Iron deficiency and risk of heart failure and cardiovascular events in CKD: Insights from the ASCEND-ND trial.

Background and Aims Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) but remains under-diagnosed and its prognosis poorly documented in the absence of anemia. Data from CKDopps showed low TSAT levels were associated with increased risk of all-cause mortality and incidence of major cardiovascular events in patients with moderate to advanced CKD, an effect that was not modified by the presence of anemia [1]. Additionally, patients with both low TSAT and high ferritin levels displayed the highest risk of all-cause mortality. The aim of the study was to assess the relationship between ID and the risk of major adverse outcomes in patients with CKD in France. Method Using data from the French CKD-REIN cohort which included and followed over 5 years, 3,033 nephrology outpatients with CKD stage 2 to 5 CKD [2], we estimated the prevalence of ID, defined by a ferritin level < 100 mg/L and/or a transferrin saturation (TSAT) < 20%, and associated hazard ratios (HR) of kidney failure with replacement therapy, kidney failure defined by an eGFR < 15 ml/min per 1.73 m2 or initiation of kidney replacement therapy, all-cause mortality, all-cause hospitalization and death or hospitalization for heart failure. The analysis was conducted using a Cox model in which ID was included as a time-dependent variable and adjusted for identified confounders (socio-demographic characteristics, comorbidities, and biological measures) and hemoglobin level. Results A total of 2 914 patients with at least one ferritin or TSAT measurement at baseline or during follow-up were included in the analysis. The majority were men (66%), with a mean age of 67 ± 13 years; 49.6%, 41.2%, and 9.2%, had CKD stage 2/3, 4, and 5, respectively. Baseline prevalence of ID in the cohort was 50% [48-52]. Mean hemoglobin was 13 ± 1.7 g/dL, and only 31% of patients with ID also had a hemoglobin < 12 g/dL. Of the 2 914 patients included in the analysis, 627 (22%) required dialysis or transplantation, and 382 (13%) died before kidney replacement therapy. The incidence rate of kidney failure with replacement therapy was 6.76 versus 3.53 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure with replacement therapy, with adjusted HRs for confounders and hemoglobin level of 1.51 [1.24-1.82] (Fig. 1). A total of 836 patients (29%) progressed to kidney failure during the study period, and 341 (12%) died before this stage. The incidence rate of kidney failure was 8.66 versus 6.43 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure, with adjusted HRs for confounders and hemoglobin level of 1.19 [1.02-1.38] (Fig. 1). Adjusted HRs for all-cause mortality, for all-cause hospitalization, and for hospitalization or death for heart failure, were 1.31 [1.04-1.66], 1.04 [0.93-1.15], and 1.38 [1.07-1.80], respectively (Fig. 2). Conclusion This study confirms that ID is common in patients with CKD and shows that ID is significantly associated with the risk for kidney failure, all-cause mortality, and heart failure, independent of the presence of anemia. An intervention trial would be needed to assess whether correction of this ID in CKD patients is associated with a reduction in associated risks.

Lowering Blood Pressure to Lower the Risk of Cardiovascular Events in CKD

Cord serum ferritin levels, fetal iron status, and neurodevelopmental outcomes: Correlations and confounding variables

Background and Aims Iron deficiency increases the transcription and cleavage of the peptide hormone, fibroblast growth factor 23(FGF23). Elevated FGF23 has been associated with increased risk of cardiovascular events and mortality. Iron deficiency also increases platelet count (PLT) in part, and higher levels PLT are associated with arterial thrombosis in the brain. Ferric citrate hydrate (FC, Riona®, Torii Pharmaceutical Co., Ltd. Tokyo, Japan) is an oral iron-based phosphate binder for patients with chronic kidney disease (CKD) and also an iron preparation approved for treatment of iron deficiency anaemia (IDA) in Japan. A phase 3 study was conducted to investigate the efficacy and safety of FC in CKD and non-CKD patients with IDA. This study aimed to evaluate the effects of FC on intact FGF23 and c-terminal FGF23 levels, and the proportion of patients with high PLT (exceeding upper limit: >35.2 × 104/µL). Method A randomized, open-label, multicentre, uncontrolled, 24-week study was conducted at 31 centres in Japan from July 2018 to December 2019 (JapicCTI-184000) in CKD and non-CKD patients with IDA (Hb: ≥8.0 g/dL and <11.0 g/dL, serum ferritin <50 ng/mL in CKD (eGFRcre <60 mL/min/1.73 m2) and <12 ng/mL in non-CKD). CKD patients scheduled to initiate maintenance dialysis were excluded. Dynamic allocation was used to randomise subjects (CKD and non-CKD with Hb at baseline) to the FC-low group (500 mg [approximately 120 mg elemental iron]/day) or FC-high group (1000 mg [approximately 240 mg elemental iron]/day) (1:1). Notably, if investigators determined that sufficient iron replacement had been achieved from week 8 onwards, the study treatment was completed. For this reason, changes from baseline to week 8 were evaluated. Results Of 73 patients (CKD n = 42, non-CKD n = 31), 36 were allocated to the FC-low group (CKD n = 21, non-CKD n = 15) and 37 to the FC-high group (CKD n = 21, non-CKD n = 16). Baseline levels of serum ferritin, transferrin saturation (TSAT), c-terminal FGF23, intact FGF23, and PLT are shown in Table 1. Regardless of CKD status, serum ferritin and TSAT increased. After FC-low treatment, mean changes from baseline to week 8 (95% CI) in serum ferritin and TSAT were 18.8 (13.3, 24.2) ng/mL and 8.1 (4.4, 11.8) % in CKD, 17.5 (13.8, 21.3) ng/mL and 13.8 (8.7, 18.9) % in non-CKD;, they were 28.1 (13.4, 42.7) ng/mL and 8.8 (5.4, 12.1) % in CKD, 15.9 (12.1, 19.8) ng/mL and 19.9 (9.8, 30.1) % in non-CKD. After administration of FC, in both groups, intact FGF23 levels did not change, whereas c-terminal FGF23 levels decreased. Median changes (interquartile range) from baseline to week 8 of c-terminal FGF23 were -58.00 (-227.50, -12.25) RU/mL in CKD and -725.00 (-1124.00, -168.50) RU/mL in non-CKD, and -66.00 (-265.70, -27.00) RU/mL in CKD and -649.50 (-1127.00, -326.65) RU/mL in non-CKD. Serum phosphate did not change regardless of CKD status. At baseline, high PLT was observed in the FC-low group in 1 CKD case (5.0%) and 8 non-CKD cases (53.3%), and in the FC-high group in 3 CKD cases (15.8%) and 8 non-CKD cases (50.0%). In all these patients, PLT reduction to below 35.2 × 104/µL was observed until week 8. Conclusion In patients with IDA, administration of FC increased serum ferritin and TSAT, decreased c-terminal FGF23, and normalized PLT in patients with high PLT at baseline regardless of CKD status. FC may decrease the potential risk of cardiovascular events in CKD or non-CKD patients with IDA.

Cardiovascular risk with DPP-4 inhibitors: latest evidence and clinical implications.

Bone Marrow Iron in CKD: Correlation With Functional Iron Deficiency

Disclosure: M. Solomon: None. A. Vaidya: None. S.S. Waikar: None. A. Verma: None. Background: Elevated aldosterone and low-density lipoprotein (LDL) are both known risk factors for major cardiovascular events (MACE) in chronic kidney disease (CKD). Method: The synergistic impact of aldosterone and LDL on incident MACE was investigated among 3453 participants in the Chronic Renal Insufficiency Cohort. The primary exposure was the interaction between aldosterone and LDL as continuous variables. We also evaluated the same interaction after categorizing each variable by the median. The primary outcome was MACE [defined as the composite of heart failure (HF), myocardial infarction (MI), or stroke, whichever occurred first]. Cox proportional hazard models and confounder-adjusted survival curves were developed after adjustment for demographic, metabolic, renal, and laboratory parameters to ensure a robust interpretation of results. Results: Over a median follow-up period of 8.9 years, 1,030 participants experienced major cardiovascular events (MACE). There was a statistically significant linear interaction between aldosterone and low-density lipoprotein (LDL) in predicting incident MACE (P = 0.005). In adjusted models, participants with aldosterone and LDL levels greater than the median had a 32% increased risk of MACE (HR 1.32, 95% CI 1.08-1.61) compared to those with values below the median. The 10-year absolute risk difference for MACE was 5.8% (95% CI 1.3 -10.3) comparing individuals with aldosterone and LDL greater than the median with those below the median. Conclusion: The combination of elevated aldosterone levels and elevated LDL cholesterol imparts a heightened risk for major cardiovascular events in CKD. These findings emphasize the potential value of mineralocorticoid receptor antagonism or aldosterone synthase inhibition in combination with LDL-lowering to mitigate adverse cardiovascular events in CKD. Presentation: 6/3/2024

Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) but remains under-diagnosed and its prognosis poorly documented in the absence of anemia. The aim of the study was to assess the relationship between ID and the risk of major adverse outcomes in patients with CKD. Using data from the French Chronic Kidney Disease - Renal Epidemiology and Information Network (CKD-REIN) cohort which included and followed over five years, 3,033 patients with CKD stages 2 to 5 CKD, we estimated the prevalence of ID, defined by a ferritin level < 100 μg/L and/or a transferrin saturation < 20%, and associated hazard ratios (HR) of kidney failure with replacement therapy, kidney failure defined by an eGFR < 15 mL/min per 1.73 m2 or initiation of kidney replacement therapy, all-cause mortality, and death or hospitalization for heart failure. Baseline prevalence of ID in the cohort (66% men; mean age 67 ± 13 years) was 50% (48-52). Mean hemoglobin was 13 ± 1.7 g/dL, and only 31% of patients with ID also had a hemoglobin < 12 g/dL. In 2,803 patients with CKD stages 2-4 at baseline, ID was associated with significant increased risk of kidney failure, and of kidney failure with replacement therapy, with HRs adjusted for confounders and hemoglobin level of 1.22 (1.03-1.45) and 1.57 (1.27-1.94), respectively. Adjusted HRs for all-cause mortality and hospitalization or death for heart failure, were 1.31 (1.04-1.66) and 1.38 (1.07-1.80), respectively. This study shows that ID is significantly associated with the risk for kidney failure, all-cause mortality, and heart failure, independent of the presence of anemia.

Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (<20%) and higher ferritin (≥100 ng/mL) levels. A time-dependent Cox hazard model was used for the evaluation of the association between dysutilization of iron for erythropoiesis and adverse events and survival. Patients with low TSAT levels showed an increased risk of cerebrovascular and cardiovascular disease (CCVD) and death compared to patients with normal or higher TSAT levels. Patients with low ferritin and high TSAT levels had a significantly lower risk of CCVD and death compared with patients with high ferritin and low TSAT levels. Higher TSAT levels were associated with male gender, age, the absence of diabetes, low levels of high-sensitivity CRP, and low β2 microglobulin levels, but not with intravenous iron administration or ferritin levels. Although patients with low TSAT levels had a significantly higher risk of CCVD or death, high TSAT levels were not linked with iron administration. Patients, who were suspected of dysutilization of iron for erythropoiesis, had a higher risk of CCVD and death. The administration of iron should be performed cautiously for improving TSAT levels, as iron administration could sustain TSAT levels for a short term.

Abdominal aortic calcification is a common complication and a predictor of cardiovascular mortality in dialysis patients. However, abdominal aortic calcification in pre-dialysis chronic kidney disease (CKD) is poorly understood. A cohort study of 101 adult Japanese patients (mean age 66.6 +/- 11.3 years old) with pre-dialysis CKD (18, 29 and 54 in stages 3, 4 and 5, respectively) was performed. At entry, a non-contrast computed tomography scan was used to determine the abdominal aortic calcification index (ACI). Clinical characteristics and laboratory variables were also assessed. The patients were followed for a mean period of 48 +/- 12 months. Among the subjects, 82% had abdominal aortic calcification (50, 83 and 91% for CKD stages 3, 4 and 5, respectively), and the median ACI was 16.7% (8.5, 20.0 and 21.4%, respectively). Multivariate logistic regression analyses identified older age, presence of diabetes and decreased estimated glomerular filtration rate (e-GFR) as independent predictors of the presence (ACI > 0%) and extent (ACI >or= 20%) of aortic calcification. Multivariate Cox proportional hazards analysis identified ACI >or= 20% and diabetes as independent predictors for de novo cardiovascular events in CKD stages 4 and 5. Decreased GFR may be associated with the presence and extent of abdominal aortic calcification, and a high level of calcification may be associated with de novo cardiovascular events in pre-dialysis CKD, suggesting that elucidation of the mechanism through which CKD contributes to vascular calcification may lead to an improved prognosis in patients with pre-dialysis CKD.

Blood Management

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

Risk of Fractures in Individuals with Hemochromatosis HFE C282Y Homozygosity and in Individuals with Low or High Levels of Plasma Iron, Transferrin Saturation, or Ferritin: A Prospective Study of 142,146 General Population Individuals

Introduction: While severe iron overload has been associated with cardiac damage, iron deficiency is related to worse outcomes in subjects with heart failure (HF).This study investigated the relationship between ferritin, a marker of iron status, and the incidence of HF in a general population based sample. Methods: We examined 1,063 participants from the Atherosclerosis Risk in Communities (ARIC) study, mean age 52±5 years, 62% women, free of heart failure, in whom ferritin serum levels were measured at baseline (1987-1989). The participants were categorized in low (200 ng/mL in women and &gt;300 ng/mL in men; n=247) ferritin levels. Multivariable Cox proportional hazards models were used to evaluate the relationship between ferritin and incident HF. Results: At 20.9±4.6 years of follow-up, HF occurred in 144 (13.5%) participants. When compared with participants with normal ferritin, those with low level had a higher risk of HF (HR 2.10, 95%CI 1.27-3.47; p=0.004), while there was no significant difference between those with normal and high ferritin levels (HR= 1.07, 95%CI= 0.71-1.63, p=0.7), after adjusting for potential confounders. Low ferritin levels remained associated with incident HF in subjects without anemia (HR= 2.06, 95%CI= 1.18-3.61, p=0.01). (Figure) Conclusion: Low ferritin levels are associated with a higher risk of incident HF. These findings suggest that iron deficiency might play a role in the development of HF.

Introduction: Iron deficiency affects 10% of adults aged 70 years or older and is associated with worse symptom burden and a higher risk of hospitalization in adults with heart failure (HF) with reduced ejection fraction (HFrEF) in mid-life. However, the relationships between iron deficiency and incident HF, HFrEF and HF with preserved EF (HFpEF) in late life remain incompletely understood. Hypothesis: Iron deficiency, as measured by lower plasma ferritin levels, is associated with an increased risk of incident HF, HFrEF, and HFpEF in older adults. Methods: We included 3,567 participants (mean age 75 years, 56% women and 14% Black) from the ongoing, ARIC study who had plasma ferritin measured by an aptamer assay (SomaLogic) and were free from prevalent HF and anemia (Hb &lt;13 for men and &lt;12 for women). The associations of log 2 -transformed plasma ferritin with adjudicated incident overall HF, HFrEF (LVEF &lt; 50%) and HFpEF were estimated using Cox proportional hazards models. The associations of plasma ferritin with echocardiographic measures of cardiac size and function at Visit 5 were estimated with linear regression models. All models were adjusted for age, sex, race, smoking, body mass index, coronary heart disease, diabetes, hypertension, atrial fibrillation and eGFR. Results: Over a median 7 years of follow-up, 312 incident HF events occurred (140 HFrEF, 137 HFpEF, 51 unknown EF). Lower ferritin level was associated with a higher risk of overall HF and HFpEF, but not HFrEF ( Figure ). Lower ferritin levels associated with a higher E/e' ratio (standardized beta [95% CI]: 0.06 [0.03-0.08]; P&lt;0.01). Plasma ferritin levels did not associate with LV mass index or measures of LV systolic function (ejection fraction, global longitudinal strain; all P &gt; 0.05). Conclusion: Lower plasma ferritin levels associate with higher LV filling pressure and greater risk of incident HF, and in particular HFpEF, in late life. Iron deficiency may contribute to the pathophysiology of HF in late life.