Jessica Kendrick

FGF-23 Associates with Death, Cardiovascular Events, and Initiation of Chronic Dialysis

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.

25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey

OBJECTIVE Serum 25-hydroxyvitamin D [25(OH)D] levels are inversely associated with important cardiovascular disease (CVD) risk factors. However, the association between 25(OH)D levels and prevalent CVD has not been extensively examined in the general population. METHODS We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) and examined the association between serum 25(OH)D levels and prevalence of CVD in a representative population-based sample of 16,603 men and women aged 18 years or older. Prevalence of CVD was defined as a composite measure inclusive of self-reported angina, myocardial infarction or stroke. RESULTS In the whole population, there were 1308 (8%) subjects with self-reported CVD. Participants with CVD had a greater frequency of 25(OH)D deficiency [defined as serum 25(OH)D levels <20 ng/mL] than those without (29.3% vs. 21.4%; p<0.0001). After adjustment for age, gender, race/ethnicity, season of measurement, physical activity, body mass index, smoking status, hypertension, diabetes, elevated low-density lipoprotein cholesterol, hypertriglyceridemia, low high-density lipoprotein cholesterol, chronic kidney disease and vitamin D use, participants with 25(OH)D deficiency had an increased risk of prevalent CVD (odds ratio 1.20 [95% confidence interval (CI) 1.01-1.36; p=0.03]). CONCLUSIONS These results indicate a strong and independent relationship of 25(OH)D deficiency with prevalent CVD in a large sample representative of the US adult population.

Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease

Patients with chronic kidney disease (CKD) have a reduced lifespan, and a substantial proportion of these individuals die from cardiovascular disease. Although a large percentage of patients with CKD have traditional cardiac risk factors such as diabetes, hypertension and abnormalities in cholesterol, interventions to address these factors—which have significantly decreased cardiovascular mortality in the general population—have not shown such benefit in the CKD population. In addition, the severity and extent of cardiovascular complications in patients with CKD is disproportionate to the number and severity of traditional risk factors. This realization has focused attention on nontraditional cardiac risk factors that are particularly relevant to patients with CKD, including decreased hemoglobin levels, microalbuminuria, increased inflammation and oxidative stress, and abnormalities in bone and mineral metabolism. However, large prospective trials in patients with advanced CKD or in those requiring chronic dialysis have not shown that normalization of these nontraditional risk factors improves survival. Moreover, the mechanisms by which these nontraditional risk factors contribute to cardiovascular disease are unknown. Therefore, although current treatment of patients with CKD includes management of traditional and nontraditional risk factors, the value of modifying some nontraditional risk factors remains unclear.

The role of phosphorus in the development and progression of vascular calcification.

Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to patients with CKD, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance the progression of vascular calcification, including (1) transition of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters, (2) induction of VSMC apoptosis, (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells, (4) elevation of fibroblast growth factor 23 levels, and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis presently is unknown. This review discusses these mechanisms in depth, exploring the interplay among vascular calcification promoters, inhibitors, and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.

25-Hydroxyvitamin D Deficiency and Inflammation and Their Association with Hemoglobin Levels in Chronic Kidney Disease

Background/Aims: There is limited information about the association of anemia with 25-hydroxyvitamin D [25(OH)D] deficiency and inflammation in the setting of decreased kidney function in the general population. Methods: We examined the association that anemia has with 25(OH)D deficiency and inflammation among 16,301 participants in the Third National Health and Nutrition Examination Survey (NHANES III). Measures of kidney function were estimated glomerular filtration rate (GFR) by using the Modification of Diet in Renal Disease equation. Results: The age-adjusted prevalence of anemia (hemoglobin <12 g/dl) at an estimated GFR of 59–30 ml/min/1.73 m2 was 17% increasing to 56% for those participants with an estimated GFR <30 ml/min/1.73 m2, while the age-adjusted prevalence of elevated C-reactive protein (CRP >0.21 mg/dl) and reduced 25(OH)D (<20 ng/ml) was 50 and 30%, respectively. After adjusting for demographics, comorbidities and laboratory results, 25(OH)D <20 ng/ml (OR: 1.17; 95% CI: 1.03–1.32; p = 0.014) and log CRP (OR: 3.63; 95% CI: 2.4–5.48 per unit increase of log CRP; p < 0.0001) were associated with hemoglobin levels <12 g/dl. Conclusion: This study provides evidence that lower 25(OH)D and higher CRP levels are independently associated with lower hemoglobin concentrations in kidney disease subjects not requiring dialysis.

The Effect of Combined Calcium and Vitamin D3 Supplementation on Serum Intact Parathyroid Hormone in Moderate CKD

BACKGROUND Studies addressing the effects of vitamin D(3) supplementation on secondary hyperparathyroidism in patients with moderate chronic kidney disease are scarce. STUDY DESIGN Post hoc analysis of the randomized clinical trial Vitamin D, Calcium, Lyon Study II (DECALYOS II) to assess effects according to baseline estimated glomerular filtration rate (eGFR). SETTING & PARTICIPANTS Multicenter, randomized, double-blinded, placebo-controlled study of 639 elderly women randomly assigned to calcium-vitamin D(3) fixed combination; calcium plus vitamin D(3) separate combination, or placebo. INTERVENTIONS Placebo or calcium (1,200 mg) and vitamin D(3) (800 IU) in fixed or separate combination. OUTCOMES & MEASUREMENTS Proportion of participants with a mean decrease in intact parathyroid hormone (iPTH) level of 30% or greater. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and categorized as 60 or greater, 45 to 59, and less than 45 mL/min/1.73 m(2). RESULTS 610 participants had an eGFR at baseline: 288 (47.2%), 222 (36.4%), and 100 (16.4%) were in each decreasing eGFR category. Across decreasing eGFR groups, 88%, 86%, and 89% had 25-hydroxyvitamin D (25[OH]D) levels less than 15 ng/mL at baseline. On treatment, similar improvements in the proportion of participants achieving 25(OH)D levels greater than 30 ng/mL at 6 months were seen in all kidney function groups (43%, 49%, and 41%, respectively). Active regimens versus placebo increased mean 25(OH)D levels from baseline in all eGFR groups at all times (P < 0.001 for all). The proportion with a 30% or greater decrease in iPTH level at 6 months was 50% in all eGFR groups on treatment versus 6% to 9% for placebo (P < 0.001 for all). The effects of the intervention on iPTH levels did not differ according to baseline eGFR (interaction P > 0.1 for all times). LIMITATIONS This study included only elderly white women. CONCLUSION Vitamin D(3) was effective in increasing 25(OH)D and decreasing iPTH levels in patients with moderate chronic kidney disease.

Effect of Lovastatin on Primary Prevention of Cardiovascular Events in Mild CKD and Kidney Function Loss: A Post Hoc Analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study

BACKGROUND Chronic kidney disease (CKD) is associated with an increased risk of incident cardiovascular disease (CVD); however, the role of statins for the primary prevention of acute cardiovascular events in patients with CKD and the effect of statins on kidney function loss in persons without prevalent CVD have not been studied. STUDY DESIGN Post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. SETTING & PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial of 5,608 men and 997 women without CVD randomly assigned to treatment with lovastatin or placebo. INTERVENTION Placebo or lovastatin, 20 mg/d. OUTCOMES & MEASUREMENTS First major acute cardiovascular event in participants with mild CKD and kidney function loss in persons with or without CKD. Estimated glomerular filtration rate was calculated using the 4-variable Modification of Diet in Renal Disease Study equation. RESULTS At baseline, mean estimated glomerular filtration rate in participants with CKD (n = 304) was 53.0 +/- 6.0 mL/min/1.73 m(2). After an average follow-up of 5.3 +/- 0.8 years, the incidence of a fatal and nonfatal CVD event was lower in participants with CKD receiving lovastatin than in those receiving placebo (adjusted relative risk [RR], 0.31; 95% CI, 0.13-0.72; P = 0.01). Tests for interaction suggested that the benefit of lovastatin was independent of the presence of CKD. Lovastatin did not reduce the annualized mean decrease in estimated glomerular filtration rate (-1.3 +/- 0.07 vs -1.4 +/- 0.07 mL/min/1.73 m(2)/y, respectively; P = 0.1) or the frequency of a > or = 25% decrease in kidney function (adjusted RR, 1.10; 95% CI, 0.96-1.28; P = 0.2) or incident CKD (adjusted RR, 1.04; 95% CI, 0.86-1.27; P = 0.6). LIMITATIONS Unable to determine the cause and duration of kidney disease, and information regarding proteinuria was not available. CONCLUSIONS Lovastatin is effective for the primary prevention of CVD in patients with CKD, but is not effective in decreasing kidney function loss in persons with no CVD.

Associations of Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations With Death and Progression to Maintenance Dialysis in Patients With Advanced Kidney Disease

BACKGROUND Low vitamin D concentrations are prevalent in patients with chronic kidney disease (CKD). We investigated the relationship between plasma 25-hydroxyvitamin D (25[OH]D) or 1,25-dihydroxyvitamin D (1,25[OH](2)D) concentrations with death, cardiovascular events, and dialysis therapy initiation in patients with advanced CKD. STUDY DESIGN The HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD (stages 4 and 5 not yet on dialysis therapy). 25(OH)D and 1,25(OH)(2)D were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (<15, 15-22, and >22 pg/mL), respectively. Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes. SETTING & PARTICIPANTS 1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers. PREDICTORS 25(OH)D and 1,25(OH)(2)D concentrations. OUTCOMES Death, cardiovascular events, and time to initiation of long-term dialysis therapy. RESULTS After a median follow-up of 2.9 years, 41% (n = 453) died, whereas 56% (n = 615) initiated dialysis therapy. Mean 25(OH)D and 1,25(OH)(2)D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)(2)D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of long-term dialysis therapy (HR, 1.78; 95% CI, 1.40-2.26) compared with the highest tertile. The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 (FGF-23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared with highest tertile). There was no association between 25(OH)D concentrations and outcomes. LIMITATIONS Participants were mostly men. CONCLUSIONS Low plasma 1,25(OH)(2)D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD. FGF-23 level may attentuate this relationship.

Relationship between serum gamma-glutamyltransferase and chronic kidney disease in the United States adult population. Findings from the National Health and Nutrition Examination Survey 2001–2006

BACKGROUND AND AIMS Elevated serum levels of gamma-glutamyltransferase (GGT) are a marker of liver injury, but may also be associated with other diseases and death. Currently, the association of serum GGT concentrations with chronic kidney disease has not been established in the U.S. general population. METHODS AND RESULTS We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey 2001 through 2006 and examined the association between serum GGT concentrations and chronic kidney disease in a nationally representative sample of 13,188 adults aged 20 years or older. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease formula. The prevalence of chronic kidney disease defined as eGFR <60 ml/min/1.73 m(2) or abnormal albuminuria in those with eGFR ≥60 ml/min/1.73 m(2) was 13.9% (n = 1842). Serum GGT elevation was associated with an increased odds of chronic kidney disease (odds ratio 2.38, 95% confidence intervals 2.02-2.80, p<0.0001). After adjustment for demographics, comorbidities, daily alcohol consumption, lipid-lowering medications, viral hepatitis status and laboratory measures, the odds ratio of chronic kidney disease per log serum GGT increase was 1.79 (1.41, 2.27; p<0.0001). CONCLUSIONS These results show a strong, independent, relationship of increased serum GGT concentrations with chronic kidney disease in the US adult population.

Low 25-hydroxyvitamin D level is independently associated with non-alcoholic fatty liver disease

BACKGROUND AND AIMS We sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S. METHODS AND RESULTS Six hundred and seven NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75 ± 17 vs. 85 ± 20 nmol/L [30 ± 7 vs. 34 ± 8 ng/mL], P<0.001). Inadequate 25(OH)D status progressively increased the odds of NAFLD when classified categorically as sufficient (25(OH)D 75 nmol/L [>30 ng/mL], reference group), insufficient (37-75 nmol/L [15-30 ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90-6.34) or deficient (<37 nmol/L [<15 ng/mL]; adjusted OR: 2.56, 95% CI: 1.27-5.19). When modeled as a continuous variable, increased log10 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064-0.96, P=0.02). CONCLUSION Compared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.