John W. Adamson

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

To the Editor: We have read the letter to the editor by Jerzy Przedlacki1 and the response from the authors2 of the Kidney Disease-Improving Global Outcomes (KDIGO) clinical practice guidelines for bisphosphonate (BP) treatment in chronic kidney disease (CKD), and would like to share our concerns regarding the use of BP treatment of CKD. The kidney is the organ that excretes many drugs, and any change in renal function will affect the pharmacology of these drugs. Existing or residual renal function of the patient will have to be taken into account while prescribing drugs. This is just as important for the patient with CKD 4 or 5, including those with CKD 5 already on peritoneal dialysis or hemodialysis, who may still have residual renal function. Nephrotoxic drugs including nonsteroidal anti-inflammatory drugs can very readily destroy whatever residual renal function patients may still have. Residual renal function is important to preserve as it contributes to less patient morbidity and mortality3 in the dialysis patient. Recently, there have been adverse reports of a certain BP that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. As of 14 August 2009, there have been 139 post-marketing reports of renal impairment following its use as an infusion worldwide. Many of these occur in patients with pre-existing medical conditions or risk factors (elderly, renal impairment, and/or concurrent dehydration), or in those on nonsteroidal anti-inflammatory drugs or other concurrent exposure to other nephrotoxic agents. There have also been cases requiring dialysis, and occasional fatal outcomes have been reported in patients with pre-existing renal impairment and concomitant risk factors.4, 5, 6, 7

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Polycythemia: Mechanisms and Management

The principal function of erythrocytes is the transport of oxygen. Erythropoiesis proceeds at a rate consistent with the demand for oxygen-carrying capacity, and the major regulator of erythrocyte production is erythropoietin. Erythropoietin is produced primarily by the kidney under control of a tissue oxygenation sensor. The recently developed erythropoietin radioimmunoassay should provide a clinically useful tool. Erythrocytosis is a pathologic state characterized by an elevated erythrocyte mass, which may result from increased proliferation of erythroid progenitors due to an intrinsic cellular defect or in response to extrinsic signals. Secondary erythrocytosis results from either physiologically appropriate compensation for inadequate tissue oxygenation or from inappropriate stimulation of erythropoiesis. Erythrocytosis increases oxygen-carrying capacity of the blood, but at high hematocrit levels increased blood viscosity may result in decreased tissue oxygen delivery. Polycythemia vera is a hematopoietic stem cell disease of clonal origin. Initial results from the Polycythemia Rubra Study Group suggest that therapy with chlorambucil is associated with an unacceptably high risk for development of acute leukemia, and 32P is preferred for situations in which phlebotomy alone is insufficient.

Improvement in the Anemia of Chronic Renal Failure with Fluoxymesterone

Abstract Fluoxymesterone was administered to 14 severely anemic patients with chronic renal failure stabilized with maintenance hemodialysis. Clinically, significant improvement in erythropoiesis w...

The Placental/Umbilical Cord Blood Program of the New York Blood Center A Progress Report

Abstract: The transplantation of placental/umbilical cord blood (P/CB) has been used successfully to reconstitute bone marrow function in both related and unrelated recipients. We report here the experience of the New York Blood Center P/CB Program. Since its inception in 1992, over 400 unrelated transplants were supported between July 1993 and September 1997. Overall, event‐free survival for all diagnoses and ages approached 0.45. Success and rapidity of engraftment correlated most strongly with the degree of human leukocyte antigen (HLA) disparity and cell dose/kg body weight recipient. Acute graft‐versus‐host disease (GVHD) was common in all patients but, surprisingly, did not differ between those patients who received grafts having one or more antigen mismatches. Chronic GVHD was uncommon and only rarely contributed to death. These results demonstrate the feasibility of large‐scale P/CB banking for the provision of cryopreserved stem cell preparations for unrelated transplants. The degree of the programs success argues strongly for additional P/CB banks in order to increase the likelihood of finding a suitable stem cell preparation for patients for whom related matched donors do not exist.

Regulation of red blood cell production

Erythropoietin, which is produced by peritubular capillary lining cells of the kidney, is critical to the production of red blood cells. Endogenously produced erythropoietin circulates in the plasma to act on specific target cells in the marrow through cell surface receptors. The primary target of erythropoietin action is the erythroid colony-forming cell. In addition to proliferative effects, high circulating erythropoietin levels result in the premature release of marrow reticulocytes and the mobilization of marrow progenitor cells. Production of endogenous erythropoietin increases in response to the stress of anemia or hypoxemia. Iron, an important element in hemoglobin synthesis, is bound to the iron transport protein transferrin, and the complex is internalized, along with the transferrin receptor, by the developing erythroid cell. Within the cell, the iron molecule is subsequently split off and either used for hemoglobin synthesis or stored within the cytoplasm as ferritin. Administration of recombinant human erythropoietin induces changes in iron metabolism, which are reflected by decreases in both the serum iron level and transferrin saturation. These reductions can be marked, even in healthy individuals, and can occur in the presence of normal or even increased iron stores.

Predicting the Hematopoietic Response to Recombinant Human Erythropoietin (Epoetin Alfa) in the Treatment of the Anemia of Cancer

Recombinant human erythropoietin (Epoetin alfa) is effective in increasing hemoglobin concentration and hematocrit, and in significantly reducing transfusion requirements in the majority of patients with either the anemia of chronic renal failure or chemotherapy-induced anemia of cancer. Identification of factors that could enable the clinician to predict individual patient hematological responses to Epoetin alfa therapy would be of great value. Changes in levels of serum transferrin receptor protein, hemoglobin, ferritin and reticulocyte count, following a short course of Epoetin alfa therapy, were useful markers for predicting later hematopoietic responses to Epoetin alfa. In addition, recent data suggest that low baseline erythropoietin levels, in association with increases of either >0.5 g/dl in hemoglobin or ≥25% in circulating levels of transferrin receptor protein after 2 weeks of Epoetin alfa therapy, are highly predictive of a response (≥2 g/dl increase in hemoglobin) to Epoetin alfa. Progress has clearly been made in the development of predictive models that can identify those patients most likely to respond to Epoetin alfa by monitoring several specific hematological parameters at baseline and early in therapy. Future studies will focus on nonhematological measures of response, such as transfusion requirement and quality of life benefit.

LONG-TERM GENERATION OF COLONY FORMING CELLS (CFC) FROM CD34+ HUMAN UMBILICAL CORD BLOOD CELLS

Human umbilical cord blood cells represent a potential alternative to bone marrow as a source of stem and progenitor cells for allogeneic transplantation. Therefore, many studies are underway to evaluate the number of cord blood stem cells and their amplification potential. We analyze here the amplification potential of CD34+ cord blood cells in liquid cultures stimulated with stem cell factor (SCF) in combination with interleukin-3 (IL-3), erythropoietin (Epo) or granulocyte colony-stimulating factor (G-CSF) under serum-deprived conditions. We report that under certain circumstances (stimulation with SCF and IL-3, replacing of the medium and growth factors every 3-4 days, no change of the initial culture flask, 37 degrees C as incubation temperature), CD34+ cells give rise to differentiated cells and progenitor cells for more than two months. During this period, more than 10(10) differentiated cells and 10(6) progenitor cells are generated from 0.25-1 x 10(4) CD34+ cells in the absence of a stromal layer. These data highlight the high proliferative and differentiative potential of cord blood stem cells and, because the culture procedures are relatively simple and do not require a stromal layer, open the way to the clinical use of ex vivo stem cell expansion.

Alternatively spliced mRNAs encoding soluble isoforms of the erythropoietin receptor in murine cell lines and bone marrow

32D Epo and 32D GM cells are subclones of the murine 32D cell line which are selectively dependent for proliferation and survival on erythropoietin (Epo) or granulocyte/macrophage colony-stimulating factor (GM-CSF), respectively. 32D GM cells were previously shown to express significant levels of the Epo receptor mRNA and protein which was retained intracellularly and did not appear on the cell surface. We have now analyzed the EpoR mRNA from the 32D GM line, using PCR followed by direct sequencing. Several alternatively spliced products were detected. In some molecules, intron 5 (I5) or part of I6 or both were retained. Retention of I5 results in a mRNA potentially encoding an almost complete extracellular domain, while retention of I6 gives rise to a mRNA encoding the complete extracellular and transmembrane domains. A different type of splicing results in the loss of exon 5 (E5), giving rise to a sequence encoding a truncated extracellular domain. These alternatively spliced sequences are differentially represented in 32D Epo versus 32D GM cells. All are additionally present in normal bone marrow cells. Apart from these alternatively spliced EpoR RNAs, no other abnormalities were detected in EpoR RNA from 32D GM cells that could account for the intracellular retention of EpoR in the non-erythroid subclones of 32D.

Cytokine biology. Implications for transfusion medicine

The development and widespread availability of recombinant products will effect blood centers through reduced product use, replacement of current products, and novel applications of new products. The greatest amount of clinical experience to date has dealt with the use of recombinant human erythropoietin (r‐HuEPO) in the treatment of anemia in end‐stage renal failure. Data also support its use in anemia associated with acquired immune deficiency syndrome (AIDS), cancer, and chronic inflammatory diseases. This article will focus on the effect of erythropoietin on the demand for erythrocyte use.