Lipoprotein(a) level as a predictor of cardiovascular disease and small apoliprotein(a) isoforms in dialysis patients: assay-related differences are important.

BACKGROUND: Lipoprotein(a) assays sensitive to apolipoprotein(a) size may underestimate associations of lipoprotein(a) with cardiovascular disease (CVD) and low molecular weight (LMW) apolipoprotein(a) isoforms. This study among 629 dialysis patients compares the value of two lipoprotein(a) assays in predicting CVD events and small isoforms. METHODS: Lipoprotein(a) level was measured by an apolipoprotein(a) size-insensitive ELISA and apolipoprotein(a) size-sensitive immunoturbidometric (IT) assay; and apolipoprotein(a) size by Western blot. Positive/negative predictive values (PPV/NPV) for small isoforms were calculated, and CVD events ascertained prospectively. RESULTS: The ELISA assay predicted CVD more strongly [Relative Hazard, RH=1.8; p=0.045, at the 85th Lipoprotein(a) percentile] than the IT assay (RH=1.3; p=0.37). The PPV for LMW isoforms using the ELISA (Whites, 98%; Blacks, 90%) were much higher than the IT assay (Whites, 75%; Blacks, 68%). Relative to the ELISA assay values, a positive bias in the IT assay values was seen for participants with larger apolipoprotein(a) isoforms, which may explain these findings. CONCLUSIONS: When measured by an apolipoprotein(a) size-insensitive ELISA assay, but not a size-sensitive IT assay, high lipoprotein(a) levels predict both incident CVD and LMW isoforms in dialysis patients. Clinicians ordering lipoprotein(a) levels and research studies of lipoprotein(a) should determine if an apolipoprotein(a)-size related bias is present in the assay they use.

Agreement of self-reported comorbid conditions with medical and physician reports varied by disease among end-stage renal disease patients.

OBJECTIVE: To compare self-report of eight diseases with review of medical records and physician reports. STUDY DESIGN AND SETTING: In a cohort of 965 incident end-stage renal disease (ESRD) patients (Choices for Healthy Outcomes in Caring for End-stage renal disease study), data on existing medical conditions were obtained from medical record abstraction, physician report (CMS Form 2728), and self-report in a baseline questionnaire. We evaluated agreement with kappa statistics (k) and sensitivity of self-report. Regression models were used to examine characteristics associated with agreement. RESULTS: The results showed excellent or substantial agreement between self-report and the medical record for diabetes (k=0.93) and coronary artery intervention (k=0.79), and poor agreement for chronic obstructive pulmonary disease (k=0.20). Physician-reported prevalence for all diseases was equal or lower than that by self-report. Male patients were more likely to inaccurately report hypertension. Compared to white patients, African American patients were more likely to inaccurately report cardiovascular diseases. CONCLUSION: In ESRD patients, self-report agreement with the medical record varies with the specific disease. Awareness of diseases of the cardiovascular system appears to be low. African American and male ESRD patients are at risk of low awareness of disease and educational interventions are needed in this high-risk population.

Small apolipoprotein(a) size predicts mortality in end-stage renal disease: The CHOICE study.

BACKGROUND: The high mortality rate in end-stage renal disease has engendered interest in nontraditional atherosclerotic cardiovascular disease (ASCVD) risk factors that are more prevalent in end-stage renal disease, such as elevated lipoprotein(a) [Lp(a)] levels. Previous studies suggest that high Lp(a) levels and small apolipoprotein(a) [apo(a)] isoform size are associated with ASCVD, but none have investigated the relationship between Lp(a) level, apo(a) size, and mortality. METHODS AND RESULTS: An inception cohort of 864 incident dialysis patients was followed prospectively. Lp(a) was measured by an apo(a) size-independent ELISA and apo(a) size by Western blot after SDS-agarose gel electrophoresis. Comorbid conditions were determined by medical record review. Time to death was ascertained through dialysis clinic and Health Care Financing Administration follow-up. Survival analyses were performed with adjustment for baseline demographic, comorbid conditions, albumin, and lipids. Median follow-up was 33.7 months, with 346 deaths, 162 transplantations, and 10 losses to follow-up during 1999 person-years of follow-up. Cox regression analysis showed no association between Lp(a) level and mortality. However, an association between small apo(a) isoform size and mortality was found (hazard ratio, 1.36; P=0.004) after adjusting for age, race, sex, comorbidity score, cause of renal disease, and congestive heart failure. The association was somewhat lower in white patients (hazard ratio 1.34; P=0.019) than in black patients (1.69; P=0.04). No interaction by age, race, sex, diabetes, ASCVD, or Lp(a) level was present. CONCLUSIONS: Small apo(a) size, but not Lp(a) level, independently predicts total mortality risk in dialysis patients.

Mild vs severe pulmonary hypertension before heart transplantation: different effects on posttransplantation pulmonary hypertension and mortality.

BACKGROUND: Pulmonary hypertension (PH) is common in severe heart failure, but the effect of mild PH on posttransplantation PH and survival after heart transplantation has not been well described. METHODS: This cohort study examined preoperative and postoperative hemodynamics in 172 heart transplant recipients at Johns Hopkins Hospital followed for up to 15.1 years. PH was defined as pulmonary vascular resistance > or =2.5 Wood units, as measured during routine right heat catheterization; mild to moderate PH was defined as PVR between 2.5 and 4.9 Wood units; and severe PH was defined as PVR > or =5.0 Wood units. RESULTS: Seventy-one patients (41.3%) had PH, mostly of mild/moderate severity (77.5%), at the last routine hemodynamic monitoring before transplantation (median time before transplantation, 2.7 months). During follow-up, 105 patients (62.9%) developed PH at some point after transplantation, and 48 patients died (cumulative incidence, 76.5%). Mild/moderate preoperative PH was associated with increased risk of posttransplantation PH at 1, 3, and 6 months, but not with later episodes of PH. Mild/moderate preoperative PH was not associated with a higher mortality rate, but each 1 Wood unit increase in preoperative PVR demonstrated a trend toward increased mortality. Severe preoperative PH was associated with death within the first year after adjusting for potential confounders, but not with overall mortality or mortality at other time points. CONCLUSIONS: Mild to moderate preoperative PH is associated with increased risk of developing early but not late posttransplantation PH and may suggest different management strategies. Although PH was not consistently associated with mortality, increasing severity of the preoperative PH suggests potentially worse prognosis.

Lipoprotein(a) and prevalent cardiovascular disease in a dialysis population: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.

BACKGROUND: Levels of lipoprotein(a) [Lp(a)], an atherogenic lipoprotein, are elevated in patients with end-stage renal disease and inversely related to the size of apolipoprotein(a) [apo(a)], a glycoprotein bound to Lp(a). We studied the association of Lp(a) level and apo(a) size with prevalent atherosclerotic cardiovascular disease (ASCVD) in 871 incident dialysis patients (261 blacks, 565 whites, 45 other). METHODS: Lp(a) was measured by an apo(a) size-independent enzyme-linked immunoassay; and apo(a) size was measured by sodium dodecyl sulfate-agarose gel electrophoresis. Prevalent ASCVD, derived from medical records, was defined as coronary heart disease or cerebral or peripheral vascular disease. Adjustment variables included age, sex, race, dialysis modality, diabetes, serum creatinine level, albumin level, and low-density lipoprotein cholesterol level. RESULTS: ASCVD prevalence was 58%. Median Lp(a) levels for those with compared with those without ASCVD were 38 versus 35 nmol/L for whites (P = 0.49) and 100 versus 74 nmol/L for blacks, respectively (P = 0.35). Lp(a) level was associated with ASCVD among those younger than 60 years (odds ratio [OR] for +1 interquartile range of Lp(a), 1.5; P = 0.02), but not among those 60 years and older (OR, 1.0; P = 0.82; P(interaction) by age, 0.08). ORs were 1.3 for all whites (P = 0.03) and 1.1 for all blacks (P = 0.87; P(interaction)by race = 0.53). ORs of ASCVD were 1.7 for whites younger than 60 years (P = 0.01) and 1.2 for blacks younger than 60 years (P = 0.77; P(interaction) by race = 0.42). No association between apo(a) isoform size and ASCVD was present. CONCLUSION: In an incident dialysis cohort, Lp(a) level was associated with prevalent ASCVD among whites younger than 60 years, but not among blacks or those older than 60 years. Apo(a) isoform size was not associated with prevalent ASCVD. These data suggest that baseline ASCVD is unlikely to strongly confound the potential associations of Lp(a) level and prospectively ascertained ASCVD among incident dialysis patients.

The relationship between treatment objectives and practice patterns in the management of urinary tract infections.

OBJECTIVE: To describe physicians' goals when treating uncomplicated urinary tract infections (UTIs) and the relationship between goals and practice patterns. STUDY DESIGN: Analysis of survey results. POPULATION: Primary care physicians. OUTCOMES MEASURED: Self-reported treatment objectives and practice patterns. RESULTS: Most physicians reported their UTI management was convenient for the patient (81.3%). Fewer stated they minimized patients' costs (53.4%), made an accurate diagnosis (56.7%), or avoided unnecessary antibiotics (40.9%). Physicians who stressed convenience or minimizing patient expenses were less likely to use many resources (urine culture, microscopic urinalysis, followup visits and tests, and prolonged antibiotic treatment) and more likely to use telephone treatment. Physicians who stressed accurate diagnoses or avoiding unnecessary antibiotics were more likely to use the same resources and less likely to use telephone treatment. CONCLUSION: UTI management goals vary across physicians and are associated with different clinical approaches. Differences in treatment objectives may help explain variations in practice patterns.

Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition.

CONTEXT: Total cholesterol level is inversely associated with mortality in dialysis patients, a group at high risk of cardiovascular disease (CVD). This paradox may be explained by systemic inflammation and/or malnutrition, which are associated with lower cholesterol levels and higher mortality. OBJECTIVE: To determine the relationship between cholesterol level and outcome in patients undergoing dialysis, accounting for inflammation and malnutrition. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 823 patients enrolled from October 1995 to June 1998 who recently initiated dialysis, from 79 clinics, classified by absence or presence of inflammation and/or malnutrition (defined as serum albumin levels <3.6 mg/dL, C-reactive protein > or =10 mg/L, or interleukin 6 > or =3.09 pg/mL). MAIN OUTCOME MEASURES: All-cause and cardiovascular disease mortality. RESULTS: During a median follow-up of 2.4 years, 324 deaths (159 CVD deaths), 153 renal transplantations, and 10 losses to follow-up occurred. Average serum cholesterol level was lower in the presence of inflammation/malnutrition than in its absence. In a Cox model adjusted for age, race, and sex, a 40-mg/dL (1.0-mmol/L) increment in baseline total serum cholesterol level was associated with a decreased risk of all-cause mortality overall (relative hazard [RH], 0.92; 95% confidence interval [CI], 0.87-0.98) and in the presence of inflammation/malnutrition (RH, 0.89; CI, 0.84-0.95). In contrast, serum cholesterol level was associated with an increased risk in the absence of inflammation/malnutrition (RH, 1.32; 95% CI, 1.07-1.63). For CVD mortality, an inverse trend was not statistically significant in the presence of inflammation/malnutrition, and a positive association was evident in the absence of inflammation/malnutrition (RH, 1.41; 95% CI, 1.04-1.89). Further adjustment for traditional CVD risk factors, dialysis modality, comorbidity, and inflammatory markers attenuated the inverse association but strengthened the positive association. CONCLUSIONS: The inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations. These findings support treatment of hypercholesterolemia in this population.

Inflammatory markers and risk of cerebrovascular events in patients initiating dialysis.

BACKGROUND AND OBJECTIVES: Stroke remains a leading cause of morbidity and mortality for patients on dialysis; however, its risk factors in this population and measures to prevent it are not well understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated whether inflammation was associated with cerebrovascular events in a national US cohort of 1041 incident dialysis patients enrolled from October 1995 to June 1998 and followed until January 31, 2004. Incident cerebrovascular events were defined as nonfatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. With Cox proportional hazards regression analysis accounting for the competing risk of nonstroke death, we assessed the independent event risk associated with baseline levels of multiple inflammatory markers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 (IL-6), matrix metalloproteinase-3 [MMP-3], and P-selectin) and hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) use, which may have pleiotropic inflammatory effects. RESULTS: 165 patients experienced a cerebrovascular event during 3548 person-years of follow-up; overall incidence rate was 4.9/100 person-years. None of the inflammatory markers were associated with cerebrovascular event risk (adjusted hazard ratios [HRs] per log unit [95% confidence interval]: hsCRP, 0.97 [0.85 to 1.11]; IL-6, 1.04 [0.85 to 1.26]; MMP-3, 1.02 [0.70 to 1.48]; P-selectin, 0.98 [0.57 to 1.68]). Statin use was also not associated with significant risk of events in unadjusted (HR 1.07 [0.69 to 1.68]) or propensity-score adjusted analyses (HR 0.98 [0.61 to 1.56]). CONCLUSIONS: In conclusion, neither inflammatory markers nor statin use was associated with risk of cerebrovascular events. Further studies are needed to understand the pathophysiology and prevention of stroke in patients on dialysis.

High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients.

Lipoprotein(a) [Lp(a)] levels are increased in dialysis patients, suggesting that they may play a role in the elevated atherosclerotic cardiovascular disease (ASCVD) risk in this population. Few prospective studies of Lp(a) level, apolipoprotein(a) [apo(a)] size, and ASCVD have been performed in the dialysis population. An inception cohort of 833 incident dialysis patients were followed prospectively. Baseline Lp(a) was measured by apo(a) size-independent ELISA and apo(a) size by Western blot after SDS-agarose gel electrophoresis. A combined prospective nonfatal and fatal ASCVD end point included myocardial infarction, coronary revascularization, cerebrovascular accident, carotid endarterectomy, peripheral revascularization, gangrene, or limb amputation. Survival analyses were performed with adjustment for baseline demographics, comorbid conditions, ASCVD risk factors, albumin, lipids, and C-reactive protein. Median follow-up was 27.4 mo, with 297 ASCVD events, 130 non-ASCVD deaths, and seven losses to follow-up over 1649 person-years. In multivariate Cox regression models, both high Lp(a) concentration (>/=53 nmol/L) and low molecular weight (LMW) apo(a) isoforms (123 nmol/L, the relative hazard (RH) of ASCVD was 1.73 (P < 0.0005), compared with high molecular weight apo(a) and Lp(a) level <123 nmol/L. No interactions by age, race, gender, diabetes, or ASCVD were present. Both LMW apo(a) size and high Lp(a) level predict ASCVD risk in dialysis patients, but the association of ASCVD with LMW isoforms is stronger than the association with high Lp(a) concentration.

Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy.

PURPOSE: Human immunodeficiency virus (HIV)-associated nephropathy is a common and serious cause of progressive renal insufficiency in patients with HIV, frequently presenting with nephrotic range proteinuria. The purpose of this study is to document the histopathologic diagnoses seen in HIV-positive patients with and without nephrotic range proteinuria and to evaluate the predictive value of both nephrotic range proteinuria and CD4 count in diagnosing HIV-associated nephropathy. METHODS: We performed a cross-sectional, single-center study of all 107 HIV-positive patients who had both a renal biopsy and urine protein measurement between 1995 and 2002. Nephrotic range proteinuria was defined as a urine protein-to-creatinine ratio > 3 or a 24-hour urine protein > 3 g. Clinical and laboratory characteristics of those patients with and without HIV-associated nephropathy were compared. Sensitivity, specificity, and positive and negative predictive values of nephrotic range proteinuria in the diagnosis of HIV-associated nephropathy were determined. RESULTS: Fifty-five biopsied patients had nephrotic range proteinuria, among whom 29 (53%) were diagnosed with HIV-associated nephropathy. Among the remaining patients, 12 had non-HIV-associated nephropathy focal segmental glomeruloscerlosis, 3 had membranoproliferative glomerulonephritis, 2 had AA Amyloid, 2 had diabetic nephropathy, and 7 had other diagnoses. Sensitivity, specificity, and positive and negative predictive values of nephrotic proteinuria in the diagnosis of HIV-associated nephropathy were 73%, 61%, 53%, and 79%, respectively. The patients with HIV-associated nephropathy had a significantly higher creatinine (8.2 mg/dL vs 2.5 mg/dL, P < .001) and a lower CD4 count (158 count/mm3 vs 349 count/mm3, P < .01) at the time of biopsy. Although significantly more patients with HIV-associated nephropathy had a CD4 count below 200 (P = .03), among those with a CD4 count below 200, 10 of 30 patients (33%) had diagnoses other than HIV-associated nephropathy. Injection drug use, presence of hepatitis C, and hypertension were not associated with HIV-associated nephropathy. CONCLUSION: Our results suggest that HIV patients with nephrotic range proteinuria warrant a kidney biopsy because the presence of nephrotic range proteinuria, even in the presence a low CD4 count, does not establish the diagnosis of HIV-associated nephropathy.

Sonography as a predictor of human immunodeficiency virus-associated nephropathy.

OBJECTIVE: To determine whether renal sonography can be used to predict the pathologic diagnosis of human immunodeficiency virus-associated nephropathy. METHODS: This cross-sectional study evaluated 87 human immunodeficiency virus-positive patients who underwent both kidney biopsy and renal sonography after referral to the Johns Hopkins Renal Clinic from January 1995 to July 2002. Using a standardized measure of echogenicity, an independent blinded radiologist reviewed the original sonographic images. Sensitivity, specificity, positive and negative predictive values, receiver operating characteristic curves, and likelihood ratios were determined with the use of the biopsy pathologic report as the criterion standard. RESULTS: Thirty-four patients (39%) had biopsy-proved human immunodeficiency virus-associated nephropathy. A higher serum creatinine level, greater proteinuria, and black race were associated with human immunodeficiency virus-associated nephropathy, whereas age, sex, hypertension, and diabetes were not. Sensitivity and specificity for the highest 2 levels of echogenicity were 96% and 51%, respectively Sensitivity and specificity for the highest level of echogenicity were 40% and 95%. The likelihood ratio for the diagnosis of human immunodeficiency virus-associated nephropathy on the basis of the highest echogenicity score was 7.4 (95% confidence interval, 1.3-73.0; P = .006). The likelihood ratio for the lowest 2 echogenicity scores was 0.08 (95% confidence interval, 0.002-0.57; P = 0.003). Kidney size was not associated with human immunodeficiency virus-associated nephropathy status. CONCLUSIONS: This study provides evidence that, among patients with human immunodeficiency virus and kidney disease, the highest and lowest levels of sonographic echogenicity have diagnostic value in respectively establishing or excluding human immunodeficiency virus-associated nephropathy.

Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.

Although atherosclerotic cardiovascular disease (ASCVD) risk in end-stage renal disease (ESRD) is 5 to 30 times that of the general population, few data exist comparing ASCVD risk factors among new dialysis patients to the general population. This cross-sectional study of 1041 dialysis patients describes the prevalence of ASCVD risk factors at the beginning of ESRD compared with estimates of ASCVD risk factors in the adult US population derived from the Third National Health and Nutrition Examination (NHANES III). CHOICE Study participants had a high prevalence of diabetes (54%), hypertension (96%), left ventricular hypertrophy by electrocardiogram (EKG) criteria (22%), low physical activity (80%), hypertriglyceridemia (36%), and low HDL cholesterol (33%). CHOICE participants were more likely to be older, black, and male than NHANES III participants. After adjustment for age, race, gender, and ASCVD (defined as myocardial infarction, revascularization procedure, stroke, carotid endarterectomy, and amputation in CHOICE; and as myocardial infarction and stroke in NHANES III), the prevalence of diabetes, hypertension, left ventricular hypertrophy by EKG, low physical activity, low HDL cholesterol, and hypertriglyceridemia were still more common in CHOICE participants. Smoking, obesity, hypercholesterolemia, and high LDL cholesterol, however, were less common in CHOICE than NHANES III participants. The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants (13%) than in the NHANES III participants (6%). In summary, many ASCVD risk factors are more prevalent in ESRD than in the general population and may explain some, but probably not all, of the increased ASCVD risk in ESRD.

Validation of comorbid conditions on the end-stage renal disease medical evidence report: the CHOICE study. Choices for Healthy Outcomes in Caring for ESRD.

Since 1995, the Medical Evidence Report for end-stage renal disease (Form 2728) has been used nationally to collect information on comorbid conditions. To date, these data have not been validated. A national cross-sectional study of 1005 incident dialysis patients (734 hemodialysis and 271 peritoneal dialysis) enrolled between October 1995 and June 1998 was conducted using clinical data to validate 17 comorbid conditions on Form 2728. Sensitivity and specificity were calculated for each condition. The relationship between patient characteristics and sensitivity was assessed in multivariate analysis. Sensitivity was fairly high (0.67 to 0.83) for HIV disease, diabetes, and hypertension; intermediate (0.40 to 0.52) for peripheral vascular disease, neoplasm, myocardial infarction, cerebrovascular disease, coronary artery disease, cardiac arrest, and congestive heart failure; and poor (<0.36) for dysrhythmia, ambulation status, pericarditis, chronic obstructive pulmonary disease, and smoking. Sensitivity did not change significantly over calendar time. The sensitivity of Form 2728 averaged across all 17 conditions was 0.59 (95% confidence interval, 0.43 to 0.75). The average sensitivity was 0.10 greater in peritoneal dialysis than hemodialysis patients. 0.11 greater in diabetic patients than nondiabetic patients, and 0.04 less with each added comorbid condition. The specificity was very good for hypertension (0.91) and excellent (>0.95) for the other 16 conditions. Comorbid conditions are significantly underreported on Form 2728, but diagnoses are not falsely attributed to patients. Scientific research, quality of care comparisons, and payment policies that use Form 2728 data should take into account these limitations. Considerable effort should be expended to improve Form 2728 coding if it is to provide accurate estimates of total disease burden in end-stage renal disease patients.

Race-specific association of lipoprotein(a) with vascular access interventions in hemodialysis patients: the CHOICE Study.

BACKGROUND: Elevated serum levels of lipoprotein(a) [Lp(a)] and low molecular weight apolipoprotein(a) [apo(a)] isoforms are associated with atherothrombotic disease in the general population and in patients with kidney failure. Lp(a) may be more atherothrombotic in whites than in blacks. Data on the relation of Lp(a) and apo(a) isoform size to hemodialysis vascular access complications are limited. METHODS: We analyzed the intervention-free survival of the first arteriovenous (AV) access among 215 white and 112 black incident hemodialysis patients participating in the CHOICE Study, a national multicenter prospective cohort study. RESULTS: Median levels of Lp(a) protein were higher among blacks than whites (81.0 versus 37.5 nmol/L; P < 0.001) and inversely correlated with apo(a) isoform size (r = -0.57; P < 0.001). The incidence rate of access interventions was much higher in synthetic grafts (N = 193) than native fistulae (N = 134; 1.0 vs. 0.5 interventions per access-year; P < 0.001) and in patients with kidney failure primarily due to diabetes mellitus (N = 161) than others (N = 166; 0.9 vs. 0.6; P < 0.01), but did not differ by race. Blacks in the highest race-specific Lp(a) quartile (>145 nmol/L) had a significantly higher incidence rate than other blacks (1.4 vs. 0.7; P = 0.04), whereas no association was found in whites. The association in blacks remained after adjustment for access type and other characteristics (relative hazard = 1.68; 95% confidence interval: 0.98 to 2.86). No association was found with apo(a) isoform size in either race. CONCLUSIONS: Elevated Lp(a) may be a risk factor for arteriovenous access complications among black hemodialysis patients. Future studies should explore this possibility and be adequately powered to allow race-specific analyses.