Authors: Pan Mingming, Li Zuolin, Liu Bicheng, Zhongda Hospital, Southeast University
Erythropoiesis-stimulating agents (ESAs) are commonly used in the clinical treatment of renal anemia. Short-acting ESAs have been widely used in mainland China and have a long history, and there are many guidelines and consensus at home and abroad. Long-acting ESAs have the advantages of long half-life, low infusion frequency, and good patient treatment compliance, and have made important progress in clinical research in recent years, but there is still a lack of guidance on the clinical standard use of long-acting ESAs.
This article interprets the "Chinese Expert Consensus on Long-acting Erythropoiesis-stimulating Agents for the Treatment of Renal Anemia" (hereinafter referred to as the "Consensus") published in the Chinese Journal of Nephrology in 2024. The "Consensus" was organized by the Renal Dialysis Professional Committee of the China Association of Non-public Hospitals, led by Professor Liu Bicheng and Professor Mei Changlin, and written by Professor Jiang Hongli and Professor Yao Li.
Consensus formation background
Renal anemia is a common complication of chronic kidney disease (CKD), which seriously affects the quality of life of patients, and is closely related to the progression of CKD, adverse cardiovascular events, and increased risk of all-cause mortality. In addition to the necessary treatment measures such as adequate dialysis and reasonable nutrition, the main treatment drugs for renal anemia include erythropoiesis-stimulating agents (ESAs), iron, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI), among which ESAs are the key drugs for the treatment of renal anemia. Recombinant human erythropoietin (rHuEPO) is currently the most commonly used ESAs in mainland China, and its efficacy and safety in the treatment of renal anemia have been clinically recognized.
Compared with short-acting rHuEPO, long-acting ESAs have a long half-life, which can effectively reduce the frequency of injections, reduce the workload of medical staff, and improve patients' treatment compliance, which has become an important direction to improve the treatment of renal anemia. In recent years, long-acting ESAs, including dayipoetin α, methoxypolyethylene glycol erythropoietin β, and erythropoietin mimetic peptide (EMP), have been launched one after another, and have completed phase III clinical trials in mainland China, and some have been approved for marketing in China, providing a new option for the treatment of renal anemia. The Dialysis Prognosis and Practice Model Study (DOPPS) and other countries analyzed the proportion of ESAs in various countries, and the results showed that the proportion of long-acting ESAs in Europe, the United States and Japan has exceeded 50%, while the mainland is dominated by short-acting ESAs. In view of the fact that long-acting ESAs are not widely used in China and the clinical experience is relatively insufficient, this expert consensus is formulated to guide clinicians to standardize the application of long-acting ESAs in the treatment of renal anemia.
Consensus Focus
Classification, mechanism of action and pharmacodynamic characteristics of long-acting ESAs
ESAs are mainly divided into rHuEPO and chemically synthesized EPO-mimetic peptides according to their molecular structure. The design strategy of long-acting ESAs mainly includes two aspects: (1) molecular biological modification methods such as increasing glycosylation sites or linking Fc fusion protein fragments, and (2) chemical modification methods such as linking polyethylene glycol chains. Combined with the approval of drugs in China, the following three long-acting ESAs are mainly introduced:
New Cystic Stimulating Protein (NESP)
The generic name is daepoetin α which is the world's first marketed formulation of long-acting ESAs. Compared with the α of epoetin, the N-terminal sugar chain of NESP was increased to 5, the content of sialic acid was increased by nearly 1 times, and the stability in vivo was significantly increased, and the renal clearance rate of the drug decreased due to the increase in relative molecular weight (37000), and the half-life was significantly prolonged.α In peritoneal dialysis patients, the half-life of subcutaneous and intravenous daepoetin α was 48.8 h and 25.3 h, respectively, while in hemodialysis patients, the half-life of once-weekly daepoetin α intravenous injection was 23.4 h, which was about three times the α of epoetin.
Methoxy polyethylene glycol erythropoietin β
A persistent EPO receptor agonist (CERA). CERA is modified by a fully glycosylated epoetin β lysine N-terminal amino or ε amino group by an amide bond linked to a methoxy polyethylene glycol chain. Pegylated epoetin β reduces renal clearance by increasing the relative molecular weight of the drug (60,000) on the one hand, and increases the stability of the modifier by producing steric hindrance effects to protect the modifier from protease hydrolysis on the other hand, which synergistically reduces the total clearance of the drug and significantly prolongs the half-life of the drug. In a pharmacokinetic study of patients with renal anemia undergoing peritoneal dialysis, the half-lives of intravenous and subcutaneous CERA were 134 hours and 137 hours, respectively.
Cultured Filmethotide (EMP)
EMP is a chemically synthesized cyclic small molecule peptide that mimics EPO independently developed by Continental. EMP is modified by pegylation on the basis of two cyclized EMP molecular structures, which increases the solubility and stability of EMP and reduces renal clearance. EMP can specifically bind to EPO receptors on the cell surface and exert similar biological effects to EPO in vitro and in vivo. Since EMP is structurally different from endogenous and recombinant EPO molecules, there is no cross-antigenicity with endogenous EPO. Pharmacokinetic studies showed that the half-life of pemosatide injected subcutaneously for the first time was 58.3~69.7 h in non-dialysis CKD patients, while that was 61.6~74.9 h in CKD patients receiving dialysis treatment.
Use of long-acting ESAs in renal anemia
(1) Target of treatment
(1) Long-acting ESAs are recommended for the treatment of renal anemia in patients with non-dialysis-dependent CKD (1A).
(2) long-acting ESAs are recommended for the treatment of adrenal anemia in dialysis-dependent CKD patients (1A);
(3) It is recommended that patients with renal anemia with low response to short-acting ESAs can be treated with long-acting ESAs (2C).
(2) Timing and target of treatment
①推荐长效 ESAs 治疗肾性贫血的起始治疗时机为Hb<100 g/L（1C）。
(2) When long-acting ESAs are recommended for the treatment of renal anemia, the target Hb target is maintained at ≥ 110 g/L, but does not exceed 130 g/L (1A).
(3) Treatment plan
(1) The initial therapeutic dose (1D) of long-acting ESAs should be determined according to the pre-treatment Hb level and clinical situation of CKD patients.
(2) It is recommended that for patients naïve with ESAs, the starting dose of dabepoetin α can be given as a fixed dose (20 μg) or based on body weight (0.45 micrograms/kg) once a week subcutaneously or intravenously, a starting dose of 0.6 μg/kg for CERA once a week or intravenously, and a starting dose of 0.04 mg/kg once a week (1A) for pemosatide.
(3) It is recommended that patients who are being treated with short-acting ESAs can be directly converted to long-acting ESAs in proportion to the current amount of short-acting ESAs (1A).
(4) It is recommended to adjust the dose according to the rate of rise of Hb level during the initial treatment of long-acting ESAs and the stability of Hb level during maintenance treatment, and maintain the Hb level at 110~120 g/L, and the growth rate of Hb should be controlled within 10~20 g/L every 4 weeks (2D).
(4) Mode of administration
The bioavailability and efficacy of daepoetin α and CERA intravenously and subcutaneously are comparable. Therefore, the administration of daepoetin α and CERA can be freely chosen according to the patient's wishes and clinical conditions. For pemosatide, due to its own drug properties, subcutaneous injection can only be chosen.
(5) Monitoring of iron metabolism indexes and the use of iron supplements during treatment
(1) It is recommended to regularly test iron metabolism-related indicators such as SF and TSAT before and during treatment with long-acting ESAs, at least once a month, and at least once every 3 months for patients in the maintenance treatment stage of anemia or Hb is relatively stable (1C);
②在长效 ESAs 治疗期间，应维持 SF 200～500 µg/L，TSAT 20%～50%（2B）。
(6) Adverse reactions and treatment of long-acting ESAs
It is recommended that patients should be observed for adverse reactions such as allergies, hypertension, thromboembolism, and PRCA during the use of long-acting ESAs, and should be treated aggressively once found (1, not graded).
(7) Application of long-acting ESAs in special populations
Long-acting ESAs may be considered in the treatment of renal anemia in special populations such as children, the elderly, hepatic insufficiency, post-kidney transplantation, and cancer (2B).
Consensus highlights
Based on systematic literature analysis, this consensus summarizes the pharmacodynamic characteristics of long-acting ESAs and the current status of clinical research at home and abroad, and provides guidance on the clinical application of such drugs, including the discussion of the optimal therapeutic dose and dose adjustment strategy, and also gives corresponding reference opinions on anemia and PRCA in patients with clinically difficult tumors. At the same time, the consensus also gives an objective description of the long-term impact on cardiovascular safety.
Initial dose selection and dose adjustment optimization strategies for long-acting ESAs
Referring to the current domestic and foreign clinical research data, the "Consensus" gives corresponding reference opinions on the dose selection and adjustment of long-acting ESAs, as follows.
(1) Starting dose selection
(1) For patients with renal anemia who are newly treated with ESAs, the initial dose, frequency and mode of administration are shown in Table 1.
Table 1: Initial therapeutic dose, frequency and mode of administration of patients with nephrogenic anemia with long-acting ESAs
(2) For patients with renal anemia who switch from short-acting ESAs to long-acting ESAs, the starting dose can be switched according to the dose of short-acting ESAs used before switching according to Table 2.
Table 2: Initial doses for the treatment of patients with renal anemia who switch from short-acting ESAs to long-acting ESAs
(3) There is a lack of relevant studies on the treatment of patients with low-response renal anemia with short-acting ESAs, and it is recommended that the switch can be made according to Table 2.
(2) Dose adjustment optimization strategy
Large cohort studies have well established that rapid rise and/or high levels of Hb are strongly associated with poor prognosis in patients with CKD, so Hb levels need to be closely monitored during the use of ESAs. It is recommended to monitor Hb once every 1~2 weeks until it tends to stabilize, and then once every 4 weeks. At present, there is a lack of specific studies on the dose adjustment of long-acting ESAs, and it is recommended to individualize the dose adjustment according to the rate of increase of Hb concentration during the initial treatment of long-acting ESAs and the stability of Hb concentration during maintenance treatment, maintain the level of Hb at 110~120 g/L, control the growth rate of Hb within 10~20 g/L every 4 weeks, and the minimum interval of dose adjustment of long-acting ESAs should not be less than 4 weeks.
(3) Medication for cancer patients
The use of ESAs has the potential to promote tumor growth and increase the risk of thromboembolism in patients with malignant tumors, which may be related to the expression of EPO receptors by tumor cells and vascular endothelial cells. Two meta-analyses have confirmed that daepoetin α can effectively increase Hb levels, reduce the number of blood transfusions, and no other adverse events were found during treatment. In addition, a recent phase III clinical study in patients with non-small cell lung cancer receiving chemotherapy found that dabepoetin α was effective in reducing the number of blood transfusions and the risk of Hb ≤80 g/L compared with placebo, and there was no significant difference in overall survival, progression-free survival, and the incidence of serious adverse events between the two groups.
and (4) anti-EPO antibody-mediated PRCA
PRCA is a rare and serious complication that occurs during the treatment of ESAs, which is caused by the stimulation of the body to produce anti-EPO antibodies, which in turn cross-react with endogenous EPO. Most of the reported cases of PRCA occur primarily in patients with epoetin α subcutaneous injections. Different from daepoetin α, CERA and pemosatide are less common because they are structurally linked to pegylated chains, which increases their stability and reduces immunogenicity, but they still need to be carefully observed in clinical applications.
(5) Cardiovascular safety
In a multicenter, randomized, open-label, non-inferiority clinical study of 2818 patients with CKD after a median follow-up of 3.4 years, CERA did not increase the risk of adverse cardiovascular events and all-cause mortality in a large population of CKD, primarily dialysis patients, compared with short-acting ESAs. This result is consistent with previous meta-analyses suggesting that there were no significant differences in the effect of different types of ESAs on hard endpoints such as all-cause mortality and cardiovascular events. Of course, there are also studies that have shown an increased risk of all-cause mortality in patients with long-acting ESAs compared with those who use short-acting ESAs. In conclusion, the available evidence is insufficient to determine which ESAs are superior in terms of cardiovascular benefit, and large prospective cohort studies and interventional clinical studies are still needed to evaluate them.
summary
Long-acting ESAs have potential unique advantages in the treatment of renal anemia because they have clinical efficacy that is not inferior to short-acting ESAs, prolong the interval between medications for patients with renal anemia, avoid the inconvenience caused by frequent commuting to and from the hospital, reduce the pain caused by frequent injections and the workload of nursing staff, and better improve the treatment compliance and quality of life of patients. The publication of this consensus will provide guidance for the better use of such drugs in the treatment of renal anemia in the future.
In general, there is not much experience in the application of long-acting ESAs in China, and in the future, attention should be paid to large-scale real-world studies in Chinese patients to further evaluate the efficacy and clinical safety of such drugs, and in addition, the efficacy of long-acting ESAs in special populations can also be discussed. In order to improve the treatment level of patients with renal anemia and improve the long-term prognosis, it provides more means.
About the Author:
Professor Liu Bicheng of Zhongda Hospital Affiliated to Southeast University
Dean of the School of Medicine of Southeast University, Director of the Institute of Nephrology, Southeast University, Chief Professor, Chief Physician, and Doctoral Supervisor of Southeast University.
Vice Chairman of the Chinese Society of Nephrology, Chairman of the Artificial Organ Branch of the Chinese Society of Biomedical Engineering, Vice Chairman of the Chinese Society of Renal Physiology, Member of the Fellowship Committee of the International Society of Nephrology, Vice Chairman of the Nephrology Branch of the Chinese Association of Research Hospitals, etc.
He enjoys the special government allowance of the State Council, a young and middle-aged expert with outstanding contributions to the National Health and Family Planning Commission, a "famous doctor of the country", a winner of the Outstanding Medical Achievement Award of Jiangsu Province, the first batch of health leaders in Jiangsu Province, an ISN Fellow, and a Fellow of the International Society of Science and Engineering.
He has published more than 600 papers, including more than 260 SCI papers, won 1 second prize of the National Science and Technology Progress Award, 4 first prizes and 3 second prizes of provincial and ministerial scientific and technological achievements such as the first prize of the Natural Science Award of the Ministry of Education, 11 other achievement awards, applied for 12 national invention patents, and authorized 7 patents.
Main research field: Engaged in clinical and research of kidney disease for 38 years, good at the diagnosis and treatment of difficult kidney disease, acute and chronic renal failure, and the main academic direction is renal fibrosis mechanism and clinical translational research.