Erythropoietin Supplementation in Patients with Refractory Anemia and Mild Renal Insufficiency - MDS Meets Renal Anemia.

Introduction Even mild renal dysfunction (e.g. creatinine 100 to 140 μmol/l) can be related to inadequate erythropoietin (EPO) response in patients with refractory anemia and bone marrow features compatible with dysplasia (Korte, Cogliatti et al. 2000). Overall, this seems not an infrequent mechanism (Fehr, Ammann et al. 2004) Therefore, patients with MDS bone marrow morphology and secondary bone marrow dysfunction due to EPO deficiency may be diagnosed as having a myelodysplatic syndrome (refracory anemia [RA] or even refractory anemia with ringed sideroblasts [RARS]).

Patients and Methods We performed a single center, prospective, non-randomized pilot study to evaluate the potential benefit of EPO therapy in patients with refractory anemia, mild renal insufficiency and low EPO levels.

Eligibility criteria were: hemoglobin (hb) concentrations <110g/l, bone marrow features of RA or RARS (according to FAB classification) normal levels of folate, cobalamin, ferritin, TSH and C-reactive protein, mild renal insufficiency (creatinine of 100 to 180 μmol/l) and EPO < 60 U/ml.

Exclusion criteria were: active solid malignant tumors, evidence of chronic inflammatory disease, evidence of hemoglobinopathies or haemolytic anemia. Patients received EPO (epoetin beta, Recormon®) for 6 weeks with the aim to increase the hb concentrations to a steady state level of 120g/l. Epo was started at a fixed dose of 150 U/kg subcutaneously three times per week (tiw) and as soon as an improvement in hemoglobin was seen, the dose was reduced as needed to keep the hemoglobin at 120 g/l. With the targetd hb increase of 10 g/l, an estimated standard deviation of 5 g/l and alpha = 0.05 (power 80%), a statistically significant differences were expected with 4 patients treated.

Results 5 patients were included in the study. One had a transient renal insufficiency, with excretory renal function normalizing during the study period, whereas the other four patients had persisting mild renal insufficiency. The patients received 150 U/kg tiw of epoetin beta for the first 4 weeks and all reached the target hb of 120g/l after this time (increase significant, p<0.05). Patents showed significantly (p<0.05) increasing levels of soluble transferrin receptor (sTFR) under EPO therapy.

Discussion Our data indicate an excellent response to epoetin beta in patients with signs of myelodysplasia and mild renal insufficiency. The response rate (5/5, 100%) was much higher than described in other low risk MDS patients. Increasing levels of soluble sTfR reflect the improved erythropoietic activity and erythroid maturation. From these results, it can be speculated that anemia in low grade MDS with (even mild) renal insufficiency might in fact include aspects of renal anemia. EPO therapy seems an excellent treatment opportunity in anemic patients with marrow MDS morphology, renal dysfunction and low EPO levels. However, this observation and the question whether at least some of this myelodysplasias are direct consequences of inadequate erythropoietin levels warrant larger studies.