Treatment of anemia in CKD is suboptimal; oral agents under investigation

Presenters: Bruce M. Robinson, MD, MS, FASN, Arbor Research Collaborative for Health, University of Michigan, Ann Arbor; Nupur Gupta, MD, Indiana University, Indianapolis

Robinson BM, Gupta N. Updates on therapeutic options for anemia in kidney diseases. Educational Symposium presented at American Society of Nephrology Kidney Week 2022, November 3, 2022, 12:45 pm – 1:45 pm.

Summary: Anemia is managed inadequately in patients with early-stage chronic kidney disease and can be improved with better attention to monitoring.

Treatment of anemia in patients with chronic kidney disease (CKD) who are not on dialysis is inconsistent and suboptimal, reflecting variability and lack of clarity in guidelines, said Bruce M. Robinson, MD. Hemoglobin (Hb) values in the 9 to 12 g/dL range are associated with lower levels of physical activity than values higher than 12 g/dL,1 but “we don’t know the true optimal Hb target within the 9 to 12 g/dL range,” he said.

 “Anemia and iron deficiency are common and undertreated,” said Dr. Robinson, Arbor Research Collaborative for Health, University of Michigan, Ann Arbor, “and in the nondialysis CKD setting, many patients are transfused, perhaps at rates of 20% per year or more.” The prevalence of anemia rises with CKD stage: 75% of patients with CKD stage 5 have a Hb lower than 12 g/dL and the level is lower than 10 g/dL in 32%. Iron deficiency has a prevalence of about 50% with little variance by CKD status or Hb level.

Although Hb should be measured at least every 3 months in anemic patients with CKD, even those with a first Hb below 10 g/dL, only 50% have a measurement 3 months later.2 The story is similar for measurement of iron.

US guidelines for use of erythropoiesis-stimulating agents (ESAs) do not recommend a starting or target Hb level other than to avoid starting when Hb is less than 10 g/dL. The lowest possible dose of ESA should be used to prevent blood transfusions and should be reduced or stopped if the Hb is above 10 g/dL (above 11 in dialysis-dependent patients). Guidelines suggest individualizing both the starting and target Hb with consideration of the rate of Hb decline, symptoms, transfusion avoidance, and cardiovascular risk. Iron deficiency, which is markedly undertreated, should be addressed before starting treatment. Among patients starting with Hb below 10 g/dL, only about 30% are treated with an ESA in 12 months; of patients with transferrin saturation (TSAT) below 20%, only about 25% are treated with iron within 12 months.3

Drugs for anemia should be easy to administer with therapeutic goals that include reduced hospitalization, improved quality of life, better iron utilization, lower risk of cardiovascular events, and decreased overall mortality, said Nupur Gupta, MD, from Indiana University, Indianapolis.

A new class of drugs, the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), is in various stages of development. Administered orally, these agents are noninferior to ESAs in hematologic efficacy and they reduce hepcidin levels compared with placebo. Cardiovascular safety concerns are preventing or delaying approval by the US Food and Drug Administration (FDA). Six HIF-PHIs are under investigation.

Roxadustat in patients with nondialysis-dependent CKD improved Hb, with Hb changes independent of iron repletion status.4,5 Fewer patients treated with roxadustat required rescue or transfusion compared with placebo. Pooled analysis of roxadustat studies demonstrated noninferiority for major adverse cardiovascular events (MACE); the there were higher incidences of thrombosis in patients on dialysis (versus epoetin alfa) and not on dialysis (versus placebo) and increased risk of seizures, hyperkalemia, and serious and fatal infections versus placebo. The FDA Cardiovascular and Renal Drug Advisory Committee did not support approval of roxadustat for anemia of CKD in patients either on or not on dialysis.

Vadadustat met the prespecified noninferiority criterion for hematologic efficacy compared with darbopoietin alfa but MACE were more common with vadadustat.6 No Cardiovascular and Renal Drug Advisory Committee review was performed, with the Committee citing safety concerns.

Daprodustat met the noninferiority criterion for change in Hb level compared with an injectable ESA in a study of patients not undergoing dialysis.7 Rates of heart failure-related hospitalization, cancer-related death, tumor progression, and esophageal/gastric erosions were higher with daprodustat. In October, the Cardiovascular and Renal Drug Advisory Committee voted 13 to 3 that the benefit of treatment with daprodustat outweighed the risks for adult patients on dialysis but, by an 11 to 5 vote, did not support that the benefit outweighed risks in adult nondialysis patients.

The long-term impact of HIF-PHIs requires further investigation with postmarketing surveillance data from countries where the agents have been approved, Dr. Gupta said, and their use, if approved in the United States, will probably be restricted to a case-by-case basis.

References

  1. Hoshino J, Muenz D, Zee J, et al. Associations of hemoglobin levels with health-related quality of life, physical activity, and clinical outcomes in persons with stage 3-5 nondialysis CKD. J Ren Nutr 2020;30:404-414. doi:10.1053/j.jrn.2019.11.003
  2. Wong MMY, Tu C, Li Y, et al. Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated. Clin Kidney J 2019;13(4):613-624. doi:10.1093/ckj/sfz091
  3. Lopes MB, Tu C, Zee J, et al. A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps. Sci Rep 2021. doi:10.1038/s41598-020-79254-6
  4. Chen N, Hao C, Liu B-C, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 2019;381:1011-1022. doi:10.1056/NEJMoa1901713
  5. Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant 2021;36:1616-1628. doi:10.1093/ndt/gfab191
  6. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med 2021;384:1589-1600. doi:10.1056/NEJMoa2035938
  7. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med 2021;385:2325-2335. doi:10.1056/NEJMoa2113379

Disclosures

Dr. Robinson is principal investigator of the DOPPS Program, which is funded by a consortium of private industry, public funders, and professional societies. All support is provided without restrictions on publications. He reports consultancy fees or travel reimbursement in the last 3 years from AstraZeneca, GlaxoSmithKline, Kyowa Kirin Co., and Monogram Health, all paid directly to his institution of employment.

Dr. Gupta reports consultant fees from AstraZeneca and Fresenius and research funding from Quanta.

Link to session: https://www.asn-online.org/education/kidneyweek/2022/program-session-details.aspx?sessId=438079

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