Faculty Bibliography

Reporting estimated glomerular filtration rate (eGFR) with serum creatinine simply provides the information for which the serum creatinine was ordered in the first place. Mass or universal screening is not the purpose of eGFR reporting. Furthermore, such mass screening does not seem justified. Rather, testing of high-risk groups with eGFR and urinary albumin is useful. Population estimates of the prevalence of chronic kidney disease in the United States that use the Kidney Disease Outcomes Quality Initiative staging system lead to disturbingly high estimates. Many of these people are elderly with marginally depressed GFRs and for whom there are no known therapeutic implications. However, an even more disturbing fraction of people with serious and progressive renal disease are not diagnosed, counseled, or treated. Reporting of eGFR is only one tool in attempting to rectify this latter problem. Nephrologists need to educate patients and their primary care colleagues in the use of this tool.

BACKGROUND:In patients undergoing dialysis, therapy with calcitriol or paricalcitol or other vitamin D agents is associated with reduced mortality. Observational data suggests that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown. METHODS:We tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000. RESULTS:In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant. CONCLUSION/CONCLUSIONS:The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

An elevated serum phosphate level in hemodialysis patients has been associated with mineral deposition in blood vessels. We studied a possible physiologic consequence of hyperphosphatemia by examining the relation between serum phosphate levels and blood pressure in 707 incident hemodialysis patients from 75 clinics who were enrolled in a prospective cohort study. We conducted cross-sectional and longitudinal multiple linear regression analyses, adjusting for demographics, medical history, and laboratory factors. In cross-sectional analyses at baseline, elevated serum phosphate was associated with higher predialysis systolic blood pressure (SBP) and pulse pressure (PP) at the start of dialysis; each 1 mg/dL higher phosphate level was associated with 1.77 mm Hg higher SBP. In multivariable adjusted longitudinal analyses, for each 1 mg/dL higher serum phosphate at baseline, SBP was higher at 3 months, 1.36 mm Hg (P = .005); 6 months, 1.13 mm Hg (P = .035); 12 months, 1.65 mm Hg (P = .008); 18 months, 1.44 mm Hg (P = .031); and 27 months, 2.54 mm Hg (P = .002). PP was higher at 3 months, 0.80 mm Hg (P = .027); 6 months, 0.91 mm Hg (P = .022); 12 months, 1.45 mm Hg (P < .001); 18 months, 1.06 mm Hg (P = .026); and 27 months, 1.37 mm Hg (P = .020). This study suggests that serum phosphate level is strongly and independently associated with blood pressure in hemodialysis patients. The effect of rigorous control of serum phosphate levels on arterial stiffness and blood pressure should be studied in clinical trials.

Contrary to most examples of disparities in health outcomes, black patients have improved survival compared with white patients after initiating hemodialysis. Understanding potential explanations for this observation may have important clinical implications for minorities in general. This study tested the hypothesis that greater use of activated vitamin D therapy accounts for the survival advantage observed in black and Hispanic patients on hemodialysis. In a prospective cohort of non-Hispanic white (n = 5110), Hispanic white (n = 979), and black (n = 3214) incident hemodialysis patients, higher parathyroid hormone levels at baseline were the primary determinant of prescribing activated vitamin D therapy. Median parathyroid hormone was highest among black patients, who were most likely to receive activated vitamin D and at the highest dosage. One-year mortality was lower in black and Hispanic patients compared with white patients (16 and 16 versus 23%; P < 0.01), but there was significant interaction between race and ethnicity, activated vitamin D therapy, and survival. In multivariable analyses of patients treated with activated vitamin D, black patients had 16% lower mortality compared with white patients, but the difference was lost when adjusted for vitamin D dosage. In contrast, untreated black patients had 35% higher mortality compared with untreated white patients, an association that persisted in several sensitivity analyses. In conclusion, therapy with activated vitamin D may be one potential explanation for the racial differences in survival among hemodialysis patients. Further studies should determine whether treatment differences based on biologic differences contribute to disparities in other conditions.

OBJECTIVE:The purpose of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) levels and the prevalence of peripheral arterial disease (PAD) in the general United States population. METHODS AND RESULTS/RESULTS:We analyzed data from 4839 participants of the National Health and Nutrition Examination Survey 2001 to 2004 to evaluate the relationship between 25(OH)D and PAD (defined as an ankle-brachial index < 0.9). Across quartiles of 25(OH)D, from lowest to highest, the prevalence of PAD was 8.1%, 5.4%, 4.9%, and 3.7% (P trend < 0.001). After multivariable adjustment for demographics, comorbidities, physical activity level, and laboratory measures, the prevalence ratio of PAD for the lowest, compared to the highest, 25(OH)D quartile (< 17.8 and > or = 29.2 ng/mL, respectively) was 1.80 (95% confidence interval: 1.19, 2.74). For each 10 ng/mL lower 25(OH)D level, the multivariable-adjusted prevalence ratio of PAD was 1.35 (95% confidence interval: 1.15, 1.59). CONCLUSIONS:Low serum 25(OH)D levels are associated with a higher prevalence of PAD. Several mechanisms have been invoked in the literature to support a potential antiatherosclerotic activity of vitamin D. Prospective cohort and mechanistic studies should be designed to confirm this association.

BACKGROUND:There has been controversy about the utility of new third-generation parathyroid hormone (PTH) assays measuring only 1-84 PTH, with few large studies comparing second- and third-generation PTH measurements in patients with ESRD. METHODS:We measured 1-84 PTH ('biointact' or 'whole' PTH) and total PTH ('intact' PTH) in a national cohort of 515 incident dialysis patients from banked frozen EDTA plasma (median follow-up, 35 months) and examined the accuracy of estimating 1-84 PTH from total PTH and the associations of these levels with patient characteristics and mortality. RESULTS:The 1-84 PTH and total PTH levels were closely correlated. Higher 1-84 PTH was associated with African-American race and higher serum phosphate and lower calcium levels. The percentage of total PTH represented by 1-84 PTH was, on average, 53%, but with a wide range (25-89%). Calculating 1-84 PTH from total PTH using a proposed standard conversion factor (54%) led to misclassification of 8% of the population compared with measured 1-84 PTH. In a multivariate Cox proportional hazards model for all-cause mortality, a 1-84 PTH value >160 pg/ml was associated with increased risk of mortality (HR = 1.62, 95% CI, 1.03-2.54) compared to a level of 80-160 pg/ml. Elevated total PTH, 7-84 PTH and the 1-84 PTH/7-84 PTH ratio were not significantly associated with mortality. CONCLUSIONS:The 1-84 PTH and total PTH are highly correlated. Elevated 1-84 PTH was significantly associated with increased mortality, whereas total PTH did not reach statistical significance. Thus, although in other respect they are similar, there may be utility in measuring 1-84 PTH for its associations with mortality.

Awareness of chronic kidney disease (CKD) has increased in part because of the definitions and treatment guidelines set out by Kidney Disease Outcomes Quality Initiative (KDOQI); however, the staging system set forth by these guidelines has led to several problems and unforeseen consequences. Stages 1 and 2 CKD are difficult to determine using the standard Modification of Diet in Renal Disease (MDRD) estimation of GFR, and their clinical significance in the absence of other risk factors is unclear. Just because microalbuminuria in people without diabetes is a cardiovascular risk factor does not make it kidney disease. Most patients who receive a diagnosis of stage 3 CKD (GFR between 30 and 59 ml/min) are elderly people, and the vast majority of these patients will die before they reach ESRD. The staging system needs to be modified to reflect the severity and complications of CKD. It is suggested that stages 1 and 2 be eliminated and stages 3, 4, and 5, be simply termed moderate impairment, severe impairment, and kidney failure, respectively. In addition, age should be a modifying factor, especially in moderate kidney impairment. These changes would allow identification and treatment of clinically relevant disease and avoidance of what can seem exaggerated prevalence estimates.

PURPOSE OF REVIEW/OBJECTIVE:Despite our understanding of how to prevent and treat traditional cardiovascular risk factors, cardiovascular disease remains the leading cause of death of both men and women in the US. Thus, there is widespread interest in a number of emerging nontraditional risk factors for the detection of early cardiovascular disease in order to implement aggressive preventive therapies. 25-Hydroxyvitamin D deficiency has been identified as a potential novel cardiovascular disease risk factor. This review outlines what is known about the association of 25-hydroxyvitamin D levels and cardiovascular disease risk. RECENT FINDINGS/RESULTS:Low 25-hydroxyvitamin D levels have been associated with the cardiovascular disease risk factors of hypertension, obesity, diabetes mellitus and the metabolic syndrome, as well as cardiovascular disease events including stroke and congestive heart failure. Studies suggest vitamin D deficiency may be a contributor to the development of cardiovascular disease potentially through associations with diabetes or hypertension. SUMMARY/CONCLUSIONS:Vitamin D deficiency is easy to screen for and easy to treat with supplementation. Further larger observational studies and randomized clinical trials are, however, needed to determine whether vitamin D supplementation could have any potential benefit in reducing future cardiovascular disease events and mortality risk.

Previous studies among elderly suggest an association between chronic kidney disease (CKD) and cognitive impairment. The purpose of this study was to determine whether moderate CKD is associated with cognitive performance among young, healthy, ethnically diverse adults. Three computerized cognitive function tests of visual-motor reaction time (Simple Reaction Time), visual attention (Symbol Digit Substitution), and learning/concentration (Serial Digit Learning) were administered to a random sample of participants, aged 20 to 59 yr, who completed initial interviews and medical examination in the Third National Health and Nutrition Examination Survey (NHANES III). Participants for this study (n = 4849) completed at least one cognitive function test. GFR was estimated using the Modification of Diet in Renal Disease (MDRD) equation. Moderate CKD was defined as estimated GFR (eGFR) 30 to 59 ml/min per 1.73 m(2). Unadjusted, residual-adjusted, and multivariate-adjusted logistic regression models were used. The cohort was 49.0% male and 11.6% black, and median (interquartile range) age was 36 yr (27 to 45) and eGFR was 107.9 ml/min per 1.73 m(2) (95.0 to 125.4). There were 31 (0.8%) prevalent cases of moderate CKD. Models were adjusted for residual effects of age, gender, race, diabetes, and other known potential confounders. In multivariate models, moderate CKD was not significantly associated with reaction time but was significantly associated with poorer learning/concentration (odds ratio 2.41; 95% confidence interval 1.30 to 5.63) and impairment in visual attention (odds ratio 2.74; 95% confidence interval 1.01 to 7.40). In summary, among those in a large nationally representative sample of healthy, ethnically diverse 20- to 59-yr-old adults, moderate CKD, reflected by eGFR 30 to 59 ml/min per 1.73 m(2), was significantly associated with poorer performance in visual attention and learning/concentration.

Elevated bone mineral parameters have been associated with mortality in dialysis patients. There are conflicting data about calcium, parathyroid hormone (PTH), and mortality and few data about changes in bone mineral parameters over time. We conducted a prospective cohort study of 1007 incident hemodialysis and peritoneal dialysis patients. We examined longitudinal changes in bone mineral parameters and whether their associations with mortality were independent of time on dialysis, inflammation, and comorbidity. Serum calcium, phosphate, and calcium-phosphate product (CaP) increased in these patients between baseline and 6 months (P<0.001) and then remained stable. Serum PTH decreased over the first year (P<0.001). In Cox proportional hazards models adjusting for inflammation, comorbidity, and other confounders, the highest quartile of phosphate was associated with a hazard ratio (HR) of 1.57 (1.07-2.30) using both baseline and time-dependent values. The highest quartiles of calcium, CaP, and PTH were associated with mortality in time-dependent models but not in those using baseline values. The lowest quartile of PTH was associated with an HR of 0.65 (0.44-0.98) in the time-dependent model with 6-month lag analysis. We conclude that high levels of phosphate both at baseline and over follow-up are associated with mortality in incident dialysis patients. High levels of calcium, CaP, and PTH are associated with mortality immediately preceding an event. Promising new interventions need to be rigorously tested in clinical trials for their ability to achieve normalization of bone mineral parameters and reduce deaths of dialysis patients.