Time-dependent trade-offs among intravenous iron formulations for iron-deficiency anemia: a longitudinal systematic review and network meta-analysis.

Iron deficiency (ID) is common in older adults and is associated with adverse clinical outcomes. Oral iron is often limited by poor absorption and gastrointestinal intolerance. The current article reviews considerations for intravenous (IV) iron therapy in older adults with ID. To review IV iron efficacy, safety, and practical use in older adults. IV iron effectively restores iron stores; improves hemoglobin, functional status, and quality of life; and reduces transfusion requirements. Comorbidities, such as chronic kidney disease, heart failure, and gastrointestinal disorders, frequently necessitate IV iron therapy. Risks include allergic reactions, infusion reactions, hypophosphatemia, and transient hypotension, although serious adverse events are rare. Therapy should be individualized based on comorbidities and practical considerations. IV iron is a safe and effective option for older adults, offering reliable and rapid repletion when oral iron is ineffective or contraindicated. Clinicians must weigh benefits and risks to optimize outcomes.

Abstract INTRODUCTION Anemia develops in more than half of glioblastoma (GBM) patients during the postoperative and early adjuvant period, driven by surgical blood loss, bone-marrow suppression, and cancer-related inflammation. Iron supplementation is widely used to correct postoperative anemia in other surgical populations, and modern intravenous preparations allow rapid repletion even when inflammation limits oral absorption. However, there is little high-quality evidence showing that proactive iron therapy improves clinical outcomes in GBM patients. METHODS This study aims to evaluate whether timely iron supplementation in patients who develop anemia within 60 days after GBM surgery is associated with improved overall survival compared with no iron treatment. We conducted a retrospective cohort study using the TriNetX U.S. Collaborative Network, a multicenter database encompassing 71 healthcare organizations across the United States. We identified adult patients with GBM who underwent surgery and were diagnosed within 60 days postoperatively with iron deficiency anemia, acute posthemorrhagic anemia, neoplasm-related anemia, or moderate-to-severe anemia (hemoglobin < 8 g/dL). Patients were classified into two groups based on whether or not they received iron supplementation. Propensity score matching (1:1) was performed to ensure balanced baseline characteristics between groups. RESULTS A total of 51 patients who received iron supplementation and 396 who did not were included. After 1:1 propensity score matching, baseline characteristics were well balanced (standardized mean differences < 0.1; mean age: 62.3 ± 15 vs. 63.0 ± 14.9). During 1-year follow-up, iron supplementation was associated with a non-significant increase in all-cause mortality (hazard ratio [HR] 1.80; 95% CI, 0.92–3.52). Similar trends were observed at 3 and 5 years (HR 1.68 [0.94–2.98] and HR 1.60 [0.91–2.82], respectively). CONCLUSION Iron supplementation within 60 days after GBM surgery showed no significant impact on overall survival. Further studies incorporating anemia severity and treatment timing are warranted.

Probing regional glycogen metabolism in humans non-invasively has been challenging due to a lack of sensitive approaches. Here we studied human muscle glycogen dynamics post-exercise with a spatial resolution of millimeters and temporal resolution of minutes, using relayed nuclear Overhauser effect (glycoNOE) MRI. Data at 5T showed a homogeneous distribution of glycogen in resting muscle, with an average concentration of 99 ± 13 mM. After plantar flexion exercise following fasting with recovery under fasting conditions, the calf muscle showed spatially heterogeneous glycogen depletion and repletion kinetics that correlated with the severity of this depletion. Three types of regional glycogen kinetics were observed: (i) single exponential repletion (type a); (ii) biphasic recovery of rapid repletion followed by additional depletion (type b); (iii) biphasic recovery where continued depletion is followed by an exponential recovery (type c). The study of the complex patterns of glycogen kinetics suggests that glycogen breakdown may be quantitatively important during the initial recovery.

Background/Objectives: Epidemiological data on vitamin D status revealed that, despite various dosage and durations of supplementation, the effectiveness often fails to achieve optimal outcomes. The need for higher doses than previously recommended was suggested, but several modifying factors should be considered, including the level of deficiency, and BMI. The objectives of this post hoc evaluation are to characterize treatment effectiveness based on the applied dose, duration and BMI; and to assess the safety aspects associated with rapid repletion of vitamin D. Methods: Vitamin D deficient subjects selected in the post-hoc analysis: seventy patients included from a combined loading-maintenance supplementation (300,000 IU followed by 60,000 IU) protocol and 62 deficient subjects who received a low-dose maintenance (1000 IU/day) therapy. The risk of overload and the incidence of hypercalciuria and hypercalcemia resulting from loading or post-loading maintenance were investigated. Results: The moderate–fast-loading schedule of 60,000 IU per week for 5 weeks, effectively achieves the target in 25(OH)D levels over 30 ng/mL for all deficient subjects, regardless of their BMI. Slower loading with lower weekly doses confirms the safety of supplementation, but the effectiveness is dependent on the subjects’ BMI; overweight and obese patients require higher doses to reach the same vitamin D levels. No difference in safety parameters observed compared to low-dose therapies. Conclusions: The loading treatment involving a total dose of 300,000 IU administered over 5 or 10 weeks is effective for repletion, does not lead to 25(OH)D overload, and poses no additional risks of hypercalcemia or hypercalciuria. Furthermore, there are no safety concerns regarding changes in bone resorption markers. A combination of the loading treatment with a subsequent maintenance dose of 2000 IU daily is adequate to achieve the target vitamin D levels.

To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

A high prevalence of iron deficiency exists in athlete populations. Various mechanisms, including increased losses through sweat, haemolysis, haematuria, and gastrointestinal micro-ischemia; inadequate dietary intake; and transient exercise-induced increases in the regulatory hormone, hepcidin, contribute to the increased prevalence in athletes. Indeed, hepcidin has been shown to peak around 3-6 hours post-exercise, limiting iron absorption from the gut. As the practitioner's ability to control losses is limited, the key to treatment of iron deficiency in athletes is optimal timing of dietary and oral iron supplementation around these periods of reduced gut absorption. While timing and dosing schedule strategies might be sufficient to treat iron deficiency non-anaemia, the significant lag to impact iron status is relatively long. Therefore, in iron deficiency anaemia, the use of parenteral iron has the benefit of rapid repletion of iron stores and normalisation of haemoglobin status, while bypassing the action of hepcidin at the gut. Furthermore, newer intravenous formulations can be administered as a single total dose over 15-60 min and have a similar safety profile to oral treatment. This review discusses the existing evidence for parenteral iron use in athletes and the unique context for consideration when choosing the parenteral route in this population.

Iron-deficiency anemia occurs most commonly in young children due to a low-iron diet and adolescent girls due to menstrual blood loss. However, children with gastrointestinal conditions such as intestinal failure, inflammatory bowel disease, celiac disease, and/or other chronic conditions, including chronic kidney disease and heart failure, also commonly have iron deficiency. Many patients with classic iron-deficiency anemia will improve with oral iron therapy. However, in children who have an incomplete response to oral iron, intravenous iron therapy is increasingly being used. Benefits of intravenous iron therapy include a rapid repletion of iron stores in addition to resolution of anemia, less gastrointestinal side effects, and relief for patients and families struggling with long-term iron supplementation. Indications for first-line therapy with intravenous iron in children with chronic conditions have also increased. Four intravenous iron formulations have approved indications in pediatrics, and many are increasingly used off-label in children as well. Here we discuss the indications and appropriate timing of intravenous iron therapy in children with a wide range of underlying etiologies.

Management of iron deficiency in various clinical conditions and the role of intravenous iron: Recommendations of the Spanish erythropathology group of the Spanish society of hematology and hemotherapy

Manejo del déficit de hierro en distintas situaciones clínicas y papel del hierro intravenoso: recomendaciones del Grupo Español de Eritropatología de la SEHH

Acidemia and alkalemia, as a result of gradual depletion of the body's buffers followed by rapid repletion during hemodialysis (HD), are linked to adverse consequences. We examined the acid-base status with dialysis bath of higher bicarbonate (HC03- ) concentration or standard HC03- bath plus oral HC03- supplementation. A total of 60 stable HD patients (pts) were evaluated according to their pre-dialysis acid-base status both before the first and the second session of the week dialyzed against standard base dialysate of 35 mmol/L. Those who presented predialysis HC03- <22 mmol/L (25 pts) were assigned to dialysis against bath of increased HC03- levels (37 mmol/L) for 2 weeks (period A) and subsequently to dialysis with the standard dialysate bath plus daily oral sodium bicarbonate at a dose of 5 g/day for 2 weeks (period B). Pre and post-dialysis acid-base status at each study period and relevant laboratory tests were recorded. Pre-dialysis acid-base values were similar between the first and the second dialysis session. Twenty-five points had pre-dialysis pH <7.35, while 42 (the younger ones) presented pre-dialysis HC03- <22 mmol/L. After dialysis session 18 pts had pH >7.45. Comparing the two study periods, interdialytic weight was similar, pre-dialysis HC03- levels were improved with oral bicarbonate, while post-dialysis HC03- were higher during period A. Three pts could not tolerate the symptoms of alkalemia during period A. The impact of conventional HC03- concentrations of 35 mmol/L results in a considerable degree of pre-dialysis acidemia. Increasing the HC03- in bath results in more prominent post-dialysis alkalemia, however, it is not sufficient to maintain acid-base status during the interdialytic period. Oral bicarbonate supplement at a dose of 5 g/day (divided in three daily doses) results in a more balanced acid-base status, avoiding post-dialysis alkalemia.

Enhanced expression of proteins involved in energy production and transfer in breast muscle of pedigree male broilers exhibiting high feed efficiency

Driving Up the Dose: Implications for High-Dose Vitamin D Therapy

Management of metabolic acidosis covers the entire spectrum from oral bicarbonate therapy and dietary modifications in chronic kidney disease to delivery of high doses of bicarbonate-based dialysate during maintenance haemodialysis (MHD). Due to the gradual depletion of the body's buffers and rapid repletion during MHD, many potential problems arise as a result of our current treatment paradigms. Several studies have given rise to conflicting data about the adverse effects of our current practice patterns in MHD. In this review, we will describe the pathophysiology and consequences of metabolic acidosis and its therapy in CKD and ESRD, and discuss current evidence supporting a more individualized approach for bicarbonate therapy in MHD.

Carbohydrate and fat are the two primary fuel sources oxidized by skeletal muscle tissue during prolonged (endurance-type) exercise. The relative contribution of these fuel sources largely depends on the exercise intensity and duration, with a greater contribution from carbohydrate as exercise intensity is increased. Consequently, endurance performance and endurance capacity are largely dictated by endogenous carbohydrate availability. As such, improving carbohydrate availability during prolonged exercise through carbohydrate ingestion has dominated the field of sports nutrition research. As a result, it has been well-established that carbohydrate ingestion during prolonged (>2 h) moderate-to-high intensity exercise can significantly improve endurance performance. Although the precise mechanism(s) responsible for the ergogenic effects are still unclear, they are likely related to the sparing of skeletal muscle glycogen, prevention of liver glycogen depletion and subsequent development of hypoglycemia, and/or allowing high rates of carbohydrate oxidation. Currently, for prolonged exercise lasting 2-3 h, athletes are advised to ingest carbohydrates at a rate of 60 g·h⁻¹ (~1.0-1.1 g·min⁻¹) to allow for maximal exogenous glucose oxidation rates. However, well-trained endurance athletes competing longer than 2.5 h can metabolize carbohydrate up to 90 g·h⁻¹ (~1.5-1.8 g·min⁻¹) provided that multiple transportable carbohydrates are ingested (e.g. 1.2 g·min⁻¹ glucose plus 0.6 g·min⁻¹ of fructose). Surprisingly, small amounts of carbohydrate ingestion during exercise may also enhance the performance of shorter (45-60 min), more intense (>75 % peak oxygen uptake; VO(₂peak)) exercise bouts, despite the fact that endogenous carbohydrate stores are unlikely to be limiting. The mechanism(s) responsible for such ergogenic properties of carbohydrate ingestion during short, more intense exercise bouts has been suggested to reside in the central nervous system. Carbohydrate ingestion during exercise also benefits athletes involved in intermittent/team sports. These athletes are advised to follow similar carbohydrate feeding strategies as the endurance athletes, but need to modify exogenous carbohydrate intake based upon the intensity and duration of the game and the available endogenous carbohydrate stores. Ample carbohydrate intake is also important for those athletes who need to compete twice within 24 h, when rapid repletion of endogenous glycogen stores is required to prevent a decline in performance. To support rapid post-exercise glycogen repletion, large amounts of exogenous carbohydrate (1.2 g·kg⁻¹·h⁻¹) should be provided during the acute recovery phase from exhaustive exercise. For those athletes with a lower gastrointestinal threshold for carbohydrate ingestion immediately post-exercise, and/or to support muscle re-conditioning, co-ingesting a small amount of protein (0.2-0.4 g·kg⁻¹·h⁻¹) with less carbohydrate (0.8 g·kg⁻¹·h⁻¹) may provide a feasible option to achieve similar muscle glycogen repletion rates.

Nutritional iron-deficiency anaemia (IDA) is the most common disorder in the world, affecting more than two billion people. The World Health Organization's global database on anaemia has estimated a prevalence of 14% based on a regression-based analysis. Recent data show that the prevalence of IDA in pregnant women in industrialized countries is 17.4% while the incidence of IDA in developing countries increases significantly up to 56%. Although oral iron supplementation is widely used for the treatment of IDA, not all patients respond adequately to oral iron therapy. This is due to several factors including the side effects of oral iron which lead to poor compliance and lack of efficacy. The side effects, predominantly gastrointestinal discomfort, occur in a large cohort of patients taking oral iron preparations. Previously, the use of intravenous iron had been associated with undesirable and sometimes serious side effects and therefore was underutilised. However, in recent years, new type II and III iron complexes have been developed, which offer better compliance and toleration as well as high efficacy with a good safety profile. In summary, intravenous iron can be used safely for a rapid repletion of iron stores and correction of anaemia during and after pregnancy.

During an industry-sponsored symposium at the ERA–EDTA meeting in Munich 2010, four experts gathered to debate and provide an update on the treatment of anaemia in chronic kidney disease (CKD) patients, especially the relative contributions of erythropoiesis-stimulating agents (ESAs) and iron in its management. I chaired this symposium and invited these experts in collaboration with the sponsor to summarize their opinions. As the results of the largest of the ESA trial, TREAT, were available, many presenters focused on those results. The expert opinions were partly supported by available data, and there were, on occasions, differences in opinion between the experts on the interpretation of the data. For example, Dr Coyne’s statement that stroke risk is independent of ESA hyporesponsiveness is not a view that I share. I believe that the analysis of Solomon et al. in which Dr Coyne’s statement was based was simply not sufficiently powered to detect this relationship. Dr Locatelli states that the TREAT study was not a ‘placebo’ randomized controlled trial because the placebo group experienced an increase in haemoglobin (Hgb) over time. I disagree. The Hgb levels increased over time because the placebo group had a rescue feature which allowed administration of darbepoietin should Hgb fall below 9 g/dL. Dr Bhandari states that the profile of the ideal iron preparation should be capable of delivering sufficient quantities of intravenous iron to correct iron deficiency rapidly, with minimal potential side effects including low catalytic/labile iron release and negligible immunogenicity (risk of anaphylaxis). Yes, but I believe that the long-term safety of intravenous iron is the most important attribute which needs to be evaluated; long-term toxicity would trump any convenience afforded by the drug. Dr Kalra states that the drug should have reduced immunogenic potential and reduced risk for free iron toxicity. Although these claims may be true, they remain to be validated in larger safety studies especially among patients with multiple drug allergies. Below are opinions provided by the experts. There are several statements where consensus was not achieved. However, the experts do have a right to their opinions, and I present them below as they were presented to me, even when I am in disagreement. The highlights of this symposium, as I see it, are as follows: Normalizing Hbg among people with CKD is associated with cardiovascular and thrombotic risk. These risks can only be partially managed by correcting anaemia. Hyporesponsiveness to ESAs is associated with increased cardiovascular risk. Whether it is the dose of ESAs, poor response to ESA dose, a combination of the two or some other traits that confer this increased risk is unknown. Therefore, it should not be taken as a foregone conclusion that the dose of ESA is toxic. However, it is prudent to limit the dose of ESA to the minimum required to achieve a satisfactory Hbg response. The upper limit of ESA dose is unknown. Iron deficiency remains an important cause of ESA hyporesponsiveness. The diagnosis of iron deficiency among patients with CKD remains difficult. The pitfalls in making a diagnosis of iron deficiency anaemia are discussed. No gold standard is established. Therefore, when in doubt, a therapeutic trial of intravenous iron may be useful to establish a firm diagnosis. Among haemodialysis patients, the preferred route of iron administration is intravenous. However, it must be noted that patients with CKD who are not on haemodialysis can receive iron either orally or intravenously; there is no preference. The various parenteral irons, which are currently marketed, and their risks and benefits are discussed. Normalizing Hbg with ESAs in patients with CKD increases cardiovascular risk, whereas hyporesponsiveness to ESAs is associated with increased risk. Thus, it is logical to hypothesize that the cardiovascular risk of ESA use in patients with CKD may be mitigated with iron administration. Whether iron administration reduces ESA hyporesponsiveness or decreases or increases cardiovascular risk is currently unknown. The risk–benefit ratio of iron administration in CKD patients needs to be evaluated in well-designed prospective randomized controlled trials with cardiovascular and renal outcomes. Iron isomaltoside 1000 may be an attractive intravenous iron that may allow rapid repletion and theoretically a better safety profile.

Abstract There is an urgent need for new strategies for inhibiting the DNA repair protein MGMT (O6-methylguanine-DNA methyltransferase) and improving the efficacy of alkylating agents. MGMT is highly expressed in human cancers and prevents the formation of cytotoxic lesions in alkylated DNA. Current clinical trials involving MGMT depletion by O6-benzylguanine (BG), although promising, are beset with severe toxicity to the bone marrow, which has necessitated the transduction of BG-resistant MGMT gene into hematopoietic stem cells. Here, we exploited the highly reactive nature of Cysteine 145 of MGMT which accepts the alkyl groups for pharmacological intervention. Cys145 has a pKa of 4.8 due to its microenvironment and is susceptible for glutathionylation (Niture &amp; Srivenugopal, Proc of AACR 47, abst. 789, 2006) and nitrosylation (Liu et al. Cancer Res. 62, 3037, 2002). S-Thiolation and S-nitrosylation are reversible posttranslational mechanisms that gauge the intracellular redox and transduce them into functional responses. This study investigated the effect of two nontoxic small molecules which readily react with reactive cysteines, namely, the NCX-4016 (nitro-aspirin capable of S-nitrosylation) and disulfiram (capable of thiol-conjugation). NCX-4016, also called a fatty aspirin, is degraded by plasma and tissue esterases to release NO in a sustained manner. In three MGMT-proficient human cancer cell lines (HT29, T47D, and HCT116), nitro-aspirin at very low concentrations (5-10 µM) caused a 90% inhibition of MGMT activity within 1 h of exposure. Interestingly, the MGMT protein also disappeared with similar kinetics after NCX-4016 treatment; approx. 80-90% of MGMT was degraded after 5 µM NO-aspirin treatment for 2 h. These data are highly comparable or better than those reported for BG. Further, purified MGMT or tumor cell extracts exposed to NCX-4016 failed to bind the biotin-labeled BG, indicating Cys145 to be the site of nitrosylation. &amp;gt;60% of MGMT protein was regenerated at 24 h when NO-aspirin treated HT29 cells were post-incubated in drug-free medium, indicating a transient inhibition and rapid repletion. Disulfiram (DS), the alcohol deterrent drug, also curtailed MGMT activity in HT29 and HCT116 cells with a 20 h 400 µM treatment causing a 95% inhibition. DS at 200 µM induced about 70% degradation of MGMT at 12 h. Other redox-sensitive proteins such as the wild-type and mutant p53, NF-κB, and ubiquitin E1 were all degraded by DS in a dose- dependent manner. Studies to evaluate MGMT inhibition by NO-aspirin and DS in animal tissues are in progress. Because NO-aspirin, is non-toxic (IC50&amp;gt;500 µM for cell lines), yields a chemopreventive by-product, unlikely to elicit tumor resistance, and is lipophilic enough to cross the BBB, we believe it can be exploited for glioma therapy. Our studies show that the redox-regulated proteins are ‘druggable’ and highlight options for redox- driven therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5505. doi:10.1158/1538-7445.AM2011-5505

Rapid Correction of Hypokalemia in a Patient with an Implantable Cardioverter-Defibrillator and Recurrent Ventricular Tachycardia

Background: It is unknown whether intravenous iron or oral iron repletion alone can correct anemia associated with chronic kidney disease (CKD). We conducted a randomized multicenter controlled trial in adult anemic, iron-deficient non-dialysis CKD (ND-CKD) patients (≧stage 3) not receiving erythropoiesis-stimulating agents (ESAs). Methods: The participants were randomized to receive either a sodium ferric gluconate complex (intravenous iron) 250 mg i.v. weekly × 4 or ferrous sulfate (oral iron) 325 mg t.i.d. × 42 days. Hemoglobin (Hgb), ferritin and transferrin saturation (TSAT) were measured serially, and the Kidney Disease Quality of Life (KDQoL) questionnaire was administered on days 1 and 43. The primary outcome variable was change from baseline (CFB) to endpoint in Hgb values. Results: Seventy-five patients were analyzed (intravenous iron n = 36, oral iron n = 39). CFB in Hgb was similar in the two groups (intravenous iron 0.4 g/dl vs. oral iron 0.2 g/dl, p = n.s.). However, the increase in Hgb was only significant with intravenous iron (p < 0.01). In comparison to oral iron, intravenous iron achieved greater improvements in ferritin (232.0 ± 160.8 vs. 55.9 ± 236.2 ng/ml, p < 0.001) and TSAT (8.3 ± 7.5 vs. 2.9 ± 8.8%, p = 0.007). Intravenous iron caused greater improvements in KDQoL scores than oral iron (p < 0.05). The most common side effect reported with intravenous iron was hypotension, while constipation was more common with oral iron. Conclusions: Oral and intravenous iron similarly increase Hgb in anemic iron-depleted ND-CKD patients not receiving ESAs. Although in comparison to oral iron, intravenous iron may result in a more rapid repletion of iron stores and greater improvement in quality of life, it exposes the patients to a greater risk of adverse effects and increases inconvenience and cost.