Impact of erythropoietin therapy on cardiorenal syndrome: A systematic review with meta-analysis

Table 1 Summary of included studies

Ref.	Study design	No. of Patients	EPO dosage and treatment duration	Average Hb level (g/dL)			EPO's effect on			Other findings
				Before EPO therapy	After EPO therapy	Without EPO treatment	Hb level	Major CV event	Hospitalization rate
Jackevicius et al[12], 2015	Retrospective cohort	2058	N/A	N/A	10.5	11.1	Inverse relationship between EPO therapy and Hb levels	N/A	N/A	The strongest predictors of EPO use include iron supplementation, markers of declining renal function, and patients concurrently taking hydralazine, nitrates, ARBs, and/or aspirin
Eisenga et al[13], 2019	Open-label, prospective, randomized trial	56	N/A	11.7	13.2	11.8	Increased Hb levels	Increased cFGFR23 and iFGFR23, increased risk of CV events and mortality	N/A	N/A
McMurray et al[14], 2011	Randomized trial	3847	N/A	N/A	N/A	N/A	N/A	Patients with CKD and anemia have an 11.2% higher risk for a major CV event. History of CHF was the highest-ranked predictor of future CV events, followed by age (hazard increase by 74% and 27%, respectively)	N/A	N/A
Fazlibegović et al[15], 2006	Prospective cohort	90	2000 to 6000 international units (I.U.) for 1-3 times per week, depending on the Hb level	8.7	10.1	N/A	Increased Hb levels	Improved functional ability of the myocardium, LV function, and quality of life	N/A	The average NYHA class before treatment with EPO was class II, with a range of I-IV; after treatment, the average class was I, with a range of I-II
Palazzuoli et al[11], 2007	A randomized, double-blind controlled study	51	6000 I.U. twice weekly	10.4	11.2	10.6	Increased Hb levels	Improved LV systolic function, LV remodeling, NYHA class, BNP levels, and quality of life compared to control group	N/A	N/A
Jie et al[16], 2011	Open-label randomized trial	65	N/A	7.5	8.4	6.9	Increased Hb levels with long term use	N/A	N/A	Reduced CD34+ KRD-EPC levels, which was associated with decreased vascular regenerative potential
Jackevicius et al[17], 2014	Retrospective cohort study	2058		10.5:		11.1	Increased Hb levels	Increased risk of major CV and acute coronary syndrome events	Increased risk of an all-cause hospitalization rate	EPO use increases the risk of mortality
Jie et al[18], 2012	Randomized trial	30	50 I.U./kg once weekly	11.8	12.3	N/A	Increased Hb levels	Modest alteration in monocyte transcriptomes, indicating imprints of inflammation and oxidative stress. The increase in oxidative stress, in turn, increased the risk of CV events	N/A	Variable response in gene expression. Unable to conclude whether EPO improved hematopoietic effects in CRS patients with such gene mutations
Emans et al[19], 2013	Open-label prospective randomized trial	62	50 I.U./kg once weekly		13.7	11.8	Increased Hb levels	N/A	N/A	Elevated serum NGAL is inversely correlated with baseline EPO levels, independent of renal function. Low-dose EPO treatment caused a moderate decrease in serum NGAL levels, therefore reflecting potential improvement in renal tubular damage

ARB: Angiotensin II receptor blocker; BNP: B-type natriuretic peptide; cFGF: C-terminal fibroblast growth factor; CKD: Chronic kidney disease; CHF: Congestive heart failure; CRS: Cardiorenal syndrome; CV: Cardiovascular; EPO: Erythropoietin; EPC: Endothelial progenitor cell: Hb: Hemoglobin; iFGFR: Intracellular fibroblast growth factor receptor; LV: Left ventricular; N/A: Not applicable; NGAL: Neutrophil-gelatinase-associated lipocalin; NYHA: New York Heart Association.