Key messages
• Acute kidney injury occurs when the kidneys suddenly lose their ability to filter waste from the blood. Erythropoietin-stimulating agents are medicines that are mainly used to treat problems with the production of red blood cells, and may be helpful for people at risk of developing acute kidney injury or when it is first detected.
• In people at risk of developing acute kidney injury, erythropoietin-stimulating agents probably make little or no difference to the risk of developing acute kidney injury or in reducing the risk of death, and may make little or no difference to the need to start dialysis (a procedure to remove waste products and excess fluid from the blood). Similarly, there may be no differences in kidney function and adverse events such as blood clots, heart attack, stroke or high blood pressure.
What is the issue?
Acute kidney injury occurs when the kidneys suddenly lose their ability to filter waste from the blood. It is most common in people who are in the hospital needing intensive care. If acute kidney injury is severe, it can be fatal, but in people who had prior good health, acute kidney injury can be reversed.
Erythropoietin-stimulating agents are medicines that are mainly used to treat problems with the production of red blood cells, usually in people with long-term kidney failure (a condition where the kidneys no longer function well enough to keep a person alive). However, erythropoietin-stimulating agents have been shown to help protect kidneys from disease in animal studies, so they may be helpful for those at risk of developing acute kidney injury (such as those undergoing heart surgery) or people with early stage acute kidney injury.
What did we do?
We searched for all trials that assessed the benefits and harms of erythropoietin-stimulating agents for people who are at risk of developing acute kidney injury or treating those who have acute kidney injury.
What did we find?
We found 20 studies enrolling 5348 people at risk of acute kidney injury. The number of people enrolled ranged from 10 to 1302, and all were treated in hospital. All the studies compared erythropoietin-stimulating agents to placebo (dummy medicine) or usual care.
In people at risk of developing acute kidney injury, erythropoietin-stimulating agents probably do not reduce the risk of AKI or death and may not reduce the need to start dialysis (a procedure to remove waste products and excess fluid from the blood). Similarly, there may be no differences in kidney function and adverse events such as blood clots, heart attack, stroke or high blood pressure.
Conclusions
We are moderately confident that erythropoietin-stimulating agents probably make little or no difference to people at risk of acute kidney injury from going on to develop acute kidney injury or dying. We are less confident in their effect on reducing the need to start dialysis and on adverse events such as blood clots, heart attack, stroke or high blood pressure.
How up to date is the evidence?
The evidence is current to 30 August 2024.
In patients at risk of AKI, ESAs probably do not reduce the risk of AKI or death and may not reduce the need for starting dialysis. Similarly, there may be no differences in kidney function measures and adverse events such as thrombosis, myocardial infarction, stroke or hypertension.
There are currently two ongoing studies that have either not been completed or published, and it is unclear whether they will change the results. Caution should be exercised when using ESAs to prevent AKI.
Acute kidney injury (AKI) is characterised by a rapid decline in kidney function and is caused by a variety of clinical conditions. The incidence of AKI in hospitalised adults is high. In animal studies, erythropoiesis-stimulating agents (ESA) have been shown to act as a novel nephroprotective agent against ischaemic, toxic, and septic AKI by inhibiting apoptosis, promoting cell proliferation, and inducing antioxidant and anti-inflammatory responses. As a result, ESAs may reduce the incidence of AKI in humans. Randomised controlled trials (RCTs) have been conducted on the efficacy and safety of ESAs, but no prior systematic reviews exist that comprehensively examine ESAs with respect to AKI prevention, although the effectiveness of these agents has been examined for a range of other diseases and clinical situations.
This review aimed to look at the benefits and harms of ESAs for preventing AKI in the context of any health condition.
We searched the Cochrane Kidney and Transplant Register of Studies up to 30 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.
We included RCTs and quasi-RCTs (in which allocation to treatment was based on alternate assignment or order of medical records, admission dates, date of birth or other non-random methods) that compared ESAs with placebo or standard care in people at risk of AKI.
Three authors independently extracted data and assessed the risk of bias for included studies. We used random-effects model meta-analyses to perform quantitative synthesis of the data. We used the I2 statistic to measure heterogeneity amongst the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with their 95% confidence interval (CI). We assessed the certainty of the evidence for each main outcome using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach.
A total of 20 studies (36 records, 5348 participants) were included. The number of participants ranged from 10 to 1302, and most studies were carried out in single centres (13/20). All the included studies compared ESAs to placebo or usual care. Many of the studies were judged to have unclear or high risk of reporting bias, but were at low risk for other types of bias.
ESAs, when compared to control interventions, probably makes little or no difference to the risk of AKI (18 studies, 5314 participants: RR 0.97, 95% CI 0.85 to 1.10; I² = 19%; moderate-certainty evidence) or death (18 studies, 5263 participants: RR 0.92, 95% CI 0.80 to 1.06; I² = 0%; moderate-certainty evidence), and may make little or no difference to the initiation of dialysis (14 studies, 2059 participants: RR 1.16, 95% CI 0.90 to 1.51; I² = 0%; low-certainty evidence). Even with standardised measurement of AKI, the studies showed no difference in results between different routes of administration (subcutaneous or intravenous), background diseases (cardiac surgeries, children or neonates, other adults at risk of AKI), or duration or dose of ESA. ESAs may make little or no difference to the risk of thrombosis when compared to control interventions (8 studies, 3484 participants: RR 0.92, 95% CI 0.68 to 1.24; I² = 0%). Similarly, ESAs may have little or no effect on kidney function measures and adverse events such as thrombosis, myocardial infarction, stroke or hypertension. However, this may be due to the low incidence of these adverse events.