Advancements in medicine and scientific research have recently shifted the way doctors approach treatment for those impacted by conditions that are dependent on managing blood-oxygen levels.
Since the 1980s, patients with chronic kidney disease (CKD) and related conditions have been treated with erythropoiesis-stimulating agents (ESAs). These agents stimulate red blood cell production in the bone marrow. Their effects are essential for maintaining proper hemoglobin levels in those with CKD, End-Stage Renal Disease (ESRD), anemia, cancer, and other neurological conditions. They can even decrease the need for blood transfusions in some more severe cases.
In recent years, there has been extensive research performed that suggests that ESAs pose a number of health and safety concerns for patients, including high risks for cardiovascular events and vascular access thrombosis, creating a need for alternative treatment solutions.
Medical scientists have since developed a new class of agents to use for treatment that could limit health risks and side effects: hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors.
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What is a HIF-PH inhibitor?
HIF is a protein that occurs when the body undergoes low oxygen (or hypoxic) conditions. The protein stimulates the body’s production of erythropoietin (EPO), a hormone that prompts the bone marrow to produce red blood cells, which then carry oxygen to tissues and organs throughout the body.
HIF-PH inhibitors, also known as HIF-stabilizers, are a part of a new class of drugs that impede prolyl hydroxylase enzymes, which break down the hypoxia-inducible factor (HIF) under normal oxygen (normoxic) conditions. Essentially, the hypoxia-inducible factor is a necessary protein complex that controls the body’s response to low oxygen concentrations, and these new agents protect that response by blocking the enzyme that corrupts HIF in the body. According to early clinical results, HIF-PH inhibitors have also helped patients better utilize and mobilize the iron they have stored.
How do HIF-PH inhibitors work?
Every day, the body produces more than 100 billion blood cells. When this process is interrupted or impaired, patients need alternative treatment to encourage or stimulate production within the body.
At the molecular level, HIF-PH inhibitors work by stabilizing the HIF protein in the body and increasing the HIF protein’s half-life. This process prolongs the effects of HIF and stimulates the production of endogenous erythropoietin and erythropoiesis hormones in CKD patients, prompting red blood cell formation.
This process has similar results as traditional erythropoiesis-stimulating agents (ESAs) while presenting significantly less risk to the patient. While several HIF-PH inhibitors are in various stages of clinical evaluation and testing, there is much hope that progress will continue and treatment will become more and more accessible for patients with CKD and related conditions.
HIF-PH inhibitors and their applications:
Since HIF-PH inhibitors help the body produce red blood cells and mobilize iron, they can be used for a multitude of health issues that are impacted by blood-oxygen levels, beginning with chronic kidney disease and extending all the way to anemia, cancer and other neurological conditions.
Chronic Kidney Disease
As previously mentioned, HIF-PH inhibitors are primarily used to treat patients with chronic kidney disease. CKD is characterized by the loss of kidney function over time, caused by the organs’ inability to filter waste out of the body’s blood supply. Over time, the kidneys begin to overwork and become damaged, which could lead to bodily fluid retention, cardiovascular disease, anemia, and other complications.
HIF-PH inhibitors for CKD help reduce the risk of these complications by stabilizing the HIF in the body and promoting the hormones needed to regulate blood cell production.
Currently, there are three oral compounds — daprodustat, roxadustat, and vadadustat — that are now in the global phase 3 development for CKD patients that are not on dialysis. With further study and testing, doctors and clinical researchers will be able to target individual cases of CKD complications and release additional compounds.
Anemia is caused by the lack of healthy red blood cells to carry oxygen to tissues and organs, particularly the heart and the brain. This process is largely dependent on the kidneys. Healthy kidneys produce the erythropoietin (EPO) hormone, which triggers the bone marrow to produce the red blood cells needed to carry oxygen throughout the body.
When the kidneys begin to lose their functionality, not only are patients at risk for CKD, but they are also at risk for anemia. This condition could start to develop in the early stages of kidney disease and may worsen as the disease progresses.
Since the two primary causes of anemia related to CKD are erythropoietin (EPO) deficiency and functional iron deficiency (FID), HIF-PH inhibitors are a desirable solution because these agents address EPO hormone production and improve the mobilization of iron to the bone marrow.
A secondary cause of anemia in CKD patients is blood loss from hemodialysis. Fortunately, patients can take HIF-PH inhibitors orally, eliminating the need for hemodialysis in many cases.
Hypoxia is a known feature of aggressive tumors and is often associated with patients’ inadequate response to standard therapy and treatments, making cancer a point of interest in the discussion about the development of HIF-PH inhibitors.
Hypoxia in tumors and malignancies is a result of rapid tumor growth and insufficient oxygen supply. This supply is often further impaired by certain cancer treatments, including chemotherapy.
Agents used in chemotherapy are known for suppressing red blood cell production. Consequently, 30 to 90 percent of patients treated with myelosuppressive chemotherapy develop anemia, which can limit functional capacity and impair a person’s quality of life. Ongoing research suggests that HIF-PH inhibitors may be able to help patients who develop anemia while undergoing chemotherapy.
Throughout the testing phase, studies have yet to abolish one significant concern regarding the long-term use of HIF-PH inhibitors in cancer patients. Due to the molecular process that is induced with these agents, it is possible that the HIF activation in hypoxic environments may help already existing tumors survive and grow.
Additional research and comparison between HIF-PH inhibitors’ and ESAs’ short- and long-term impact on patients with cancerous tumors will reveal whether or not the advantages of using HIF-PH inhibitors in these cases is safe and plausible.
As seen with the previously mentioned conditions, a prolonged or severe state of hypoxia can lead to damage in a number of organs throughout the body, including the brain. However, as long as cerebral blood flow is maintained, the risk of permanent neurological damage is manageable. This requires careful observation and testing of all drugs and treatments that impact the brain’s blood and oxygen supply.
Scientific research has shown that there are some hypoxia-inducible factors – namely, HIF-1α – that play an important role in the development of neurological conditions, such as Parkinson’s disease (PD). HIF-1α is the primary regulator of cellular responses to hypoxia, and therefore, medical researchers suspect it could be a major neurological pathway that can be utilized in the protection against PD and even ischemic stroke. Current evidence has shown that HIF-PH inhibitors may have neuroprotective effects on these conditions by increasing patients’ HIF-1α levels.
Since these agents are still in a testing stage, there is little concrete evidence to support the widespread use of HIF-PH inhibitors to treat neurodegenerative diseases at this time. However, all research has pointed toward a bright future for these agents and their role in neurological treatment.
In just over a decade, the development of HIF-PH inhibitors has opened up an entirely new breadth of treatment options and medical research. With additional time and study, these agents could change the way medical professionals approach chronic kidney disease and related conditions, eventually eliminating side effects and risks that accompany the only treatment options available thus far. Only time will tell just how much these agents will impact science and medical history.