Review
Pharmacology & Pharmacy
Mai Sugahara, Tetsuhiro Tanaka, Masaomi Nangaku
Summary: For the past 3 decades, erythropoiesis-stimulating agents (ESA) in conjunction with iron supplementation has been the mainstay of treatment for anemia in chronic kidney disease (CKD). However, recent studies have raised concerns about the cardiovascular risks associated with high hemoglobin (Hb) targets. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as novel agents that stimulate endogenous erythropoietin production and induce erythropoiesis in CKD patients. While HIF-PHIs have shown noninferiority to ESA in clinical trials, there are still concerns about their long-term safety and potential risks.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Transplantation
Masaomi Nangaku, Youssef M. K. Farag, Emil DeGoma, Wenli Luo, Dennis Vargo, Zeeshan Khawaja
Summary: The results of the studies support the development of vadadustat for the treatment of anemia in patients with CKD, showing significant efficacy in increasing Hb levels and adjusting iron utilization and mobilization. The incidence of adverse events during the primary efficacy period was similar to or slightly higher than the placebo group, with common events including nausea, hypertension, diarrhea, and nasopharyngitis.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2021)
Article
Cell Biology
Jun Chen, Xinyang Shou, Yanyan Xu, Lie Jin, Chaoyong Zhu, Xiaolan Ye, Ziwei Mei, Peipei Chen
Summary: This study compared the clinical effectiveness of HIF-PHIs and ESAs in dialysis CKD patients, and found that roxadustat was the most effective treatment for hemoglobin correction. However, roxadustat also increased the risk of hypertension and thrombosis. Molidustat and ESAs may be preferable options for patients at risk for hypertension and thrombosis. Clinicians should monitor ferritin levels when administering roxadustat and daprodustat.
Review
Pharmacology & Pharmacy
Song Ren, Xiaoxiu Yao, Yi Li, Ying Zhang, Chao Tong, Yunlin Feng
Summary: This umbrella review summarizes the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). The results suggest that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and improve iron metabolism. The safety profiles of HIF-PHIs are generally comparable to other therapies or placebos.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Urology & Nephrology
Volker H. Haase
Summary: HIF-PHIs are a promising new class of orally administered drugs for the treatment of anemia of chronic kidney disease. They activate the HIF oxygen-sensing pathway, promoting erythropoiesis and modulating iron metabolism to potentially reduce the need for i.v. iron supplementation. These drugs are predicted to have effects beyond erythropoiesis.
KIDNEY INTERNATIONAL SUPPLEMENTS
(2021)
Review
Cell Biology
Wen-Chin Lee, Chien-Hua Chiu, Tian-Huei Chu, Yu-Shu Chien
Summary: This review discusses the correlation between HIF-PHIs and cancer development in treating anemia in CKD patients, and proposes monitoring strategies and WT1 inhibition to reduce the risk of cancer progression.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Agriculture, Multidisciplinary
Suqin Zhu, Lingyu Wu, Meichao Zhang, Shiyang Li, Wenshuo Xing, Zifang Zhao, Hongxing Guo, Lei Ma, Haohao Wu
Summary: Iron intervention is not always safe and effective. Porcine collagen hydrolysate and collagen-derived dipeptide prolyl-hydroxyproline were found to increase iron absorption and transportation, activate hypoxia-inducible factor-2 alpha signaling, and inhibit prolyl hydroxylase-3 activity. These findings suggest that collagen peptides can stimulate intestinal iron absorption.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Physiology
Hanako Kobayashi, Olena Davidoff, Shiuli Pujari-Palmer, Malin Drevin, Volker H. Haase
Summary: This study aimed to investigate whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone kidney fibrosis.
Review
Pharmacology & Pharmacy
Limei Xiong, Hui Zhang, Yannan Guo, Yue Song, Yuhong Tao
Summary: Vadadustat appears to be a safe and effective treatment for anemia in CKD patients, improving Hb levels and promoting iron utilization. Compared to placebo, it significantly reduces levels of hepcidin and ferritin and increases iron-binding capacity. However, compared to placebo or darbepoetin alfa, it may increase the risk of nausea and diarrhea.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
George Z. Wei, Sujata Saraswat Ohri, Nicolas K. Khattar, Adam W. Listerman, Catherine H. Doyle, Kariena R. Andres, Saravanan S. Karuppagounder, Rajiv R. Ratan, Scott R. Whittemore, Michal Hetman
Summary: PHD inhibition can reduce neuronal death driven by ATF4, but does not improve long-term hindlimb locomotion or increase chronic white matter sparing after SCI. In the context of traumatic CNS pathologies involving acute white matter injury, PHDs may not be suitable targets for improving outcomes.
Review
Urology & Nephrology
Mercedes Kile, Patcharaporn Sudchada
Summary: The study aims to investigate current treatment practices for anemia in patients with chronic kidney disease (CKD) and issues surrounding these practices, as well as the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) currently in clinical trials. Challenges exist in the treatment of anemia in CKD patients, and new agents like HIF-PHIs may provide attractive alternatives to traditional treatments like iron supplementation and erythropoiesis-stimulating agents (ESAs).
INTERNATIONAL UROLOGY AND NEPHROLOGY
(2021)
Review
Urology & Nephrology
Hanxue Zhao, Peiyun Li, Hong-Liang Zhang, Linpei Jia
Summary: This study conducted a meta-analysis of clinical randomized controlled trials (RCTs) and found that HIF-PHI treatment can effectively improve renal anemia in NDD-CKD patients. It increases the level of hemoglobin (Hb) and improves iron metabolism, while demonstrating comparable safety to ESAs.
Article
Transplantation
Mark J. Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C. P. Chowdhury, Kai-Uwe Eckardt, Carlos R. Gonzalez, Laura A. Kooienga, Mark J. Koury, Kwabena A. Ntoso, Wenli Luo, Patrick S. Parfrey, Dennis L. Vargo, Wolfgang C. Winkelmayer, Zhiqun Zhang, Glenn M. Chertow
Summary: This study is a post hoc analysis of two global, randomized, sponsor-blind, noninferiority trials evaluating the safety and efficacy of vadadustat compared to darbepoetin alfa in patients receiving peritoneal dialysis. The results demonstrate that vadadustat has comparable cardiovascular safety and hematological efficacy to darbepoetin alfa in this patient population.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Review
Pharmacology & Pharmacy
Jing Li, Qiong-Hong Xie, Li You, Ning-Xin Xu, Chuan-Ming Hao
Summary: In non-dialysis-dependent CKD patients, HIF-PHIs decreased TSAT, ferritin, and hepcidin levels, increased TIBC, and did not affect serum iron despite enhanced erythropoiesis. This suggests that HIF-PHIs promote iron utilization in non-dialysis-dependent CKD patients, leading to a reduction in TSAT, which should not be interpreted as iron deficiency but rather as increased transferrin levels.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Urology & Nephrology
Siliang Zhang, Jing Guo, Shuqin Xie, Jianwei Chen, Shenrun Yu, Yuan Yu
Summary: The study demonstrated that HIF-PHI effectively improved Delta Hb levels in NDD patients without significantly increasing adverse events.
INTERNATIONAL UROLOGY AND NEPHROLOGY
(2021)
Article
Physiology
Andres A. Urrutia, Nan Guan, Claudia Mesa-Ciller, Aqeela Afzal, Olena Davidoff, Volker H. Haase
Summary: The study investigates the role of NG2 cells in HIF-regulated cerebral vascular homeostasis and finds that HIF2 activation in NG2 cells promotes neurovascular expansion independently of EPO. The activity of HIF2 in NG2 cells is controlled by both PHD2 and PHD3, and PHD1 modulates HIF2 transcriptional responses when PHD2 and PHD3 are inactive.
Article
Urology & Nephrology
Ken Ishii, Hanako Kobayashi, Kensei Taguchi, Nan Guan, Andraia Li, Carmen Tong, Olena Davidoff, Pamela Tran, Madhulika Sharma, Navdeep S. Chandel, Meghan E. Kapp, Agnes B. Fogo, Craig R. Brooks, Volker H. Haase
Summary: TFAM deficiency disrupts mitochondrial function in kidney cells, leading to impaired nephron maturation and severe cystic disease development; reduced TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease, suggesting their contribution to pathogenesis.
KIDNEY INTERNATIONAL
(2021)
Article
Urology & Nephrology
Jun Zou, Jaewon Yang, Xiaoye Zhu, Jianyong Zhong, Ahmed Elshaer, Taiji Matsusaka, Ira Pastan, Volker H. Haase, Hai-Chun Yang, Agnes B. Fogo
Summary: The study found that stabilizing hypoxia-inducible factor-alpha (HIF-alpha) can ameliorate tubulointerstitial injury and reduce its impact on subsequent glomerular injury. Restoring HIFs may blunt the adverse crosstalk between tubular injury and glomerular injury.
KIDNEY INTERNATIONAL
(2021)
Article
Physiology
Mikhail Burmakin, Angelica Fasching, Hanako Kobayashi, Andres A. Urrutia, Anastasios Damdimopoulos, Fredrik Palm, Volker H. Haase
Summary: The study reveals that systemic administration of HIF-PHIs in rats leads to a dose-dependent reduction in renovascular resistance, along with increased glomerular filtration rate, urine flow, and tubular sodium transport rate. However, higher doses of HIF-PHIs also result in a decrease in metabolic efficiency.
Article
Immunology
Mark R. Boothby, Ariel Raybuck, Sung Hoon Cho, Kristy R. Stengel, Volker H. Haase, Scott Hiebert, Jingxin Li
Summary: Evidence suggests that immune responses are influenced by local nutrient concentrations, with a focus on humoral immunity and germinal centers. The impact of hypoxia on antibody response during immunization was explored, challenging previous concepts through genomic data analysis. Standardizing new data comparisons with prior cell type fingerprints is proposed for transparency and accuracy in scientific reports on immunity and antibody responses.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Urology & Nephrology
Volker H. Haase
Summary: HIF-PHIs are a promising new class of orally administered drugs for the treatment of anemia of chronic kidney disease. They activate the HIF oxygen-sensing pathway, promoting erythropoiesis and modulating iron metabolism to potentially reduce the need for i.v. iron supplementation. These drugs are predicted to have effects beyond erythropoiesis.
KIDNEY INTERNATIONAL SUPPLEMENTS
(2021)
Article
Urology & Nephrology
Jodie L. Babitt, Michele F. Eisenga, Volker H. Haase, Abhijit Kshirsagar, Adeera Levin, Francesco Locatelli, Jolanta Malyszko, Dorine W. Swinkels, Der-Cherng Tarng, Michael Cheung, Michel Jadoul, Wolfgang C. Winkelmayer, Tilman B. Drueke
Summary: Chronic kidney disease is often associated with anemia and disordered iron homeostasis, which have significant adverse consequences. In 2012, KDIGO issued guidelines for managing anemia in chronic kidney disease, and in 2019, they convened conferences to review new evidence and controversies related to iron and anemia treatment. The first conference focused on iron-related issues like diagnostic challenges, treatment options and patient outcomes.
KIDNEY INTERNATIONAL
(2021)
Article
Physiology
Hanako Kobayashi, Olena Davidoff, Shiuli Pujari-Palmer, Malin Drevin, Volker H. Haase
Summary: This study aimed to investigate whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone kidney fibrosis.
Editorial Material
Urology & Nephrology
Volker H. Haase
Summary: This article introduces the clinical application of ferric citrate and demonstrates through genetic models that the iron delivery by ferric citrate depends on ferroportin expression rather than paracellular iron transport.
KIDNEY INTERNATIONAL
(2022)
Article
Urology & Nephrology
Nan Guan, Hanako Kobayashi, Ken Ishii, Olena Davidoff, Feng Sha, Talat A. Ikizler, Chuan-Ming Hao, Navdeep S. Chandel, Volker H. Haase
Summary: This study investigates the role of mitochondrial electron transport in kidney homeostasis by inactivating a subunit of mitochondrial complex III in kidney progenitor cells. The results show that mitochondrial oxidative metabolism is critical for kidney development, and inactivation of specific proteins can lead to severe kidney dysplasia or smaller functional kidneys.
KIDNEY INTERNATIONAL
(2022)
Article
Hematology
Mark J. Koury, Rajiv Agarwal, Glenn M. Chertow, Kai-Uwe Eckardt, Steven Fishbane, Tomas Ganz, Volker H. Haase, Mark R. Hanudel, Patrick S. Parfrey, Pablo E. Pergola, Prabir Roy-Chaudhury, James A. Tumlin, Robert Anders, Youssef M. K. Farag, Wenli Luo, Todd Minga, Christine Solinsky, Dennis L. Vargo, Wolfgang C. Winkelmayer
Summary: Vadadustat has beneficial effects on three aspects of erythropoiesis in patients with anemia associated with chronic kidney disease: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Review
Urology & Nephrology
Jing Li, Volker H. H. Haase, Chuan-Ming Hao
Summary: HIF-PHI is an effective class of drugs for treating renal anemia, promoting erythropoiesis and increasing hemoglobin levels. Roxadustat's erythropoiesis effect is less affected by inflammation, but thromboembolic events and tumors need to be carefully monitored during treatment.
Article
Multidisciplinary Sciences
Wenqiang Song, J. Luke Postoak, Guan Yang, Xingyi Guo, Heather H. Pua, Jackie Bader, Jeffrey C. Rathmell, Hanako Kobayashi, Volker H. Haase, Katrina L. Leaptrot, Alexandra C. Schrimpe-Rutledge, Stacy D. Sherrod, John A. McLean, Jianhua Zhang, Lan Wu, Luc Van Kaer
Summary: The lipid kinase PIK3C3 plays a crucial role in maintaining adipose tissue homeostasis and systemic metabolism. Its deficiency disrupts adipocyte autophagy and hinders adipocyte differentiation, survival, and function, leading to abnormalities in adipose tissue and the development of metabolic diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Urology & Nephrology
Elaine Ku, Lucia Del Vecchio, Kai-Uwe Eckardt, Volker H. Haase, Kirsten L. Johansen, Masaomi Nangaku, Navdeep Tangri, Sushrut S. Waikar, Andrzej Wiecek, Michael Cheung, Michel Jadoul, Wolfgang C. Winkelmayer, David C. Wheeler
Summary: Anemia is common in chronic kidney disease patients and is associated with adverse clinical outcomes. Recent research has focused on hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) as a potential treatment for anemia in these patients.
KIDNEY INTERNATIONAL
(2023)
Article
Physiology
Douglass B. Clayton, Ching Man Carmen Tong, Belinda Li, Abby S. Taylor, Shuvro De, Matthew D. Mason, Anne G. Dudley, Olena Davidoff, Hanako Kobayashi, Volker H. Haase
Summary: Our study demonstrates that pharmacological inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylation can prevent bladder injury and protect against urinary dysfunction in a mouse model of cyclophosphamide-induced disruption of the blood-urine barrier. This highlights the potential role of HIF-activating small-molecule compounds in the prevention or therapy of bladder injury and urinary dysfunction and provides a rationale for future clinical studies.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2022)
