Canagliflozin and iron metabolism in the CREDENCE trial.

Bone Marrow Iron in CKD: Correlation With Functional Iron Deficiency

Blood Management

A NEMIA occurs frequently in critically ill patients, with 60–66% of them having anemia when admitted to the intensive care unit (ICU), and is associated with worse outcomes (such as increased length of stay and increased mortality). Anemia is only partially corrected during ICU stay because recent recommendations have led to a decrease in transfusion triggers. Today the prevalence of anemia in patients being discharged from the ICU is very high, being found in at least 75% of the patients upon final hemoglobin measurement. This common, and severe anemia at ICU discharge may also be prolonged after the ICU stay. The median time to recovery of anemia is 11 weeks. One observational study reports that more than half of such patients are still anemic at 6 months. Although the impact of anemia on rehabilitation after ICU discharge or quality of life has not been fully evaluated, it is well accepted that anemia is associated with worse outcomes for postoperative rehabilitation and for patients with chronic diseases such as cancer and thus should retain our interest at the bedside and in the research unit. Because blood transfusion is not an option for complete correction of this anemia, one may advocate the use of other treatments, such as erythropoiesis-stimulating agents (ESA) or iron. ESA efficacy has been studied in critically ill patients and has not proven to be indicated, at least according to the design of the studies. Iron is needed for erythropoiesis and thus may be indicated for the treatment of this anemia, but iron is also a toxic compound with the ability to induce oxidative stress or promote bacterial growth. A better understanding of iron metabolism regulation may help to define the place of iron in these indications. The recent discovery of hepcidin (i.e., the master regulator of iron metabolism) has shed new light on the regulation of iron homeostasis and has increased understanding of the physiopathology of anemia in complex clinical situations where several regulatory circuits interfere with iron metabolism, such as anemia of inflammation and anemia of critically ill patients. This article reviews the link between iron metabolism and anemia in critically ill patients and discusses therapeutic perspectives in this area.

Background: Hepatocellular carcinoma (HCC) is the 6th most commonly diagnosed cancer and the 3rd leading cause of cancer death in the US. Around 85-90% of primary liver cancer is HCC. Besides identified risk factors for HCC including chronic infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, dietary aflatoxin exposure and hereditary hemochromatosis, nonalcoholic fatty liver disease (NAFLD) is as another important risk factor for HCC. NAFLD is a spectrum of liver disease that ranges from hepatic steatosis through non-alcoholic steatohepatitis (NASH) with or without fibrosis and may progress to cirrhosis or HCC. Iron is an essential metal and hepatocytes are its main storage site. Increased body iron from the intestine due to high dietary iron or hereditary or acquired hemochromatosis may result in hepatic iron overload. NAFLD is frequently associated with elevated serum iron indices when hepatic iron in the absence of hemochromatosis. Epidemiologic data on the association between serum iron markers and risk of HCC are sparse. The aim of the study was to examine the association of iron related serum markers with risk of HCC in NAFLD patients. We hypothesized that elevated serum iron levels, which reflects hepatic iron, are associated with increased risk of HCC among NAFLD patients. Methods: 48,328 patients with NAFLD were identified in the electronic health records (EHR) of the University of Pittsburgh Medical Center (UPMC) between 1/1/2004 to 12/31/2018. Among them, 19,908 had at least one measurement of serum iron, transferrin saturation, total iron binding capacity (TIBC) and serum ferritin. After an average 4.47 years of follow-up, 363 patients with NAFLD were diagnosed with HCC at least 30 days after measurement of iron markers. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and the 95% confidence intervals (CIs) for HCC incidence associated with elevated levels of the four iron markers adjusted for age, sex, race, body mass index, history of diabetes and tobacco smoking. Results: Serum iron and transferrin saturation were significantly elevated in NAFLD patients who developed HCC compared to others who remained free of HCC during the study. The HR of HCC for elevated serum iron >175 mcg/dl was 3.41 (95% CI 1.48 - 7.85) compared to its normal range at 75-175 mcg/dl. Similarly, the HR for HCC associated with elevated transferrin saturation >35% was 2.56 (95% CI 1.49-4.39) relative to the normal range at 25-35%. The associations were not statistically significant for TIBC and serum ferritin with HCC risk. Conclusions: Elevated serum iron and transferrin saturation levels, but not TIBC or serum ferritin, were significantly associated with increased risk of developing HCC in NAFLD patients. These findings support future studies evaluating serum iron level in risk stratification of NAFLD patients at risk of HCC and potential links to pathogenesis of HCC. Citation Format: Yi-Chuan Yu, Renwei Wang, Jaideep Behari, Ada Youk, Nancy W. Glynn, Jian-Min Yuan. Serum iron markers in relation to hepatocellular carcinoma risk among patients with non-alcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 754.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Hepcidin: clinical utility as a diagnostic tool and therapeutic target

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

Moderating Effects in Randomized Trials—Interpreting the P Value, Confidence Intervals, and Hazard Ratios

The aim of the study: to assess the relationship between ferrokinetic parameters and the state of cardiac remodeling in patients with coronary artery disease (CAD) depending on the stage of iron deficiency (ID). Materials and methods. The study involved 90 patients with CAD: stable angina pectoris II–III FC (35 men and 55 women, age – 69 (61; 72) years). All patients were divided into 4 clinical groups depending on the parameters of iron metabolism and hemogram: I (n = 16) – patients with absolute ID; II (n = 15) – with latent ID; III (n = 14) – with functional ID; IV (n = 45) – patients with CAD without iron metabolism disorders. The parameters of cardiac remodeling, iron metabolism and their relationship were analyzed. Results. During the analysis of ferrokinetic parameters, a decrease in transport (serum iron, transferrin saturation) and tissue (ferritin) reserve of iron on the background of an increase in the total and latent iron-binding capacity depending on the stage of sideropenia was established. At the same time, latent iron-binding capacity in patients with absolute ID was less by 43 % than in patients with latent ID. Patients with latent ID demonstrated a significantly higher level of transferrin saturation by 59.9 % than in the group of patients with CAD without concomitant ID. Patients with absolute ID, compared to patients without iron metabolism disorders, demonstrated significantly higher size of RAd by 14.18 % (U = 2.0; p < 0.05); increase EDVI of LV in 1.7 times (U = 4.0; p < 0.05); higher value of LV MI by 16 % (U = 17.0; p < 0.05). Also, patients with ferrokinetics disorders demonstrated a tendency to increase LVIDd, EDV LV, ESV LV, ESVI, LV mass, Ao, RAd, RVd, IVSd compared to patients without concomitant ID. For patients with absolute ID, it was established that there a relationship between the level of ferritin and IVSd (r = +0.84; p < 0.05); serum iron and LAd (r = -0.73; p < 0.05); total iron-binding capacity and Ao (r = -0.78; p < 0.05); latent iron-binding capacity and LVIDs (r = +0.71; p < 0.05). Patients with latent ID demonstrated relationships only between the transferrin saturation and LV MI (r = +0.60; p < 0.05). There were no statistically significant correlation relationships between indicators of iron metabolism and cardiac remodeling in patients with CAD and functional ID. Conclusions. The intensity of the processes of cardiac remodeling in patients with CAD and iron deficiency increases in direct proportion to the degree of progression of sideropenia, what is confirmed by the relevant correlation relationships.

Evaluating iron sufficiency: A clearer view

Normalization of Hemoglobin in Patients With CKD May Cause Harm: But What Is the Mechanism?

Restless leg syndrome (RLS), or Willis-Ekbom disease, is a common yet underdiagnosed neurological disorder characterized by an uncontrollable urge to move the legs, often accompanied by unpleasant sensations. Symptoms are worse during rest and at night, significantly affecting sleep and quality of life. Its prevalence is notably higher among patients with chronic kidney disease (CKD), particularly those undergoing dialysis, and is closely linked with disturbances in iron metabolism. Iron is vital for dopamine synthesis, and its deficiency - common in CKD due to inflammation, poor intake, and blood loss - has been implicated in RLS pathogenesis. This study investigates the prevalence of RLS among CKD patients across various treatment modalities and its association with iron deficiency using serum ferritin, transferrin saturation (TSAT), serum iron, and total iron-binding capacity (TIBC). A cross-sectional observational study was conducted at Madras Medical College, Chennai, over six months, involving 150 adult CKD patients (Stages 3-5). Participants were grouped as hemodialysis-dependent (HD), peritoneal dialysis-dependent (PD), conservatively managed (non-dialysis), and post-renal transplant. Patients with non-CKD neurological/psychiatric disorders or those on RLS-inducing medications were excluded. RLS diagnosis was based on the International Restless Legs Syndrome Study Group (IRLSSG) criteria. Clinical interviews, case records, and laboratory tests were used for data collection. Statistical analysis was performed using SPSS (IBM Corp., Armonk, NY, USA), with significance set at p < 0.05. The average participant age was 51.6 ± 12.3 years; 58% were male. The distribution included HD (40%), conservative (28%), PD (18%), and transplant (14%) groups. RLS was diagnosed in 42% of patients (63 out of 150), with the highest prevalence in HD patients (51.7%), followed by PD (40.7%), conservative (26.2%), and transplant (23.8%). Elderly patients (≥60 years) and females had higher RLS prevalence (46.7% and 47.6%, respectively). Diabetics were more affected than non-diabetics (47.8% vs. 37%). Patients with RLS had significantly lower iron indices: mean serum ferritin (88.4 ± 25.6 ng/mL vs. 126.7 ± 30.1 ng/mL), TSAT (16.3 ± 4.7% vs. 22.1 ± 5.6%), and serum iron (48.2 ± 11.4 µg/dL vs. 64.7 ± 13.1 µg/dL). TIBC was higher in RLS patients (295 ± 36 µg/dL vs. 273 ± 30 µg/dL). These findings were statistically significant (p < 0.01). RLS is highly prevalent among CKD patients, especially those on dialysis, and shows a strong association with iron deficiency. Reduced serum ferritin, TSAT, and serum iron levels indicate that impaired iron metabolism contributes significantly to RLS in this population. Functional iron deficiency, even with normal ferritin, may underlie persistent symptoms. Early recognition and targeted iron therapy could reduce RLS burden and improve sleep, mood, and quality of life in CKD patients. Further multicenter studies are needed to validate these findings and develop standardized management protocols.

Plasma soluble transferrin receptor assay when screening for iron-deficiency in an unselected population of elderly anaemic patients

Exploring the Use of Iron and Hematologic Indicators for Surveillance of Iron Deficiency in Pregnant and Nonpregnant Women in the United States.

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.