Patients with ESRD have a greatly elevated risk for atherosclerotic cardiovascular disease (ASCVD). This increased risk is only partially explained by traditional risk factors associated with ESRD (1–4), prompting interest in novel ASCVD risk factors, such as lipoprotein(a) [Lp(a)], levels of which are elevated in ESRD (5). Lp(a) is composed of an LDL particle covalently bonded to apolipoprotein(a) [apo(a)], a glycoprotein with a highly variable number of Kringle-IV (K-IV) units related to a polymorphism encoded in the apo(a) gene. Lp(a) levels are inversely related to apo(a) isoform size (6).
Many previous studies in the general population have found that high Lp(a) levels (7) and small apo(a) size (8–12) are associated with ASCVD. The few studies of Lp(a) in ESRD have provided conflicting results (13–15), with the only prospective study to evaluate both Lp(a) and apo(a) size reporting that small apo(a) size but not Lp(a) level is associated with increased ASCVD (13).
The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study, a prospective study of outcomes among black and white incident dialysis patients, previously found that small apo(a) size but not Lp(a) level was associated with total mortality (16). The current study, based on the CHOICE cohort, tested the a priori hypothesis that small apo(a) size but not high Lp(a) level is associated with prospectively ascertained ASCVD in a national, biracial cohort of patients who begin dialysis.
Materials and Methods
Study Design and Population
The CHOICE Study enrolled 1041 participants in 19 states from 81 dialysis clinics associated with Dialysis Clinic, Incorporated (DCI; Nashville, TN; n = 923 from 79 clinics), New Haven CAPD (New Haven, CT; n = 86 from one clinic), or Saint Raphael's Hospital (New Haven, CT; n = 32 from one clinic) from October 1995 to June 1998. Enrollment occurred a median of 1.6 mo after first dialysis (98% within 4 mo). Blood was obtained only at the DCI clinics, and samples were available for determination of Lp(a) level and apo(a) size for 872 (93.6%) of the 923 DCI participants; 833 (90.2%) were eligible for Lp(a)-related analysis. Enrollment criteria included initiation of dialysis in the preceding 3 mo, ability to give written informed consent, age over 17 yr, and ability to speak English or Spanish. The Johns Hopkins University School of Medicine Institutional Review Board approved the protocol.
Baseline comorbidity was ascertained using a validated comorbidity score (range 0 to 3) derived from the Index of Co-Existent Disease (ICED) as described previously (17). Baseline ASCVD was defined as any history of myocardial infarction, cardiac revascularization procedure, stroke, carotid endarterectomy, extremity gangrene or peripheral revascularization procedure, limb amputation, or abdominal aortic aneurysm repair.
A composite ASCVD outcome was composed of the first cardiovascular event (fatal or nonfatal) during follow-up, including the same events as ascertained for the baseline ASCVD. Hospital records were requested for all deaths and for potential nonfatal events when any of four sources (quarterly dialysis nurse assessment, annual dialysis clinic record review, annual patient questionnaire, or periodic Health Care Financing Administration [HCFA] billing data) indicated a hospitalization for a potential ASCVD event or for congestive heart failure. A study physician reviewed all charts, flagging charts with a possible event for review by the ASCVD Outcomes Committee. Two ASCVD Outcome Committee physicians then independently reviewed all records with a potentially positive ASCVD event. Any disagreement between the two independent reviewers was adjudicated by a third reviewer.
All nonfatal events had specific written criteria for classification (myocardial infarction: history, EKG, and enzymes; stroke: symptoms, physical examination, and radiologic criteria; surgical procedures: operative note or date documented in the medical record). Depending on the combination of data observed, events were coded as “definite,” “probable,” “suspect,” or “no event.” Hospitalization charts were reviewed for 177 (92%) of 192 nonfatal events. The 15 events without an available hospital record were coded on the basis of the agreement of two of the four sources listed above, with a condition that one of the sources included the HCFA discharge diagnosis. The κ statistic between the two initial reviewers regarding the strength of diagnosis (definite, probable, suspect, and none) was 0.86 for myocardial infarction and 0.85 for cerebrovascular accident. After it became apparent that the agreement on strength of diagnosis between two reviewers was essentially 100% for procedure events, a single review was deemed sufficient for accurate coding. “Definite” and “probable” events were included as events in the final analysis.
Vital status is verified actively every 3 mo, and records are sent to the coordinating center upon a participant's death. Fatal outcome events were adjudicated by two independent physicians using a written algorithm for ASCVD cause of death ascertainment (see Table 1 for ASCVD cause of death classification codes modified from the HEMO Study ). The same criteria used for nonfatal events were used for fatal events. Medical records were available and reviewed for 92 (62%) of the 148 in-hospital deaths. Out-of-hospital deaths and in-hospital deaths with no chart available were coded according to the HCFA Death Notification Form (see Table 2). Agreement between the two independent reviewers on ASCVD causes of death was excellent (κ = 0.88 for coronary artery disease, 0.92 for cerebrovascular disease, and 0.82 for peripheral vascular disease).
Serum was collected and stored at −80°C. Sample draw occurred at a median of 4.4 mo after first dialysis (95% within 6.8 mo). Lp(a) concentration was measured by a direct binding double mAb-based ELISA, as previously reported (6). The detection antibody is directed to a nonrepeating epitope present in apo(a) K-IV type 9, making this assay insensitive to apo(a) size. Lp(a) concentrations were expressed in nmol/L. The analytical coefficient of variation of Lp(a), based on five duplicate samples of varying Lp(a) concentrations (12 to 120 nmol/L) in each ELISA plate, ranged from 4.0 to 6.7%.
Apo(a) isoforms were characterized using a high-resolution SDS-agarose gel electrophoresis method followed by immunoblotting, as previously reported (19). We used a size designation related to each isoform's number of K-IV repeats (19,20). The coefficient of variation for apo(a) size in the CHOICE cohort was 11.7% (n = 49). An exact match of the smallest allele size for the 49 blindly split samples was present for 48.9%, and a match ± 1 repeat was present for 93.8%.
Statistical analyses were performed with Stata (version 6.0). The Mann-Whitney U test was used to test for differences in median values of skewed variables. Lp(a) was dichotomized at the median (52.5 nmol/L) and log-transformed when analyzed continuously. Low molecular weight (LMW) apo(a) isoforms were designated by convention as ≤22 K-IV repeats. Both were also analyzed by quartile and tested for trend across quartiles. In addition, some analyses evaluated an Lp(a) cutoff of ≤206 nmol/L (≤90th percentile) and an apo(a) size cutoff of ≤16 K-IV repeats (≤10th percentile). All analyses of apo(a) size used the predominantly expressed isoform.
Survival time was defined as time from blood draw to outcome event or censoring. The time scale used in the analysis was time from first dialysis, with staggered entry at time of exposure ascertainment. Of the 872 individuals with Lp(a) data, 29 were excluded from analysis owing to a new ASCVD event between enrollment and Lp(a) determination, and 10 individuals were excluded to allow for left truncation at 4.0 mo for the purpose of producing more stable Kaplan-Meier curves.
Several groups of covariates were selected a priori for inclusion in Cox regression models. Group 1 (demographics and modality) included age, race, gender, and baseline dialysis modality. Group 2 (comorbid conditions) added the ICED score, cause of renal disease, and baseline ASCVD. Group 3 (other CVD risk factors) added total cholesterol, HDL cholesterol, smoking status, and systolic BP. Group 4 (nutrition) added albumin, body mass index, and creatinine. C-reactive protein (CRP) was also added to group 4 in separate models. A priori stratified analyses investigating interactions were also performed by age, race, gender, dialysis modality, diabetes, prevalent ASCVD, LDL cholesterol, and CRP level. The proportionality assumption of the Cox models was tested using −ln[−ln(survival)] curves and regression of scaled Schoenfeld residuals on functions of time. No variables were found to violate model assumptions.
Those with prevalent ASCVD outcomes were included in the primary analysis for several reasons. First, an analysis that was restricted to those without prevalent ASCVD found a similar association to that of the analysis that was restricted to those with a history of ASCVD (there was no interaction). Importantly, those with previous ASCVD events remain at risk (and higher risk) for future ASCVD events. There is no scientific evidence that Lp(a) ceases to be a risk factor for future events after a first event. Furthermore, because the prevalence of ASCVD is almost 50%, to exclude prevalent cases significantly reduces the statistical power of the analysis. Excluding so many in the cohort would also likely render the results less generalizable to the whole dialysis population. Last, in the dialysis population, those without a history of CVD events have a far higher level of atherosclerosis than is found among those in the general population without a history of CVD. Therefore, the difference in the degree of atherosclerosis between those with and without CVD in the dialysis population is not as great as would be seen in other populations. For all of these reasons, it was decided to include those with prevalent CVD and to adjust for this factor in the primary analyses.
Median follow-up was 27.4 mo, with 297 ASCVD events (192 nonfatal and 105 fatal) during 1649 person-years at risk. A total of 130 (15.6%) died from non-ASCVD causes, seven (0.8%) were lost to follow-up, 144 (17.3%) were censored upon renal transplantation, and the remainder were followed until the end of follow-up.
Table 3 shows that age, gender, and race in the CHOICE cohort are similar to the contemporary US dialysis population (1997 US Renal Data System data) (21). Table 4 demonstrates that those who were censored at renal transplantation (n = 163), compared with those who remained under follow-up, were significantly younger and included more men, whites, participants on peritoneal dialysis, participants with a low ICED comorbidity score, and causes of renal disease other than diabetes and hypertension. The transplant group had a lower Lp(a) level (45.0 versus 54.4 nmol/L) but did not differ significantly by apo(a) subtype.
Figure 1A presents unadjusted Kaplan-Meier curves showing a marginal association between Lp(a) level and ASCVD events among whites but no association among blacks. A stronger association exists between LMW apo(a) isoform size and ASCVD in both whites and blacks (Figure 1B).
In multivariate Cox models, Lp(a) level >52.5 nmol/L was independently associated with a 30 to 40% increased risk for ASCVD events (Table 5). A 60 to 90% increased risk for ASCVD was seen for Lp(a) levels ≥206 nmol/L (90th percentile), compared with Lp(a) <206 nmol/L. LMW apo(a) size was associated with a 60 to 90% increase risk for ASCVD events, with adjustment for the same covariates, and apo(a) size ≤16 K-IV repeats (≤10th percentile) was associated with a 40 to 100% increase in ASCVD risk, compared with apo(a) size >16 K-IV repeats (Table 6).
Figure 2 presents ASCVD risk by Lp(a) concentration and apo(a) size quartile, showing that the adjusted risk for ASCVD events is significantly increased both with higher Lp(a) concentrations (A) and with smaller apo(a) size (B), although the association with smaller apo(a) size is stronger than the association with increased Lp(a) concentration. For Lp(a) ≥206 nmol/L (≥90th percentile) compared with the first quartile, the relative hazard (RH) was 1.71 (1.11-2.65; P = 0.015). For apo(a) isoforms ≤16 K-IV repeats (≤10th percentile) compared with the fourth apo(a) size quartile, the RH was 2.0 (1.27-3.14; P = 0.003).
The same associations were present when only individuals with no prevalent ASCVD were included in the analysis (n = 410 with 92 events; for LMW isoforms, RH = 1.82, P = 0.007; for Lp(a) ≥52.5 nmol/L, RH = 1.33, P = 0.23; and for Lp(a) ≥206.0 nmol/L, RH = 2.53; P = 0.003]. The association was similar in whites (n = 460 with 188 events; for Lp(a) ≥52.5 nmol/L, RH = 1.44, P = 0.02; and for LMW apo(a) size, RH = 1.63, P = 0.001) and blacks, although the estimates for blacks were not statistically significant (n = 230 with 59 events; for Lp(a) ≥52.5 nmol/L, RH = 1.43, P = 0.26; and for LMW apo(a) size, RH = 1.44, P = 0.24). No significant interactions by age, race, gender, dialysis modality, diabetes, prevalent ASCVD, LDL cholesterol, and CRP level were present for either Lp(a) level or apo(a) size.
When high Lp(a) concentration (quartile 4 cutoff) and LMW apo(a) size are entered simultaneously into a Cox regression model, the effect of small apo(a) size remains (RH = 1.52; P = 0.004), whereas the effect of high Lp(a) concentration becomes insignificant (RH = 1.15; P = 0.238). Figure 3 demonstrates that there is no interaction between Lp(a) concentration and apo(a) size in the risk for ASCVD events and that the effect size of LMW apo(a) size is much larger than that of high Lp(a) concentration, when considered together. Similar associations were seen when Lp(a) level and apo(a) size were dichotomized at the median or the quartile 4 cutoff.
Previous studies have found either high Lp(a) concentration or small apo(a) size but not both to be risk factors for ASCVD in the dialysis population. This prospective study of 833 incident dialysis patients found a moderate, independent association between ASCVD and high Lp(a) concentration and a stronger association with LMW apo(a) isoform size. Although no multiplicative interaction was seen between small apo(a) size and high Lp(a) level, the group with LMW isoforms and Lp(a) concentration >123 nmol/L had the highest risk (RH = 1.73; P < 0.0005).
A large number of prospective studies in the general population have found an association between high Lp(a) level and coronary heart disease (7), but few prospective studies of apo(a) isoform size and CHD in the general population have been published (8,12). The largest nested case-control study of Lp(a), apo(a), and incident CHD in the general population (n = 134 cases) found an association between Lp(a) and CHD but not between apo(a) size and CHD, although the crude analysis showed a trend toward smaller apo(a) size among cases (12). Conversely, the Bruneck Study found that LMW isoform size was prospectively associated with advanced atherosclerosis, especially in the presence of elevated Lp(a) concentrations, and that Lp(a) concentration was associated with early atherosclerosis, but this was restricted to those with elevated LDL cholesterol levels (8).
Kronenberg et al. reported the only previously published prospective study that investigated both Lp(a) level and apo(a) size as risk factors for CHD in the dialysis population (13). They found that LMW isoform size, not Lp(a) level, was associated with the development of CHD (n = 66 CHD events; adjusted RH = 2.3; P = 0.0008). The same authors reported earlier that, among those with high molecular weight apo(a) isoforms, Lp(a) levels are much higher in hemodialysis patients than in apo(a) phenotype-matched population control subjects (17.2 versus 10.8 mg/dl; P < 0.0001), whereas among those with LMW isoforms, the Lp(a) level in ESRD patients is only slightly higher than that of phenotype-matched population control subjects with high Lp(a) levels (40.8 versus 36.9 mg/dl; P = 0.14) (5,22). If such a differential increase in Lp(a) by apo(a) subtype occurs as renal failure develops, then the association between Lp(a) and ASCVD would be altered toward the null, while maintaining the association between small apo(a) size and ASCVD. This hypothesis is supported by our study in that the association between Lp(a) and ASCVD was weaker than that seen with small apo(a) size. Our earlier finding that small apo(a) size but not Lp(a) level prospectively predicts total mortality also is consistent with the above hypothesized mechanism (16).
Other explanations are possible, however. Because apo(a) size remains the strongest predictor of Lp(a) levels in the ESRD population, one would expect that Lp(a) would still predict ASCVD to some extent, which this study demonstrates. Several features may explain why our study found an association between Lp(a) and ASCVD whereas some other studies may not. First, most other studies recruited prevalent ESRD patients, leading to a potential survival bias. If a risk factor is associated with an outcome that can lead to death (e.g., death from myocardial infarction), then those with the highest levels tend to be underrepresented in a prevalent population, because they die sooner. This “survival” bias, which tends to bias associations toward the null, is particularly strong in the setting of extremely high mortality rates in the dialysis population. Because this study recruited all participants soon after initiation of dialysis, the Lp(a) association is less affected by such a bias, although it is probably still affected to some extent. Second, because the association between Lp(a) and ASCVD is moderate in magnitude, other studies with fewer outcome events may not have had the statistical power to find associations. Third, as shown in Table 4, there may be significant informative censoring associated with transplantation, which would affect a prevalent study population much more than a cohort of incident dialysis patients. Among the much healthier group that received a transplant, Lp(a) levels were lower than among the less healthy adherent group. This selective removal of healthier patients with lower Lp(a) levels biases the association of Lp(a) with ASCVD toward the null. Last, this study used an apo(a) size-independent assay for Lp(a), whereas other studies generally used assays that are sensitive to apo(a) size. Assays for which the antibody detects all K-IV repeats may result in misclassification of Lp(a) level. The larger the test sample apo(a) isoform size [i.e., in those with lower Lp(a) levels] relative to the apo(a) size of the reference standard, the more the Lp(a) mass value will be overestimated. The smaller the test sample apo(a) isoform size [i.e., in those with higher Lp(a) levels] relative to the apo(a) size of the reference standard, the more the Lp(a) mass value will be underestimated. This process results in a type of misclassification that biases relationships between Lp(a) and associated outcomes toward the null while leaving associations with apo(a) size intact. Apo(a) size-independent assays, such as used in this study, avoid this source of misclassification.
Some other studies have suggested that high Lp(a) levels are most atherogenic when present in conjunction with other ASCVD risk factors such as elevated LDL cholesterol (23) or elevated fibrinogen (24). However, in this study, no significant interactions by age, race, gender, diabetes, dialysis modality, prevalent ASCVD, LDL cholesterol, or CRP level were present for either Lp(a) level or apo(a) size.
The strengths of this study include the enrollment of incident dialysis patients; inclusion of a sample of blacks and whites from a wide geographic area; a high follow-up rate; the measurement of Lp(a) concentration, not mass; and the accuracy of the apo(a) assay. The most important limitation of this study is the problem of informative censoring as a result of the high transplantation rate (17.3%), which may have biased the Lp(a) results toward the null. This may partially explain why Lp(a) level is more weakly associated with ASCVD than is apo(a) size in this cohort. For apo(a) size, however, informative censoring is probably not a major issue because the distribution of apo(a) size did not differ by transplantation status.
Lp(a) may produce atherogenic effects through its action as a lipid or through inhibition of fibrinolysis by the apo(a) glycoprotein (25). The apo(a) glycoprotein moiety displays an 80% homology with plasminogen (26) and inhibits fibrinolysis (27). Small apo(a) isoforms also have been found to bind more strongly to fibrin than larger isoforms (28), suggesting that small apo(a) isoform size itself, not only the associated Lp(a) level, may be important in accelerating atherosclerosis. Nevertheless, in this mechanism, Lp(a) level would probably still be expected to play a significant role because more apo(a) glycoprotein particles would be available to inhibit fibrinolysis.
If the risk of ASCVD related to Lp(a) is mediated by both apo(a) isoform size and the attendant Lp(a) level, then Lp(a)-lowering therapy has potential to prevent ASCVD, particularly among those with LMW apo(a) isoforms. The finding that high Lp(a) levels are associated with an approximately 40% increase in ASCVD event rate suggests that successful lowering of Lp(a) level has potential to lower ASCVD risk in dialysis patients. The recent Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease (29) presented a brief review of treatment strategies to decrease Lp(a) levels, including niacin, ascorbic acid with l-lysine, estrogen, aspirin, statins, diet, and apheresis. Overall, Lp(a) level is difficult to lower, and most of the medications that do have an effect on Lp(a) levels also treat other atherogenic lipids. Sorting out the beneficial effect of Lp(a)-lowering medications beyond the cardiovascular benefit of such medications will require carefully designed, randomized, clinical trials.
Whether lowering Lp(a) levels is feasible or ultimately reduces ASCVD risk, elevated Lp(a) level or the presence of LMW apo(a) phenotype may be clinically useful in risk stratification and identification of dialysis patients who warrant more aggressive ASCVD prevention efforts. If part of the atherogenic effect of Lp(a) is mediated specifically through the antifibrinolytic action of LMW apo(a) isoforms, then future therapies that are designed specifically against the fibrin-binding action of LMW isoforms might also be effective. Further studies should explore whether the risk associated with LMW isoforms is mediated through the associated long-term elevation in Lp(a) levels or other mechanisms related to apo(a) size.
CHOICE was supported by R01-HS-08365 (Agency for Healthcare Research and Quality [AHRQ]) from June 1995 to May 2000 and is currently supported by R01-HL-62985 (National Heart, Lung, and Blood Institute [NHLBI]) and R01-DK-07024 (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]). Other grants supporting this research are R29-DK-48362 (NIDDK; J.C.), K24-DK-02856 (NIDDK; M.J.K.), K08-HL-03896 (NHLBI; J.C.L.), K24-DK-02643 (NIDDK; N.R.P.), American Heart Association Grant-in-Aid [J.C., principal investigator; Lp(a) and apo(a) assays], and National Center for Research Resources (National Institutes of Health) General Clinical Research Center grant M01-RR00052 (J.C., principal investigator; lipid assays). B.G.J. is the recipient of the Richard Ross Clinician Scientist Award from the Johns Hopkins School of Medicine.
We thank the CHOICE Study Cardiovascular Endpoint Committee. Current members are Bernard G. Jaar, MD, MPH; J. Craig Longenecker, MD, PhD; Josef Coresh, MD, PhD; Yongmei Liu, MD; Joseph A. Eustace, MD, MHS; Richard M. Ugarte, MD; and Melanie H. Katzman, MD, MHS. Former members of the Committee include Michael Klag, MD, MPH; Neil R. Powe, MD, MPH, MBA; Michael J. Choi, MD; Renuka Sothinathan, MD, MHS; and Caroline Fox, MD, MPH. Cardiovascular events adjudicators are Nancy E. Fink, MPH; and Laura C. Plantiga, ScM.
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