Uremic Inhibitors of Erythropoiesis: A Study during Treatment with Recombinant Human Erythropoietin

Abstract

The effects of increasing amounts of uremic sera (US) on the growth of erythroid progenitor cells [burst-forming unit erythroid (BFU-E)] collected from peripheral blood of normal subjects were evaluated to assess the potential role of uremic inhibitors of erythropoiesis during a treatment with recombinant human erythropoietin (r-HuEpo). US were collected from 8 patients on regular dialysis with marked anemia (Hb 6 ± 0.5 g%) before and after a treatment with high doses of r-HuEpo (from 300 to 525 U/kg/week). Standard cultures for BFU-E were performed in a-metylcellulose with fetal calf serum (FCS) and 4 U/ml of r-HuEpo (Cilag, Ortho). In successive cultures, US were added at increasing amounts to the standard culture in order to assess a possible inhibitory effect on BFU-E growth. Finally, in order to assess a possible lack of stimulatory factors, we partially substituted FCS with US. The addition of US collected either before or after therapy with r-HuEpo to the standard culture had no effect on the growth of BFU-E. Vice versa, the number of cultured BFU-E decreased when FCS was partially substituted with US collected before r-HuEpo. This effect was not evident when FCS was partially substituted with US collected after r-HuEpo. No significant differences were recorded in the tested sera collected before and after therapy considering erythropoietin levels and amino acid levels. We hypothesized that some other factors with erythropoietic stimulatory activity (burst-promoting activity?) may be deficient in uremic patients with marked anemia and can be induced during therapy with r-HuEpo.

Serum Erythropoietin and Reticulocyte Maturity Index after Renal Transplantation: A Prospective Longitudinal Study

“…Our results show that RMI seems to be a more accurate index of erythropoietic re sponse after RT than ARC providing earlier information on the erythropoietic response. Apart from low serum EPO lev els due to absence of graft function, several factors such as persistent uremic inhibitors, iron storage deficiency, alu minium bone deposits, osteitis fibrosa, hyperparathyroi dism per se [20] or deficiency in factors with erythropoietic stimulatory activity [21] may prevent normal erythropoiesis in the immediate posttransplantation period. In this context RMI combined with EPO measurement would enable earli er detection o f a functional abnormality in the EPO-bone marrow axis.…”

Nonregenerative Anemia

“…96 Of the 3 clinically important FeLV subgroups, FeLV-C has a unique erythrocytopathic effect. While all FeLV subgroups have a similar hematopoietic cell tropism and may cause 1 or Decreased renal excretion of hepcidin 195 Presence of factors in uremic serum that inhibit erythropoiesis, 101 erythyropoietin, 47 and/or heme synthesis 47 Lack of stimulating factors in uremic serum 25 Myelotoxicity of factors in uremic serum 29 Iron deficiency secondary to chronic blood loss associated with uremic toxin-induced platelet dysfunction, 18 gastric ulceration 161 Depletion of iron stores by erythropoiesis-stimulating agents 51 PTH-induced inhibition of EPO synthesis 178 PTH-induced myelofibrosis 139 Anti-EPO antibodies secondary to recombinant EPO therapy 42 Antierythropoietic effects of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists 135 Complications of dialysis (vitamin/mineral deficiency, 92 aluminum toxicity 140 ) Heart failure Inflammation 9 GI dysfunction 118 Neurohormonal activation 189 Cardiorenal syndrome 150…”

Anemia of Renal Disease

“…It is thought that each of these substances affects erythropoiesis at various stages within the bone marrow. 26,27 Secondary hyperparathyroidism as a consequence of CKD can cause erythropoietin hyporesponsiveness. Parathyroid hormone in excess may have a direct toxic effect on erythroid progenitor cells, and also an indirect effect by inducing bone marrow fibrosis.…”