Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:This review examines associations between fibroblast growth factor 23 (FGF-23) and cardiovascular disease. RECENT FINDINGS/RESULTS:FGF-23 is a hormone produced by osteocytes and osteoblasts that aids with phosphate excretion by the kidney and acts as a negative feedback regulator for activated vitamin D synthesis. Recent studies have found associations between elevated FGF-23 levels and a number of cardiovascular diseases, including hypertension, left ventricular hypertrophy, endothelial dysfunction, cardiovascular events and mortality. CONCLUSION/CONCLUSIONS:Recent studies have explored the possible effects of FGF-23 on the cardiovascular system. In animal and observational human studies, there is a link between elevated FGF-23 levels and multiple cardiovascular outcomes, including hypertension, left ventricular hypertrophy and cardiovascular events and mortality. Further studies are required to evaluate whether decreasing FGF-23 levels improves cardiovascular outcomes.

BACKGROUND:Intermittent smoking is prevalent among Hispanics, but little is known about whether this smoking pattern associates with increased chronic kidney disease (CKD) risk in this population. The objective of the present study is to identify patterns of exposure associated with CKD in US Hispanics. METHODS:We used cross-sectional data on 15 410 participants of the Hispanics Community Health Study/the Study of Latinos, a population-based study of individuals aged 18-74 years, recruited in 2008 to 2011 from four US field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). Smoking exposure was obtained through a questionnaire. CKD was defined by an estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or a urine albumin-to-creatinine ratio of ≥30 mg/g. RESULTS:Approximately 14% of individuals were daily and 7% were intermittent smokers, and 16% were past smokers. There was a significant interaction between smoking status and pack-years of exposure (P = 0.0003). In adjusted models, there was an increased odds of CKD among daily, intermittent and past smokers by pack-years compared with never smokers. The association of intermittent smokers was significant at 10 pack-years [odds ratio (OR) = 1.38, 95% confidence intervals (CI) 1.06, 1.81], whereas for daily smokers this association was observed at 40 pack-years (OR = 1.43, 95% CI 1.09, 1.89). CONCLUSIONS:Our findings of increased risk of CKD among Hispanics who are intermittent smokers support screening and smoking cessation interventions targeted to this population for the prevention of CKD. It also suggests novel mechanistic pathways for kidney toxicity that should be further explored in future studies.

BACKGROUND:The regulation of fibroblast growth factor-23 (FGF23) secretion in patients with chronic kidney disease (CKD) is incompletely understood. An in vitro study showed that metabolic acidosis increased FGF23 in mouse bone. The objective of this study is to evaluate the effect of oral sodium bicarbonate on circulating FGF23 levels in patients with CKD. METHODS:This was a single-blind pilot study. Twenty adults with estimated glomerular filtration rate between 15-45 mL/min/1.73 m(2) and serum bicarbonate between 20-24 mEq/L were treated with placebo for 2 weeks, followed by increasing doses of oral sodium bicarbonate (0.3, 0.6 and 1.0 mEq/kg/day) in 2 week intervals for a total of 6 weeks. C-terminal FGF23 levels were measured at the initial visit, after 2 weeks of placebo and after 6 weeks of bicarbonate therapy. Wilcoxon matched-pairs signed-rank test was used to compare FGF23 before and after sodium bicarbonate. RESULTS:After 6 weeks of oral sodium bicarbonate, the median FGF23 increased significantly from 150.9 RU/mL (IQR 107.7-267.43) to 191.4 RU/mL (IQR 132.6-316.9) (p = 0.048) and this persisted after excluding participants who received activated vitamin D. CONCLUSIONS:FGF23 increased after short-term oral sodium bicarbonate therapy in patients with CKD and mild metabolic acidosis. It is unclear whether this was due to the alkalinizing effect of sodium bicarbonate or other factors. TRIAL REGISTRATION:The study was registered at ClinicalTrials.gov ( NCT00888290 ) on April 23, 2009.

Patients with CKD stages 4 and 5 experience biochemical derangements associated with CKD-mineral bone disorder. Some of the key abnormalities are hyperparathyroidism, hyperphosphatemia, hypocalcemia, and metabolic acidosis. We review the available treatments for these conditions and the evidence behind the treatments. We conclude that there is greater evidence for treating hyperphosphatemia than hyperparathyroidism. Treatment of metabolic acidosis in small clinical trials appears to be safe. We caution the reader about side effects associated with some of these treatments that differ in patients with CKD Stages 4 and 5 compared with patients on dialysis. The use of cinacalcet has been associated with hyperphosphatemia in patients with functioning kidneys. Activated vitamin D therapy has been associated with elevated creatinine levels, which may or may not be a reflection of true decrement in kidney function. Finally, the use of non-calcium-containing phosphate binders may be associated with improved clinical outcomes in patients; however, many more clinical trials are needed in this important area of medicine.

BACKGROUND: Pathologic changes that are associated with the cardiorenal syndrome (CRS) are seldom described. The two theories that address renal physiology in CRS include chronic indolent ischemia from renal vasoconstriction and chronic glomerular venous congestion from increased venous pressures. We report on the glomerular histologic changes that occur with long standing heart failure. OBJECTIVE: To examine whether CRS causes renal ischemia that manifests as glomerular size reduction. METHODS: We performed a case-control study where we measured total glomerular areas in 16 adult cases with end-stage heart disease and compared them with matched controls. Control biopsy samples were obtained from renal tissue included in nephrectomies. Glomerular size was measured using the BioQuant Image Analysis program. Cases and controls were matched on the following variables: age (within 10 years), race, body mass index (BMI), diabetes mellitus (DM), glomerular filtration rate (GFR) (within 10 mL/min/1.73 m2), and history of tobacco use. RESULTS: The age range of all patients at the time of biopsy was 40 - 73 years. Nine of the case patients had DM. Estimated GFR ranged from 29 to 55 mL/min/1.73 m2. Mean BMI was 30.8 (SD 4.7) kg/m2. The average median glomerular area in the case patients was 23,944 pixels (1 pixel = 1 mum2), (IQR 22,549 - 27,990) vs. in controls 38,566 pixels (IQR 31, 227 - 45,938) (p = 0.004). CONCLUSIONS: This case-controlled cohort study demonstrates that patients with long standing heart failure have smaller glomerular size as compared with controls matched for relevant clinical variables but not for heart failure.

BACKGROUND:Vitamin D plays an important role in the mineral and bone disorder seen in chronic kidney disease (CKD). Deficiency of 25-hydroxyvitamin D (25OHD) is highly prevalent in the adult CKD population. METHODS:The prevalence and determinants of 25OHD deficiency (defined as a level <20 ng/ml) were examined longitudinally in 506 children in the CKiD cohort. Predictors of secondary hyperparathyroidism and the determinants of 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were also evaluated. RESULTS:Deficiency of 25OHD was observed in 28 % of the cohort at enrollment. Significant predictors of 25OHD deficiency were older age, non-white race, higher body mass index, assessment during winter, less often than daily milk intake, non-use of nutritional vitamin D supplement and proteinuria. Lower values of glomerular filtration rate (GFR), serum 25OHD, calcium and higher levels of FGF23 were significant determinants of secondary hyperparathyroidism. Lower GFR, low serum 25OHD, nephrotic-range proteinuria, and high FGF23 levels were significant determinants of serum 1,25(OH)2 D levels. CONCLUSIONS:Deficiency of 25OHD is prevalent in children with CKD and is associated with potentially modifiable risk factors such as milk intake, nutritional vitamin D supplement use, and proteinuria. 25OHD deficiency is a risk factor for secondary hyperparathyroidism and decreased serum 1,25(OH)2D in children with CKD.

We aimed to determine the prevalence and clinical significance of complement-binding donor-specific antibodies (DSA) detected up to 30 years after kidney transplantation. Group 1 patients included 284 consecutive DSA negative patients who underwent kidney transplantation after 1 May 2009. Group 2 included 405 patients transplanted before this date and followed at our center with functioning allografts. DSA were tested using Luminex Single Antigen and the C1q assay. In Group 1 patients, who were monitored prospectively, 31 (11%) developed de novo DSA during a median follow-up of 2.5 (1.9, 3.6) years. Of these, 11 (4%) had C1q+ and 20 (7%) had C1q negative DSA. In Group 2 patients, 77 (19%) displayed DSA. Among these, 33 (8%) had C1q+ and 44 (11%) had C1q negative DSA. The incidence of acute antibody-mediated rejection (AMR) was significantly higher in C1q+DSA patients in both Group 1 (45%) and Group 2 (15%) compared with C1q negative DSA (5% and 2%) and DSA negative patients (1% and 3%; P < 0.001 and P = 0.001). The incidence of chronic AMR was 36% (Group 1) and 51% (Group 2) in patients with C1q+DSA. In contrast, chronic AMR occurred in 5% and 25% of C1q negative DSA, and 2% and 6% of DSA negative Group 1 and 2 patients, respectively (P < 0.001). Although the graft survival was lower in Group 1 C1q+DSA patients (73%) compared with C1q negative DSA (95%) and DSA negative (94%) patients, the difference was not statistically significant by Kaplan-Meier survival analysis (P = 0.21). Our results indicated that the presence of C1q+ DSA was associated with acute and chronic AMR.

OBJECTIVE:Kidney dysfunction in obesity may be independent of and may precede the development of hypertension and/or diabetes mellitus. We aimed to examine if abdominal obesity is associated with early markers of CKD in a young healthy population and whether these associations differ by race and/or ethnicity. METHODS:We analyzed data from the NHANES 1999-2010 for 6918 young adults ages 20-40 years. Abdominal obesity was defined by gender criteria of waist circumference. CKD markers included estimated glomerular filtration rate and albuminuria ≥30 mg/g. Race stratified analyses were done overall and in subgroups with normal blood pressures, normoglycemia and normal insulin sensitivity. Awareness of CKD was assessed in participants with albuminuria. RESULTS:Abdominal obesity was present in over one-third of all young adults and was more prevalent among non-Hispanic blacks (45.4%) versus Mexican-Americans (40.6%) or non-Hispanic whites (37.4%) (P-value = 0.004). Mexican-American young adults with abdominal obesity had a higher odds of albuminuria even among those with normal blood pressure, normal glucose, and normal insulin sensitivity [adjusted odds ratio 4.5; 95% confidence interval (1.6-12.2), p = 0.004]. Less than 5% of young adults with albuminuria of all races and ethnicities had been told they had kidney disease. CONCLUSION:Abdominal obesity in young adults, especially in Mexican-Americans, is independently associated with albuminuria even with normal blood pressures, normoglycemia and normal insulin levels. Greater awareness of CKD is needed to protect this young population from long-standing exposure to abdominal obesity and early progressive renal disease.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The prevalence of ESRD among Hispanics/Latinos is 2-fold higher than in non-Hispanic whites. However, little is known about the prevalence of earlier stages of CKD among Hispanics/Latinos. This study estimated the prevalence of CKD in US Hispanics/Latinos. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:This was a cross-sectional study of 15,161 US Hispanic/Latino adults of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds enrolled in the multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL). In addition, the prevalence of CKD in Hispanics/Latinos was compared with other racial/ethnic groups in the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Prevalent CKD was defined as an eGFR <60 ml/min per 1.73 m(2) (estimated with the 2012 Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C equation) or albuminuria based on sex-specific cut points determined at a single point in time. RESULTS:The overall prevalence of CKD among Hispanics/Latinos was 13.7%. Among women, the prevalence of CKD was 13.0%, and it was lowest in persons with South American background (7.4%) and highest (16.6%) in persons with Puerto Rican background. In men, the prevalence of CKD was 15.3%, and it was lowest (11.2%) in persons with South American background and highest in those who identified their Hispanic background as "other" (16.0%). The overall prevalence of CKD was similar in HCHS/SOL compared with non-Hispanic whites in NHANES. However, prevalence was higher in HCHS/SOL men and lower in HCHS/SOL women versus NHANES non-Hispanic whites. Low income, diabetes mellitus, hypertension, and cardiovascular disease were each significantly associated with higher risk of CKD. CONCLUSIONS:Among US Hispanic/Latino adults, there was significant variation in CKD prevalence among Hispanic/Latino background groups, and CKD was associated with established cardiovascular risk factors.