scholarly journals Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

2021 ◽  
Vol 52 (6) ◽  
pp. 450-466
Author(s):  
Matthew R. Weir
Keyword(s):  
Drug Targets ◽  
Iron Status ◽  
Therapeutic Option ◽  
Attractive Potential ◽  
Dialysis Modality ◽  
Erythroid Progenitors ◽  
Prolyl Hydroxylases ◽  
Erythropoiesis Stimulating Agents ◽  
Sustained Effects ◽  
Concomitant Medications

<b><i>Background:</i></b> Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. <b><i>Summary:</i></b> The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. <b><i>Key Messages:</i></b> Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.

scholarly journals Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 620 ◽  
Author(s):  
Connor O’Leary ◽  
Wen Xu ◽  
Nick Pavlakis ◽  
Derek Richard ◽  
Ken O’Byrne
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Response Rates ◽  
Small Cell ◽  
Small Cell Lung ◽  
Asian Ethnicity

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

scholarly journals Graft immaturity and safety concerns in transplanted human kidney organoids

2019 ◽  
Vol 51 (11) ◽  
pp. 1-13 ◽  
Author(s):  
Sun Ah Nam ◽  
Eunjeong Seo ◽  
Jin Won Kim ◽  
Hyung Wook Kim ◽  
Hong Lim Kim ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Ips Cells ◽  
Attractive Potential ◽  
Transplanted Kidney ◽  
Filtration Barrier ◽  
Kidney Organoids

AbstractFor chronic kidney disease, regeneration of lost nephrons with human kidney organoids derived from induced pluripotent stem (iPS) cells is proposed to be an attractive potential therapeutic option. It remains unclear, however, whether organoids transplanted into kidneys in vivo would be safe or functional. Here, we purified kidney organoids and transplanted them beneath the kidney capsules of immunodeficient mice to test their safety and maturity. Kidney organoid grafts survived for months after transplantation and became vascularized from host mouse endothelial cells. Nephron-like structures in grafts appeared more mature than kidney organoids in vitro, but remained immature compared with the neighboring mouse kidney tissue. Ultrastructural analysis revealed filtration barrier-like structures, capillary lumens, and tubules with brush border in the transplanted kidney organoids, which were more mature than those of the kidney organoids in vitro but not as organized as adult mammalian kidneys. Immaturity was a common feature of three separate differentiation protocols by immunofluorescence analysis and single cell RNA sequencing. Stroma of transplanted kidney organoid grafts were filled with vimentin-positive mesenchymal cells, and chondrogenesis, cystogenesis, and stromal expansion were observed in the long term. Transcription profiles showed that long-term maintenance after kidney organoid transplantation induced transcriptomic reprogramming with prominent suppression of cell-cycle-related genes and upregulation of extracellular matrix organization. Our data suggest that kidney organoids derived from iPS cells may be transplantable but strategies to improve nephron differentiation and purity are required before they can be applied in humans as a therapeutic option.

scholarly journals Influence of Dialysis Modality on the Treatment of Anemia in Patients with End-stage Kidney Disease

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Nedim Hamzagic ◽  
Marija Andjelkovic ◽  
Marijana Stanojevic Pirkovic ◽  
Petar Canovic ◽  
Milan Zaric ◽  
...  
Keyword(s):  
Vitamin D ◽  
Kidney Disease ◽  
Iron Status ◽  
Hemoglobin Level ◽  
Lower Grade ◽  
Dialysis Modality ◽  
End Stage Kidney Disease ◽  
Blood Hemoglobin ◽  
End Stage ◽  
Regular Hemodialysis

Abstract Anemia is a common complication among the patients with end-stage kidney disease. Management of anemia is influenced by several factors: iron deficiency, subtherapeutic dosage of erythropoietin, microinflammation, vitamin D deficiency, increased iPTH levels and inadequate hemodialysis. The aim of the study was to examine impact of dialysis modality on blood hemoglobin level as well as status of iron, status of vitamin D, hemodialysis adequacy and erythropoietin dose. The study included 120 patients which were divided into two groups: the group of patients treated with hemodiafiltration and the group of patients treated with standard hemodialysis. For statistical analysis Kolmogorov-Smirnov test, Student’s t-test and Mann-Whitney U-test were used. Blood hemoglobin level and parameters of hemodialysis adequacy (Kt/V index, spKt/V index, URR index), hematocrit ad protein catabolic rate (nPCR) were statisticaly significant lower in patients treated with regular hemodialysis compared to patients treated with regular hemodiafiltration. Serum ferritin level, C-reactive protein level and average monthly dose of intravenous iron were higher in the patients treated with regular hemodialysis compared to patients treated with hemodiafiltration. Patients treated with hemodiafiltration have lower grade of microinflammation, better iron status and better control of anemia compared to the patients treated with regular hemodialysis. Dialysis modality is an important factor that influences management of anemia in the patients with end-stage kidney disease.

Initial Change Of Iron Metabolic Flux Prior To Differentiation Of Erythroid Progenitors After Epoetin Beta Pegol (C.E.R.A.) Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3444-3444
Author(s):  
Yusuke Sasaki ◽  
Mariko Noguchi-Sasaki ◽  
Yukari Matsuo ◽  
Junko Fukumura ◽  
Fumi Sato-Inomata ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Metabolism ◽  
Serum Iron ◽  
Metabolic Flux ◽  
Iron Status ◽  
Erythroid Progenitors ◽  
Epoetin Beta Pegol ◽  
Epoetin Beta ◽  
Serum Hepcidin ◽  
Initial Change

Abstract Introduction Erythropoiesis and iron metabolism are inextricably linked. Developing immature erythroblasts have an extremely high iron requirement, especially during hemoglobin synthesis. Hepcidin, which inhibits iron efflux by binding to iron exporter ferroportin, is suppressed to promote the supply of required iron. Suppression of hepcidin after erythropoiesis-stimulating agent (ESA) treatment is mainly in an indirect manner, especially via erythropoietic activity, but the nature of suppressive mechanism of hepcidin is still unknown. Epoetin beta pegol (C.E.R.A.) is a novel long-acting ESA, which potentially has intensive and continuous effects on reduction of hepcidin. In the present study, we investigated change of iron metabolic flux associated with enhanced erythropoiesis by C.E.R.A. to analyze the mechanism underlying suppression of hepcidin. Methods Initial change of iron metabolism was analyzed in C57BL/6N mice intravenously treated with 10 μg/kg of C.E.R.A. or vehicle. Hematological indices such as reticulocyte counts and iron indices including serum hepcidin and iron levels were measured. Reticulocyte hemoglobin equivalent (Ret-He) which reflects the iron status of reticulocyte was also determined. Ter119 and transferrin receptor (CD71) expression on bone marrow cells was evaluated by flow cytometry for analysis of the maturation status of bone marrow erythroblasts. Results C.E.R.A. suppressed serum hepcidin levels after 9 hours, while serum iron levels were significantly decreased at 9 hours followed by recovery to the control levels at 24 hours. Ter119(+)CD71(high) immature erythroblasts were decreased and CD71 expression levels on the same cells were increased at 9 hours after C.E.R.A. treatment. C.E.R.A. elevated reticulocyte counts and Ret-He levels at 48 hours. Discussion and Conclusion Transient decrease in serum iron levels and continuous suppression of serum hepcidin levels were observed in early phase after C.E.R.A. treatment, prior to increase in erythroblasts through proliferation and differentiation of erythroid progenitors. Furthermore, considering decrease in immature erythroblasts followed by increase in hemoglobin-rich reticulocytes, it is possible that initial change of iron metabolic flux occurred by the accelerated iron incorporation into immature erythroblasts through CD71 recycling after C.E.R.A. treatment. These results suggest that sensing initial change of iron metabolic flux leads to suppression of hepcidin after C.E.R.A. treatment, but further analysis is needed for the mechanism of increase in iron absorption into immature erythroblasts immediately after C.E.R.A. treatment independent of differentiation of erythroid progenitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Didier Ducloux ◽  
Mathieu Legendre ◽  
Jamal Bamoulid ◽  
Jean-Michel Rebibou ◽  
Philippe Saas ◽  
...  
Keyword(s):  
Iron Status ◽  
Clinical Implications ◽  
Dialysis Modality ◽  
Immune Phenotype

scholarly journals Bioluminescent High-Throughput Succinate Detection Method for Monitoring the Activity of JMJC Histone Demethylases and Fe(II)/2-Oxoglutarate-Dependent Dioxygenases

2017 ◽  
Vol 23 (3) ◽  
pp. 242-254 ◽  
Author(s):  
Juliano Alves ◽  
Gediminas Vidugiris ◽  
Said A. Goueli ◽  
Hicham Zegzouti
Keyword(s):  
Drug Targets ◽  
Detection Method ◽  
Biological Processes ◽  
Histone Demethylases ◽  
Rna Repair ◽  
Prolyl Hydroxylases ◽  
Histone Lysine ◽  
Enzyme Superfamily ◽  
Detection Assay ◽  
Potential Drug Targets

The modification of a diverse array of substrates by Fe(II)/2-oxoglutarate-dependent dioxygenases is central to the modulation of distinct biological processes such as epigenetics, hypoxic signaling, and DNA/RNA repair. Of these, JumonjiC domain–containing histone lysine demethylases (JMJCs) and prolyl hydroxylases are potential drug targets due to their relevance to human diseases. Thus, assays to interrogate this enzyme superfamily are needed to identify selective and potent inhibitors as leads for drug development and that could also be useful research tools. Since succinate is a common product to all Fe(II)/2-oxoglutarate-dependent dioxygenase reactions, a method that detects succinate would be suitable to all members of this enzyme superfamily. We therefore developed a bioluminescent and homogenous succinate detection assay and validated its use with diverse sets of enzyme classes. We evaluated the substrate specificities of these enzymes, their apparent kinetic constants, and inhibition profiles and mode of action of reported and novel inhibitors. Our results indicate that succinate detection is a useful readout for the monitoring of enzymatic activities with distinct substrate entities, as well as for the discovery of novel inhibitors. By investigating a large number of Fe(II)/2-oxoglutarate-dependent enzymes, this method could have a significant impact on the field of dioxygenase research.

scholarly journals Iron and Chronic Kidney Disease: Still a Challenge

2020 ◽  
Vol 7 ◽  
Author(s):  
Ewa Wojtaszek ◽  
Tomasz Glogowski ◽  
Jolanta Malyszko
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Homeostasis ◽  
Kidney Diseases ◽  
Iron Status ◽  
Therapeutic Option ◽  
Fibroblast Growth Factor 23 ◽  
Clinical Feature ◽  
General Interest ◽  
Therapeutic Tools

Anemia is a clinical feature of chronic kidney disease (CKD). Most common causes are iron and erythropoietin deficiency. The last two decades have yielded significant advances in understanding iron balance's physiology, including iron trafficking and the crosstalk between iron, oxygen, and erythropoiesis. This knowledge sheds new light on the regulation and disturbance of iron homeostasis in CKD and holds the promise for developing new diagnostic and therapeutic tools to improve the management of iron disorders. Hepcidin–ferroportin axis has a central role in regulating body iron balance and coordinating communication between tissues and cells that acquire, store, and utilize iron. Recent research has revealed a bidirectional relationship between fibroblast growth factor 23 (FGF23) and iron status, anemia, and inflammation, as well as the role of erythroferrone (ERFE) in iron homeostasis. However, ERFE concentrations and actions are not well-characterized in CKD patients. Studies on ERFE in CKD are limited with slightly conflicting results. Despite general interest in iron metabolism in kidney diseases, studies on the less prevalent renal replacement therapy mode, such as peritoneal dialysis or hemodiafiltration, are scarce. Slightly more was published on hemodialysis. There are several novel options on the horizon; however, clinical data are limited. One should be aware of the potential risks and benefits of the novel, sophisticated therapies. An inhibition of hepcidin on the different pathways might be also a viable adjunctive therapeutic option in other clinical situations.

scholarly journals Hepcidin mediates hypoferremia and reduces the growth potential of bacteria in the immediate post-natal period in human neonates

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sarah Prentice ◽  
Amadou T. Jallow ◽  
Edrissa Sinjanka ◽  
Momodou W. Jallow ◽  
Ebrima A. Sise ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Cord Blood ◽  
Low Income ◽  
Ex Vivo ◽  
Iron Status ◽  
Therapeutic Option ◽  
Transferrin Saturation ◽  
Growth Potential ◽  
Klebsiella Pneumonia ◽  
Normal Reference Range

Abstract Septicemia is a leading cause of death among neonates in low-income settings, a situation that is deteriorating due to high levels of antimicrobial resistance. Novel interventions are urgently needed. Iron stimulates the growth of most bacteria and hypoferremia induced by the acute phase response is a key element of innate immunity. Cord blood, which has high levels of hemoglobin, iron and transferrin saturation, has hitherto been used as a proxy for the iron status of neonates. We investigated hepcidin-mediated redistribution of iron in the immediate post-natal period and tested the effect of the observed hypoferremia on the growth of pathogens frequently associated with neonatal sepsis. Healthy, vaginally delivered neonates were enrolled in a cohort study at a single center in rural Gambia (N = 120). Cord blood and two further blood samples up to 96 hours of age were analyzed for markers of iron metabolism. Samples pooled by transferrin saturation were used to conduct ex-vivo growth assays with Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli and Klebsiella pneumonia. A profound reduction in transferrin saturation occurred within the first 12 h of life, from high mean levels in cord blood (47.6% (95% CI 43.7–51.5%)) to levels at the lower end of the normal reference range by 24 h of age (24.4% (21.2–27.6%)). These levels remained suppressed to 48 h of age with some recovery by 96 h. Reductions in serum iron were associated with high hepcidin and IL-6 levels. Ex-vivo growth of all sentinel pathogens was strongly associated with serum transferrin saturation. These results suggest the possibility that the hypoferremia could be augmented (e.g. by mini-hepcidins) as a novel therapeutic option that would not be vulnerable to antimicrobial resistance. Trial registration: The original trial in which this study was nested is registered at ISRCTN, number 93854442.

Pathways to the Best Fit of Triptans for Migraine Patients

Cephalalgia ◽  
2008 ◽  
Vol 28 (2_suppl) ◽  
pp. 21-27 ◽  
Author(s):  
MG Buzzi
Keyword(s):  
Drug Targets ◽  
Therapeutic Option ◽  
Therapeutic Benefit ◽  
Metabolizing Enzymes ◽  
Major Barrier ◽  
Migraine Pain ◽  
Genes Encoding ◽  
Intrapatient Variability ◽  
Genetically Determined ◽  
Best Fit

Variability in drug response is a major barrier to the successful treatment of migraine, and most treatments are only optimal in a subset of patients. Although triptans provide the best therapeutic option for the treatment of acute migraine, it has not previously been possible to predict how well patients will respond to a specific triptan or whether they will experience unpleasant adverse events. Hence, it has been difficult for physicians to match individual patients with the most suitable agent to treat their migraine pain. Intrapatient variability has been associated with polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets. Pharmacogenetics provides the possibility of tailoring the therapeutic approach to individual patients, in order to maximize treatment efficacy while minimizing the potential for unwanted side-effects. This review demonstrates how almotriptan may overcome genetically determined responses by utilizing diverse metabolic pathways to provide therapeutic benefit to many migraineurs.

scholarly journals COVID-19: molecular pathophysiology, genetic evolution and prospective therapeutics—a review

2021 ◽  
Author(s):  
C. T. Dhanya Raj ◽  
Dinesh Kumar Kandaswamy ◽  
Ravi Chandra Sekhara Reddy Danduga ◽  
Raju Rajasabapathy ◽  
Rathinam Arthur James
Keyword(s):  
Drug Targets ◽  
Continuous Monitoring ◽  
Drug Repositioning ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Specific Treatment ◽  
Medical Emergency ◽  
Life Threatening ◽  
Molecular Machinery ◽  
Molecular Pathophysiology

AbstractThe Covid-19 pandemic is highly contagious and has spread rapidly across the globe. To date there have been no specific treatment options available for this life-threatening disease. During this medical emergency, target-based drug repositioning/repurposing with a continuous monitoring and recording of results is an effective method for the treatment and drug discovery. This review summarizes the recent findings on COVID-19, its genomic organization, molecular evolution through phylogenetic analysis and has recapitulated the drug targets by analyzing the viral molecular machinery as drug targets and repurposing of most frequently used drugs worldwide and their therapeutic applications in COVID-19. Data from solidarity trials have shown that the treatment with Chloroquine, hydroxychloroquine and lopinavir-ritonavir had no effect in reducing the mortality rate and also had adverse side effects. Remdesivir, Favipiravir and Ribavirin might be a safer therapeutic option for COVID-19. Recent clinical trial has revealed that dexamethasone and convalescent plasma treatment can reduce mortality in patients with severe forms of COVID-19.

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