline]
Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger M, Pribasnig A, Meisl T, Konig P, Dieplinger H: The low molecular weight apo (a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: A prospective follow-up.
J Am Soc Nephrol 10
: 1027
–1036, 1999[Abstract/Free Full Text]
Shoji T, Emoto M, Tabata T, Kimoto E, Shinohara K, Maekawa K, Kawagishi T, Tahara H, Ishimura E, Nishizawa Y: Advanced atherosclerosis in predialysis patients with chronic renal failure.
Kidney Int 61
: 2187
–2192, 2002[CrossRef][Medline]
Clyne N, Lins LE, Pehrsson SK: Occurrence and significance of heart disease in uraemia. An autopsy study.
Scand J Urol Nephrol 20
: 307
–311, 1986[Medline]
Ikram H, Lynn KL, Bailey RR, Little PJ: Cardiovascular changes in chronic hemodialysis patients.
Kidney Int 24
: 371
–376, 1983[Medline]
Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.
Am J Kidney Dis 27
: 394
–401, 1996[Medline]
Matsuoka M, Iseki K, Tamashiro M, Fujimoto N, Higa N, Touma T, Takishita S: Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis.
Clin Exp Nephrol 8
: 54
–58, 2004[CrossRef][Medline]
Bursztyn M, Motro M, Grossman E, Shemesh J: Accelerated coronary artery calcification in mildly reduced renal function of high-risk hypertensives: A 3-year prospective observation.
J Hypertens 21
: 1953
–1959, 2003[CrossRef][Medline]
Buzello M, Tornig J, Faulhaber J, Ehmke H, Ritz E, Amann K: The apolipoprotein e knockout mouse: A model documenting accelerated atherogenesis in uremia.
J Am Soc Nephrol 14
: 311
–316, 2003[Abstract/Free Full Text]
Bro S, Bentzon JF, Falk E, Andersen CB, Olgaard K, Nielsen LB: Chronic renal failure accelerates atherogenesis in apolipoprotein e-deficient mice.
J Am Soc Nephrol 14
: 2466
–2474, 2003[Abstract/Free Full Text]
Massy ZA, Ivanovski O, Nguyen-Khoa T, Angulo J, Szumilak D, Mothu N, Phan O, Daudon M, Lacour B, Drueke TB, Muntzel MS: Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice.
J Am Soc Nephrol 16
: 109
–116, 2005[Abstract/Free Full Text]
Suganuma E, Zuo Y, Ayabe N, Ma J, Babaev VR, Linton MF, Fazio S, Ichikawa I, Fogo AB, Kon V: Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction.
J Am Soc Nephrol 17
: 433
–441, 2006[Abstract/Free Full Text]
Moorhead JF, Chan MK, El-Nahas M, Varghese Z: Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.
Lancet 2
: 1309
–1311, 1982[Medline]
Wheeler DC, Nair DR, Persaud JW, Jeremy JY, Chappell ME, Varghese Z, Moorhead JF: Effects of dietary fatty acids in an animal model of focal glomerulosclerosis.
Kidney Int 39
: 930
–937, 1991[Medline]
Guijarro C, Kasiske BL, Kim Y, O’Donnell MP, Lee HS, Keane WF: Early glomerular changes in rats with dietary-induced hypercholesterolemia.
Am J Kidney Dis 26
: 152
–161, 1995[Medline]
Bussolati B, Deregibus MC, Fonsato V, Doublier S, Spatola T, Procida S, Di Carlo F, Camussi G: Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway.
J Am Soc Nephrol 16
: 1936
–1947, 2005[Abstract/Free Full Text]
Attman PO, Alaupovic P, Samuelsson O: Lipoprotein abnormalities as a risk factor for progressive nondiabetic renal disease.
Kidney Int Suppl 71
: S14
–S17, 1999[Medline]
Fried LF, Orchard TJ, Kasiske BL: Effect of lipid reduction on the progression of renal disease: A meta-analysis.
Kidney Int 59
: 260
–269, 2001[CrossRef][Medline]
Olbricht CJ, Wanner C, Thiery J, Basten A: Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.
Kidney Int Suppl 71
: S113
–S116, 1999[CrossRef][Medline]
Sandhu S, Wiebe N, Fried LF, Tonelli M: Statins for improving renal outcomes: A meta-analysis.
J Am Soc Nephrol 17
: 2006
–2016, 2006[Abstract/Free Full Text]
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial.
Lancet 361
: 1149
–1158, 2003[CrossRef][Medline]
Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G: Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency.
Ann Intern Med 138
: 98
–104, 2003[Abstract/Free Full Text]
Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC: Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.
J Am Soc Nephrol 14
: 1605
–1613, 2003[Abstract/Free Full Text]
Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P, Gronhagen-Riska C, Madsen S, Neumayer HH, Cole E, Maes B, Ambuhl P, Olsson AG, Hartmann A, Solbu DO, Pedersen TR: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial.
Lancet 361
: 2024
–2031, 2003[CrossRef][Medline]
Holdaas H, Fellstrom B, Cole E, Nyberg G, Olsson AG, Pedersen TR, Madsen S, Gronhagen-Riska C, Neumayer HH, Maes B, Ambuhl P, Hartmann A, Staffler B, Jardine AG: Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: The ALERT extension study.
Am J Transplant 5
: 2929
–2936, 2005[CrossRef][Medline]
Fathi R, Isbel N, Short L, Haluska B, Johnson D, Marwick TH: The effect of long-term aggressive lipid lowering on ischemic and atherosclerotic burden in patients with chronic kidney disease.
Am J Kidney Dis 43
: 45
–52, 2004[CrossRef][Medline]
Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
N Engl J Med 353
: 238
–248, 2005[Abstract/Free Full Text]
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK: Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med 352
: 1425
–1435, 2005[Abstract/Free Full Text]
Holmberg B, Brannstrom M, Bucht B, Crougneau V, Dimeny E, Ekspong A, Granroth B, Grontoft KC, Hadimeri H, Ingman B, Isaksson B, Johansson G, Lindberger K, Lundberg L, Mikaelsson L, Olausson E, Persson B, Welin D, Wikdahl AM, Stegmayr BG: Safety and efficacy of atorvastatin in patients with severe renal dysfunction.
Scand J Urol Nephrol 39
: 503
–510, 2005[CrossRef][Medline]
Gross M-L, Amann K, Berger I, Ritz E: Calcification of coronary intima and media: Immunohistochemistry, backscatter imaging and x-ray analysis in renal and non-renal patients [Abstract].
J Am Soc Nephrol 16
: 103A
, 2005[CrossRef]
Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH: Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.
Arch Intern Med 164
: 659
–663, 2004[Abstract/Free Full Text]
Baigent C, Landry M: Study of Heart and Renal Protection (SHARP).
Kidney Int Suppl 84
: S207
–210, 2003[Medline]
Landray M, Baigent C, Leaper C, Adu D, Altmann P, Armitage J, Ball S, Baxter A, Blackwell L, Cairns HS, Carr S, Collins R, Kourellias K, Rogerson M, Scoble JE, Tomson CR, Warwick G, Wheeler DC: The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: A randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD.
Am J Kidney Dis 47
: 385
–395, 2006[CrossRef][Medline]
Shlipak MG, Fried LF, Cushman M, Manolio TA, Peterson D, Stehman-Breen C, Bleyer A, Newman A, Siscovick D, Psaty B: Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors.
JAMA 293
: 1737
–1745, 2005[Abstract/Free Full Text]
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
N Engl J Med 351
: 1296
–1305, 2004[Abstract/Free Full Text]
Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
N Engl J Med 351
: 1285
–1295, 2004[Abstract/Free Full Text]
Ritz E, McClellan WM: Overview: Increased cardiovascular risk in patients with minor renal dysfunction—An emerging issue with far-reaching consequences.
J Am Soc Nephrol 15
: 513
–516, 2004[Abstract/Free Full Text]
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med 339
: 229
–234, 1998[Abstract/Free Full Text]
This article has been cited by other articles:
I. H. de Boer, B. C. Astor, H. Kramer, W. Palmas, S. L. Seliger, M. G. Shlipak, D. S. Siscovick, M. Y. Tsai, and B. Kestenbaum Lipoprotein Abnormalities Associated with Mild Impairment of Kidney Function in the Multi-Ethnic Study of Atherosclerosis
Clin. J. Am. Soc. Nephrol.,
January 1, 2008;
3(1):
125 - 132.
[Abstract][Full Text][PDF]
Top
Abstract
Introduction
