Association of oral iron replacement therapy with kidney failure and mortality in CKD patients.

Background: Oral iron is the predominant route of iron replacement (IRT) but its benefits and safety are unclear in patients with chronic kidney disease (CKD). Methods: We examined the association of oral IRT vs no IRT with end-stage kidney disease (ESKD) and mortality in a national cohort of US Veterans. We identified 17 413 incident new users of oral IRT with estimated glomerular filtration rates <60 mL/min/1.73 m2 and 32 530 controls who did not receive any IRT during 2004-18. We used propensity score-overlap weighting to account for differences in key baseline characteristics associated with the use of oral IRT. We examined associations using competing risk regression and Cox models. Results: In the cohort of 49 943 patients, 1616 (3.2%) patients experienced ESKD and 28 711 (57%) patients died during a median follow-up of 1.9 years. Oral IRT was not associated with ESKD [subhazard ratio (HR) (95% confidence interval, CI) 1.00 (0.84-1.19), P = .9] and was associated with higher risk of all-cause mortality [HR (95% CI) 1.06 (1.01-1.11), P = .01]. There was significant heterogeneity of treatment effect for mortality, with oral IRT associated with higher mortality in the subgroups of patients without congestive heart failure (CHF), anemia or iron deficiency. In patient with blood hemoglobin <10 g/dL oral IRT was associated with significantly lower mortality. Conclusion: Oral IRT was associated with lower mortality only in patients with anemia. In patients without anemia, iron deficiency or CHF, the risk-benefit ratio of oral IRT should be further examined.

Association of iron therapy with incidence of chronic kidney disease.

OBJECTIVE: We investigated the association of oral iron replacement with the incidence of chronic kidney disease (CKD) in a population with normal kidney function to study the effects of iron replacement on the development of new onset CKD. METHODS: In a national cohort of US Veterans with no pre-existing CKD, we identified 33 894 incident new users of oral iron replacement and a comparable group of 112 780 patients who did not receive any iron replacement during 2004-2018. We examined the association of oral iron replacement versus no iron replacement with the incidence of eGFR <60 mL/min/1.73 m2 and the incidence of urine albumin creatinine ratio (UACR) ≥30 mg/g in competing risk regressions and in Cox models. We used propensity score weighing to account for differences in key baseline characteristics associated with the use of oral iron replacement. RESULTS: In the cohort of 146 674 patients, a total of 18 547 (13%) patients experienced incident eGFR <60 mL/min/1.73 m2 , and 16 117 patients (11%) experienced new onset UACR ≥30 mg/g. Oral iron replacement was associated with significantly higher risk of incident eGFR <60 mL/min/1.73 m2 (subhazard ratio, 95% confidence interval [CI]: 1.3 [1.22-1.38], p < .001) and incident albuminuria (subhazard ratio, 95% CI: 1.14 [1.07-1.22], p < .001). CONCLUSION: Oral iron replacement is associated with higher risk of new onset CKD. The long-term kidney safety of oral iron replacement should be tested in clinical trials.

Fibroblast Growth Factor 23 and Incident Cardiovascular Disease and Mortality in Middle-Aged Adults.

Background Higher circulating fibroblast growth factor 23 (FGF23) associates with greater risk of cardiovascular disease (CVD) and mortality in older adults. The association of FGF23 with cardiovascular outcomes in younger populations has been incompletely explored. Methods and Results We measured C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) in 3151 middle-aged adults (mean age, 45±4) who participated in the year 20 examination of the CARDIA (Coronary Artery Risk Development in Young Adults) study. We used separate Cox proportional hazards models to examine the associations of cFGF23 and iFGF23 with incident CVD and mortality, adjusting models sequentially for sociodemographic, clinical, and laboratory factors. A total of 157 incident CVD events and 135 deaths occurred over a median 7.6 years of follow-up (interquartile range, 4.1-9.9). In fully adjusted models, there were no statistically significant associations of FGF23 with incident CVD events (hazard ratio per doubling of cFGF23: 1.14, 95%CI 0.97,1.34; iFGF23: 0.76, 95%CI 0.57,1.02) or all-cause mortality (hazard ratio per doubling of cFGF23, 1.17; 95% CI, 1.00-1.38; iFGF23, 0.86; 95% CI, 0.64-1.17). In analyses stratified by CVD subtypes, higher cFGF23 was associated with greater risk of heart failure hospitalization (hazard ratio per doubling of cFGF23, 1.52; 95% CI, 1.18-1.96) but not coronary heart disease or stroke, whereas iFGF23 was not associated with CVD subtypes in any model. Conclusions In middle-aged adults with few comorbidities, higher cFGF23 and iFGF23 were not independently associated with greater risk of CVD events or death. Higher cFGF23 was independently associated with greater risk of heart failure hospitalization.

Association of FGF23 with Incident Sepsis in Community-Dwelling Adults: A Cohort Study.

Background: Fibroblast growth factor 23 (FGF23) is a hormone that regulates vitamin D activity. Higher circulating FGF23 concentrations have been associated with an increased risk of infection-related hospitalization, but the association of FGF23 with risk of sepsis remains unclear. Methods: We examined the association of FGF23 with incident sepsis events in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national longitudinal cohort of black and white adults ≥45 years of age. Using a case-cohort design, we measured baseline FGF23 in 703 sepsis cases and in 991 participants randomly selected from the REGARDS cohort. We defined sepsis as the presence of a serious infection plus two or more Systemic Inflammatory Response Syndrome criteria. We identified first sepsis hospitalizations during 2003-2012 by adjudicated medical record review. Cox proportional hazards models were used to examine associations of FGF23 with incident sepsis, adjusting for age, sex, race, income, education, smoking, body mass index, physical activity, chronic pulmonary disease, eGFR, urine albumin-creatinine ratio, and high-sensitivity C-reactive protein. We also examined whether associations differed by age, race, sex, and CKD by testing interaction terms. Results: Higher FG23 concentrations were associated with greater risk of sepsis (hazard ratio [HR] per doubling of FGF23, 1.37; 95% CI, 1.22 to 1.54) in models adjusted for sociodemographic and clinical variables. After further adjusting for eGFR, urine albumin-creatinine ratio, and high-sensitivity C-reactive protein, the association was attenuated and no longer statistically significant (HR per doubling, 1.01; 95% CI, 0.85 to 1.21). The results did not statistically differ by strata of age, sex, race, or CKD. Conclusions: In community-dwelling adults, higher FGF23 concentrations were not independently associated with higher risk of sepsis.

Association of 25-hydroxyvitamin D with incident coronary heart disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

BACKGROUND: Low circulating 25-hydroxyvitamin D (25[OH]D) has been associated with increased risk of coronary heart disease (CHD), but whether this association differs by race is unclear. METHODS: We examined the association of 25[OH]D with incident CHD in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective cohort study of black and white adults ≥45 years of age enrolled between 2003 and 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured 25[OH]D in 829 participants who developed incident CHD (cases) and in 813 participants without CHD randomly selected from the REGARDS cohort (comparison subcohort). Cox proportional hazards models were used to examine associations of 25[OH]D with incident CHD adjusting for established CHD risk factors in the study sample overall and stratified by race. RESULTS: In the fully adjusted model, lower quintiles of 25[OH]D were associated with a greater risk of incident CHD (25[OH]D > 33.6 ng/mL reference; 25[OH]D > 27.1-33.6 ng/mL, hazard ratio [HR] 2.79, 95% CI 1.64-4.76; 25[OH]D > 22.4-27.1 ng/mL, HR 2.77, 95% CI 1.57-4.89; 25[OH]D > 16.5-22.4 ng/mL, HR 5.52, 95% CI 3.21-9.50; 25[OH]D ≤ 16.5 ng/mL, HR 7.46, 95% CI 4.19-13.25). The results were similar when 25[OH]D was examined on a continuous scale (HR per 10-ng/mL decrement in 25[OH]D 2.04, 95% CI 1.65-2.52). The results did not statistically differ by race whether 25[OH]D was examined as a categorical or continuous variable (Pinteraction > .10). CONCLUSIONS: Lower plasma 25(OH)D concentrations were associated with higher risk of incident CHD. In contrast to prior studies, these associations did not differ by race.