Faculty Bibliography

BACKGROUND:Elevations in serum phosphorus are associated with renal decline in animal models and progression of established chronic kidney disease (CKD) in human observational studies. We examined whether serum phosphorus levels increase the risk of incident CKD or end-stage renal disease (ESRD) in two population-based prospective cohort studies. METHODS:Overall, 2269 participants free of CKD [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73(2)] from the Framingham Heart Study (FHS; mean age 42 years; 53% women) and 13,372 participants from the Third National Health and Nutrition Examination Survey (NHANES III; mean age 44.3 years, 52% women) contributed to the present study. In the FHS, we evaluated the relationship between baseline phosphorus category (<2.5 mg/dL, 2.5-3.49 mg/dL, 3.5-3.99 mg/dL and ≥4 mg/dL) and incident CKD (n = 267). In NHANES, we examined the relationship between phosphorus below and above 4 mg/dL in relation to incident ESRD (n = 65). RESULTS:FHS participants in the highest phosphorus category had an increased risk of CKD [odds ratio 2.14; 95% confidence interval (CI), 1.07-4.28; P = 0.03] in multivariable-adjusted models when compared to the referent group (2.5-3.49 mg/dL). Similarly, NHANES III participants with phosphorus levels ≥4 mg/dL demonstrated an increased risk of incident ESRD compared to those <4 mg/dL (relative risk 1.90; 95% CI 1.03-3.53; P = 0.04). CONCLUSIONS:In prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESRD.

BACKGROUND:Metabolic acidosis is associated with skeletal muscle proteolysis, and alkali supplementation has shown improvements in lean body mass and urinary nitrogen wasting in several studies. However, the association of acidosis with functional outcomes has not been examined on a population-based level. STUDY DESIGN/METHODS:Cross-sectional study. SETTING & PARTICIPANTS/METHODS:2,675 nationally representative adults 50 years or older in the National Health and Nutrition Examination Survey 1999-2002. FACTOR/METHODS:Serum bicarbonate level. OUTCOMES/RESULTS:Low gait speed and low peak torque were defined as being in the lowest sex-specific quartile of gait speed and peak torque, respectively. MEASUREMENTS/METHODS:Serum bicarbonate was measured in all participants. Gait speed was determined from a 20-foot timed walk. Peak torque was calculated using peak isokinetic knee extensor force. RESULTS:Serum bicarbonate level <23 mEq/L was present in 22.7% of the cohort. Compared with participants with bicarbonate levels ≥23 mEq/L, those with bicarbonate levels <23 mEq/L had higher body mass index and serum albumin levels; were more likely to have low socioeconomic status, a diagnosis of diabetes mellitus, or glomerular filtration rate <60 mL/min/1.73 m(2); and were less likely to use diuretics. Serum bicarbonate level <23 mEq/L compared with ≥23 mEq/L was associated with low gait speed (OR, 1.43; 95% CI, 1.04-1.95) and low peak torque (OR, 1.36; 95% CI, 1.07-1.74) after multivariable adjustment. The association with low peak torque was modified by race/ethnicity in women, but not men (ORs, 1.52 [95% CI, 1.08-2.13] for men, 2.33 [95% CI, 1.23-4.44] for nonwhite women, and 0.93 [95% CI, 0.47-1.82] for white women). LIMITATIONS/CONCLUSIONS:Cross-sectional study using a single bicarbonate measurement. CONCLUSIONS:Lower serum bicarbonate levels are associated with slower gait speed and decreased quadriceps strength in older adults. Further studies should examine the effect of alkali therapy on functional outcomes.

Low vitamin D levels are more common in women than in men. Low vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus and cancers. In this article we review recent evidence regarding associations between low vitamin D levels and cancers and cardiovascular disease. We also review evidence regarding associations between high vitamin D levels and vascular calcifications and pancreatic cancer. It appears that there is probably an optimal level of vitamin D that is neither too high nor too low that is required to maximize health. On going clinical trials should aid in elucidating the optimal levels of 25-hydroxyvitamin D for numerous health outcomes.

BACKGROUND:Previous research supports a possible link between low vitamin D levels and atopic disease. However, the association between low vitamin D levels and total and allergen-specific IgE levels has not been studied. OBJECTIVE:We sought to test the association between serum 25-hydroxyvitamin D (25[OH]D) deficiency (<15 ng/mL) and insufficiency (15-29 ng/mL) and allergic sensitization measured by serum IgE levels in a US nationally representative sample of 3136 children and adolescents and 3454 adults in the National Health and Nutrition Examination Survey 2005-2006. METHODS:The association of 25(OH)D deficiency with 17 different allergens was assessed after adjustment for potential confounders, including age; sex; race/ethnicity; obesity, low socioeconomic status; frequency of milk intake; daily hours spent watching television, playing videogames, or using a computer; serum cotinine levels; and vitamin D supplement use. RESULTS:In children and adolescents allergic sensitization to 11 of 17 allergens was more common in those with 25(OH)D deficiency. Compared with sufficient vitamin D levels of greater than 30 ng/mL, after multivariate adjustment, 25(OH)D levels of less than 15 ng/mL were associated with peanut (odds ratio [OR], 2.39; 95% CI, 1.29-4.45), ragweed (OR, 1.83; 95% CI, 1.20-2.80), and oak (OR, 4.75; 95% CI, 1.53-4.94) allergies (P < .01 for all). Eight other allergens were associated with 25(OH)D deficiency, with P values of less than .05 but greater than .01. There were no consistent associations seen between 25(OH)D levels and allergic sensitization in adults. CONCLUSION/CONCLUSIONS:Vitamin D deficiency is associated with higher levels of IgE sensitization in children and adolescents. Further research is needed to confirm these findings.

Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.

Accumulating data linking hypovitaminosis D to cardiovascular (CV) events has contributed to large increases in vitamin D testing and supplementation. To evaluate the merits of this practice, we conducted a systematic review with meta-analysis providing a framework for interpreting the literature associating hypovitaminosis D with increased CV events. Prospective studies were identified by search of MEDLINE and EMBASE from inception to January 2010, restricted to English language publications. Two authors independently extracted data and graded study quality. Pooled relative risks (RR) were calculated using a random effects model. Ten studies met criteria for review and 7 were included in meta-analysis. Pooled RR for CV events using FAIR and GOOD quality studies was 1.67 (95% confidence interval, 1.23-2.28) during an average follow-up of 11.8 years. There was evidence of significant heterogeneity across studies (Q statistics = 16.6, P = 0.01, I = 63.8%), which was eliminated after omitting 2 studies identified by sensitivity analysis (RR, 1.34 [1.08-1.67]; P for heterogeneity =0.33). When restricting analysis to GOOD quality studies (RR, 1.27 [1.04-1.56]), no significant heterogeneity was found (P = 0.602). Systematic review identified significant shortcomings in the literature, including variability in defining vitamin D status, seasonal adjustments, defining and determining CV outcomes, and the use of baseline vitamin D levels. In conclusion, a modest increased risk of CV events associated with hypovitaminosis D is tempered by significant limitations within the current literature. These findings underscore the importance of critical appraisal of the literature, looking beyond reported risk estimates before translating results into clinical practice.

Dialysis patients are at greater risk for cancers, cardiovascular disease, and all-cause mortality than people in the general population. Novel risk factors have been identified that may help explain these risk elevations. We discuss medical radiation exposure as a novel risk factor in dialysis patients and suggest the need for future research on this topic.

Recent studies indicate that the Notch signaling pathway plays an important role in the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we analyzed the degree of expression and localization of Notch ligands (Jagged1 and Delta1) and activated (cleaved) receptors (Notch1 and Notch2) in healthy human kidneys and in renal biopsies from a wide variety of kidney diseases. These included patients with minimal change disease, membranous nephropathy, lupus nephritis ISN/RPS classes III/IV/V, hypertensive nephrosclerosis, crescentic glomerulonephritis, tubulointerstitial fibrosis, IgA nephropathy, diabetic kidney disease, and FSGS. We found that cleaved Notch1, Notch2, and Jagged1 are expressed on podocytes in proteinuric nephropathies and their level of expression correlated with the amount of proteinuria across all disease groups. The degree of glomerulosclerosis correlated with podocyte expression of cleaved Notch1, while the severity of tubulointerstitial fibrosis and the estimated glomerular filtration rate correlated with expression of cleaved Notch1 in the tubulointerstitium. Hence, our results raise the possibility that Notch pathway activation is a common mechanism in the pathophysiology of a wide range of acquired renal diseases.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Elevated alkaline phosphatase (AlkPhos) and phosphate levels are associated with cardiovascular morbidity and mortality in patients receiving dialysis. A retrospective cohort study was conducted to test these associations in outpatients with an estimated GFR > or =60 ml/min/1.73 m(2). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:Patients with serum AlkPhos and phosphate levels measured between 2000 and 2002 (n = 10,743) at Montefiore Medical Center (MMC) clinics were followed through September 11, 2008 (median 6.8 years). Mortality data were obtained via Social Security Administration records (n = 949 deaths). Hospitalization data were obtained from MMC records. RESULTS:The mean age was 51 years, 64% were women, 22% were white, 26% were non-Hispanic black, 16% were Hispanic, 13% had a diagnosis of hypertension, 9% had diabetes mellitus, and 8% had cardiovascular disease at baseline. AlkPhos and phosphate were independently associated with mortality and cardiovascular-related hospitalization after multivariable adjustment. Comparing patients in the highest (> or =104 U/L) versus lowest quartile of AlkPhos (< or =66 U/L), the adjusted hazard ratio (HR) for mortality was 1.65 (P trend across quartiles <0.001). For the highest compared with the lowest quartile of serum phosphate (> or =3.8 mg/dl versus < or =3.0 mg/dl), the adjusted HR for mortality was 1.29 (P trend across quartiles = 0.008). High AlkPhos but not phosphate levels were also associated with all-cause, infection-related, and fracture-related hospitalization. CONCLUSIONS:Higher levels of serum AlkPhos and phosphate were associated with increased mortality and cardiovascular-related hospitalization in an inner-city clinic population. Further studies are needed to elucidate mechanisms underlying these associations.

BACKGROUND:It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations. OBJECTIVE:The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status. DESIGN/METHODS:A random sample of 3055 postmenopausal women (aged 50-70 y) participating in 3 nested case-control studies of the Women's Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995-2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Women's Health Initiative baseline (1993-1998), were used. RESULTS:More than half of the women (57.1%) had deficient (<50 nmol/L) concentrations of 25(OH)D. Distributions of 25(OH)D concentrations by level of latitude of residence, mean annual regional solar irradiance, and intake of vitamin D varied considerably. The predictive model for 25(OH)D explained 21% of the variation in 25(OH)D concentrations. After adjustment for month of blood draw, breast cancer status, colorectal cancer status, fracture status, participation in the hormone therapy trial, and randomization to the dietary modification trial, the predictive model included total vitamin D intake from foods and supplements, waist circumference, recreational physical activity, race-ethnicity, regional solar irradiance, and age. CONCLUSIONS:Surrogate markers for 25(OH)D concentrations, although somewhat correlated, do not adequately reflect serum vitamin D measures. These markers and predictive models of blood 25(OH)D concentrations should not be given as much weight in epidemiologic studies of cancer risk.