THE EFFECT OF DIFFERENT IMMUNOSUPPRESSION THERAPY ON ERYTHROPOIETIN PRODUCTION IN RENAL TRANSPLANTATION

Abstract

51 Anemia in chronic renal failure is due to erythropoietin (Epo) deficiency that is expected to normalize after successful kidney transplantation. We previously studied 40 children with excellent graft function for 12 months post kidney transplantation and found a mean hematocrit (Hct) -2 SD from the mean for age and sex. Human hepatoma (Hep3B) cells were chosen as a model to study the effect of immunosuppression therapy on Epo production. Cyclosporine(CSA), Azathioprine (AZA), FK506, and Mycophenolate Mofetil (MPM), under 21% O2 and 1% O2 (hypoxic) conditions were tested. Epo levels were measured in mU/mg protein ± SEM and compared to baseline conditions. Both CSA(10µg/mL) and AZA (40µg/mL) inhibited Epo production under 21% O2, (p<.03, p<.002) and hypoxic conditions (p<.02, p<.05) respectively. Increased concentration of CSA and AZA (100µg/mL) resulted in greater inhibition. FK506 (.0001 -1 µM) and MPM(.01-10µM) did not inhibit Epo production. CSA added to high dose AZA or MPM depressed Epo production further than either agents alone in 21% O2(p<.002 and p<.007) and 1% O2 (p<.004 and p<.0001). We then measured Hct %, plasma Epo, and ferritin, in 4 pediatric renal transplant recipients, ages 4-8 years, 3 were on CSA and one on FK506 at 1, 2, 3, 6, 9 months post transplantation. Simultaneous blood trough levels for CSA were done (whole blood TDx), and for FK506 (whole blood MEIA). No acute rejection episodes or blood transfusions occurred in any patient. Mean Hct% for all patients pre transplant, and then at 1, 3, 6, 9 months post transplantation were 36%, 33%, 38%, 37%, and 38%. All patients had adequate ferritin levels (range of 30-167 ng/ml) in the first 6 months post transplantation. Mean serum creatinine at 6 months was 0.65±2 mg/dl. Epo levels were compared to each Hct value according to a Reference Regression Graph. An inverse linear relationship between log Epo levels and Hct (R2 = 0.341, p=.0002) was found that was less steep than for healthy adults, and similar to patients with renal failure. No correlation was found between CSA or FK506 levels and Hct. Conclusion: CSA and AZA suppress in-vitro Epo production while FK506 and MPM appear to have no effect. The Epo levels produced after transplantation is inappropriately low compared to Hct. We speculate that the mild anemia in children post renal transplantation is due to inhibition of renal interstitial Epo production related to immunosuppression therapy, specifically CSA. The effect of FK506 and MFM on Epo production in-vivo needs further study.