Erythropoietin Safety and Efficacy in Chronic Allograft Nephropathy

Erythropoietin Safety and Efficacy in Chronic Allograft Nephropathy J. Baltar, N. Moran, F. Ortega, T. Ortega, P. Rebollo, F. Cofan, and J.M. Campistol ABSTRACT Background. Patients with chronic allograft nephropathy (CAN) very frequently suffer anemia. Correction of anemia by means of recombinant erythropoietin (rEpo) is possible and useful, but safety and efficacy must be assessed. Methods. This multicenter, prospective, open study included patients with a cadaver renal transplant, CAN, and non-ferropenic anemia. The aim of the study was to determine the safety and efficacy of treatment with rEpo to target hematocrit (HCT) values around 35% and/or hemoglobin (Hb) levels of 11 g/dL. Results. Twenty-four patients were included: 71% males and 29% females aged 49.5 ⫾ 14 years. At last follow-up, 48% did not show anemia-related symptoms, and 19% experienced adverse events possibly or probably related to rEpo. In 86% of cases, anemia was corrected and in 71%, graft survival was conserved. Patients whose anemia was not corrected had poor initial renal function (sCr 5 ⫾ 1 mg/dL vs sCr 3.2 ⫾ 1 mg/dL, P ⫽ .028). Patients with graft survival showed correction of anemia (P ⫽ .001) on a relatively low dose of rEpo and without a significant increase in blood pressure. Conclusions. All patients who had graft survival and only half of those who lost their graft showed a correction of anemia. The rEpo treatment neither accelerated nor decelerated renal failure. The difference between patients in whom anemia was corrected, or not, did not depend upon the previous level of HCT/Hb, but upon worse renal function. Thus, rEpo in patients with CAN is safe and effective, so administration should be initiated early to avoid adverse events deriving from anemia.

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ATIENTS with chronic allograft nephropathy (CAN) frequently suffer from anemia. Posttransplant anemia is caused by an erthropoietin (Epo) deficit or resistance to recombinant Epo (rEpo), which is related to graft dysfunction, immunosuppression (azathioprine, mycophenolic acid, sirolimus), angiotensin-converting enzyme and angiotensin II-receptor blocker inhibition, iron deficit, lymphoproliferative disorder, or other neoplasias, CMV and parvovirus B19 infections, recurrent or de novo uremic hemolytic syndrome following cyclosporine CyA, tacrolimus, sirolimus, OKT3 or influenza virus, or ABO incompatibility.1 Tissue hypoxia due to anemia stimulates the synthesis of proteins of the extracellular matrix, promoting the liberation of proinflammatory molecules that cause interstitial fibrosis and progressive renal failure.2 Correction of anemia with rEpo increases the liberation of oxygen, thus reducing hypoxia and tubular damage.3 The aim of this study was to determine the safety and efficacy of rEpo treatment to target hematocrit (HCT) around 35% and/or hemoglobin (Hb) levels at 11 mg/dL.

METHODS This multicenter, prospective, and open study included patients with a cadaveric renal transplant, chronic renal insufficiency (CRI), defined by a glomerular filtration rate ⬍25 mL/min 1.70 m2 of body surface or serum creatinine (sCr) ⬎2 mg/dL and anemia (HCT ⱕ30% or Hb ⬍10 g/dL), non-ferropenic (ferritin ⬎100 ␮g/L and a transferrin saturation index ⬎20%). A single weekly dose of 2000 IU of rEpo was administered subcutaneously, increasing the dosage 2000 IU every 4 weeks to target HCT or/and Hb up to a maximum dose of 12,000 IU/week. Informed consent was obtained. We excluded patients with uncontrolled hypertension, epilepsy, thrombocytosis, folic acid and vitamin B12 deficiency, serious coagulation difficulties, known hypersensitivity to rEpo, pregnancy From Hospital Universitario Central de Asturias and Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. Address reprint requests to José Marı´a Baltar Martin, Hospital Universitario Central de Asturias, Instituto Reina Sofı´a de Investigación Nefrológica, C/Celestino Villamil s/n, 33006 – Oviedo Spain. E-mail: [email protected]

© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.020

Transplantation Proceedings, 39, 2245–2247 (2007)

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BALTAR, MORAN, ORTEGA ET AL Table 1. Data Corresponding to the Studied Variables at the Beginning (Basal) and at the End of the Study All Patients (n ⫽ 21)

Persistent Anemia (n ⫽ 3)

Mean (SD)

Basal

End

P

Basal

HTC (%) Hb (g/dL) crC GRF* sCr SBP (mm Hg) DBP (mm Hg) rEpo dose† rEpo dose‡

28.5 (2.4) 9.2 (0.8) 28.1 (10) 27.2 (10.8) 3.4 (1.1) 140 (17) 78 (12) 3059 (1886) 46.5 (30)

34.5 (4.3) 10.9 (1.4) 20.1 (10.4) 20.9 (11.1) 4.9 (2.3) 143 (21) 83 (9) 4588 (3392) 65 (48)

⬍.001 ⬍.001 .001 ⬍.001 .004 .476 .081 .029 .102

End

Anemia Correction (n ⫽ 18) P

Basal

End

P

28.7 (2.5) 9.2 (0.8) 30.1 (8.7) 28 (10.5) 3.2 (1) 138 (17) 78 (12) 2714 (1490) 42 (25)

35.1 (4.3) 11.2 (1.3) 21.3 (10.5) 21.4 (11.2) 4.7 (2.4) 138 (15) 82 (8) 3857 (2905) 58 (42)

.000 ⬍.001 .001 ⬍.001 .009 .991 .119 .139 .165

27.5 (1.7) 8.8 (1) 13.1 (4.4)

31 (3) 9.6 (1) 11.2 (2.6)

.174 .316 .364

5 (1) 151 (1.4) 79 (1.4) 4667 (3055)

6.4 (0.01) 187 (3.5) 87 (18) 8000 (4000)

.295 .026 .642 .033

SD, standard deviation; HTC, hematocrit; Hb, hemoglobin; TSI, transferrin saturation index; iPTHi, intact parathyroid hormone; GFR, glomerular filtration rate; crC, creatinine clearance; sCr, serum creatinine; SBP, systolic blood pressure; DBP, diastolic blood pressure; rEpo, recombinant erythropoietin. Patients’ data are shown according to whether or not their anemia was corrected (student t test). *Cockroft-Gault. † IU/week. ‡ IU/kg/week.

and lactation, artificial vascular access, tumors, alcoholism, active use of illegal drugs, risk of deep vein thrombosis or venous thrombo-embolic disease, as well as prior myocardial infarction, stroke or unstable angina, or chronic hepatic insufficiency.

RESULTS

The twenty-four included patients were 71% males and 29% females of mean age 49 ⫾ 14 years. At last follow-up, 48% did not show anemia-related symptoms, 19% experienced adverse events probably related to rEpo, 86% had corrected anemia, and 71% had conserved graft survival. Table 1 shows the patient data according to whether the anemia was corrected. Patients whose anemia was not corrected had poor initial renal function (sCr 5 ⫾ 1 mg/dL vs sCr 3.2 ⫾ 1 mg/dL, P ⫽ .028). Patients with graft survival showed corrected anemia (P ⫽ .001) on a relatively low dose of rEpo without a significant increase in blood pressure (BP). Table 2 reflects the characteristics of patients depending on their entry into dialysis. The renal function expressed by the slope of inverse creatinine (Cri) in patients before the study did not vary with the initiation of rEpo.

DISCUSSION

All patients who had a functioning allograft on completion of follow-up showed anemia correction, whereas this was the case in only half of those who lost their grafts. The HCT/Hb target was achieved with relatively low doses of rEpo with hardly any variation in BP, which, indeed, changed little throughout the study. Deterioration in kidney function was seen for patients with stage 4 CRI.4 Renal function expressed by Cri before the study did not vary after initiation of treatment with rEpo, which seemed to show that the administration of rEpo neither accelerates nor decelerates renal function deterioration. Administration of rEpo to these patients was effective. Thus, with regard to correction of anemia, it was observed that anemia was corrected in 86% patients in approximately 4 months. Administration of rEpo to these patients proved safe. At the end of the study, 48% of patients did not present symptoms related to anemia. The difference between patients in whom anemia was or was not corrected lay not in the previously existing level of HCT/Hb, but in worse previous renal function. Patients who started dialysis had

Table 2. Characteristics of Patients Depending on Their Entry or Not in Dialysis (Student t test) Renal Allograft Function (n ⫽ 15)

Return to Dialysis (n ⫽ 6)

Mean (SD)

Basal

End

P

Basal

End

P

Hematocrit (%) Hemoglobin (g/dL) crC (mL/min) GFR (Cockroft-Gault) sCr (mg/dL) SBP (mm Hg) DBP (mm Hg) rEpo dose (IU/week) rEpo dose (IU/kg/week)

28.8 (2.5) 9.2 (0.8) 31 (9) 30 (10.6) 3.0 (1.0) 136 (19) 76 (13) 2769 (1536) 43 (25.7)

35.9 (4.3) 11 (1.3) 23 (9.6) 24 (10.8) 3.9 (1.2) 138 (16) 81 (8.5) 3385 (2399) 51.7 (35.5)

.000 .000 .008 .003 .011 .836 .147 .275 .337

28.0 (2.3) 9.1 (1) 19 (7.6) 18 (4.7) 4.5 (0.9) 148 (5) 84 (6) 4000 (2828) 69.4 (58.9)

31.2 (2.1) 9.9 (0.9) 9.5 (2.9) 11 (3) 7.5 (2.7) 159 (26) 88 (9) 8500 (3416) 151.9 (11.4)

.034 .053 .120 .133 .078 .364 .400 .037 .246

HCT, hematocrit; Hb, hemoglobin; crC, creatinine clearance; GFR, glomerular filtration rate; sCr, serum creatinine; SBP, systolic blood pressure; DBP, diastolic blood pressure; rEpo, recombinant erythropoietin.

ERYTHROPOIETIN SAFETY AND EFFICACY

worse initial renal function, and anemia was corrected in only 50% of patients. These patients showed a poorer response to rEpo, perhaps the result of resistance to Epo due to the presence of a hardly functioning allograft, causing a chronic inflammatory response.5 It might be advisable not to delay the return to dialysis in this subgroup of patients showing advanced CRI. Perhaps they should go on dialysis slightly earlier than nontransplanted patients. Given the effectiveness and safety of rEpo in patients with CAN, its administration should be initiated at an early stage to avoid the undesirable consequences from anemia. This course of action may make the use of rEpo more efficient in CAN. However, there is some recent evidence that high levels of Hb achieved using rEpo can be deleterious.6 ACKNOWLEDGMENTS The authors thank Roche Pharmaceuticals for its support.

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REFERENCES 1. European Best Practice Guidelines II Working Group: Revised European best practice guidelines for the management of anemia in patients with chronic renal failure. Nephrol Dial Transplant 19(suppl 2):111, 2004 2. Rossert J, Fouqueray B, Boffa JJ: Anemia management and the delay of chronic renal failure progression. J Am Soc Nephrol 14(suppl 2):S173, 2003 3. Choukroun G, Martinez F: Benefits of erythropoietin in renal transplantation. Transplantation 79(suppl 3):S49, 2005 4. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39(suppl 1):S1, 2002 5. Lopez-Gomez JM, Perez-Flores I, Jofre R, et al: Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 15:2494, 2004 6. Phrommintikul A, Haas SJ, Maros E, et al: Mortality and target hemoglobin concentrations in anemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 369:381, 2007