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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with chronic kidney disease (CKD), sensitivity to recombinant human erythropoietin (r-HuEPO, epoetin) is of clinical and economic importance. Insight into factors that influence sensitivity and response to epoetin is essential for the adequate management of anaemia. Some factors influencing response to epoetin, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as haemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be controlled. Iron deficiency is the most common factor that limits the response to epoetin. Adequate monitoring of iron status and iron supplementation in patients with CKD will result in a more efficient epoetin response. Increased dialysis dose is associated with improvements in haemoglobin outcome and reduced requirements for epoetin. Dialysis water quality (both chemical and biological) is also important in determining the response to epoetin; 'ultrapure' water reduces epoetin requirements. Some patients, despite adequate epoetin and iron therapy, still have epoetin resistance (low haemoglobin and/or high epoetin requirements). Raised C-reactive protein and/or low albumin may reflect long-standing inflammatory pathology and indicate a need for investigation.
Nephrol Dial Transplant 2002
PMID:Clinical factors influencing sensitivity and response to epoetin. 1181 14

Most patients receiving anemia therapy respond well, with a significant rise in hemoglobin concentration. However, approximately 5%-10% of patients fail to show a satisfactory response despite high doses of erythropoietin. The definition of hyporesponsiveness to anemia therapy is somewhat arbitrary, but it is generally regarded as a failure to achieve a hemoglobin concentration of 10-11 g/dL despite a dose of erythropoietin in excess of 200 U/kg weekly. The condition has many causes, the most important ones being iron deficiency, infection or inflammation, and underdialysis. Investigating a patient's poor response to erythropoietin should begin with a check for compliance, followed by screening for iron deficiency. If doubt exists about the presence of iron deficiency, then a trial of intravenous iron may be given. A reticulocyte count may be helpful. A significantly elevated count suggests the presence of blood loss or hemolysis. The level of C-reactive protein (CRP) may be useful as an indicator of underlying inflammation, and underdialysis may be corrected by increasing the dialysis prescription. If other, minor causes of hyporesponsiveness to erythropoietin have been excluded, then a bone marrow biopsy should be performed. Some patients may require higher doses of erythropoietin, and it is not unreasonable to increase the dose to 10,000 U thrice weekly. Some causes of hyporesponsiveness to erythropoietin, such as iron deficiency and underdialysis, are easily corrected; but others, such as primary bone marrow disorders and hemoglobinopathies, are not possible to overcome.
Perit Dial Int 2001
PMID:Hyporesponsiveness to anemia therapy--what are we doing wrong? 1188 26

An increasing number of reports documenting resistance to human recombinant erythropoietin (rHuEPO) therapy are challenging the concept that erythropoietin deficiency is the main cause of the anaemia of chronic kidney disease (CKD). In an attempt to establish whether other factors play a more predominant role in the anaemia of CKD, 988 patients receiving dialysis were assessed for a wide range of variables. Data were collected on haematocrit (Hct) levels, rHuEPO dose, dry weight, serum ferritin, transferrin saturation, serum albumin, serum aluminium, serum parathyroid hormone intact, eKt/V for urea, gender, dose of i.v. iron administered, time in hospital, and use of i.v. vancomycin. Hyporesponsiveness to rHuEPO was defined as patients requiring >500 IU/kg/week or failing to achieve Hct levels of >30%. Ninety-two (9.2%) of the 988 patients met the above criteria for hyporesponsiveness to rHuEPO. In 21 of these patients, Hct concentrations remained <30% at 6-month follow-up. There were known haematological causes of refractoriness to rHuEPO in nine of these patients. During extended follow-up, probable causes of hyporesponsiveness were discovered in all but two of the remaining 13 patients. Of 62 dialysis patients who received rHuEPO at doses >500 IU/kg/week, 45 (73%) had Hct concentrations of 33-42%. These patients were responding to the higher doses of rHuEPO with no obvious adverse effects. Lower values of serum ferritin, transferrin saturation, and eKt/V, or higher levels of parathyroid hormone or serum aluminium were not associated with higher rHuEPO dose requirements. These results suggest that erythropoietin deficiency is still the main cause of the anaemia of CKD. Erythropoietin replacement therapy can correct the anaemia in almost all iron replete patients providing enough hormone is given, functional iron deficiency is avoided, aluminium levels and parathyroid toxicities are controlled and that no de novo haematological condition that affects erythropoiesis or red blood cell survival develops. Consideration should be given to modifying the definition of rHuEPO hyporesponsiveness. The US Hct target of 33-36% for haemodialysis patients is narrow and the European target of Hct >33% may be significantly more practical and physiologically relevant.
Nephrol Dial Transplant 2002
PMID:Is it time for a paradigm shift? Is erythropoietin deficiency still the main cause of renal anaemia? 1209 99

Our knowledge of erythropoiesis and iron in renal disease is limited. The accepted view of the control of erythropoiesis was founded on observations made in a variety of disorders, but the control mechanism in healthy individuals may not be quite the same. Evidence suggests that mechanisms other than erythropoietic stimulation may play a role in increased red blood cell production. Measuring erythropoiesis is complex. The quantitative reticulocyte count is probably the closest practical assessment of erythropoietic activity we can achieve, yet there is very little correlation between circulating erythropoietin level and reticulocyte count in normal and near normal subjects. Oxygen transport in humans depends entirely upon iron. In renal disease, the failure of the erythropoietin positive feedback mechanism can be readily and directly remedied; recombinant human erythropoietin therapy can replace the missing erythropoietin, but this will be negated if iron supply to the erythroid marrow falls short of demand. Measurement of iron stores is also complex. The use of serum ferritin concentration as a direct quantitative estimate of iron in the stores is not advisable, and in practice we have not found the transferrin receptor assay to be useful in identifying patients who require iron therapy. Use of percentage hypochromia as a measure of iron deficiency is complicated by the fact that hypochromic cells are not exclusively a consequence of functional iron deficiency. There are clearly lessons still to be learned in this field and there is much that we do not yet understand about the control of erythropoiesis and iron metabolism in humans.
Nephrol Dial Transplant 2002
PMID:Iron and erythropoietin in renal disease. 1209 2

Hyperparathyroidism is usually listed among the possible reasons for impaired response to recombinant human erythropoietin (rHuEPO) in patients with renal disease. However, its relevance in the context of other causes of renal anaemia, and the mechanisms by which it may worsen anaemia, are not entirely clear. Possible pathogenic links between anaemia and parathyroid hormone (PTH) include reduced erythropoiesis due to calcitrol deficiency, and direct or indirect effects of PTH on erythropoietin release, red blood cell (RBC) production, survival, and loss. Studies of these mechanisms have produced disparate results, possibly because secondary hyperparathyroidism may have only a relatively minor role in anaemia that may be masked by the confounding effects of other factors with greater impact. Variations in medical treatment or study methodology may also have affected study results. Severe parathyroid overfunction may contribute to the severity of anaemia in uraemic patients and diminish rHuEPO responsiveness in a minority of patients. However, overall, the importance of hyperparathyroidism appears to be minor compared with other factors such as iron deficiency or inflammation.
Nephrol Dial Transplant 2002
PMID:Role of secondary hyperparathyroidism in erythropoietin resistance of chronic renal failure patients. 1209 4

End-stage renal disease (ESRD) is characterized by a high mortality rate, derived largely from cardiovascular disease (CVD). In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features that may contribute to malnutrition, anaemia, recombinant human erythropoietin (rHuEPO) resistance, and atherosclerosis. Inflammation predicts poor outcome in ESRD. It is multifactorial in cause and, while it may reflect the underlying CVD, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. In patients with ESRD, the acute-phase response may be influenced by a number of factors unrelated to dialysis and perhaps by the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels resulting in reduced erythropoiesis, accelerated destruction of erythrocytes, and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, rHuEPO resistance has been linked with inflammation, the latter of which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity to handle oxidative stress. There is recent evidence that a relationship may exist between inflammation and oxidative stress and treatment of anaemia with rHuEPO. However, iron may also generate oxidative stress. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to rHuEPO can be defined.
Nephrol Dial Transplant 2002
PMID:Anaemia, rHuEPO resistance, and cardiovascular disease in end-stage renal failure; links to inflammation and oxidative stress. 1209 5

Renal anaemia starts earlier in the progression of chronic kidney disease (CKD) than was previously thought and is often inadequately monitored and treated. Current treatment guidelines recommend giving recombinant erythropoietin (rHuEPO) as soon as haemoglobin (Hb) concentration falls below 11 g/dl and alternative causes of anaemia have been ruled out. Recent studies show that, in practice, few patients receive rHuEPO in the pre-dialysis period and Hb concentrations are often <9 g/dl at the start of haemodialysis. This is at odds with best practice since renal anaemia is a major risk factor for left ventricular hypertrophy. Many factors other than provision of rHuEPO therapy can affect the occurrence and severity of renal anaemia. Iron deficiency is the most common cause of resistance to rHuEPO and appropriate use of iron supplementation in patients with CKD is still being debated. The acute-phase immune response has a more significant role in renal anaemia and rHuEPO resistance than previously believed, as demonstrated by the need for higher rHuEPO doses in patients with raised levels of C-reactive protein. Women often need higher doses of rHuEPO than men, which may be related to differences in androgen levels between the sexes. Low erythropoietin concentrations are a major factor in diabetic nephropathy. Correction of anaemia with rHuEPO may slow progression of CKD by reducing oxidative stress. These and other factors need to be considered for the optimal treatment of patients with anaemia of CKD.
Nephrol Dial Transplant 2002
PMID:Non-erythropoietin-based anaemia management in chronic kidney disease. 1238 56

Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and under dialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.
Nephrol Dial Transplant 2002
PMID:Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. 1238 57

End-stage renal disease (ESRD) is characterized by a high mortality rate, which is mainly caused by cardiovascular disease. In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features and may contribute to the development of malnutrition, anaemia, resistance to recombinant human erythropoietin (epoetin) and atherosclerosis. The onset of inflammation is multi-factorial and is a predictor of poor outcome in ESRD. Although the inflammation may reflect the underlying cardiovascular disease, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. The acute-phase response in these patients may be influenced by a number of factors, and possibly the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels, resulting in reduced erythropoiesis, accelerated destruction of erythrocytes and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, epoetin resistance has been linked with inflammation, which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity in their control of oxidative stress and there is evidence that suggests that a relationship may exist between inflammation, oxidative stress and the treatment of anaemia with epoetin. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to epoetin can be defined.
Nephrol Dial Transplant 2003 Nov
PMID:Anaemia and inflammation: what are the implications for the nephrologist? 1460 95

Oral iron is typically insufficient for the iron deficiency of hemodialysis patients. Intravenous (IV) iron is well tolerated by most patients and non-dextran-containing iron preparations are associated with few allergic reactions. However, there is the potential for an increased risk of infection with IV iron that appears to increase bacterial growth as well as inhibit the host's innate immune response to bacterial infection. Clinical studies suggest a link between iron therapy and infection. Practicing nephrologists should be aware of this issue, but should not hesitate to use IV iron in iron-deficient patients while avoiding the development of iron overload and administration of iron to patients who have active infection.
Semin Dial
PMID:Intravenous iron and the risk of infection in end-stage renal disease patients. 1471 13


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