Nephrology · Medical Literature
Application of high-flux hemodialysis combined with hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of renal anemia in patients with uremia: A randomized controlled trial.
Abstract
This study aimed to explore the efficacy of combining high‑flux hemodialysis (HFHD) with a hypoxia‑inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for the treatment of renal anemia among patients with end-stage kidney disease. Sixty-four newly treated maintenance hemodialysis (MHD) patients were allocated to 4 groups (n = 16 each): low-flux hemodialysis (LFHD) plus recombinant human erythropoietin (rhEPO), LFHD plus HIF-PHI, HFHD plus rhEPO, and HFHD plus HIF‑PHI. All patients underwent hemodialysis 3 times per week, each session lasting 4 hours. After 2 months of treatment, we measured and compared changes in hemoglobin (HB), red blood cells (RBC), hepcidin, total iron‑binding capacity (TIBC), ferritin, transferrin saturation (TSAT), parathyroid hormone (PTH), and β2-microglobulin (β2-MG), along with the incidence of adverse events in each group. All groups showed increases in HB and RBC post‑treatment (P <.05). The increases in hemoglobin (ΔHB) and RBC (ΔRBC) were significantly greater in the HFHD + HIF-PHI and LFHD + HIF-PHI groups than in the LFHD + rhEPO and HFHD + rhEPO groups. Posttreatment PTH and β2-MG levels were elevated in the LFHD + rhEPO and LFHD + HIF-PHI groups compared with pretreatment (P <.05). Furthermore, posttreatment PTH and β2-MG were lower in the HFHD + HIF-PHI and HFHD + rhEPO groups than in the other 2 groups (P <.05). Posttreatment hepcidin was significantly reduced in the HFHD + HIF-PHI and LFHD + HIF-PHI groups compared to pretreatment. Posttreatment TIBC and TSAT were higher in the HFHD + HIF-PHI and LFHD + HIF-PHI groups than pretreatment (P <.05). The incidence of adverse reactions was numerically lower in the HIF-PHI groups than in the rhEPO group, but the difference was not statistically significant. Compared to low-flux dialysis plus rhEPO, the combination of HFHD and HIF-PHI shows more favorable improvements in hemoglobin levels, iron metabolism markers, and clearance of middle-molecule toxins in patients with incident MHD. However, the safety profile requires further evaluation in larger trials.
Clinical relevance
In newly initiated maintenance hemodialysis patients with end-stage kidney disease and renal anemia, does combining high-flux hemodialysis (HFHD) with a HIF-prolyl hydroxylase inhibitor (HIF-PHI) produce superior improvements in hemoglobin, iron metabolism markers, and middle-molecule clearance compared with low-flux hemodialysis (LFHD) plus recombinant human erythropoietin (rhEPO)? __SNAPSHOT__ {"studyDesign":"Randomized controlled trial (4-arm, parallel group)","setting":"Not reported (country/institution not specified in available abstract); clinical setting: incident maintenance hemodialysis","sampleSize":"n = 64 total (n = 16 per arm): Arm 1 — LFHD + rhEPO; Arm 2 — LFHD + HIF-PHI; Arm 3 — HFHD + rhEPO; Arm 4 — HFHD + HIF-PHI","population":"Newly treated (incident) maintenance hemodialysis patients with end-stage kidney disease and renal anemia; specific baseline hemoglobin thresholds, comorbidity profile, and additional inclusion/exclusion criteria not reported in the available abstract","intervention":"High-flux hemodialysis (HFHD) combined with a HIF-prolyl hydroxylase inhibitor (HIF-PHI); specific HIF-PHI agent (e.g., roxadustat, daprodustat) not specified in the available abstract; hemodialysis prescribed 3 sessions/week, 4 hours per session","comparator":"Three active comparator arms: (1) LFHD + rhEPO [primary reference comparator], (2) LFHD + HIF-PHI, and (3) HFHD + rhEPO; no placebo arm","primaryOutcome":"Change in hemoglobin (ΔHB) and red blood cell count (ΔRBC) after 2 months of treatment; secondary outcomes included hepcidin, total iron-binding capacity (TIBC), transferrin saturation (TSAT), ferritin, parathyroid hormone (PTH), β2-microglobulin (β2-MG), and incidence of adverse events","followUp":"2 months","fundingSource":"Not reported; authors declare no conflicts of interest"}
Key findings
All four treatment arms demonstrated statistically significant post-treatment increases in hemoglobin and RBC (P < .05 for all groups). The magnitude of hemoglobin and RBC increases (ΔHB and ΔRBC) was significantly greater in the two HIF-PHI arms (HFHD + HIF-PHI and LFHD + HIF-PHI) than in either rhEPO arm (LFHD + rhEPO and HFHD + rhEPO); absolute values, confidence intervals, and between-group effect sizes were not reported in the available abstract. Regarding middle-molecule clearance, PTH and β2-MG levels rose significantly post-treatment in both LFHD arms (P < .05), whereas PTH and β2-MG were significantly lower post-treatment in the two HFHD arms compared with either LFHD group (P < .05), consistent with the expected superior middle-molecule clearance of high-flux membranes. HIF-PHI therapy was associated with significant reductions in hepcidin and significant increases in TIBC and TSAT compared with pre-treatment values (P < .05), indicating improved iron mobilization. These iron metabolism benefits were not observed to the same degree in rhEPO-treated arms, though direct pairwise comparisons and exact between-group delta values are not reported. The incidence of adverse events was numerically lower in HIF-PHI groups compared with rhEPO groups, but this difference did not reach statistical significance. NNT and NNH cannot be calculated from the available data.
Practice implications
This trial establishes that, over a short 2-month observation period in incident MHD patients, the combination of HFHD and HIF-PHI produced numerically greater hemoglobin increments and more favorable iron metabolism profiles (lower hepcidin, higher TIBC and TSAT) compared with the conventional LFHD + rhEPO standard. The additive benefit of HIF-PHI over rhEPO appears independent of dialysis membrane flux, as LFHD + HIF-PHI also outperformed both rhEPO arms on erythropoiesis endpoints. HFHD's superiority in clearing middle molecules (PTH, β2-MG) is well-established and confirmed here, but is not attributable to the anemia therapy chosen. Critical limitations of the available data preclude definitive clinical translation: (1) only the abstract is available — exact effect sizes, confidence intervals, p-values for between-group pairwise comparisons, and safety event types are not reported; (2) the 2-month follow-up is insufficient to assess durability of hemoglobin response, clinically meaningful hard outcomes (hospitalizations, MACE, mortality, quality of life, or transfusion rates), or long-term HIF-PHI safety signals such as thromboembolic events or tumor promotion; (3) the study enrolled only incident MHD patients, so results are not generalizable to prevalent dialysis patients, those with ESA hyporesponsiveness, significant inflammatory comorbidities, or non-dialysis CKD; (4) sample sizes of 16 per arm are very small and likely underpowered to detect clinically meaningful safety differences. The specific HIF-PHI agent used is not identified in the abstract, limiting direct clinical application. Overall, the findings are biologically plausible and directionally consistent with larger HIF-PHI trials, but do not independently justify a change in practice. __LIMITATIONS__ Very small sample size (n = 16 per arm) severely limits statistical power for between-group safety comparisons and increases the risk of type I and type II errors.,Short follow-up of only 2 months precludes evaluation of sustained hemoglobin response, hard clinical outcomes (mortality, cardiovascular events, hospitalizations, transfusion requirement), or durable iron metabolism effects.,Only abstract available for review; exact absolute and relative effect sizes, confidence intervals, pairwise p-values, adverse event types, and randomization/allocation concealment methods cannot be verified.,No placebo arm; all comparisons are active-controlled, which is appropriate but limits quantification of the magnitude of benefit over untreated baseline.,The specific HIF-PHI agent is not identified, limiting applicability given that HIF-PHIs are not pharmacologically interchangeable and may differ in safety profiles.,Blinding status is not reported; open-label design (likely given the differing modalities and routes of administration) introduces performance and detection bias.,Restriction to incident MHD patients limits generalizability to prevalent dialysis patients, ESA-hyporesponsive patients, or patients with significant systemic inflammation.,Surrogate endpoints (hemoglobin, hepcidin, TIBC, β2-MG) were the sole outcomes measured; no patient-reported outcomes, transfusion rates, or clinical event data are provided.,The adverse event analysis was underpowered, and the non-significant trend toward fewer adverse events in HIF-PHI groups should not be interpreted as evidence of superior safety.,Funding source is not reported, which limits assessment of potential sponsorship bias; however, no conflicts of interest are declared. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ In this small, 2-month RCT of incident maintenance hemodialysis patients, HFHD combined with a HIF-PHI produced greater hemoglobin increments and more favorable iron metabolism parameters than LFHD plus rhEPO, with no statistically significant difference in adverse events. The findings are hypothesis-generating but are substantially limited by very small per-arm sample sizes, a short follow-up insufficient to assess hard clinical outcomes, and the absence of key quantitative data in the available abstract. This study should be considered preliminary; current practice should not change based on these results alone, and confirmation in larger, adequately powered trials with clinically meaningful endpoints is required.