The Low Molecular Weight Apo(a) Phenotype Is an Independent Predictor for Coronary Artery Disease in Hemodialysis Patients: A Prospective Follow-Up FLORIAN KRONENBERG,* ULRICH NEYER, † KARL LHOTTA, ‡ EVI TRENKWALDER,* MARTIN AUINGER, § ANDREAS PRIBASNIG,  THOMAS MEISL, ¶ PAUL K ¨ ONIG, ‡ and HANS DIEPLINGER* *Institute of Medical Biology and Human Genetics, University of Innsbruck; † Feldkirch Hospital; ‡ Department of Clinical Nephrology, Innsbruck University Hospital; § Lainz Hospital;  St. Po ¨lten Hospital; and ¶ Wilhelminenspital, Vienna, Austria. Abstract. Patients with end-stage renal disease treated by he- modialysis have a tremendous risk for cardiovascular compli- cations that cannot be explained by traditional atherosclerosis risk factors. Lipoprotein(a) (Lp(a)), a risk factor for these complications in the general population, is significantly ele- vated in these patients. In this study, it was determined whether Lp(a) and/or the genetically determined apo(a) phenotype are risk predictors for the development of coronary artery disease in these patients. A cohort of 440 unselected hemodialysis patients were followed for a period of 5 yr independent of the cause of renal disease, duration of preceding treatment, and the preexistence of coronary artery disease at study entry. Coro- nary events defined as definite myocardial infarction, percuta- neous transluminal coronary angioplasty, aortocoronary by- pass, or a stenosis 50% in the coronary angiography were the main outcome measure. Sixty-six (15%) of the 440 patients suffered a coronary event during follow-up. In univariate anal- ysis, patients with events were significantly older and showed a trend to lower HDL cholesterol concentrations, and higher apolipoprotein B and Lp(a) concentrations without reaching significance. Apo(a) phenotypes of low molecular weight, however, were significantly more frequent in patients with compared to those without events (43.9% versus 21.9%, P  0.001). The other lipids, lipoproteins, and apolipoproteins were similar in both groups. Multiple Cox proportional hazards regression analysis found age and the apo(a) phenotype to be the best predictors for coronary events during the observation period, independent of whether patients with a preexisting coronary artery disease or an age 65 yr at the study entry or both were excluded from the analysis. Diabetes mellitus was a risk factor only in presence of a low molecular weight apo(a) phenotype. The genetically determined apo(a) phenotype is a strong and independent predictor for coronary events in hemo- dialysis patients. Apo(a) phenotyping might be helpful to iden- tify hemodialysis patients at high risk for coronary artery disease. Cardiovascular disease is still the most frequent cause of death in patients with end-stage renal disease (1–3). Besides other lipoprotein abnormalities, lipoprotein(a) (Lp(a)) has been sug- gested to be associated with these complications (reviewed in reference (4)). Most prospective studies in the general population have described Lp(a) as an independent risk factor for coronary artery disease (CAD) (5–17). Interest in this atherogenic par- ticle was raised because of the high heritability of Lp(a) plasma concentrations. These are mainly determined by the size poly- morphism of apo(a) (18), which originates from a varying number of kringle-IV (K-IV) repeats in the apo(a) gene (19 – 21). This results in a negative correlation between the number of K-IV repeats and the Lp(a) plasma concentrations. From studies considering the apo(a) size polymorphism, it was con- cluded that the apo(a) gene locus determines the risk for coronary heart disease through its allelic control of Lp(a) plasma concentration (12,17,22–26). In recent years, numerous studies have described elevated Lp(a) plasma concentrations in patients with renal disease (4). Some of them, including one prospective investigation (7), found a correlation with atherosclerotic complications that was not confirmed by other studies (4). In cross-sectional studies, we and others observed a higher frequency of apo(a) pheno- types with low molecular weight in hemodialysis patients with atherosclerotic complications (27–29). Prospective studies investigating coronary events are hard to perform in the general population because they require a high number of subjects and a long follow-up time to observe the required number of cases for reliable statistical analysis. The prospective study of the Framingham offspring cohort, for example, included 2191 men followed for 15.4 yr. During this time, 129 CAD events were observed (11). Therefore, this “gold standard” of epidemiologic study is time-consuming and Received August 10, 1998. Accepted November 13, 1998. Correspondence to Dr. Florian Kronenberg, Institute of Medical Biology and Human Genetics, Scho ¨pfstr. 41, A-6020 Innsbruck, Austria. Phone: +43 512 507-3474; Fax: +43 512 507-2861; E-mail: Florian.Kronenberg@uibk.ac.at 1046-6673/1005-1027$03.00/0 Journal of the American Society of Nephrology Copyright © 1999 by the American Society of Nephrology J Am Soc Nephrol 10: 1027–1036, 1999