Erythropoietin Administration for Anemia Due to Chronic Kidney Disease - Subcutaneous OR Intravenous, What Do We Know So Far?

The prevalence of anemia in chronic kidney disease (CKD) patients is almost twice that of the normal population and its severity increases exponentially as the disease worsens, dramatically affecting the quality of an individual’s life. The advent of erythropoiesis stimulating agents (ESA) in the 1980s saw a revolutionary change in the treatment of anemia in CKD patients, drastically improving quality of life (QoL), overall health and reducing the need for blood transfusions. Numerous ESAs have been developed ever since and are in current use, with the primary routes of administration being intravenous (IV) and subcutaneous (SC) injections. Their use, however, has stirred significant controversy over the last two decades. Additionally, despite numerous studies and trials, the latest international recommendations for their use do not provide clear cut guidance with well-grounded evidence on the recommended route of administration for different sets of patients. Instead, this decision has mainly been left up to the physician’s discretion, whilst keeping certain key factors in mind. This review shall summarize, discuss and compare the findings of previous studies on various factors governing the two aforementioned routes of administration and identify areas that need further exploration.


Introduction And Background
Anemia, defined as serum haemoglobin (Hb) levels ≤12 gm/dL in women and ≤13 gm/dL in men, is a common complication of chronic kidney disease (CKD), being prevalent twice as much in the affected adult population (15.4%) as opposed to the general population (7.4%). The prevalence of anemia tends to be correlated with the severity of underlying kidney disease, prevailing in 8.1% of patients with stage 1 CKD to 53.4% in stage 5 CKD [1]. It is frequently associated with a poorer quality of life (QoL) that deteriorates further as the disease progresses, and commonly results in cognitive impairment, reduced exercise capacity, worsening of cardiac function, increased cardiovascular morbidity and ultimately contributes to an increased overall mortality rate [1,2].
Poor kidney function and accumulation of uremic toxins is a known cause of anemia in CKD patients in addition to reduced erythropoietin (EPO) production due to loss of functioning renal  These were then further filtered for articles that were pertinent to the confines of this review by another search carried out using "EndNote X9 ®", a citation management software, by utilizing a comprehensive list of relevant MeSH terms and regular keywords (see Table 2). Ultimately we were able to narrow down our search to 160 articles that we felt were pertinent to the scope of this review. Out of 160 articles, 38 full-text publications were then chosen for discussion in this literature review, with the merit of selection being individual article relevance and comprehensiveness.

Discussion
The major factors that govern the route of ESA administration include the patient's stage of CKD, efficacy considerations, the type of ESA used, dosing frequency, convenience, healthcare costs, and drug safety and tolerability [8,12]. This literature review aims to discuss the existing, relevant literature for these factors with respect to the route of ESA administration and to define areas that need further exploration.

Dosing Frequency
Numerous studies and trials have documented evidence strongly suggestive of the advantages that the SC route of erythropoietin administration has, in terms of requiring a lower dose and frequency of administration, over the IV route (see Table 3).

Drug Safety and Tolerability
As with any other drug, recombinant Human EPO (r-HuEPO) or epoetin carries with it a certain set of side effects. While both IV and SC share some of these adverse effects, the extent and frequency differ between the two (see Table 4). Common to both routes include injection site pain sensation, the development of hypertension, arteriovenous fistulae thrombosis, an increased overall risk of thrombotic and cardiovascular as well as cerebrovascular events, hyperkalemia, depletion of iron stores, flu-like symptoms, a prolonged duration of dialysis and rarely, PRCA and seizures [9,11,12,20].

Drug-associated Costs
Patients with severe anemia secondary to CKD < Hb 9.0 gm/dl and those with advanced CKD, for example those on regular HD, need prolonged periods of ESA therapy to improve their QoL, to prevent anemia-related symptoms, and to minimize the need for blood transfusion [8]. This can incur significant recurring costs on individuals and on healthcare systems. Dealing with this by employing a cost effective yet efficacious means of ESA therapy is therefore crucial (see Table 5). 2020

Drug Efficacy
There are various factors that underpin ESA efficacy, i.e., the dose needed to attain a certain target Hb concentration or hematocrit level, which can be adequately summarized under the umbrella of individual ESA pharmacokinetics and pharmacodynamics [12]. Discussed further are factors that have been found relevant to ESA efficacy (see Table 6). Numerous studies have provided support to the SC route of administration due to multiple advantages over the IV route, most notably a lower overall dose to achieve a similar target Hb concentration as well as hematocrit levels and a reduced dosing frequency, i.e., the SC route offers more efficacy for administration of r-HuEPO [13][14][15][16][17]19]. Although the SC route offers a much lower level of bioavailability as compared to the IV route, it results in a significantly longer half-life, attaining peak plasma levels that are substantially lower than the IV route but persist for a much longer period of time. The reasons theorized behind this low bioavailability but a paradoxically prolonged maintenance of modest serum plasma levels can be attributed to a multiple injection site, drug inherent and systemic factors. This persistence and delayed absorption of EPO from SC administration has been pivotal in the explanation for this route's effectiveness over the IV route. As erythropoiesis is not as dependent on peak plasma EPO levels as it is on the maintenance of EPO levels above a critical threshold for a prolonged time duration, the SC route offers an advantage. IV EPO dosing results in a fall in serum r-HuEPO levels during the interdialytic period and ultimately in the apoptosis of EPO-dependent erythrocyte precursor cells in the bone marrow. SC EPO dosing prevents this apoptosis due to maintenance of plasma EPO levels for a longer duration therefore enabling a more protracted, efficient and effective process of erythropoiesis [29,30].

Route of Administration and Stage of CKD (Non-Dialysis Dependent and Patients on Peritoneal Dialysis vs Haemodialysis Patients)
Non-dialysis CKD patients with preserved GFR, or those undergoing peritoneal dialysis, benefit from SC administration of ESAs, considering that it's least invasive and can be carried out without any monitoring. Furthermore, intraperitoneal administration in patients on continuous ambulatory peritoneal dialysis (CAPD), can dilute ESA concentration, limiting its use [34,35]. The advantage of IV administration lies in the fact that it can be conveniently administered during the process of haemodialysis. Numerous studies have shown that SC doses of ESAs in non-dialysis dependent and patients on peritoneal dialysis, were found to effectively increase Hb concentrations and were well-tolerated and may even be more efficacious than IV EPO formulations in HD patients as well [36,37]. However, more work needs to be done comparing the efficacy of SC versus IV EPO administration in non-dialysis and patients on continuous ambulatory peritoneal dialysis (see Table 7). The use of EPO in HD patients has been covered under other sections.

Convenience of Drug Administration
Between the two routes, convenience depends on factors like the stage of CKD, the dose and dosage frequency, the type of ESA being used, ease-of-use, the type of dialysis being utilized, the associated healthcare costs, and patient satisfaction.
For non-HD patients, the SC route may be more generally convenient due to the lack of a continuous IV access, the ease of self administration, comparatively lower dosage, less frequent hospital visits, a reduced dosing frequency and ultimately reduced costs. Even in HD patients, the SC route has been tied to similar advantages and may therefore be more beneficial overall as compared to the IV route, despite the obvious convenience that an arteriovenous fistula confers to IV EPO administration [13-17, 19, 26-28, 31-35]. This may be particularly beneficial in low-income countries where affordability and access to newer, longer acting ESAs may be difficult [40]. Evidence lending support to the efficacy, cost effectiveness and safety of the SC route of ESA administration has been presented in earlier sections.
A multicenter study, non-randomized, open-label study conducted by Grzeszczak et al. in 128 stable, chronic PD patients already on once to thrice-weekly SC EPO administration who were enrolled in a study where the effect of shifting them to once-weekly and once-fortnightly administration of SC Epoetin-beta in maintaining their Hb concentrations, was investigated. The findings concluded that shifting patients to SC Epoetin-beta once-weekly did not result in a significant change in mean Hb levels over a period of 25 weeks. In the oncefortnightly group, the dose needed to be increased slightly and even then, more than 50% of patients could still be maintained on baseline EPO-beta doses or lower. This study paves way for a means of ESA administration that could result in greater convenience, compliance, patient satisfaction, reduced dosage frequency and greater cost savings [41].
The convenience of use for the IV formulation in HD has its possible roots in the preference for its use by HD Staff. This may be due to the routine use of the IV route by HD staff [16] as well as the issue of pain or 'stinging' or discomfort at the injection site associated with the initial use of SC epoetin-alfa which some studies have cited in the past [42]. The KDIGO guidelines have also cited 'pain' secondary to SC administration, in terms of using short-acting ESAs, as a reason to prefer IV EPO administration, referring to the results of a single centre trial of 30 patients [8,26]. In a randomized, un-blinded trial carried out by Kaufman et al. among 208 patients, 86% of the 107 candidates who received SC epoetin injections reported experiencing pain as none to mild [43]. Similar findings were found in a multi-center randomized, doubleblind, prospective study among 90 ESRD patients already on HD, who were subjected to different regimes of IV and SC EPO treatment. None of the patients treated SC complained of injection site pain nor were there any identifiable local adverse reactions [23]. Nonetheless the pain reported in previous studies has mainly been tied to the citrate component of the epoetinalfa buffered solution that is administered SC to patients [44]. However, it has largely been controlled by replacement of the citrate preservative with Benzyl Alcohol saline and other newly developed stabilizer solutions, using large gauge needles, and smaller volume doses, all of which were highly effective in reducing pain whilst maintaining drug efficacy [43,45,46].

Type of ESA Formulation Used
ESA can generally be classified as short-acting or long-acting. The former usually refers to the 1st generation ESAs like Epoetin-alfa and beta while the latter normally refers to 2nd generation ESAs and beyond, including formulations like Darbepoetin-alfa and continuous erythropoietin receptor activator (C.E.R.A) [4]. The choice of ESA depends on factors like drug availability, affordability, patient preference, and local policies. Each of these agents also has its own unique pharmacokinetic and pharmacodynamic profiles [4,8]. In this review we shall only discuss common ESA types from the first and second generations (see Table 8).

Limitations
As no review or study is perfect, this literature review has an important set of limitation: papers were excluded if they were published in a language other than English, study types that met our exclusion criteria like commentaries or animal-based studies were excluded, our focus was mainly limited to studies based on adult CKD patients, and we mainly covered 1st and 2nd generation ESAs in our review. Additionally, the majority of studies in anemic CKD patients included in this review pertain to HD dependent ESRD patients. While significant efforts were made to review a broad range of publications from different years, it is still pertinent to mention the selection bias that may be present in this review with regards to the articles chosen for review and their relevance. Future research work that corrects these limitations may very well lead to different outcomes or impressions on the reader.