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Subcutaneous (sub-Q) InjectionErythropoiesis-stimulating agents (ESAs) -
Choukroun [ 11 ] was an anemia correction trial on renal transplant patients and not CKD patients so it was omitted. In 3 trials, ESAs were given prior to renal transplant [ 12 — 15 ] and omitted because there could be no direct effect of ESA on the ischemic transplanted kidney.
Duplications were identified; Oh [ 16 ] was a reanalysis of Song [ 17 ] and Revicki [ 18 ] was a follow-up of Roth [ 19 ]. The Park [ 20 ] and Olweny [ 21 ] trials were excluded from meta-analysis because they were retrospective trials without AKI endpoints. Measures of renal function sCr, eGFR, and enzymatic varied, methods and times , or were not reported in many papers.
Therefore, we chose not to perform meta-analyses using those markers but instead summarize available data in the tables. Meta-analyses Forrest plots using the selected hard endpoints, are shown in Figs.
Trial quality potential bias was evaluated utilizing Jadad [ 22 ] and Cochrane recommendations. With the exception of Kamar [ 23 ] which was a observational trial all the trials used in meta-analysis were RCTs.
Risk of bias assessment is shown in Table 1 and Fig. Most trials provided an ITT analysis with reporting of lost patients. The trials also had adequate methods to randomly distribute subjects into intervention vs control groups.
Blinding of subject distribution and blinding of outcome to assessors was inadequate in most trials, particularly the anemia correction trials. However, the hard renal endpoints used in these meta-analyses are strengths.
Most AKI and transplant trials were double-blinded with few dropouts, while the anemia correction trials were mostly open-label with variable numbers of dropouts. Overall, the trials had a risk of bias that was considered acceptable and thus results from meta-analysis would be informative.
Nine trials were identified [ 16 , 20 , 21 , 24 — 29 ] that assessed whether ESAs might reduce the risk of AKI Table 2. In 8 trials the subjects underwent cardiac surgery coronary artery grafting, or valvular heart surgery involving cardiopulmonary bypass and in 1 trial the subjects underwent partial nephrectomy.
The combined number of subjects was ; in the ESA groups and in the control groups. The trial sizes ranged from 71 to subjects. Four of the trials were performed by overlapping members of the same study groups [ 16 , 17 , 27 , 29 ].
Song and Oh analyzed the same 71 patients and patient data, but used different definitions of AKI. They increased the duration of observation to 72 instead of 48 h, and therefore had different numbers of patients that progressed to AKI.
We used the determinations from Oh because it is more recent and the definition used is more complete AKIN. The RR slightly favored the ESA arm, but it did not reach statistical significance using either the random effects 0. This heterogeneity is further apparent when other renal endpoints were examined Table 2.
In 1 trial [ 20 ] there was no difference in renal recovery, in 4 trials there was no difference in creatinine-based markers. However, in a 5th mixed results were reported.
In 3 trials there was no difference in eGFR between groups, while in another trial, eGFR was improved in the ESA arm. Overall the secondary outcome analyses using non-creatinine-based renal biomarkers did not demonstrated significant reno-protection by ESAs.
In 3 trials urine or plasma NGAL or serum cystatin C were the same in both groups; in the 4th, urinary NGAL was lower in the ESA arm, although the significance of this difference is uncertain.
Reinstitution of blood flow in cadaveric or live donor kidneys activates a sequence of events that results in renal injury, which may result in the development of DGF.
DGF can translate into a decrease in long-term graft survival. In most ESA trials in transplant patients [ 14 , 23 , 30 — 36 ], DGF was defined as a requirement for dialysis within 7 days of the transplant [ 37 ].
In trials where multiple definitions were presented, data according to this definition was used. However, in some papers the definition of DGF was not disclosed, or an alternate measure was used Table 3.
The trial sizes were small to moderate in size 29— subjects. A meta-analysis with subjects utilizing the DGF endpoint 7 trials , is shown in Fig.
The RR was neutral using random or fixed effects models 0. Meta-analysis of long term graft loss over 1 year in four trials showed similar outcomes Fig. Fifteen of subjects 6. The RR 0. In the 7 trials, additional renal outcomes were reported that showed no differences between ESA and no-ESA groups Table 3.
These included creatinine-based endpoints 6 trials , eGFR 3 trials , proteinuria 1 trial , histological indices in graft biopsies at 6 weeks and 6 months post-transplant 1 trial , and low molecular weight urinary protein AKI biomarkers NGAL and IL 1 trial [ 34 ].
CKD patients are often anemic, and ESA treatment to increase and maintain Hb levels is long-term. Therefore, analysis of ESA anemia correction clinical trials is a potentially useful method to assess the effect of Hb increases, and oxygen delivery to renal tissues, on renal disease progression.
In the 19 anemia correction trials identified, CKD patients were typically divided into 2 groups; those remaining at their starting Hb control and those where ESAs were used to target a higher Hb. ESAs in the 19 trials [ 18 , 38 — 55 ] were typically given times per week to raise and maintain target Hb levels Table 4.
The achieved Hb levels in most trials were 11— Trial duration ranged from 2 to 48 months. Many subjects in the lower Hb groups received ESAs, but at lower doses. In some trials, there was no ESA treatment of patients in the control groups.
We performed meta-analysis on all trials and a separate meta-analysis of trials where subjects in the control groups did not receive ESAs Fig. ESAs in anemic CKD patients. The 18 trials were divided into 2 groups. In 6 trials there was no ESAs administered in the control group.
In 12 trials some patients in the control groups were given ESAs. The RR and range for each group filled diamonds and the overall RR open diamond are shown. Patients that progressed to RRT included those that began dialysis or received a transplant. In one trial a patient withdrew because of sepsis and AKI [ 48 ].
This event was included in the RRT endpoint of that study. No patients progressed to dialysis in either arm of the Lim [ 42 ] trial making it unsuitable for inclusion in a meta-analysis with a RRT endpoint. The remaining 18 anemia correction trials had a combined total of subjects; in the treatment arm higher Hb and in the comparator low Hb control arm.
Trials were of varying size; 3 had over subjects. The initial and achieved Hbs in the 2 groups are shown in Table 4. Overall, With meta-analysis, the RR random effects of progression to RRT was 1. This lack of effect on disease progression is supported in 18 trials by other assessments of change in renal function, including proteinuria, or creatinine based markers where there were no significant differences reported between groups Table 4.
However, in one trial time to a doubling in serum creatinine was significantly slower in the ESA group Kuriyama [ 41 ]. This anemia correction meta-analysis does not assess direct ESA effects per se because subjects in both arms may have received ESAs.
Thus the absence of benefit argues that anemia correction per se is not reno-protective. In 6 of the 18 anemia correction trials, subjects in the comparator arm did not receive ESAs [ 18 , 19 , 38 — 43 ].
These trials included a total of subjects. Meta-analysis showed a trend towards improvement in the progression to RRT in the ESA treatment group but this did not reach statistical significance; the RR according to the random effects model was 0.
The result was similar using the mixed effects model. Heterogeneity was low. Measures of serum creatinine over time showed no statistical difference in 6 of the 7 trials.
Thus this select analysis also does not support either direct or indirect anemia correction beneficial effect on renal disease progression by ESAs. We assessed potential beneficial effects of ESA treatment on acute or chronic renal disease. One potential benefit is that ESAs might increase renal tissue survival and therefore renal function following ischemic events due to an interaction of ESAs with receptors resident on the surface of renal cells resulting in an anti-apoptotic effect.
Alternatively, there may be mitigation of the negative effects of anemia, since anemia is associated with an increased risk of renal disease progression and allograft loss over the long term [ 56 , 57 ].
However, these meta-analyses showed no clear benefit of short-term ESAs in AKI and transplant trials, where there was little change in Hb levels, arguing an absence of direct benefit.
There was also no significant ESA benefit in longer-term anemia correction trials, regardless of whether the comparator group received or did not receive ESAs. Thus there appeared to be little short or long-term reno-protective benefit of ESAs, via direct via activation of EPOR or via an interaction of ESA with an EPOR:CD hybrid receptor [ 9 ] or indirect increased Hb mechanisms.
The lack of clear benefit of ESAs on renal disease is consistent with earlier meta-analyses. A meta-analysis with patients at risk for AKI showed no benefit of ESAs on incidence of AKI [ 58 ].
Another meta-analyses of effects of ESAs on CKD patients also showed no clear benefit on progression to RRT, comparing ESA treatment to no treatment [ 59 ] or comparing high vs low Hb targets [ 60 , 61 ], nor was there was an association between ESA dose and annual GFR change or progression to ESRD [ 62 ].
Overall and to date, the potential cyto-protective effects of ESAs reported in animal models have generally not translated into benefit in humans, according to other studies examining benefit with other ischemic tissues [ 63 ].
There was no significant benefit of ESAs on infarct size in a meta-analyses of patients with acute ST-segment elevation myocardial infarction [ 64 , 65 ], and no effect on nonfatal heart related events in a meta-analysis of ESA-treated patients with heart failure [ 66 ]. There was also no difference in a meta-analysis of retinopathy of prematurity in infants treated with ESAs [ 67 ].
There was no benefit of either ESA or increased Hb in an ESA trial on patients with traumatic brain injury [ 68 , 69 ], and there was no benefit in a phase 3 trial with ESA treatment of stroke patients [ 70 ]. Taken together, these observations suggest that ESAs may not have the broad, robust, non-hematopoietic protective abilities described by some investigators, at least not in humans.
The gap between preclinical reports of benefit of ESAs in animals, and the absence of similar robust benefit in humans, has several explanations. Dose and dose regimens may be different, or the animal studies used homogeneous animal types under controlled conditions that cannot be mimicked in the clinic.
Another possibility is that a benefit may have been unobservable because of the trial designs used. In this AKI meta-analysis the subjects were primarily cardiac patients and did not have only ischemia to the kidney as in animal studies and therefore may be immune to potential reno-protective ESA benefits.
There could also be other induced mechanisms that may confound the outcome data. For example, sepsis can affect outcomes and blood pressure can increase with ESA treatment and can negatively correlate with renal outcomes [ 71 , 72 ].
However, control of blood pressure did not affect progression to ESRD in a clinical trial [ 73 ]. Alternatively, the beneficial conclusions of preclinical animal studies need to be reconsidered. There are many reports in animals showing a lack of effect of ESAs [ 1 , 74 ].
The reno-protective hypothesis assumes that EPOR is present, and functional, at significant level on the surface of renal cells. However reports of EPOR presence are either assumed according to responses in tissue culture and in animals, or based on western or immunohistochemistry studies with anti-EPOR antibodies now shown to be nonspecific [ 75 ].
Recently a specific antibody to EPOR was discovered and western blots on renal tissue showed few, if any, detectable EPOR raising further questions about the validity of the hypothesis [ 10 ].
These meta-analyses have limitations. Majorities of included trials were small, single center, and had modest event rates. The anemia correction trials were larger, but conclusions around direct effects were confounded by the frequent use of ESAs in the comparator arm, though trials where the comparator arm did not receive ESAs similarly showed no benefit.
Within each grouping CKD progression, AKI, transplantation there were differences in patient selection, treatment regimen and outcome definition.
Finally, the meta-analyses were based on aggregated, not individual patient level data, which precluded adjustments for confounding factors such as age and comorbidities.
In contrast to some preclinical studies demonstrating reno-protection by ESAs in animals, anemia correction, prophylaxis or post-injury intervention with ESAs provided no significant clinical reno-protection in humans.
This suggests that ESAs may not have robust, nor reproducible direct, or indirect, benefits on renal function. Elliott S, Sinclair AM. The effect of erythropoietin on normal and neoplastic cells.
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Main Content. Important Phone Numbers. Topic Contents Introduction Examples Possible side effects What to know about taking these medicines.
Top of the page. Introduction Erythropoietin stimulating agents also called ESA medicines are used to treat anemia caused by chronic kidney disease or chemotherapy for cancer treatment.
Examples Darbepoetin alfa Aranesp Epoetin alfa Eprex. Possible side effects Side effects may include: High blood pressure. Having too many red blood cells. This may raise your risk for heart failure, heart attack, and stroke. Deep vein thrombosis. This is a blood clot in a vein.
A clot can be deadly if it travels to a lung. A blood clot in a dialysis access. Patients using ESAs should:. Patients with chronic kidney failure includes patients on dialysis and those not on dialysis.
The ESA APPRISE Oncology program requires that all healthcare professionals who prescribe ESAs for patients with cancer do the following:. Healthcare professionals not enrolled in the ESA APPRISE Oncology program will not be able to prescribe ESAs for use in patients with cancer.
As part of the enrollment in the ESA APPRISE Oncology program, healthcare professionals must attest to their understanding of the following:.
Skip to main content Skip to FDA Search Skip to in this section menu Skip to footer links. Index to Drug-Specific Information. For the most current information on ESAs, please see Information on Erythropoiesis-Stimulating Agents ESA Epoetin alfa marketed as Procrit, Epogen , Darbepoetin alfa marketed as Aranesp.
The goals of the REMS for the ESAs are: To support informed decisions between patients and their healthcare professionals who are considering treatment with an ESA by educating them on the risks of ESAs.
Additional Information for Patients: Patients with cancer Patients using ESAs should: Understand the risks associated with use of ESAs.
These risks include: ESAs may cause tumors to grow faster. Be aware that their healthcare professional has received special training about the use of ESAs in patients with cancer. Read the Medication Guide to understand the benefits and risks of using an ESA. Talk with their healthcare professional about any questions they may have about using ESAs.
Be aware that they will be asked to sign an acknowledgment form that says they have talked with their healthcare professional about the risks of ESAs. This form must be signed before patients begin a course of treatment with an ESA. Patients with chronic kidney failure includes patients on dialysis and those not on dialysis Patients using ESAs should: Know that the use of ESAs can increase the risk for stroke, heart attack, heart failure, blood clots, and death.
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