Anemia is a major problem in patients with end-stage renal failure because of defective production of erythropoietin (EPO) by the diseased kidneys (1). Renal anemia can be corrected by the administration of recombinant EPO (RhuEPO).
In the immediate posttransplantation period, a severe and persistent anemia might occur because of blood losses during surgery, inflammatory status, and defective EPO production by the transplanted kidney. Anemia in the immediate postsurgery period might lead to inadequate tissue perfusion and cellular hypoxia, which might be a risk factor in patients with atheromatosis in a stressful situation (2). Therefore, a fast correction of anemia might be useful. In addition, RhuEPO has been linked in animal models to a faster correction of ischemic acute tubular necrosis (3). This raises the possibility that RhuEPO may positively influence renal recovery after transplantation.
The present study evaluates in a randomized way the impact of subcutaneous RhuEPO on the speed of correction of posttransplantation anemia and of kidney function in the first 3 months after renal transplantation.
Patients receiving a renal transplant at the University Hospital Ghent were randomized to receive or not receive 100 U/kg RhuEPO (Recormon, Hoffman-La Roche, Basel, Switzerland) subcutaneously three times per week (EPO and non-EPO groups, respectively). As long as the hemoglobin (Hb) level was less than 12 g/dL, the dose was increased with 20 U/kg on a weekly basis. If the Hb level was more than 12.5 g/dL, the RhuEPO was discontinued.
The immunosuppressive regimen consisted of methylprednisolone 0.5 mg/kg per day, tapered over 2 months to 8 mg/day, azathioprine 1.5 mg/kg, and antithymocyte globulin (ATG Fresenius). Cyclosporine A was only started when serum creatinine decreased 50% below the pretransplant value.
All statistical analyses were performed with SPSS11.1 for Windows (SPSS Inc., Chicago, IL). Continuous variables were compared using the Student t test; when multiple time points were compared, one-way analysis of variance and post hoc testing with Scheffé were used. The time to reach an Hb level greater than 12.5 g/dL between the EPO and non-EPO groups was compared using the log-rank for univariate analysis and Cox regression to correct for confounding factors.
The baseline characteristics of the enrolled patients are shown in Table 1.
In the EPO and non-EPO groups, 14 and 12 patients, respectively, demonstrated Hb levels greater than 12.5 g/dL (P=not significant [NS]). The time to reach this goal was slightly shorter in the EPO group compared with the non-EPO group (52.6±23.7 days vs. 66.5±14.5 days, respectively, P=0.05). Six patients received a transfusion of 1 unit of packed cells because the Hb level was less than 8 g/dL (two in the EPO group and four in the non-EPO group) (P=NS).
The evolution of Hb levels in both groups over time is shown in Figure 1. Hb levels at day 15 and after 3 months were not different between the groups. However, Hb was lower in the EPO group (8.4±1.1 g/dL vs. 9.2±1.1 g/dL, P=0.02) the first day after transplantation, resulting in a more significant increase in Hb in the EPO group (4.1±1.1 g/dL vs. 3.2±1.1 g/dL, P=0.02).
There was no difference in serum creatinine values in the two groups at any of the time points. Two patients demonstrated delayed graft function in both the EPO and non-EPO groups.
Univariate analysis of risk factors favoring non-achievement of an Hb level greater than 12.5 g/dL is shown in Table 2. Only serum creatinine at 3 months was significantly different: It was higher in those patients who did not demonstrate an Hb level greater than 12.5 g/dL (1.5±0.3 g/dL vs. 1.3±0.3 g/dL, P=0.02). Fourteen of the patients with an Hb level greater than 12.5 g/dL received EPO versus eight patients whose Hb levels were not greater than 12.5 g/dL (P=NS).
In a Cox regression analysis, EPO use (relative risk [RR] 10.5, P=0.009), EPO dose (RR=0.63, P=0.04), and the need for a transfusion (RR=0.1, P=0.03) were retained as independent variables predicting the time to reach an Hb level greater than 12.5 g/dL.
The total administered EPO dose was 112,250±66,900 units per patient (minimal: 57,000 units, maximal 258,000 units).
This study evaluated the usefulness of RhuEPO in the period immediately after renal transplantation.
Administration of RhuEPO in the immediate posttransplantation period reduces the time before a serum Hb level of 12.5 g/dL is reached in patients, but this effect was marginal, and the doses needed were high. There was no difference observed in adverse events between the two groups.
In animal models, RhuEPO has been linked to a faster recovery of acute tubular necrosis (3). In this study, no evidence of a better renal function of the transplanted kidney was observed in terms of frequency of delayed graft function or evolution of serum creatinine. However, the frequency of delayed graft function was low in this study, probably because of the short cold ischemia times and high prevalence of patients who had peritoneal dialysis as the pretransplantation dialysis modality, both of which are protective factors for the development of delayed graft function (4).
RhuEPO is an expensive drug, and the doses used in this study were high, with a mean of 100,000 units per patient administered over the 3-month period.
Thus, although the use of RhuEPO in the immediate posttransplantation period was safe and effective in decreasing the time that patients remain anemic after transplantation, its general recommendation is hampered by the limited effect and high cost.
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