REVIEW Recombinant Human Erythropoietin for Kidney Transplantation: A Systematic Review and Meta-Analysis Jiaojiao Zhou1, Jing Lu2, Diming Cai1*. Purpose: The protective effect of recombinant human erythropoietin (rHuEPO) on kidney transplantation has not been established. Therefore, we conducted a systematic review and meta-analysis to evaluate the potential influ- ence of rHuEPO on transplanted kidneys. Materials and methods: To identify relevant studies, we searched electronic databases (PubMed, Medline, EM- BASE, Ovid, the Cochrane Library, and major nephrology journals) from inception until June 15, 2018. Two inde- pendent reviewers assessed study quality. The systematic review and meta-analysis were performed with fixed- or random-effects models according to heterogeneity, and results are expressed as risk ratios (RR) or weighted mean differences. Results: Six randomized controlled trials with a total of 435 patients met the inclusion criteria. rHuEPO, compared with placebo, had no statistically significant effect on delayed graft function (RR = 0.89, 95% confidence interval [CI] , 0.73 to 1.07; P = 0.22) and slow graft function (RR = 0.93, 95% CI, 0.60 to 1.43; P = 0.73). The rHuEPO and control groups did not differ in thromboembolic events, mortality, acute rejection, and blood transfusion. A significant difference was found in long-term estimated glomerular filtration rate (RR = 3.65, 95% CI, -4.45 to 11.75; P = 0.003). Conclusion: Our findings suggests that rHuEPO has a limited nephroprotective effect in patients undergoing kid- ney transplantation and does not increase the susceptibility to adverse events. Keywords: recombinant human erythropoietin; kidney transplantation; allograft function; delayed graft function; systematic review and meta-analysis INTRODUCTION Erythropoietin (EPO) is a hematopoietic growth fac-tor synthesized in response to hypoxemia by fibro- blast-like cells in the kidney cortex. It is widely used to treat renal and non-renal anemia, especially in chronic kidney disease and hematopoietic diseases.(1) However, it has pleiotropic effects beyond the maintenance of red blood cell mass,(2,3) playing a role in the protection from inflammation and apoptosis due to of hypoxia, toxici- ty, or injury.(4) Previous studies suggested recombinant human EPO (rHuEPO) has important cytoprotective ef- fects on various cells and organs, as well as providing protection from ischemia-reperfusion injury (IRI).(5-7) Kidney transplantation is the treatment of choice for pa- tients with end-stage renal disease to optimize survival, with more favorable lifestyle results and a reduction in mortality rate.(8,9) Delayed graft function (DGF), lead- ing to major comorbidities including IRI, plays a cru- cial role in long-term graft function after transplanta- tion.(10,11) A previous report estimated an average annual DGF rate of 21.9% for deceased-donor kidney trans- plants and 3.5% for living-donor kidney transplants in the United States.(12) Improving renal allograft function and survival is a significant challenge in kidney trans- plantation. Therefore, rHuEPO is also included in the post-kidney transplantation management, which is a classical model of acute kidney injury (AKI) due to IRI. To verify this finding, several randomized controlled trials (RCTs) have been performed in adult patients undergoing kid- ney transplantation; nevertheless, the results have been controversial. In this study, we performed a comprehensive system- atic review and meta-analysis of RCTs to examine the efficacy and safety of rHuEPO on allograft function in patients receiving kidney transplantation. MATERIALS AND METHODS This study was conducted in accordance with the Pre- ferred Reporting Items for Systematic Reviews and Me- ta-analysis (PRISMA) statement.(13) Literature search and selection criteria Two reviewers (Jiaojiao Zhou and Jing Lu) inde- pendently searched PubMed, Medline, EMBASE, Ovid, the Cochrane Library, and major nephrology journals from inception to January 28, 2015 without any limita- tion. To identify eligible RCTs comparing the effect of rHuEPO versus placebo on the prevention of DGF and 1Division of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan, China. 2Division of Nephrology, The Seventh People's Hospital of Chengdu, The Oncology Hospital of Chengdu, Cheng- du, Sichuan, China. *Correspondence:Address: Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, P.R.China Telephone and fax: 86 28 85423193. E-mail: doccai@163.com. Received June 2019 & Accepted December 2019 Urology Journal/Vol 17 No. 3/ May-June 2020/ pp. 217-223. [DOI: 10.22037/uj.v0i0.5399] slow graft function (SGF) after transplantation, we used the search terms “EPO” OR “epoetin” OR “erythropoi- etin” OR “rHuEPO” AND “renal transplantation” OR “kidney transplantation.” Reference lists of identified articles were searched for relevant studies and manually scanned to include additional eligible studies. We included studies that met the following criteria: (1) study population composed of adult patients (≥18 years of age) undergoing kidney transplantation; (2) rHuEPO was compared with placebo; (3) the primary outcomes were the incidence of DGF and SGF; (4) RCT study design. Only articles that met all inclusion criteria were included in this study. Definitions The classical definition of DGF as the need for dialysis within the first week after kidney transplantation was generally used, either totally unaltered or with minor additions. SGF was defined as a ≤40% decrease in se- rum creatinine at postoperative day 3. Short- and long- term estimated glomerular filtration rates (eGFRs) were considered as the values obtained 4 to 6 weeks and 6 months postoperatively, respectively. Short-term blood pressure was defined as the value obtained 4 to 6 weeks postoperatively. Data extraction and outcomes Data extraction was performed by two reviewers (Ji- aojiao Zhou and Jing Lu); the following items of were extracted: first author, publication year, baseline char- acteristics of patients, sample size, study design, inter- vention in the rHuEPO group, intervention in the con- trol group, the incidence of DGF and SGF, and adverse events related to rHuEPO. Additionally, extracted data were reexamined by a third reviewer (Diming Cai), and any disagreements were resolved by discussion. The primary outcomes were the incidence of DGF and SGF. Secondary outcomes were allograft function, adverse events related to rHuEPO, and mortality. Statistical Analysis Outcome data were analyzed quantitatively using RevMan software version 5.3 (Cochrane Collaboration, 2014, London, UK). Study quality was independently evaluated by two reviewers (Jiaojiao Zhou and Jing Lu) using a risk of bias summary graph. For categorical out- comes, risk ratios (RR) with 95% confidence intervals (CI) were estimated. For continuous outcomes, weight- ed mean differences (WMD) with 95% CI were calcu- lated. Cochran’s Q-test and Ι2 index were used to as- sess statistical heterogeneity. Fixed-effects analysis (I2 < 50%) and random-effects analysis (I2 > 50%) were used in the systematic review and meta-analysis accord- ing to standard protocol. For sensitivity analyses, we re- moved each study separately, calculating RR or WMD after each removal for related outcomes and examined whether any significant changes occurred. RESULTS Study Characteristics Of the 427 records identified, 404 were excluded af- ter initial screening: 43 were duplicate records and 361 studies were rejected based on the title and abstract. Of the remaining 23 full texts, 15 were excluded and 8 stud- ies were retrieved for detailed evaluation. Finally, six RCTs fulfilled the inclusion criteria and were included in our study.(14-19) A flow diagram of the systematic lit- erature search is presented in Figure 1, and the basic characteristics of the included RCTs are summarized in Table 1. In total, 435 patients were included; of these, 212 patients (48.7%) were treated with rHuEPO and 223 (51.3%) served as controls. Most included studies showed a low to moderate risk of bias; detailed find- ings are displayed in Table 2. Remarkably, the RCT of Martinez et al.(17) had a high risk of bias because it was an open-label study in which the control group did not receive EPO. Moreover, the method of allocation rHuEPO in Kidney transplantation-Zhou et al. Table 1. The basic characteristics of studies included in the meta-analysis. Author and year Country Study design rHuEPO group Control group Patients (EPO/CON) Follow-up time Martine,2010 France Open-label RCT EPO-β NA 51/53 3 months Aydin, 2012 Netherlands Double-blind RCT EPO-β Saline 45/47 12 months Hafer, 2012 Germany Double-blind RCT EPO-α Saline 44/44 12 months Sureshkumar, 2012 USA Double-blind RCT EPO-α Saline 36/36 1 month Nafar, 2012 Iran Double-blind RCT EPO-α NA 17/23 6 months Coupes, 2015 UK Double-blind RCT EPO-β Saline 19/20 3 months rHuEPO: recombinant human erythropoietin; EPO: erythropoietin; NA: not available; RCT: randomized controlled trial; CON:control. References Random Allocation Blinding of Blinding of outcome Selective Incomplete Other sequence generation Concealment participans and assessment reporting Outcome data personnel Martine, ? ? _ + + ? + 2010 Aydin, + ? + + + + ? 2012 Hafer, ? ? + ? + + + 2012 Sureshkumar， + ? + ? + ? ? 2012 Nafar, + ? + ? + + ? 2012 Coupes, + ? + ? + + + 2015 Table 2. The risk of bias summary graph. Symbol explanation: (+): low risk of bias, (?): unclear risk of bias, (_): high risk of bias. Review 218 Vol 17 No 03 May-June 2020 219 concealment was unclear in all studies.(14-19) Details of rHuEPO treatment, as well as demographic and clinical characteristics of recipients and donors, are shown in Tables 3 and 4, respectively. Allograft function The incidence of DGF and SGF, primary non-function (PNF), and eGFR values were recorded as the com- mon parameters of allograft function endpoints. As described in Figure 2A, a trend of reduced incidence of DGF was found in the rHuEPO group (rHuEPO vs. control groups: RR=0.89). However, this decrease did not reach statistical significance (five RCTs, 95% CI, 0.73 to 1.07; P = 0.22). There was also no statistically significant difference in the occurrence of SGF between the two groups (three RCTs, RR = 0.93, 95% CI, 0.60 to 1.43; P = 0.73). Statistical heterogeneity across studies was not significant (P = 0.57, I2 = 0%, Figure 2B). PNF rates were documented in three studies, and no signif- icant difference was detected between patients treated with rHuEPO and the control groups (Figure 2C). No significant difference was detected in the occurrence of graft loss between the two groups (Figure 2D). Short- term eGFR data are shown in Figure 3A; no significant difference was found between groups. On the contrary, a significant difference was seen in long-term eGFR between the rHuEPO and control groups (Figure 3B). Adverse events Based on 435 patients in 6 trials, thromboembolic events were observed in 21 (10%) of 212 patients in the rHuEPO groups and in 13 (5.8%) of 223 patients in the control groups. An efficacy meta-analysis indicated that, compared with control groups, rHuEPO groups did not show a significant increase in the risk of thrombo- embolic events (five RCTs, RR =1.64, 95% CI, 0.86 to Table 3. The detail and method of rHuEPO. Author Type Single rHuEPO dose Total rHuEPO dose No. of doses Method of rHuEPO Martine, 2010 EPO-β 30 000 IU 120 000 IU 4 0.5–3 h before KT 12–24 h after KT 7 days after KT 14 days after KT Aydin, 2012 EPO-β 33 000 IU 99 000 IU 3 3 h before KT 24 h after KT 48 h after KT Hafer, 2012 EPO-α 40 000 IU 120 000 IU 3 At intraoperation 3 days after KT 7 days after KT Sureshkumar,2012 EPO-α 40 000 IU 40 000 IU 1 At intraoperation Nafar, 2012 EPO-α 2000 U 6000 U 3 Thrice per week, 1 day after KT for one week Coupes, 2015 EPO-β 33 000 IU 99 000 IU 3 At intraoperation 24 h after KT 48 h after KT rHuEPO: recombinant human erythropoietin; EPO: erythropoietin; KT: kidney transplantation Study Martine Aydin Hafer Sureshkumar Nafar Coupes EPO/CON EPO/CON EPO/CON EPO/CON EPO/CON EPO/CON Age(years) 60.0 ± 7.7/58.9±9.5 51.0 ± 14.0 53.6 ± 1.8/49.8±1.6 58.0 ± 11.0/56.0 ± 13.0 45.4 ± 12.2/48.3 ± 15.5 51(43-63)/53(46-66) Gender(males %) 66.7%/56.6% 71.0%/70.0% 56.8%/59.1% 56.0%/53.0% 59.0%/52.0% 53.0%/65.0% BMI(Kg/m2) 25.1 ± 4.6/23.8 ± 4.1 NA 25.3 ± 0.6/25.9 ± 0.6 27.8 ± 5.4/28.3 ± 6.4 NA 25(23-27)/ 25(23-29) Cold ischemia 18.8 ± 4.9/19.9 ± 6.9 17.0 ± 4.0/17.0 ± 4.0 12.5 ± 0.6/13.4 ± 0.8 24.1 ± 6.1/26.3 ± 8.0 NA 16.9/16.8 time (hours) Donor age (years) 65.3 ± 9.4/65.1 ± 8.4 45.0 ± 13.0/49.0±17.0 NA 39.0 ± 17.0/41.0 ± 17.0 NA 52(45-58)/ 53(46-66) Donor death 64.7%/73.6% 44%/40% NA 19%/39% NA 74%/70% from CVA(%) Donor renal function 91.6 ± 39.5/92.3 ± 36.0 0.86 ± 0.58/0.93 ± 0.57 NA 1.14 ± 0.85/1.18 ± 0.90 NA 61(51-87)/ 77(66-96) (eGFR,ml/min) (sCr, mg/dl) (sCr, mg/dl) (μmol/L) Induction Basiliximab Daclizumab Basiliximab Basiliximab or NA Basiliximab Immunosuppr-ession alemtuzumab or ATG Maintenance Immunosuppr-ession Tacrolimus, Cyclosporine, Tacrolimus or Tacrolimus or Cyclosporine Tacrolimus, MMF, prednisone MMF, steroids cyclosporine, cyclosporine, MMF, prednisone MMF, MMF, prednisone MMF, steroids prednisolone Recipient Previous 48%/50% 4.3 ± 1.7 /4.0 ± 1.9 88.4 ± 5.1/67.6 ± 4.9 NA NA 30(6-51)/42(22-52) dialysis (%) (years) (month) (month) EPO: erythropoietin; CON:control; BMI: body mass index; NA: not available; CVA: cerebral vascular accident; MMF: mycophenolate mofetil; eGFR: estimated glomerular filtration rate; sCr: serum creatinine ; ATG: antithymocyte globulin. Data are presented as percent- ages or mean±standard deviation or median (IQR). Table 4. The demographic and clinical characteristics of recipients and donors. rHuEPO in Kidney transplantation-Zhou et al. 3.13; P = 0.13) with negligible statistical heterogeneity (I2 = 41%, Figure 4A). Four studies showed no statis- tically significant difference in the occurrence of acute rejection between the two groups (Figure 4B). Further- more, the incidence of blood transfusion was similar in the two groups (Figure 4C). Mortality was documented in all studies; Sureshkumar et al.(14) and Nafar et al.(18) reported no deaths in their studies (Figure 4D). Blood pressure was assessed at different timepoints in each study. In the studies by Sureshkumar et al. 14) and Martinez et al.(17) blood pressure was reported at 4 weeks after transplantation, while Aydin et al. recorded blood pressure 6 weeks postoperatively.(15) We defined blood pressure recorded 4 to 6 weeks postoperatively as short-term blood pressure. No significant difference was found in short-term systolic blood pressure (SBP) and diastolic blood pressure (DBP, P > 0.05, Figure 3C, 3D). DISCUSSION Our findings of this individual patient data systemat- ic review and meta-analysis show that rHuEPO has a certain nephroprotective effect in patients with kidney transplantation without increasing the susceptibility Figure 1. Flow diagram of systematic literature search Figure 3. Forest plot of the effects of rHuEPO on short-time eGFR (A), long-time eGFR (B), short-time SBP (C), and short-time DBP (D) in patients treated with rHuEPO compared with controls. Figure 2. Forest plot with 95% confidence interval in DGF (A), SGF (B), PNF (C), and graft loss (D) in patients treated with rHuE- PO compared with controls. Figure 4. Forest plot with 95% confidence interval in thrombo- embolic events (A), acute rejection (B), blood transfusion (C), and mortality (D) in patients treated with rHuEPO compared with controls. A B C D A D C B rHuEPO in Kidney transplantation-Zhou et al. Review 220 Vol 17 No 03 May-June 2020 221 to adverse events. A recent large clinical study with a total of 3716 kidney transplantations with a long-term follow-up of 25-30 years showed that the outcomes of living unrelated and related donors were compara- ble in terms of patient and graft survival.(20) Therefore, transplants from living unrelated donors might be an acceptable management alternative for patients with end-stage renal disease. Recent trials and meta-analy- ses have raised concerns about the safety of rHuEPO use in patients with renal failure, malignancies, chronic heart failure, and acute ST-segment elevation myocar- dial infarction, but also in kidney transplantation.(21-23) Although Vlachopanos et al.(24) and Xin et al.(25) have conducted meta-analyses examining the clinical effica- cy and safety of high-dose rHuEPO in kidney transplant recipients including four RCTs, we included additional studies, one of which was recently published.(18,19) The six RCTs were of relatively high quality and included samples from Europe, America, Oceania, and Asia. Except for the study by Martinez et al., which was an open-label study, there was a low risk of bias since the other studies were double-blind RCTs.(17) Although Na- far et al.(18) used lower rHuEPO doses than other stud- ies, the impact of rHuEPO administration on DGF was not examined. The use of low-dose rHuEPO was also evaluated as part of the endpoints. Since their results may be different or explained from a new perspective, their study was also included. There were various differences in dosage and timing administration between the studies, which warrant cau- tion when interpreting the results. The doses of rHuE- PO used in the included studies ranged from 2000 to 40,000 IU of singe doses and 6000 to 120,000 IU of total dosage. Single doses of 30,000 to 40,000 IU were used in most RCTs, which was considered enough to confer a routine nephroprotective effect and to increase hypertension and thromboembolic events. We consid- ered that this rHuEPO dosage was the smallest dose administered in experimental studies for safety reasons. (18) The timing of rHuEPO dosing also varied considera- bly among the included studies. Some patients received the first dose of rHuEPO every 3 h or thrice per week, while others received the first dose during surgery. Af- ter successful transplantation, the timing of administra- tion ranged from 12 h to 14 days. Previous data have suggested that nephroprotective drugs should be admin- istered from at least 30 min before ischemia until 6 h after ischemia. However, the included RCTs continued rHuEPO administration until postoperative day 14.(17) We conducted a systematic review and meta-analysis of RCTs evaluating early and rHuEPO administration for DGF as the primary endpoint. This review (Figure 2A) including data from five trials yielded an overall estimate of the RR for DGF of 0.89, a modest effect in favor of rHuEPO, but not demonstrating a signifi- cant difference between rHuEPO and control groups. The result was very close to previous studies including four RCTs.(24, 25) In the latest RCT by Coupes et al.(19) DGF was higher than that reported in three previous studies (10/19 = 52.6% and 11/20 = 55.0% in rHuEPO and control groups, respectively), but lower than that reported in the study by Aydin et al.(15) We also found that the occurrence of SGF was not significantly differ- ent between the two groups. Including two more RCTs and performing a meta-analysis did not did not lead to different results regarding DGF, PNF, and graft loss compared to previous reviews.(24,25) However, it was encouraging that long-term eGFR, which was not in- cluded in previous meta-analyses, was improved in the rHuEPO group compared with the control group.(24,25) This finding indicates that high-dose rHuEPO could im- prove eGFR 6 months after transplantation. Sureshkumar et al.(14) and Coupes et al.(19) measured two novel biomarkers, neutrophil gelatinase-associated lipocalin and IL-6, which have been demonstrated to identify patients at risk of developing IRI-AKI earlier. However, they found similar levels between rHuE- PO-treated patients and controls. Three of the stud- ies(14,15,19) showed no significant differences between groups, while two(16,17) found higher hemoglobin levels in rHuEPO-treated patients. As for adverse events, we mainly included thromboem- bolic events, which are common in patients receiving rHuEPO. After pooling data from six RCTs, we demon- strated that high-dose rHuEPO could increase the in- cidence of thromboembolic events. Seizures were only noted in one patient treated with rHuEPO in Coupes et al.(19) In the meta-analysis by Vlachopanos et al., SBP was significantly higher in rHuEPO-treated patients at 4 weeks after kidney transplantation.(24) Nevertheless, short-term SBP and DBP were significantly different in rHuEPO-treated patients in our analysis. On the con- trary, rHuEPO did not affect mortality, acute rejection, and the incidence of blood transfusion. Some potential limitations should be considered. First, only six RCTs with a total of 435 patients were includ- ed. An incorrect estimation of the effect of rHuEPO is more likely to occur in smaller trials. Second, the tim- ing of administration and type of rHuEPO varied across the six RCTs. Based on the existing literature, selection models centered on heterogeneity testing have some limitations. However, the analysis of binary data using fixed-effect models uses large sample asymptotic var- iances, so it may perform poorly for studies with very low or very high event rates or small sample sizes. On the other hand, in random-effect models, the weight dis- tribution mainly depends on its accuracy. The weight of each study is equal to the reciprocal of variance (W=1/V). Therefore, the contribution of studies with large samples to the total merged effect is larger than that of studies with small samples, which makes the findings from small sample studies easier to overlook, resulting in them having less weight allocated to them. CONCLUSIONS In summary, although there was a trend in favor of rHuEPO in all studies, it failed to reach statistical sig- nificance regarding allograft function; however, long- term eGFR was improved. The clinical safety of high- dose rHuEPO was explored in patients with kidney transplantation. Primary adverse events occurring dur- ing the transplantation procedure and follow-up period, including thromboembolic events, acute rejection, sei- zures, and mortality, were distributed equally between the rHuEPO and control groups. To verify the clinical relevance of rHuEPO administration, additional larger, prospective studies of patients undergoing kidney trans- plantation with uniform rHuEPO administration meth- ods and long follow-up periods are needed. rHuEPO in Kidney transplantation-Zhou et al. ACKNOWLEDGMENTS This study was supported by grants from the Sichuan Provincial Science and Technology Key R & D Projects [No.2019YFS0282 and 2017SZ0113]. REFERENCES 1. Brines M, Cerami A. Discovering erythropoietin’s extrahematopoietic functions: biology and clinical promise. Kidney Int. 2006; 70: 246-50. 2. Lappin TR, Maxwell AP, Johnston PG. EPO’s alter ego: erythropoietin has multiple actions. Stem Cells. 2002; 20: 485-92. 3. Goldman SA, Nedergaard M. 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