Deregulating iron-erythropoiesis regulation: transferrin receptor 2 as potential target for treating anemia in CKD
Both insufficient kidney production of erythropoietin and inflammation-mediated reduction of transferrin-bound iron are major factors in anemia of chronic kidney disease. Improved therapies for anemia in chronic kidney disease may involve modifying regulators of erythropoiesis and iron availability. Olivari et al. show in a model of chronic kidney disease that transferrin receptor 2 in hepatocytes, where it is required for hepcidin production, and in erythroid cells, where it downregulates erythropoietin receptor activity, is a potential therapeutic target. > …
KDIGO Conference Report on Optimal Anemia Management II
Novel Anemia Therapies in CKD: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Beginning in 2019, KDIGO planned two Controversies Conferences to review new evidence and its potential impact on the management of anemia associated with chronic kidney disease. The second of these conferences was held virtually in December 2021 and focused on a new class of agents, the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research. > …
Erythropoietic effects of vadadustat in phase 3 trials
Congrats to Mark Koury and colleagues. This study investigates the effects of vadadustat on erythropoiesis and iron metabolism
Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
Patients with chronic kidney disease develop anemia largely because of inappropriately low erythropoietin production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non−dialysis-dependent patients with chronic kidney disease and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was non-inferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum erythropoietin, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. > …
HIF activation prevents bladder injury
This study from our lab demonstrates that HIF-activating compounds protect from cystitis
Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from cyclophosphamide-induced bladder injury and urinary dysfunction
Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the oxygen-regulated hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing inflammation. The activity of HIF is controlled by prolyl hydroxylase domain (PHD) dioxygenases, which have been exploited as therapeutic targets for the treatment of anemia of chronic kidney disease. Here we established a mouse model of acute cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of dimethyloxalylglycine (DMOG) or molidustat, two small molecule inhibitors of HIF-prolyl hydroxylases (HIF-PHIs), profoundly mitigated CYP-induced bladder injury and inflammation as assessed by morphologic analysis of transmural edema and urothelial integrity and by measuring tissue cytokine expression. > …
Kidney EPO production in CKD is limited by myofibroblast transdifferentiation
This study from our lab demonstrates that HIF-PHIs do not stimulate EPO production in myofibroblasts
EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis
Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. > …
Ferric citrate is used clinically for the treatment of hyperphosphatemia in patients with chronic kidney disease and is approved as an oral iron replacement product for patients with iron-deficiency anemia. In this issue of Kidney International, Hanudel and colleagues take advantage of genetic models with and without chronic kidney injury to demonstrate that the enteric absorption of iron delivered by ferric citrate is dependent on ferroportin expression and does not involve paracellular iron transport. > …
Mitochondrial electron transport in renal development
This study from our lab identifies a differential role for mitochondrial electron transport in renal progenitors
Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.
Oxidative metabolism in mitochondria regulates cellular differentiation and gene expression through intermediary metabolites and reactive oxygen species. Its role in kidney development and pathogenesis is not completely understood. Here we inactivated ubiquinone-binding protein QPC, a subunit of mitochondrial complex III, in two types of kidney progenitor cells to investigate the role of mitochondrial electron transport in kidney homeostasis. Inactivation of QPC in sine oculis-related homeobox 2 (SIX2)-expressing cap mesenchyme progenitors, which give rise to podocytes and all nephron segments except collecting ducts, resulted in perinatal death from severe kidney dysplasia. > …
New insights into the effects of pharmacological HIF activation on renal hemodynamics
This study from our lab identifies a major role for HIF-dependent NO generation in GFR regulation
Pharmacological HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation
HIF-activating compounds are currently in late-stage clinical development for the treatment of anemia associated with chronic kidney disease. Although the effects of hypoxia on renal hemodynamics and function have been studied in animal models and in humans living at high altitude, the effects of pharmacologic HIF activation on renal hemodynamics, O2 metabolism and metabolic efficiency are not well understood. This cross-sectional study in healthy rats provides new mechanistic insights into dose-dependent effects of short-term pharmacologic HIF activation on renal hemodynamics, glomerular filtration and O2 metabolism. > …
KDIGO Conference Report on Optimal Anemia Management I
Controversies in Optimal Anemia Management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference
In 2019, KDIGO decided to convene two Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of CKD, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. > …
Anemia of CKD
Update on the clinical science of HIF-prolyl hydroxylase inhibitors in anemia of CKD
Hypoxia-inducible factor-prolyl hydroyxlase inhibitors in the treatment of anemia of chronic kidney disease
This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD. > …
Mitochondrial transcription factor TFAM in renal cystic disease
This study from our lab uncovered a critical role for TFAM in nephron maturation and renal cystogenesis using mouse genetics
Renal epithelial TFAM deficiency results in progressive mitochondrial depletion associated with severe cystic disease
Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. > …
A role for hypoxic signaling in glomerular-tubulointerstitial cross-talk during renal injury
Congrats to Agnes, Hai-Chun and colleagues on the acceptance of their paper
Stabilization of Hypoxia-Inducible Factor Ameliorates Glomerular Injury Sensitization after Tubulointerstitial Injury
Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. > …
Dissecting the role of HIF-prolyl 4-hydroxylase oxygen sensors in neurovascular homeostasis
Congratulations to Andres Urrutia on his new paper in Acta Physiologica
Inactivation of HIF-prolyl 4-hydroxylases 1, 2 and 3 in NG2-expressing cells induces HIF2-mediated neurovascular expansion independent of erythropoietin (cover)
The study looks at the role of brain pericyte oxygen sensing and erythropoietin in neurovascular homeostasis.
The Haase lab welcomes Dr. Kyoji Yamaguchi. Dr. Yamaguchi joined the Vanderbilt faculty coming from Japan where he led a drug discovery program in a prominent pharmaceutical company and developed HIF-prolyl hydroxylase inhibitors for the treatment of anemia and chronic kidney disease.
for information on current Haase group members and alumni click here
Review published on current clinical experience with HIF-activators in renal anemia therapy
Hypoxia-inducible factor activators in renal anemia: Current clinical experience
Prolyl hydroxylase domain (PHD) oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF). Small molecule inhibitors of PHD dioxygenases stimulate the production of endogenous EPO and improve iron metabolism resulting in effective anemia management in patients with chronic kidney disease. In this review Volker Haase and Neil Sanghani survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages and deliberate over safety concerns regarding long-term administration in patients with renal anemia. > …
Dr. Belinda Li received her M.D. from the State University of New York (SUNY) Downstate College of Medicine. She completed her Urology residency at Loyola University in Chicago, IL and currently is a fellow in Pediatric Urology. Dr. Li works with Drs. Clayton and Tong on the role of hypoxia and HIF signaling in bladder injury and inflammation. Welcome to the Haase lab.
for information on current Haase group members and alumni click here
HIF in T cell metabolism
Congratulations to our collaborator Mark Boothby on the acceptance of his PNAS paper
Hypoxia-inducible factors in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity
T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. > …
In the Literature Editorial by Volker Haase: ARNT as a novel target for anti-fibrotic therapy
Per-Arnt-Sim (PAS) domain proteins are involved in the regulation of cellular responses to environmental stresses such as hypoxia and exposure to polycyclic aromatic hydrocarbons. In a new preclinical study, the research group of Michael Zeisberg at the University of Göttingen has identified the obligatory HIF-α binding partner ARNT as an anti-fibrotic and pro-regenerative inducer of activin-like kinase (ALK) 3 / SMAD signaling. The study suggests that ARNT has therapeutic potential for the treatment of chronic kidney disease (CKD). More …
Phase II study on HIF-PHI vadadustat in hemodialysis patients
Effects of Vadadustat on Hemoglobin Concentrations in Patients Receiving Hemodialysis Previously Treated with Erythropoiesis Stimulating Agents
Erythropoiesis-stimulating agents (ESAs) can correct anemia in chronic kidney disease (CKD) but are associated with increased risks of cardiovascular events. Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain (HIF-PHD) dioxygenases, is an oral investigational agent in development for the treatment of anemia in patients with CKD.
In a 16-week, open-label, multicenter, Phase 2 trial, Haase and colleagues evaluated vadadustat in 94 patients receiving maintenance hemodialysis previously maintained on ESA therapy. Patients were converted to vadadustat and assigned to a prospective dose cohort: 300 mg daily, 450 mg daily, or 450 mg thrice weekly. The primary endpoints were the mean hemoglobin change from baseline to mid-trial and from baseline to end-of-trial.
No significant changes in hemoglobin concentrations were observed for the two time points in any of the three treatment groups. Hemoglobin concentrations remained stable after conversion from ESA therapy for the duration of the trial, with a single excursion >13 g/dL. Plasma concentrations of vadadustat or its metabolites were not affected by hemodialysis.
Post-hoc analyses found no association between the final vadadustat dose and achieved hemoglobin, baseline hepcidin, C-reactive protein, or previous ESA dose. The overall incidence of adverse events (AEs) was comparable across treatment groups. No deaths occurred during the study. No serious AEs were attributed to vadadustat.
In summary this new study concluded that Vadadustat maintained hemoglobin concentrations in patients on hemodialysis previously receiving ESA therapy.
click herefor link to erythropoiesis, iron metabolism and renal anemia
Haase lab identifies a new role for HIF-PHD oxygen sensors in kidney development
Insufficient oxygenation during pregnancy negatively influences kidney development, which predisposes to chronic kidney disease at later stages in life. Kobayashi et al. demonstrate that deletion of HIF prolyl-hydroxylase (PHD) 2 and 3, in FoxD1 lineage cells reduces kidney size and inhibits nephrogenesis in mice. Temporo-spatial expression pattern and studies on additional knockouts suggest the involvement of hypoxia-inducible factor (HIF)-2. More …
click here to read the associated commentary in Kidney International
click herefor link to research themes in the Haase lab
The Haase lab will present at the Keystone meeting on hypoxia in Killarney, Ireland
Hypoxia: From Basic Mechanisms to Emerging Therapies
May 28-31, 2023
Scientific Organizers: Sonia Rocha, Edurne Berra and M. Celeste Simon. For information on the meeting please click here.
The Haase lab will present at the Keystone meeting on hypoxia and HIF responses, Keystone, CO
Hypoxia: Molecules, Mechanisms and Disease
January 19-23, 2020
Scientific Organizers: José López-Barneo, Sarah R. Walmsley, Hesham A. Sadek and Jacques Pouysségur
Doug Clayton, Nan Guan, Hanako Kobayashi and Andres Urrutia will each present their work on HIF and mitochondrial signaling in kidney, bladder and brain.
Meet Haase lab members at the Annual Meeting of the American Society of Nephrology (ASN), Washington, DC
November 7-10, 2019
Meet Nan Guan, Volker H. Haase and Hanako Kobayashi at the ASN in Washington.
Hanako Kobayashi will present work on “Mitochondrial dysfunction in tubular epithelial cells causes renal cysts” on November 9. Poster Session: Cystic Kidney Diseases: Basic/Translational [PO1001-3]; Session Date, Time: November 9, 2019 from 10:00 AM to 12:00 PM Poster Board #: SA-PO480.
Nanjing International Nephrology Forum and Annual Meeting of Jiangsu Hospital Association on Blood Purification, Nanjing, China
June 28-29, 2019
Volker Haase will discuss the role of mitochondrial and oxygen metabolism in kidney disease. More information to follow soon.
Meet Volker Haase at the 2019 National Kidney Foundation Spring Clinical Meeting in Boston, MA
May 8-12, 2019
Professor Haase to speak on “Emerging Therapies for Renal Anemia” on Friday, May 10, 7:00 PM – 9:00 PM,
Ballroom A, Hynes Convention Center
Session Title: “Anemia In Chronic Kidney Disease: Arming Clinicians with Meaningful Solutions”.
This session will review the pathophysiology and associated risks of anemia in CKD, as well as the best practices in the evaluation and management of anemia in patients with CKD. The potential role for emerging anemia therapies, such as PHD inhibitors for the optimal management of CKD related anemia will also be reviewed. The faculty will allocate ample time to interact with participants, allowing learners to challenge the speakers with practical questions, speakers, in return, can push learners to think deeper and learn through analogies.
Topics to be discussed:
Pathophysiology of Anemia in CKD and Associated Risks and Outcomes, 7:30 PM-7:55 PM – Speaker: Anil Agarwal, MD, FNKF
Current Management of Anemia in Patients with CKD, 7:55 PM-8:20 PM – Speaker: Jay Wish, MD, FACP, FASN
Clinical Update: Emerging Therapies to Manage CKD Related Anemia, 8:20 PM-8:45 PM – Speaker: Volker Haase, MD
Meet Haase lab members at the Annual AUA Meeting in Chicago, IL
May 3-6, 2019
Carmen Tong will present her work on “Preliminary Results of Diffusion Tensor Imaging in the Pediatric Spinal Cord” on Saturday, May 4.
Podium session #9: Societies for Pediatric Urology: Genitourinary Imaging and Diagnostics Session Date, Time: May 4, 2019 from 1:15-1:45 PM Marriott Marquis at McCormick Convention Center, Chicago IL
Meet Haase lab members at the Annual Meeting of the American Society of Nephrology (ASN), San Diego, CA
October 25-28, 2018
Meet Aqeela Afzal, Volker Haase, Hanako Kobayahi and Nan Guan at the ASN in San Diego.
Aqeela Afzal will present her work on “High throughput metabolic flux analysis of intact kidney tissue reveals abnormal mitochondrial respiration during AKI to CKD transition” on Saturday, October 27. Poster Session: AKI: Other Mechanisms and Cell Cultures [PO0103-3]; Session Date, Time: October 27, 2018 from 10:00 AM to 12:00 PM; Poster Board #: SA-PO584.
Hanako Kobayashi will present work on “Mitochondrial dysfunction in FOXD1 lineage cells is associated with renal fibrogenesis and anemia” on Saturday, October 27. Poster Session: Molecular Mechanisms of CKD – III [PO1903-3]; Session Date, Time: October 27, 2018 from 10:00 AM to 12:00 PM; Poster Board #: SA-PO837.
Volker Haase will speak on ” The Role of Interstitial Cell Oxygen Sensing in Nephrogenesis” in the educational symposium session 23A: Old Cells in New Roles: Unusual Mechanisms in Kidney Remodeling, on Friday, October 26, at 2:30 PM.
You can also meet Professor Haase at the oral poster session: Inflammation and Repair, on Saturday 27, 4:30-6:30 PM.
Fondation D.E.V.E.N.I.R (Démarches Visant à enrayer l’Émergence des conséquences Néfastes de l’Insuffisance Rénale), 5ème Forum Éducationnel pour les Néphrologues, Ville de Québec, Canada