Pathogenesis of Renal Anemia
Section snippets
Epidemiology of Renal Anemia
In 1836, Bright6 first described the association between anemia and chronic renal failure, and Brown and Roth7 later concluded in 1922 that the anemia of chronic nephritis was caused by decreased bone marrow production. By 1933 Parsons and Ekola-Strolberg8 recognized that the Hb concentration in uremia had roughly the same prognostic significance as the creatinine level. Before epoetin became available, about 25% of hemodialysis (HD) patients needed regular transfusions of red blood cells.
Production of EPO in the Kidney
The gene encoding human EPO is located on chromosome 712 and encompasses about 3,000 base pairs. It contains 5 exons and 4 introns and encodes for a 193–amino-acid polypeptide.4, 5 The recent cloning of the EPO gene from the puffer fish showed that the synteny of genes at the EPO locus is highly conserved during evolution.13
A 27–amino-acid leader sequence at the N-terminal part and a carboxy-terminal arginine molecule of human EPO are cleaved off during secretion so that the mature 34-kd
EPO Receptor and Signaling
EPO is considered an essential growth factor for late erythroid progenitor cells. This view has been confirmed by observations in patients developing anti-EPO antibodies in response to epoetin.20 The occurrence of such antibodies leads to an almost complete cessation of red cell production, with an absence of erythroid progenitors from the bone marrow, very low reticulocyte counts, and regular transfusion dependence.
Physiologically, activation of the EPO receptor on the immature erythroid cells
Regulation of EPO Expression by Hypoxia-Inducible Transcription Factors
The main determinant of EPO synthesis is the transcriptional activity of its gene, which is related to local oxygen tensions. EPO production is related inversely to oxygen availability, so that an effective feedback loop is established, which controls erythropoiesis.25 In isolated perfused kidneys, EPO messenger RNA and EPO secretion are modulated in response to alterations of the oxygen tension of the perfusate.26, 27 Thus, although humoral signals from extrarenal sensing systems may
Other Transcriptional Regulators of EPO
Although HIF-1α and HIF-2α can activate the EPO gene, GATA-2 and NF-κB inhibit EPO gene transcription.
Imagawa et al36, 37 showed that GATA-2 inhibits EPO gene transcription by binding to the EPO promoter under normoxic conditions. For example, the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine decreases EPO production by increasing GATA-2 DNA binding.38 In contrast, the addition of L-arginine inhibited the binding activity of GATA-2 and rescued decreased expression of EPO.39
EPO Deficiency and Renal Anemia
Normal serum EPO concentrations in human beings are of the order of 10 to 30 mU/mL as determined by radioimmunoassays, which corresponds to between 2 and 7 pmol/L. EPO concentrations are increased under a variety of conditions, largely reflecting alterations of oxygen delivery to tissues. The expected compensatory response to anemia is a heightened rate of erythropoiesis, with an inverse relationship between the concentration of the hormone and the Hb concentration.43 In severely anemic
Impaired EPO Production in Diabetic Nephropathy
Although renal anemia develops largely independent of the underlying cause of kidney disease, anemia appears to develop earlier and to be more severe in patients with diabetes.50, 51 Bosman et al52 compared 27 type 1 diabetic patients with nephropathy and 26 nondiabetic patients with glomerulonephritis and persistent proteinuria. Although one half of the diabetic nephropathy patients were anemic, none of the glomerulonephritis patients showed a decrease in Hb levels. In the diabetic nephropathy
Increased Destruction of Red Blood Cells in Uremia
Although insufficient production of EPO by the diseased kidneys is the primary cause of renal anemia, additional factors contribute to renal anemia.
Hemolysis in the terminal stages of kidney disease was observed by several investigators,62, 63 and Eschbach et al64 observed a diminished red blood cell lifespan in HD patients using P-labeled di-isopropyl fluorophosphate. A correlation between red blood cell survival time and serum blood urea nitrogen level was inverse,65 and exposure to uremic
Uremic Suppression of Erythropoiesis
The role of uremic suppression on erythropoiesis remains controversial.70 The presence of inhibitors of erythropoiesis in uremic plasma was postulated in the light of the report that anemia improves after HD is started.71 It was shown later that the hematocrit level increases after the start of regular dialysis despite a significant decrease in endogenous serum EPO levels, suggesting that HD removes a bone marrow inhibitor.72, 73 Adequacy of dialysis is a key to correcting anemia and optimizing
Iron Deficiency
Iron is a critical body substance, transporting oxygen to tissues via Hb and functioning as a cofactor in a number of enzyme systems. The most common factor that confounds renal anemia is iron deficiency, whether it is related to or independent of blood loss from repeated laboratory testing, needle punctures, or blood retention in the dialyzer and tubing at the end of each dialysis treatment.77 It has been estimated that 1 to 3 g of iron are lost annually from these causes,78 and uptake of iron
Chronic Inflammation
Uremia is a chronic inflammatory state,81, 82 and thus patients with renal failure may develop anemia and become refractory to EPO because of mechanisms associated with chronic inflammation.83 A significant association has been shown between hyporesponsiveness to EPO and high levels of inflammatory markers in HD patients.84, 85, 86 Hyporesponsiveness to EPO in patients with chronic inflammation often can be explained by functional iron deficiency. This is characterized by apparently
Other Contributing Factors
In patients with renal disease, agents that block the renin-angiotensin system also may contribute to reduced EPO levels and anemia.91 Sophisticated experiments by Kato et al92 showed a molecular interaction of erythropoiesis and the renin-angiotensin system in transgenic mice. Although animals carrying both the human renin and human angiotensinogen genes displayed persistent erythrocytosis, the introduction of both transgenes into the AT1a receptor null background restored the hematocrit level
Consequences of Renal Anemia
Anemia in CKD patients is associated inversely with quality of life and life expectancy and associated directly with cardiovascular morbidity and progressive loss of renal function. To which extent these relationships reflect causality so that anemia correction improves patient well-being and outcome is a matter of ongoing investigation and debate.
From a pathophysiologic point of view it is clear that unless anemia is very severe (Hb level <4 g/dL) whole-body oxygen consumption is not reduced,
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