Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-I and its binding proteins.

BACKGROUND: Secondary erythrocytosis is classically defined by an increase in erythropoietin (EPO) production. Despite increased levels of EPO often seen in secondary erythrocytosis, some of these forms such as that seen after renal transplantation remain undefined. Our group has recently investigated the in vivo function of insulin-like growth factor-I (IGF-I) in erythropoiesis both in humans and in a murine model of chronic renal failure. These data, and the recently recognized role of IGF-I in polycythemia vera, suggested that IGF-I might be involved in secondary erythrocytosis. METHODS: Renal transplant recipients who developed erythrocytosis after transplantation were compared to normal individuals and to renal transplant recipients without erythrocytosis. We measured fasting serum EPO and IGF-I in all three groups. Because binding proteins may modify IGF-I function, IGF-I-binding proteins (IGFBP) 1 and 3, major binding proteins of IGF-I, were also measured. RESULTS: Renal transplant recipients have significantly elevated serum of IGF-I and IGFBP3 compared to normal individuals. When transplant recipients with and without posttransplant erythrocytosis were compared, similar levels of IGF-I were found; however, the group with erythrocytosis had significantly elevated IGFBP1 and IGFBP3. No other significant differences including EPO levels were found between the groups. CONCLUSIONS: Erythrocytosis after renal transplantation represents an anomaly of both IGF-I and its major binding proteins. Further studies are under way to better define this dysregulation and determine whether IGF-I can play a more generalized role in secondary forms of erythropoiesis.

Successful treatment of acquired factor VIII inhibitors with cyclosporin.

The treatment of Factor VIII inhibitors remains controversial and no standard therapy exists. We describe in this report two consecutive patients with this inhibitor that responded to cyclosporin. Clinical improvement of the bleeding diathesis, a return to normal of the PTT, a decrease in the level of the inhibitor, and a return to normal of the factor VIII level followed use of this drug. We believe that cyclosporin is effective in the treatment of factor VIII inhibitors and deserves further investigation.

Effect of chronic renal failure on the expression of erythropoietin message in a murine model.

The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.

Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse.

Chronic renal failure (CRF) is associated with a hyporegenerative anemia, which is caused primarily by inadequate production of erythropoietin (EPO) by the diseased kidneys and is responsive to exogenous EPO administration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations in vitro suggest an important role for insulin-like growth factor-1 (IGF-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, singly and in combination with EPO, in CRF in vivo. This study examined mice with surgically-induced renal failure of six weeks duration that were treated for three weeks with the combination of subtherapeutic doses of both EPO and IGF-1. The single administration of each cytokine caused no significant change in hemoglobin in all CRF mice. In marked contrast the combined administration of the two cytokines produced a striking rise in hemoglobin, resulting in anemia correction in the majority of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a dose-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in hemoglobin observed with the combination therapy indicates that these two cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum levels of low molecular weight binding proteins for IGF-1, potentially reducing the bioavailability of IGF-1. These findings taken together suggest that the anemia of CRF may represent both an EPO and a functional IGF-1 deficient state.

Anemia of chronic renal failure: characterization in the mouse and correction with human recombinant erythropoietin.

Anemia is a cardinal feature of chronic renal failure (CRF) which contributes significantly to the clinical syndrome of chronic uremia. We have conducted a detailed examination of the hematological changes in CRF in the inbred mouse strain C57BL/6J. As in the human situation, CRF mice presented major hematological changes affecting primarily the erythroid cell series. Despite the presence of abundant iron stores in the bone marrow, the CRF mice developed a hypoproliferative anemia of a severity commensurate with the degree of renal impairment. The levels of circulating erythropoietin (EPO) in CRF mice were not significantly different from those in normal control littermates and were therefore inappropriately low for the degree of anemia. In contrast acutely bled control mice with normal renal function showed a significant inverse correlation between the serum EPO level and hemoglobin concentration, indicating an appropriate response to anemia. The chronic administration of recombinant human EPO raised the hemoglobin concentration of CRF mice, a therapeutic effect which was independent of the initial degree of anemia. These observations suggest that this animal model has wide applicability for the study of anemia secondary to CRF.

Identification and characterization of an 8-kd peptide stimulating late erythropoiesis.

Chronic renal failure is often associated with severe anemia, subnormal levels of erythropoietin (EPO), and the presence of erythropoietic inhibitors. We studied an anephric patient with polycystic kidney disease maintaining a hemoglobin level of 13-14 g. Biochemical, endocrine, and hematological parameters were all within normal limits. EPO levels examined on two occasions during the clinical investigation were found to be low to subnormal. Plasma of this patient supported human bone marrow erythroid colony formation without the addition of exogenous EPO. Following reversed-phase high pressure liquid chromatography (HPLC) and gel filtration HPLC of the patient's plasma, a small polypeptide was identified that stimulated thymidine incorporation into fetal calf liver cells and supported erythroid colony formation of human marrow cells. This molecule is different from EPO with respect to its molecular weight and its functional and chromatographic properties. In this report we provide evidence of a human plasma-derived peptide of an anephric patient regulating late erythropoiesis.

Treatment of idiopathic thrombocytopenic purpura with ascorbate.

The treatment of idiopathic thrombocytopenic purpura (ITP) includes corticosteroids, danazol, splenectomy and various immunosuppressives. Treatment can be difficult for those patients refractory to these modalities and/or those patients intolerant of the secondary effects. In this paper we report on the use of ascorbate in the treatment of ITP and its successful use in seven of 11 patients studied. We found that therapy with ascorbate appeared to improve the platelet count and the intravascular survival of platelets. Because of excellent patient compliance and its lack of toxicity, it may be an alternative for the treatment of ITP. The exact role of ascorbate in the treatment of ITP, as well as its mechanism of action, await further study.

Hemolytic anemia following intravenous gamma globulin administration.

A young homosexual man with immune thrombocytopenia recently had transient intravascular hemolysis during intravenous gamma globulin treatment. The hemolysis, manifested by a sharp decrease in hemoglobin and by a direct Coombs' test with a positive result, was mediated by anti-A antibody present in the gamma globulin preparation. In view of the increasing use of intravenous gamma globulin in the treatment of patients with immune cytopenia, this problem may result in crossmatching difficulties and should be recognized as a potential complication of therapy.

Expression of common acute lymphoblastic leukemia-associated antigen on germ cell tumor.

A mediastinal germ cell tumor is described that reacts with the anti-common acute lymphoblastic leukemia-associated antigen antibody J5 using both immunofluorescence and immunoperoxidase techniques. This antigen has been reported recently on various cell lines including melanoma, colon, and breast. It has also been seen on normal fibroblasts and peripheral granulocytes. This is believed to be the first description of a solid nonlymphoid neoplasm possessing this antigen, and the implications regarding prognosis and therapy are discussed.