Effect of High-Dose Erythropoietin on Graft Function after Kidney Transplantation

Abstract

SummaryBackground and objectives Delayed graft function (DGF) is associated with adverse long-term outcomes after deceased-donor kidney (DDK) transplantation. Ischemia-reperfusion injury plays a crucial role in the development of DGF. On the basis of promising animal data, this study evaluated any potential benefits of erythropoietin-alfa (EPO-a) given intra-arterially at the time of reperfusion of renal allograft on the degree of allograft function, as well as tubular cell injury measured by urinary biomarkers in the early post-transplant period.Design, setting, participants, & measurements A prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the influence of EPO-a administered intraoperatively on the outcomes of DDK transplantations performed at the study center between March 2007 and July 2009.Results Seventy-two patients were randomly assigned to EPO-a (n=36) or placebo (n=36). The incidences of DGF, slow graft function, and immediate graft function did not significantly differ between the treatment and control groups (41.7% versus 47.2%, 25.0% versus 36.1%, and 33.3% versus 16.7%, respectively; P=0.24). The groups had similar levels of urinary biomarkers, including neutrophil gelatinase-associated lipocalin and IL-18 at multiple times points soon after transplantation; urinary output during the first 3 postoperative days; 1-month renal function; and BP readings, hemoglobin, and adverse effects during the first month.Conclusions This study did not show any clinically demonstrable beneficial effects of high-dose EPO-a given intra-arterially during the early reperfusion phase in DDK transplant recipients in terms of reducing the incidence of DGF or improving short-term allograft function.

Erythropoiesis stimulating agents and reno-protection: a meta-analysis

“…The randomization allocation sequence was generated by a random-number tableLow risk: patients, physicians, data managers and investigators were kept blinded throughout the studyLow risk: data managers and investigators were kept blinded throughout the studyLow risk: No dropoutsLow risk: No dropoutsLow risk: No dropoutsCoupes 2015 [30]Transplant: DB, SSLow risk: patients were randomly assigned by the trial pharmacy by computerLow risk: all study participants and the study team were blinded to the trial drugUnclear riskLow risk: 1 patient withdrew but was included in the analysisLow risk: lost patients reportedLow riskHafer 2012 [32]Transplant: DB, SSUnclear risk: randomization methodology not disclosedLow risk: vials containing ESA and placebo had identical appearanceUnclear riskLow risk for DGF. High risk for graft loss (3 patients died 1 in ESA group and 2 in placebo group)Low risk: lost patients reportedHigh risk: 2 untreated patients (not included in analysis) and 3 patients diedMartinez 2010 [33]Transplant: OL, MCUnclear risk: randomization method not disclosedHigh risk: comparator arm was untreatedLow risk: Blinded evaluation of end-pointsUnclear risk: 1 died in ESA groupLow risk: lost patients reportedLow riskSureshkumar 2012 [34]Transplant: DB, SSLow risk: the hospital pharmacy created a schedule using random assignments to a series of patient study numbersLow risk: ESA and placebo were both 1 ml syringes. The medications were administered in a double-blinded mannerUnclear riskLow riskLow risk: no dropoutsLow riskVan Biesen 2005 [35]Transplant: OL, SSUnclear risk: randomization method not disclosedHigh risk: open labelHigh riskUnclear riskHigh riskUnclear riskVan Loo 1996 [36]Transplant: OL, SSUnclear risk: randomization method not disclosedHigh risk: open labelHigh riskLow risk: no deaths or withdrawalsLow risk: no deaths or withdrawalLow risk: no deaths or withdrawalsAbraham 1990 [38]Anemia correction: DB then OL, Anemia correction: SSUnclear risk: randomization method not disclosedUnclear risk: unspecifiedHigh riskLow risk: no dropoutsLow risk: no dropoutsLow riskClyne 1992 [39]Anemia correction: OL, 2 centerUnclear riskHigh riskHigh...…”

“…No difference in sCr at any time point. No difference in eGFR at 1 or 3 monthsSureshkumar 2012 [34]Pennsylvania (USA) (Allegheny General Hospital, Pittsburgh, Pennsylvania)Epoetin α (100,000 U (iv); Procrit) intraarterially immediately after reperfusionMatched placebo (not disclosed) N  = 72: ESA (36), control (36)The need for dialysis within the first wk of transplantationNo difference in Hb, sCr, eGFR or urinary biomarkers of AKI (NGAL or IL-18)Van Biesen 2005 [35]Belgium (University Hospital Ghent)Epoetin β (100/IU/kg; Recormon) immediately after transplantation then thrice weekly to maintain Hb above 12 g/dLNo ESA N  = 26: ESA (14), control (12)Not definedShorter time to target Hb in ESA arm. No difference in transfusions or sCr at 3 monthsVan Loo 1996 [36]Belgium (University Hospital, Gent, Belgium)Epoetin β (within 1 week post transplant).…”

“…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-18) (1 trial) [34]. …”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…Due to their close contact with blood flow, endothelial cells are an easy-to-reach therapeutic target during organ preservation. Different possibilities for controlling ischemia-reperfusion injury and the rate of delayed graft function by targeting immune components, coagulation effectors or genes involved in cell survival are currently being tested in clinical trials on adult kidney transplantation (summarized in Table 3) [74][75][76]. Similarly, our laboratory has obtained promising results from an ongoing investigation into blockade of the C1 component of the complement in our porcine model.…”

Kidney Ischemia and Reperfusion Injury – Field of Glory or Warterloo for Erythropoietin?

“…18 Results that were also seen in other studies dealing with high-dose EPO in renal transplantation. 19,20 Another interesting field of clinical use would be the protection of renal organ function after cardiac surgery. Two studies examined EPO effects in this setting.…”