Year : 2002 | Volume
: 13 | Issue : 3 | Page : 331--335
Anemia Management in Patients with Chronic Renal Disease: Current Recommendations
Department of Medicine, King Saud University, Riyadh, Saudi Arabia
Department of Medicine (38), King Saud University, P.O. Box 2925, Riyadh 11461
Anemia is common in renal failure in both predialysis and in patients maintained on dialysis. Consequences of anemia include decreased cognitive function, decreased exercise tolerance and a feeling of inadequate well being as well as increased left ventricular hypertrophy and dilatation that result in increased cardiovascular morbidity and mortality. Iron deficiency is the most common factor for erythropoietin resistance even in predialysis patients. This article reviews the factors involved in anemia in predialysis patients, management issues and current recommendations.
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Tarif N. Anemia Management in Patients with Chronic Renal Disease: Current Recommendations.Saudi J Kidney Dis Transpl 2002;13:331-335
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Tarif N. Anemia Management in Patients with Chronic Renal Disease: Current Recommendations. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Aug 4 ];13:331-335
Available from: http://www.sjkdt.org/text.asp?2002/13/3/331/33800
Anemia generally appears in patients with chronic renal failure (CRF) once the glomerular filtration rate (GFR) declines to , Recently, the Canadian Multicenter study in 446 chronic renal failure patients showed that anemia developed in >50% of patients with GFR of  Development of anemia is mainly due to the decrement in the levels of erythropoietin (EPO) reflecting a reduced number of EPO producing cells. With any degree of anemia, EPO levels are low compared to a patient with anemia and normal GFR.  This is however not the only factor as shown in [Table 1].
Uremic milieu is responsible for the decreased life span of the red blood cells (RBCs) and thus, a demand of rapid replacement on the bone marrow. Early experiments showed that transfusion of RBCs from uremic subjects increased their life span in the nonuremic individuals. , Uremic environment usually leads to susceptibility of RBCs to destruction under various stresses. 
EPO producing fibroblasts may still mount a response to severe hypoxemia thus suggesting that the uremic state itself may increase the threshold to produce EPO.  This state could be corrected by intensive dialysis with or without EPO use as was shown by Ifudu et al. 
This may also reflect decreased responsiveness of erythroid precursors to EPO. Furthermore, uremia is associated with a decreased immune state with propensity to infections and or cytokine production especially in hemodialysis patients due to bioincompatible membranes. Such inflammatory factors are known to cause anemia through resistance to EPO effect. ,
Moreover, the bone marrow itself may be replaced by fibrous tissue in severe hyper-parathyroidism. 
Iron deficiency has been clearly shown in recent years to be a major factor for persistent anemia in patients undergoing maintenance dialysis as well as anemia unresponsive to EPO administration. This has led to many recent guidelines with major emphasis on iron management in anemic patients. ,,
The majority of CRF patients also have iron deficiency due to chronic blood loss secondary to several factors including platelet dysfunction, coagulation abnormalities, gastrointestinal losses due to uremic enteritis and blood withdrawal for repeated investigations. 
Uremic patients are anorexic and malnourished. The ability of the gut to absorb iron may be decreased due to uremic enteritis or increased gastric pH with the frequent use of H 2 blockers, thus worsening the iron deficiency due to chronic blood losses.  Deficiency of other factors such as folate and vitamin B 12 may have an additional negative effect. 
Besides the deficiency of cofactors for hemoglobin synthesis, other factors such as hypothyroidism should be evaluated in resistant cases to EPO therapy.
Angiotensin converting enzyme-Inhibitors (ACE-I) are the corner stones in preserving the decline of renal function and many of the patients with CRF receive these medications. However, ACE-I are known to suppress the production of RBCs especially in renal transplant patients and are used for this purpose to avoid post-transplant polycythemia. Concern about the role of ACE-I in causing resistant anemia was recently addressed by Abu-Alfa et al.  They studied 33 chronic hemodialysis patients for four months with and without ACE-I therapy in a cross-over fashion, and no change in the hematocrit (HCT) was noted in both periods. Although this is convincing, there are no studies to address the issue conclusively in predialysis patients.
Thus, anemia in CRF patients results from the interaction of multiple factors [Table 1] and these should be tackled in order to improve anemia at a lower cost. For example, it may be possible to improve anemia with higher doses of EPO while, prior or concomitant, correction of iron deficiency can achieve the same result with lower doses of EPO, thus significantly saving costs. This has been proven in many studies. 
Is the correction of anemia beneficial and safe?
Persistent anemia leads to decreased oxygen delivery to the tissues and malfunction of different organs. Cardiac output increases as a response to the increased oxygen demand due to anemia. This results in left ventricular hypertrophy (LVH) and eventually cardiomyopathy. LVH is a strong predictor of sudden death in CRF patients and correction of anemia may prevent such complication. , In recent studies, LVH has been shown to regress effectively with treatment of anemia using EPO. , This may result in a decrease in cardiovascular morbidity and mortality.
Treatment of anemia in dialysis patients was shown to have a dramatic effect on the cognitive function and overall mood and behavior of patients. , Moreover, the skeletal muscle dysfunction that manifests as easy fatiguability and reduced exercise tolerance improves dramatically once the anemia is corrected; thus positively affecting the feeling of well-being. 
In a patient with CRF, the control of factors that lead to the decline of GFR is of paramount importance. , Correction of anemia may also have a beneficial effect in this regard. Earlier animal experiments raised considerable concern that normalizing the HCT may lead to possible deterioration of renal function. However, human studies did not confirm a decline in the GFR after long term use of EPO in predialysis patients with controlled blood pressure;  they rather showed a significant protective effect instead of a decline in GFR.
A major concern with the use of EPO has been the increase in blood pressure after initiation of therapy, which may enhance the decline in renal function. This elevation in blood pressure results from the increase in peripheral vasoconstriction due to correction of anemia (a stimulus for vasodilatation) and also hyperviscosity with the increase of red cell mass.  However, hypertension is less often observed if EPO is started in mild rather than severe anemia, with careful follow-up in the initial weeks to monitor HCT and blood pressure control. In fact, the majority of the studies did not find a significant increase in blood pressure. ,
[Figure 1] outlines the current recommendations for the management of anemia in CRF patients.
Initially, the correctable causes of anemia, including blood loss, should be excluded and the body-iron stores should be evaluated. Replacement of depleted iron stores by oral or intravenous route depends on the level of deficiency. It is better to start with intravenous iron supplementation.
Silverberg et al have shown that in anemic CRF patients on oral iron therapy, intravenous administration of iron even without EPO administration improved anemia.  More recently, studies have shown that such improvement may not be enough with intravenous iron alone and concomitant use of EPO is necessary for meaningful results.  Thus, after attaining adequate iron stores (Ferritin levels 100-500 ng/ml or Transferrin Saturation 20-40%) one should start EPO administration and tailor the treatment according to the response, paying attention to blood pressure control, iron stores and HCT response. Of course proper attention to other factors as outlined in the table is also important.
Besareb et al, in their study of normalization of HCT, found adverse trends in patients on maintenance dialysis with cardiac disease. 27 They discontinued the study early due to a trend towards increased mortality in the higher HCT level group and no added benefit compared to the group with HCT levels of 33-39%. The majority of patients in this group, although they never reached the target, felt better and had significant improvement in exercise tolerance.
In another study by Hayashi et al, regression of LVH was noted with partial correction of anemia to HCT of 30% and significant regression was noted when the correction was aimed to normal levels of 40%. 
No clear target HCT has been defined by NKF-DOQI guidelines quoting the levels of anemia by world health organization in normal people; Hgb 28
Currently, in our predialysis patients, we at least target the HCT to >33% as suggested for the maintenance dialysis patients while avoiding normalization till the results of the ongoing studies such as CREATE, UK (GBR-2) and others are available to settle the issue conclusively.
In conclusion, anemia in patients with CRF has significant adverse effects on patient morbidity and mortality. There is some evidence that along with other measures, correction of anemia may help in slowing the decline in renal function. Response to erythropoietin replacement therapy depends on certain factors, the most important being iron stores. Current recommendations suggest aiming for at least HCT level of 33% to get the beneficial effects of anemia management in CRF patients.
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