Ask the Experts – Robert Provenzano, MD

Expert Perspective
Novel Agent May Improve Renal Anemia Management
Robert Provenzano, MD
Robert Provenzano, MD

Robert Provenzano, MD

Practice Community: Detroit, Michigan

Hospital and Institutional Affiliations: Associate Professor of Medicine at Wayne State University School of Medicine in Detroit and Vice President of Medical Affairs at DaVita Healthcare in Denver.

Practice Niche: Nephrology

Dr Provenzano has conducted extensive research on the management of anemia in patients with kidney disease. At Kidney Week 2019 in Washington, DC, he presented findings of a phase 3 clinical trial (HIMALAYAS) he led showing that roxadustat, an inhibitor of hypoxia-inducible factor (HIF), is superior to epoetin alfa, an erythropoiesis-stimulating agent (ESA), at improving hemoglobin levels in incident dialysis patients regardless of iron status and with a lower risk of major cardiovascular events. His study was among several presented at the conference examining the efficacy and safety of roxadustat and other HIF inhibitors in the treatment of renal anemia. Renal & Urology News sat down with Dr Provenzano to discuss the results of these trials and the potential clinical implications of HIF inhibitors.

Question 1. What most impressed you overall about the research presented at this year’s Kidney Week meeting?
There’s a standard cadence to Kidney Week meetings. But every once in a while there’s a meeting that stands out. This is one of those meetings. We are transitioning from the 20th century model of kidney care to the 21st century model of care. When you look at how our knowledge of kidney disease has evolved, we’ve learned a lot and are building upon that. Twenty years ago, we used to think all kidney disease patients were basically the same. We now know they’re not. We know that CKD is different from ESRD, and we know incident ESRD patients are different from prevalent ESRD patients. We know that how we treat them, both pharmacologically and clinically, is different. At this year’s meeting, the data presented on roxadustat really has set us on a new direction for managing anemia.
Question 2. What is the basis for how this drug works?
Roxadustat is a fascinating drug from a physiologic perspective. It builds on the work of this year’s Nobel Prize winner in physiology or medicine on the cellular sensing mechanism for oxygen. Billions of year ago, the earth had no oxygen. When plants began producing oxygen, which can be toxic, animals had to adapt. The HIF [hypoxia-inducible factor] system is what evolved to enable single-cell animals to survive. Under low oxygen conditions or when inhibited by roxadustat or another stabilizer, the HIF alpha subunit remains stable and allows translation of the appropriate genes that physiologically increase erythropoietin levels, improves iron absorption through the gut, and moves iron from the circulation into the bone marrow. Instead of a pharmacologic approach where we hammer patients with synthetic erythropoietin, inhibiting HIF is a more elegant approach using a system that has evolved over billions of years.
Question 3. What were the key findings from the phase 3 trials you and others presented?
In the OLYMPUS trial,1 which enrolled non-dialysis CKD patients, roxadustat increased hemoglobin levels compared with placebo regardless of iron-repletion status or inflammation, and it was as safe as placebo. In incident dialysis patients [the HIMALAYAS study] we were able to show not only that it was effective, it was effective irrespective of iron status and required administration of less iron than the epoetin alfa control arm.2 We also saw that it worked in inflamed patients. A good number of kidney patients are inflamed. A huge home run.
We learned from the TREAT and CHOIR studies that if hemoglobin levels get too high, they can increase the incidence of stroke, myocardial infarction, and other cardiovascular events. In the HIMALAYAS trial, we looked at major adverse cardiovascular events (MACE), defined as all-cause mortality, stroke, and myocardial infarction, and MACE+, which included MACE as well as hospitalization for unstable angina or congestive heart failure. Roxadustat was significantly safer with regard to MACE and MACE+ than using epoetin alfa. And there was a trend toward lower mortality.
In the ROCKIES study,3 we looked at prevalent dialysis patients and found remarkable efficacy. Roxadustat outperformed epoetin alfa, and patients required less rescue therapy such as blood transfusion or IV iron. When we looked at MACE and MACE+ and mortality, we did see an improved signal for MACE+. So roxadustat was not any worse and maybe a little bit better.
Question 4. Do you think HIF inhibitors, if approved for use in the United States, will increase treatment of anemia in patients with nondialysis CKD?
We basically don’t treat anemia in the CKD population today in the United States. Payers want nephrologists to deliver value, but it’s hard to deliver value in the CKD population. There’s not much that can forestall progression of kidney disease. ESAs are inconvenient to administer in these patients. Therefore, that population is left untreated. But if I can manage their anemia with a pill and no iron, it’s a game changer. If it forestalls worsening of their kidney function, it’s a home run. In the OLYMPUS trial, the roxadustat group had slower progression of CKD compared with placebo. If this delays dialysis initiation, patients have more time to get a transplant. That is critical.
Personally, I’ve always felt uncomfortable not treating anemia in CKD patients. I believe anemia is not asymptomatic. If a normal hemoglobin level is 14 (g/dL), and patients have a hemoglobin of 10, treating that hemoglobin of 10 may have benefits. Patients may feel slightly better so they might stay at work. If they’re employed, they’ll be less depressed, which has been shown to decrease hospitalization rates. Logistics matter when delivering kidney care. Delivering IV erythropoietin to a CKD patient is really difficult. And giving them IV iron, which is required, is very difficult. I just think this is one of the most exciting times in our field.
Question 5. A large study presented at Kidney Week revealed a 23.3% prevalence of severe anemia (hemoglobin levels below 10 g/dL) among patients with CKD patients not on dialysis. Should a finding such as this prompt nephrologists and payers to reconsider the clinical management of anemia in this patient population?
Yes. We need to construct appropriate trials that look at this population and determine the impact of anemia management on quality of life, sense of well-being, employment, [progression] to dialysis, and potential cardiovascular events.
Question 6. What are the possible adverse effects of roxadustat?
The drug stimulates approximately 3800 different genes. This has raised concerns of unintended consequences. What are we going to see long term? That is a question with all new drugs that enter the market, especially drugs used in a chronically ill population such as kidney patients. We see that it lowers cholesterol, so that’s a positive unintended benefit. We see that it delays progression. That’s a positive unintended consequence. But when you look at patients who have super-high HIF levels, such as patients with pulmonary fibrosis or polycythemia vera, we see no safety issues. I feel pretty confident that the lower HIF dose that we’re administering to treat anemia is going to be safe.


Dr Provenzano is on the editorial advisory board of Renal & Urology News. He also is Vice President of Medical Affairs at DaVita Healthcare and is on the board of directors for Nephroceuticals. He receives study funding from FibroGen, AstraZeneca, and Astellas.


  1. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. OLYMPUS: A phase 3, randomized, double-blind, placebo-controlled, international study of roxadustat efficacy in patients with non-dialysis-dependent (NDD) CKD and anemia. Presented on November 7, 2019, at the American Society of Nephrology’s 2019 Kidney Week in Washington, DC. Abstract TH-OR023.
  2. Provenzano R, Besarab A, Leong R, et al. HIMALAYAS: A Phase 3, Randomized, open-label, active-controlled study of the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis patients. Presented at the American Society of Nephrology’s Kidney Week 2019 meeting held November 5 to 10 in Washington, DC. Abstract TH-OR021.
  3. Fishbane S, Guzman NJ, Pergola PE, et al. ROCKIES: An international, phase 3, randomized, open-label, active-controlled study of roxadustat for anemia in dialysis-dependent CKD patients. Presented November 7, 2019, at the American Society of Nephrology’s 2019 Kidney Week meeting in Washington, DC. Abstract TH-OR022.