Treating Anemia in Patients With Erythropoietin Hyporesponsiveness

The most common renal replacement therapies for patients with end-stage renal disease (ESRD) are peritoneal dialysis and hemodialysis. More than 500,000 individuals in China are receiving dialysis treatment, and more than 90% of patients on dialysis experience renal anemia. Anemia has been associated with increased risk for cardiovascular complications, diminished quality of life, and mortality.

Insufficient erythropoietin (EPO), iron deficiency, and inflammation are among the main causes of renal anemia. In the past 30 years, erythropoiesis-stimulating agents (ESAs) have been used to treat EPO deficiency. However, for patients with poor initial responses to ESAs, increasing the dose to achieve target hemoglobin levels has been associated with an increase in the risk of cardiovascualr events and death. Approximately 10% of patients treated with ESAs have EPO hyporesponsiveness, defined as a sustained substandard hemoglobin (<10.0 g/dL), despite sufficient iron levels (ferritin >100 ng/dL), and exogenous EPO administration (≥6000 IU/week). Management of patients with EPO hyporesponsiveness is challenging.

When activated, hypoxia-inducible factors (HIFs) induce the production of EPO. Roxadustat is a prolyl hydroxylase inhibitor that can simulate hypoxic stimulation to stabilize HIF expression under normoxic conditions. Junjie Chen, MD, and colleagues conducted a single center, before and after treatment, self-controlled study to examine the efficacy and safety of roxadustat in patients with renal anemia and EPO hyporesponsiveness who are receiving continuous ambulatory peritoneal dialysis (CAPD). Results were reported in the Journal of Renal Nutrition [2022;32(5):595-604].

The study enrolled 55 patients on CAPD with renal anemia and EPO hyporesponsiveness. The primary follow-up parameters were routine blood, liver, and kidney function, electrolyte, blood lipid, high-sensitivity C-reactive protein (hsCRP), and iron tests. Interleukin-6 (IL-6) and tumor necrosis factor-a levels (TNF-a) were determined using serum samples via enzyme linked immunosorbent assay. The Modified Quantitative Subjective Global Assessment (MQSGA) score and Malnutrition-Inflammation Score (MIS) prior to and following treatment were recorded, as were adverse events during treatment. Follow-up observation time was 12 weeks. The researchers also collected data 12 to 24 weeks prior to enrollment as well as post-follow-up data at 36 weeks.

Of the 55 individuals in the study cohort, the intent-to-treat population, two withdrew consent and three others did not return to the hospital in a timely manner for re-examination and dropped out at week 2. The remaining 50 patients completed the 12-week follow-up.

Mean age of the overall cohort was 47.6 years, 47.3% (n=26) were male, mean weight was 60.4 kg, mean body mass index was 25.0 kg/m2, mean duration of peritoneal dialysis was 2.5 years, and 100% (n=55) were receiving oral iron therapy. The baseline EPO dose was 11,166.7 IU/week.

The mean hemoglobin level at baseline was 8.0 g/dL, compared with 11.2 g/dL after 12 weeks of treatment with roxadustat. At all measured time points, the increases in hemoglobin with roxadustat treatment were statistically significant compared with the baseline value (P<.05). Hematocrit and erythrocyte counts were also correspondingly higher than baseline values. No one in the study cohort received a blood transfusion during the follow-up period.

The target hemoglobin level was defined as ≥11.0 g/dL. At 12 weeks, 50% of the patients reached that target. A hemoglobin increase of 1.0 g/dL was considered a response, resulting in a response rate of 80% at 12 weeks. The doses of roxadustat were reduced compared with baseline; at 12 weeks the reduction was ~14.3%, and hemoglobin was still well maintained. Up to week 36, the final dose was achieved at 4.2 mg/kg/week.

Subgroup analyses divided patients into two groups: low hsCRP (hsCRP <5 mg/L, n=24) and high hsCRP (hsCRP ≥5 mg/L, n=23) based on baseline hsCRP level. There was no statistically significant difference in hemoglobin levels between the two subgroups at all time points (0, 4, and 12 weeks) (P>.05). The hemoglobin increases at 4 weeks and 12 weeks were statistically significant for both groups (P<.05 for both time points).

Clinical biochemical indices related to inflammation were measured at baseline and following treatment with roxadustat (hsCRP, white blood cell counts, neutrophilic percentage, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, IL-6 levels, and TNF-a levels). Following treatment with roxadustat, there were no statistical differences in levels of any of the prespecified clinical biochemical indices and the corresponding baseline levels (P<.05). Analysis of serum samples of the IL-6 and TNF-a levels were also not significantly different between 4 weeks and baseline. Results demonstrated that treatment with roxadustat did not affect the inflammation status of CAPD patients.

There were no significant changes in mean overall blood lipid indices (triglycerides, total cholesterol, and lipoproteins). In addition, there were no statistically significant changes in nutrition-related indicators such as albumin, pre-albumin, creatinine, and blood urea nitrogen from baseline values. The mean MQSGA score at 12 weeks was slightly reduced from baseline (13.0 points vs 14.4 points, respectively; P<.05). There was also a slight decrease in mean MIS from baseline  (10.6 points vs 9.8 points; P<.05).

There were no serious adverse events observed during the follow-up period.

In citing limitations to the study, the researchers included the small sample size, the lack of a parallel control group with EPO, and insufficient follow-up time. The authors noted the need for clinical trials with larger sample size and longer follow-up times.

“Our research suggests that for patients with EPO hyporesponsiveness on CAPD, roxadustat can effectively and safely improve anemia and nutritional status without promoting inflammation. Roxadustat provides an effective and safe treatment strategy for these populations,” the researchers said.

Takeaway Points

  1. Researchers reported results of a study designed to assess the efficacy and safety of roxadustat in patients with renal anemia and erythropoietin hyporesponsiveness who are on continuous ambulatory peritoneal dialysis.
  2. Hemoglobin increased at all time points during the study period; the increases over baseline values were statistically significant.
  3. No serious adverse events were observed during the study period.