Anemia of chronic renal failure

 

Anemia of chronic renal failureIntroduction:

The IRC publications on anemia are extremely numerous and American, European and more recently French recommendations, under the aegis of the French Agency for the Safety of Health Products (AFSSAPS), have been produced on this subject.

Definition of anemia of chronic renal failure:

The classic definition of anemia in the general population is that proposed by World Health Organization (WHO) experts in 1968: hemoglobin (Hb) in the venous blood less than 13 g / dl adult male, less than 12 g / dl in non-pregnant women, less than 11 g / dl in pregnant women. This definition is currently under discussion and experts stress the importance of taking age into account as Hb decreases in humans physiologically with age due to a decrease in testosterone. Thus, the European recommendations on anemia of the IRC propose to carry the diagnosis of anemia for an Hb rate lower than 13,5 g / dl in the man under 70 years, lower than 12 g / dl in men above 70 years and below 11.5 g / dl in women. It is important not to wait for lower Hb values ​​to explore anemia. This is justified by two arguments: on the one hand, anemia, even moderate, can reveal an underlying pathology; on the other hand, there is growing evidence that moderate anemia can induce complications.

Anemia of CKD is usually normochromic, normocytic and arterenative. However, it can be microcytic in case of iron deficiency that is common during kidney failure. Anemia may become macrocytic when treatment with erythropoietin (EPO) is initiated because EPO increases the proportion of young erythrocytes in the circulation.

Macrocytosis must also seek a vitamin B 12 or folate deficiency.

For what severity of chronic renal failure can we talk about anemia of chronic renal failure?

It was classically considered that anemia could be attributed to CKD when the glomerular filtration rate (GFR) became less than 30 ml / min / 1.73 m 2 . In reality, this limit must be reviewed. Anemia of CKD can be observed as soon as the GFR falls below 60 ml / min / 1.73 m 2 . For example, in the NHANES study, the prevalence of anemia, defined as Hb less than 12 g / dl in men and 11 g / dl in women, increases by 1% for a GFR estimated at 60 ml / min / 1.73 m 2 , at 9% for an estimated GFR of 30 ml / min / 1.73 m 2 and at 33-67% for an estimated GFR of 15 ml / min / 1 , 73 m 2 .Some studies particularly emphasize the precocity of anemia in CKD of diabetic origin and encourage particular vigilance in these patients.

Mechanisms of anemia of chronic renal failure:

Classically advanced causes of CKD anemia are EPO deficiency, decreased life span of erythrocytes, inhibition of erythropoiesis by uremic toxins, iron deficiency and iron deficiency. hypersplenism. The efficacy of recombinant human EPO in correcting CKD anemia suggests that EPO deficiency is the main mechanism of this anemia. This idea is only partially true, because other causes also intervene.

Production, regulation and action of erythropoietin:

The kidney is the main production site for EPO in adults.

The kidney contributes 85% to the production of EPO, the liver provides only a minor contribution, and the lung and spleen play an accessory role. The kidney cells that produce EPO have not been identified with certainty. It could be interstitial cells such as fibroblasts or endothelial cells, or tubular cells. EPO acts on erythroid medullary progenitors: burst forming unit erythroblast (BFU-E) and colony forming unit erythroblast (CFUE).

EPO acts on the late stages of their development by stimulating their proliferation and maturation. This stimulation is actually an inhibition of apoptosis.

The action of EPO is by binding to surface receptors present on BFU-E and especially on CFU-E. The number of EPO receptors decreases during the differentiation of erythroid cells. Reticulocytes and mature erythrocytes do not contain EPO receptors. The production of EPO is mainly regulated by hypoxia and this, very quickly. The cells subjected to hypoxia begin to express the transcription factor of EPO in 30 minutes.

Erythropoietin deficiency:

Serum EPO levels are low during CKD anemia. They are not increased as one would expect during iron deficiency anemia where EPO levels are 10 to 100 times higher. However, these low levels of EPO do not seem to be due to an inability to produce EPO but rather to an abnormality of response to anemia. Indeed, the production capacities of EPO remain intact. Patients with CKD under severe hypoxic stress have a normal increase in EPO production showing that hypoxia-EPO feedback is working properly. The abnormality of EPO response to CKD anemia may be similar to that observed in other chronic anemias such as cancer.

There is also resistance in the course of CKR to EPO. In fact, mean serum EPO levels, although not adapted to anemia, are nearly five times higher than in nonanemic healthy subjects: 29.5 ± 4.0 mU / ml compared to 6.2 ± 4 , 3 mU / ml. This resistance to EPO highlights the role of erythropoiesis inhibitors.

Inhibitors of erythropoiesis:

Bone marrow cultures from healthy subjects, incubated with uremic serum, showed a decrease in BFU-E and CFU-E colony growth of 72% and 82% relative to the control serum. Radtke et al. analyzed hematocrit and EPO levels in 42 patients after 3 to 27 months of hemodialysis treatment. Compared with the rates observed before dialysis, hematocrit increases in all patients and EPO decreases in all patients. This suggests the elimination of erythropoiesis inhibitors by hemodialysis. The main toxins involved are certainly pro-inflammatory cytokines. Other toxins such as parathyroid hormone, polyamines, and furan carboxylic acid (CMPF) have a more discussed role.

Pro-inflammatory cytokines:

The existence of an inflammatory syndrome in patients with CKD has been clearly associated with a decrease in hemoglobin levels. Inflammation leads to anemia by several mechanisms:

• an inhibition of the proliferation of erythrocyte stem cells. Allen et al. showed that the suppressive effect of serum from uremic patients on the growth of CFU-E colonies could be nullified by the addition in the culture of anti-tumor necrosis factor (TNF) -a and / or anti-interferon antibodies. (IFN) – c ;

• an inhibition of the production of EPO. The proinflammatory cytokines are capable of inhibiting the expression of the EPO gene in the rat kidney;

• direct lesions of red blood cells by cytokines and free radicals, as well as an increase in phagocytosis of red blood cells. These factors contribute to the decrease in the life of red blood cells;

• decreased availability of iron because proinflammatory cytokines decrease iron release from reticuloendothelial stocks. Inflammation is also involved in the decrease of intestinal absorption of iron. Recent data show that inflammation stimulates hepcidin which is the negative regulating hormone of iron absorption. The increase in hepcidin is accompanied by a decrease in iron absorption.

Hyperparathyroidism:

The role of parathyroid hormone (PTH) on erythropoiesis is controversial. The crude extract of bovine parathyroid glands inhibits in vitro BFU-E and heme synthesis, however this has not been confirmed with purified bovine PTH or human PTH. In contrast, anemia is improved in some hemodialysis patients after subtotal parathyroidectomy. It seems that erythropoiesis is more limited by bone marrow fibrosis than by high levels of PTH. PTH may affect the life of red blood cells. Some studies have shown an association between high levels of PTH and osmotic fragility of red blood cells. Overall, however, the role of hyperparathyroidism appears to be minor compared with other factors such as iron deficiency and inflammation.

Decrease in the life of red blood cells:

The decrease in the life of red blood cells is attributed to a particular fragility of red blood cells during the CKD. The cause of this fragility is not known precisely. The role of uremic toxins such as urea and PTH has been discussed.

Recently, this problem has been revisited by Ly et al. The life expectancy of red blood cells remains reduced in patients with end-stage CKD, whether they are treated with conventional hemodialysis, short daily hemodialysis, or long-term daily hemodialysis. Some   The authors suggested that EPO treatment improves the life of red blood cells, but this improvement is controversial.

Hypersplenism:

Increased spleen volume may, in some cases, contribute to CKD anemia. Hypersplenism is responsible for splenic sequestration of red blood cells and some degree of intrasplenic haemolysis. Hypersplenism is also accompanied by hemodilution related to increased splenic blood flow. Hypersplenism is not due to CKD but to an intercurrent pathology such as hemoglobinopathy or hepatopathy with portal hypertension.

Several articles from the 1970-1980s described the more or less favorable effects of splenectomy on CKD anemia. In a series of 25 patients with anemic CKD, 18 patients saw their condition improve after splenectomy, that is, they no longer required transfusion. However, only 11 of them saw their hematocrit become greater than 20%. Splenic sequestration of red blood cells had to be authenticated by scintigraphy before deciding on splenectomy.

Iron deficiency:

Iron deficiency is common during CKD. It is almost constant when the GFR is less than 15 ml / min / 1.73 m 2 . Iron deficiency anemia is microcytic and hypochromic. It is diagnosed by the decrease in the transferrin saturation factor (CST), which reflects the reduction of circulating iron directly available for erythropoiesis. In patients with CKD, a CST lower than 20% indicates circulating iron deficiency. The CST has the disadvantage of being very changeable from one day to another. Ferritinemia is a marker of iron stored in tissues. In patients with CKD, a value of less than 100 μg / l indicates absolute iron deficiency. Iron storage for erythropoiesis is in the bone marrow. During CKR, ferritin is a poor marker of bone marrow stores as it further reflects hepatic and splenic overload. Other tests have been proposed to evaluate the iron stores: the percentage of hypochromic red blood cells, the reticulocyte content in Hb, the soluble receptors of transferrin. These tests are not available in all laboratories. The percentage of hypochromic red blood cells is only performed on Bayer Diagnostics automated systems. The determination of soluble receptors for transferrin is not a routine test. The CST remains the most used. However, a study comparing all tests showed that a percentage of hypochromic red blood cells greater than 6% had the best performance in identifying patients who could improve their Hb levels after intravenous (iv) iron administration.

Several mechanisms explain iron deficiency in patients with CKD:

• gastrointestinal bleeding is common. Their screening is based on endoscopic examinations. The interest of stool blood testing is not formally demonstrated in patients with CKD. However, European experts consider that this test is justified because it is simple, inexpensive and that digestive bleeding is frequent;

• The blood losses during hemodialysis sessions are considerable and have been evaluated at 1 to 2 g of iron per year.

These losses are in the extracorporeal circuit and they are also due to multiple blood samples;

• Intestinal absorption of iron is decreased during CKD.

This may be due in part to elevated plasma levels of prohepcidin;

• iron requirements are significantly increased by erythropoiesis during EPO treatment.

Manifestations of anemia:

Many events have been described during the anemia of CKD. These descriptions are based on either classic notions of chronic anemia or observations made in patients with EPO-treated CRF. It must be emphasized, however, that these observations do not make it possible to demonstrate with certainty the existence of a causal relationship between anemia and manifestations. Only intervention studies comparing patients receiving different treatments can demonstrate this type of relationship. We will rely here, whenever possible, on intervention studies.

The box below summarizes all of the manifestations attributed to CKD anemia that we found in the literature.

Decrease in the quality of life:

The correction of anemia of CKD by EPO improves the quality of life of patients with CKD. This has been shown by several controlled prospective studies. Several parameters are improved such as asthenia, anorexia, sleep, libido, physical abilities and depression. The best controlled study on this topic is the randomized, double-blind, placebo-controlled study conducted by the Canadian Erythropoietin Study Group. One hundred and eighteen hemodialysis patients aged 18 to 75 years were randomized into three groups: placebo (n = 40); EPO with Hb target of 9.5 to 11 g / dl; and EPO with an Hb target of between 11.5 and 13 g / dl (n = 38). Patients receiving EPO had an improvement in quality of life scores. On the other hand, Hb levels between 11.5 and 13 g / dl were not accompanied by better scores compared to Hb levels between 9.5 and 11 g / dl. Moreno et al. showed that the improvement in quality of life was observed in an equivalent way in patients under 60 and in patients over 60 years. Another study from the same team showed an improvement in the quality of life in patients whose mean Hb went from 10.2 to 12.5 g / dl.

Unfortunately, there is no control group in this study and all patients with a history of cardiovascular disease and diabetes who were older than 65 years were excluded. A cross-over study in 14 hemodialysis patients showed an improvement in exercise capacity of 25% with an increased Hb level of 14 g / dL compared to a rate of 10 g / dL.Exercise capacity remains lower than that of the general population. In this study, only patients without a cardiovascular history were included. Furuland et al. compared a target Hb level of 135-160 g / l with a target rate of 90-120 g / l. They show an improvement in the quality of life in the group 135-160 g / l. Only patients without a history of heart disease were included. There is therefore no formal evidence today to say that increasing Hb above 11 g / dl improves the quality of life for all patients with CKD.

Left ventricular hypertrophy:

The mechanism by which anemia is usually associated with left ventricular hypertrophy (LVH) is the chronic increase in cardiac output which is a compensatory mechanism for anemia. The increase in cardiac output during anemia results from three phenomena: increased ejection volume related to arterial vasodilatation with decreased vascular resistance; increased preload by increased venous return due to decreased viscosity; increase in heart rate by activation of the sympathetic system. In the long run, these coping mechanisms lead to enlargement and LVH.

The permanent increase in cardiac output also leads to hypertrophy and arterial remodeling responsible for an increase in arterial resistance. This follows the initial vasodilatation and further aggravates the LVH. Finally, during CKD, myocardial changes are aggravated and rendered irreversible by other factors such as hyperparathyroidism and calcium phosphate-related calcifications.

Therapeutically, the increase in Hb by transfusions is able to correct the increase in cardiac output induced by CKD anemia. All studies show that correction of EPC anemia by EPO results in a 20% decrease in left ventricular volume.The regression of LVH is, however, incomplete, probably due to the late and partial nature of anemia correction, or due to other cardiomyopathy factors in patients with CKD. Recently, some work has attempted to answer the question of Hb target values. Foley et al. compared the impact of Hb target values ​​at 10 or 13.5 g / dl on LVH in hemodialysis patients. They did not observe any benefit in the group with Hb at 13.5 g / dl compared to the group with Hb at 10 g / dl.

Roger et al. initiated a study of the influence of early treatment of CKD anemia in patients with GFR between 50 and 15 ml / min and followed for 2 years. They compared a group with target Hb between 120 and 130 g / l with a target group with Hb between 90 and 100 g / l. No difference in the evolution of the left ventricular mass index was observed between these two groups.

Coronary artery disease:

While healthy subjects can tolerate Hb levels as low as 5 g / dL without hypoxia or electrocardiographic changes, it has been well documented that in coronary subjects the cardiac tolerance of anemia is impaired. In subjects with CKD, correction of anemia with EPO is considered to improve the symptoms of exercise-induced myocardial ischemia.However, a recent controlled study found no difference in the prevalence of silent ischemia between a 42% target hematocrit group and a 30% target hematocrit group.

Strokes and convulsions:

The neurological manifestations of anemia in CKD have been poorly studied. An observational study showed an association between anemia of CKD and a history of stroke. Seizures, classically presented as a side effect of EPO treatment, are actually more common in patients without EPO than in treated patients. This could be related to a protective effect of EPO on neurons that develop EPO receptors during ischemia.

Mortality:

There is a debate about optimal Hb concentrations in patients with CKD. More specifically, there is a discrepancy between the results of the observational studies and those of the intervention studies. Observational studies show an association between the highest Hb values ​​(greater than 12 g / dl) and survival. However, these studies can not demonstrate a cause-and-effect relationship between elevated Hb and survival. The patients with the highest Hb levels are the subjects with the best response capacity to EPO: absence of inflammatory syndrome, absence of bleeding, adequate dialysis dose. These characteristics also influence survival. Only randomized interventional studies can show whether changing Hb values ​​improves survival because, in this case, survival factors are evenly distributed among the groups due to randomization. However, intervention studies do not show any benefit in increasing Hb beyond 12 g / dl in terms of survival. The two main intervention studies we have are Besarab and Furuland. Besarab et al. have studied hemodialysis patients with cardiac pathology. They compared 618 patients with a hematocrit target of 42% and 615 patients with a target rate of 30%.

After 29 months, 202 deaths or infarcts were observed in the “42%” group and only 164 in the “30%” group.

The study was then stopped because it could not show any benefit for the “42%” group. As a result of this study, the question was whether these findings were found in patients without cardiac pathology. Furuland et al. studied patients on hemodialysis, peritoneal dialysis and predialysis. Patients with cardiac pathology were excluded. In a follow-up of 48 to 76 weeks, the authors compared 216 patients with target Hb at 13.5-16 g / dl and 200 patients with target Hb at 9-12 g / dl. The mortality rate was identical in both groups (13.4 and 13.5%). Thus, based on intervention studies, there is no current justification for treating Hb above 12 g / dl as a therapeutic goal. This has been well underscored by Strippoli’s recent meta-analysis.

Aggravation of chronic renal failure:

At the beginning of the era of EPO treatment, experiments in the rat had raised fears that the correction of anemia could aggravate high blood pressure and accelerate glomerular lesions. Several studies in humans have shown that the correction of anemia has no deleterious effect on renal function. The most important is that of Roth et al. who followed 43 patients on EPO and 40 untreated patients for 48 weeks. DFG decreased by 2.1 ml / min in the treated group and 2.8 ml / min in the untreated group. Subsequently, it has been suggested that CKD anemia itself may be an aggravating factor for CKD and that treatment of anemia with EPO may delay the progression of CKD. The best study we currently have is Gouva et al. who followed for 45 months 45 patients treated early with EPO, as soon as the Hb was less than 11.6 g / dl and 43 patients treated late, when the Hb became less than 9 g / dl . The end-of-study criterion was doubling of creatinine, arrival at the dialysis stage or death. The number of patients achieving the end-of-study endpoint was 13/45 in the early group and 23/43 in the late group.

These results are spectacular. It is not clear, however, whether they can be extrapolated to all patients with CKD because the study did not include diabetic subjects or subjects treated with ACE inhibitors or angiotensin receptor antagonists. II.

Treatment of anemia:

The management of anemia in CKD before the availability of EPO included a multitude of more or less effective measures:

• quality extra-renal treatment;

• a reduction to the strict minimum of blood loss and blood samples for biological assessments;

• Parenteral iron administration, as well as pharmacological doses of folic acid and androgens.

Nephrectomies were avoided and transfusions performed as little as possible to avoid suppressing endogenous EPO production. All these measures made it possible to obtain at best an average Hb rate of 8 g / dL, but 10% of the patients nevertheless required regular transfusions. EPO treatment has revolutionized the management of anemia in CKD. It should be noted, however, that a number of the measures listed above continue to be applied to facilitate the response to COOL.

Management of iron deficiency:

His screening is essential. The correction of iron deficiency often helps to partially correct anemia. Iron deficiency limits the effectiveness of EPO treatment. In addition, iron deficiency often occurs in patients treated with EPO because erythropoiesis stimulates the use of iron stores in the body.

Oral iron administration:

Iron is poorly absorbed digestive in patients with CKD and its digestive tolerance is sometimes bad. In addition, intravenous administration is more effective than oral administration. It is recognized, however, that martial therapy can be started orally, particularly in patients with non-hemodialysis CKD for whom the iv route is not practical. Stoves et al.did not show a difference in efficacy between iv iron and oral iron in patients with CKD prior to the dialysis stage provided that large doses of oral iron were used.

Deira et al. have shown that patients with CKD have sufficient iron intestinal absorption to compensate for daily iron losses. To be effective orally, iron should be administered at a daily dose of 600 mg ferrous sulfate, or about 190 mg iron. As an indication, the daily doses will therefore be three tablets of Fumafer ® (66 mg of iron per tablet) or two tablets of Tardyferon ® (80 mg of iron per tablet) or four tablets of Tardyferon B 9 ® (50 mg of iron per tablet).

Intravenous iron administration:

The injectable iron currently available in France is ferric hydroxide sucrose or iron sucrose (Venofer ® ) which seems to be a particularly safe product. Iron gluconate and dextran iron are not marketed in France in 2005.

The optimal frequency of iv administration of iron is not known. The European recommendations propose a fairly wide dose range: 100 to 600 mg per month during the first 6 months of treatment with EPO. Other publications suggest higher doses: 400 to 600 mg in the first two weeks for Besarab et al. ; 200 mg per week for 5 weeks in patients undergoing predialysis. Besarab insists on the interest of a regular, weekly administration, without waiting until the martial assessment reveals a deficiency. This strategy appears to decrease the need for EPO. Protocols in which the iron administration strategy is guided by more stable martial markers than the CST would result in lower iron doses.

Problem of high doses of iron:

There is controversy regarding the administration of high doses of iron in patients with CKD. High doses of iron are accompanied by a reduction in the need for EPO. Besarab et al. studied the effect of high doses of iron dextran by comparing a group of patients in which the CST was maintained between 30 and 50% with a control group in which the CST was maintained between 20 and 30%. Iron doses were 504 mg / month in the first group and 191 mg / month in the second group. Ferritinemia after 6 months was 730 μg / l in the first group against 297 μg / l in the control group.EPO requirements were reduced by 40% in the first group compared to the control group. Despite these dramatic results, there is a fear of high doses as iron may exacerbate oxidative stress and predispose patients to infections.Feldman et al. analyzed patient survival from the USRDS registry based on the dextran injection dose prescribed during the period January to June 1994. Compared to patients who had no iron iron less than or equal to 10 ampoules in 6 months (1000 mg) did not have an increase in mortality while patients with an iron prescription of more than 10 ampoules had a risk of mortality increased by 11% after adjustment for different comorbidities. In contrast, the Besarab study did not show increased morbidity or mortality in the high iron dextran group. However, in this study, follow-up was limited to 6 months. The association between iron and infections has been mostly shown with transfusion-related martial overloads. The EPIBACDIAL observational study found no association between bacteremia and ferritin levels or iron treatment. In practice, there is no clear argument at present for setting a dose of iron or a ferritinemia value beyond which iron treatment must be discontinued. According to experts, this value varies between 500 and 800 μg / l.

Perspectives on martial treatment:

A new oral form of iron, the heme-iron polypeptide, is currently marketed in the United States under the name Proferrin®. It is a molecule produced by hydrolysis of bovine Hb in which the bioavailability of the heme-iron complex is much greater than that of ionized iron. A recent study in 34 hemodialysis patients has shown that the heme-iron polypeptide is capable of effectively replacing iv iron. In practice, however, there may be some reluctance to use a product made from bovine Hb in Europe. .

Erythropoietin treatment:

History and manufacture:

Human EPO was purified for the first time by the Miyake team in 1977. To obtain a few milligrams of homogeneous EPO, 2,500 l of urine from anemic subjects were needed! Thus, this technique did not make it possible to meet the hormone requirements for a substitution treatment. The Jacobs and Lin teams were able, through genetic engineering, to produce human in vitro EPO in sufficient quantities to allow clinical studies. They opened the era of treating CKD anemia with recombinant human EPO. Schematically, the human EPO gene is isolated from a deoxyribonucleic acid (DNA) library complementary to human fetal liver, and then transfected into mammalian cells (CHO-K1 Chinese hamster ovary cancer cells). ; the gene expresses itself and it is translated. These cells thus produce in their supernatant active EPO having physical, structural, immunological and biological properties that are perfectly identical to those of endogenous EPO. There are currently four EPOs, a , b , d and x . However, only EPO- a (Eprex®) and EPO- b (NeoRecormon®) are marketed. Recently, a new erythropoiesis stimulating protein has been synthesized, darbepoetin a (Aranesp ® ). It stimulates erythropoiesis according to the same mechanism as that of the endogenous hormone. It has five N-carbohydrate chains while endogenous hormone and recombinant human EPO have only three. The presence of additional carbohydrate residues gives darbopoetin a longer biological half-life, which reduces the frequency of injections. Darbepoetin a is produced in the same way as EPO by the recombinant DNA technique in Chinese hamster cells.

Target values ​​of hemoglobin:

As we have seen, the controlled prospective studies of mortality and left ventricular hypertrophy do not justify target Hb levels above 12 g / dl in patients with cardiac disorders as in patients without cardiac pathology. Only one study justifies the increase of the Hb beyond 12 g / dl because it shows a benefit on the quality of life. This study only involved subjects with normal heart function.

Route of administration of erythropoietin:

Before the dialysis stage or in patients on peritoneal dialysis, the route of administration of choice is the subcutaneous route (sc). In patients treated with hemodialysis, the iv route is often preferred because it avoids potential pain at the injection site. The sc path is possible and achieves the same efficiency as the iv route with lower doses. Dose reductions vary between 10 and 50% depending on the studies and there is interindividual variability. SC administration of EPO has been associated with a higher incidence of anti-EPO antibodies in patients treated with Eprex®-treated IRC. Finally, in patients on peritoneal dialysis, intraperitoneal administration should be avoided because of insufficient bioavailability (3 to 8%).

Dosage:

As an indication, the dosages of EPO recommended by manufacturers vary between 60 and 150 international units (IU) kg -1 week -1 . The objective is to increase the Hb level very gradually, from 1 to 2 g / dl maximum in 1 month, up to the rate of 11 to 12 g / dl. A faster increase leads to an increased risk of high blood pressure and convulsions.

Dose adjustment is done every 15 days during the attack period and every month during the maintenance period.Dosage adjustment protocols have been proposed to maintain Hb between 11 and 12 g / dl. For Aranesp ® , the starting dose is 0.45 μg / kg / week in a single weekly injection. The dosage should not be increased more than once every 4 weeks. Dosage adjustment is the same as for EPO.

Side effects :

They are largely prevented by careful monitoring of Hb. High blood pressure is the most common side effect. On the neurological level, convulsions are possible, favored by a too rapid correction of anemia, by hypertension or by a history of comitiality. Thromboses of vascular access can be observed. They could be favored by an excessive correction of anemia. Thus, in the Besarab study, the incidence of vascular access thrombosis was 39% in the group aiming at a hematocrit at 42% compared to 29% in the group aiming for a hematocrit at 30%. These thromboses can be explained by the increase of the blood viscosity and the improvement of the primary hemostasis under EPO. Very rarely have episodes of flu-like syndrome and allergic-type reactions been reported. Injection site pain can occur with sc administration.

In very rare cases, anti-EPO antibodies may appear during the treatment with EPO.

Resistance to erythropoietin treatment:

The resistance to EPO is defined by the impossibility of reaching target Hb concentrations with a dosage of EPO greater than 300 IU / kg / week (sc) or 450 IU / kg / week (iv) after 4 to 6 months of treatment. Resistance to EPO can be linked to many causes (Box).

The effect of ACE inhibitors or angiotensin II receptor antagonists on anemia remains controversial. The mechanism by which these drugs induce anemia is not known. It could be the inhibition of angiotensin II which is a substance capable of stimulating erythropoiesis and the production of EPO. It could also be an increase in plasma levels of Ac-SDKP (acetyl-N-seryl-aspartyl-lysyl-proline) which is a peptide that blocks the hematopoietic stem cell cycle. This peptide is usually degraded by the conversion enzyme.

Clinically, several studies have not confirmed the influence of ACE on anemia.

Pure red cell aplasia should be suspected when no other cause of resistance to EPO is present. It results in a therapeutic escape occurring after several months of treatment, with a rapid fall in Hb, the need for weekly transfusions and an aregenerative character confirmed by a reticulocyte rate below 20 Å ~ 10 9 / l. A myelogram must be performed. It shows an erythroblast level of less than 5%. The PRCA is most often due to the appearance of anti-EPO antibodies. This hypothesis is confirmed by a collapsed serum level of EPO and the detection of antibodies.These antibodies cross-react with all erythropoietins, thus rendering EPO treatment impossible. Patients become transfusion dependent again.

While recombinant EPO has been on the market since 1988, PRCA did not appear until after 1998.

The majority of cases occurred in patients treated with EPO (Eprex ® ). In addition, almost all cases occurred in patients receiving Eprex ® sc. These factors led drug agencies to contraindicate in 2002 the use of Eprex ® sc. This measure reduced the incidence of erythroblastopenia more than 80%. At the same time, various investigations have suggested that modifications to the Eprex ® formula, which occurred in 1998, had contributed to reducing its stability and increasing its immunogenicity. Thus, the human albumin that entered the formulation of Eprex ® was replaced by another stabilizer, polysorbate 80, probably less effective and able to react with the rubber syringe pistons.Therapeutically, in case of erythroblastopenia with anti-EPO antibodies, the treatment with EPO must be interrupted.Immunosuppressive therapy (corticosteroids, cyclophosphamide, ciclosporin) led to the recovery of erythropoiesis in more than two-thirds of the cases where it was tried. Finally, transplantation, again allowing the adequate synthesis of endogenous EPO, is effective for the treatment of erythroblastopenia.

Other treatments for anemia of chronic renal failure:

Optimization of dialysis:

It is well established that the dialysis dose has an influence on the correction of anemia. This is probably related to better elimination of erythropoiesis inhibiting toxins.

The usual criteria for adequate dialysis based on Kt / V urea are required to ensure a correct response to EPO (Balanced Kt / V greater than 1.2 for a hemodialysis program of three sessions per week and greater than 1, 8 for a weekly peritoneal dialysis program). Conventional hemodialysis ensures an excellent correction of anemia. The interest of unconventional techniques such as haemofiltration, biofiltration or haemodiafiltration is discussed, as well as that of daily hemodialysis. In practice, the European recommendations emphasize above all the interest of optimizing treatment by conventional dialysis before considering other forms of treatment.

Bacteriological quality of the dialysate:

The interest of an ultrapure dialysate is to be emphasized. In a randomized, controlled study, the use of ultrapure dialysate reduced the doses of EPO.

Vitamin E:

Vitamin E treatment may reduce oxidative stress, which is associated with resistance to EPO treatment.

Only two uncontrolled, low-strength studies suggest a benefit of vitamin E on CKD anemia. Dialysis membranes coated with vitamin E developed recently seem to allow better control of anemia. Here again, the results are small and controversial. The beneficial role of vitamin E on anemia needs to be confirmed by large-scale controlled studies.

Vitamin C:

Vitamin C is able to mobilize iron stores of the reticuloendothelial system; it also potentiates the enzymatic incorporation reaction of iron for the synthesis of heme. Some studies have shown that vitamin C supplementation improves the response to EPO in patients with functional iron deficiency and elevated ferritinemia, as well as in patients with normal martial status. There is, however, a reluctance to supplement patients with CKD because vitamin C overload could result in secondary oxalosis. Unfortunately, no long-term prospective controlled study has measured oxalate levels and the risk of oxalosis with vitamin C. Finally, the European experts, considering this risk, decided not to make a recommendation for routine use of vitamin C.

Vitamins B 6 , B 12 , folates:

Deficiencies of water soluble dialysable vitamins such as folic acid and vitamin B 12 are well-defined causes of anemias associated with macrocytosis. These deficits can occur in patients with CKD and should be investigated and corrected if the response to treatment with EPO decreases. One article suggests a dose of pyridoxine (vitamin B 6 ) of 5 mg j -1 in patients not treated with EPO and 20 mg j -1 in patients on EPO. However, there is no study showing the value of vitamin B 6 intake for the correction of anemia. Regarding folate supplements, the evidence is inconclusive in hemodialysis patients receiving adequate balanced nutrition. A single, uncontrolled study of 13 patients suggested a benefit of folate supplementation in patients receiving EPO.

Most studies show that erythrocyte folate levels are normal in patients with CKD.

Carnitine:

Carnitine is a low molecular weight compound that accumulates during CKD but is eliminated by dialysis. There may be a deficit in dialysis patients. L-carnitine may have an impact on anemia by correcting metabolic abnormalities such as oxidative stress or phospholipid turnover. A meta-analysis suggests a beneficial effect of L-carnitine supplements on the control of anemia, particularly in patients resistant to EPO. However, L-carnitine is of interest only in patients treated with hemodialysis who are the only ones who can have a deficit.

Studies are few in number, the number of subjects is low and the effects of carnitine supplements are limited and heterogeneous. None of the studies considered other causes of resistance to EPO. This supplementation is not recommended routinely.

Impact of nutritional status on anemia:

The malnutrition-inflammation-atherosclerosis syndrome is very often associated with anemia. There is an association between low body mass index and severe anemia.

In contrast, patients with obese CRF have higher hemoglobin levels and lower EPO requirements than non-obese patients. One study showed that high caloric intake in hemodialysis patients was able to increase serum leptin levels and improve response to EPO.

Androgens:

They work by stimulating the renal and hepatic production of endogenous EPO. They can potentiate the effect of exogenous EPO and stimulate erythropoiesis by increasing stem cell differentiation. They increase the hematocrit by 5%. Injectable forms, such as nandrolone decanoate (200 mg week -1 intramuscular [im]) seem more effective on anemia than oral forms. Androgens do not appear to improve the response to EPO in hemodialysis patients responding well to low doses of EPO. In contrast, the interest of androgens has been shown when used alone, and particularly in patients over 55 years of age who show better anemia correction than younger patients. This has been confirmed by Navarro et al. which showed, in men over 50 years, as effective anemia with nandrolone decanoate as with EPO. In addition, in this population, androgens improve nutritional parameters. Androgens can be an effective alternative when you do not have EPO. However, the side effects are many: risk of liver disease and neoplasia, hirsutism, virilization, voice modification, priapism, severe acne.

Antioxidants:

Preliminary and relatively old studies have suggested a beneficial effect of reduced parenteral glutathione at a dose of 1200 mg at the end of each dialysis session. This study was without result. More recently, in a pilot study, pentoxyfillin has been shown to improve resistance to EPO by inhibiting the production of pro-inflammatory cytokines.

Transfusions:

Erythrocyte transfusions should be avoided as far as possible in patients with CKD given the risk of viral infections, human leukocyte antigen (HLA) immunization and hemochromatosis. Transfusions should not be made except in the following specific cases: symptomatic anemia (fatigue, angina, dyspnoea) and / or associated with risk factors (diabetes, heart failure, coronary artery disease, arterial disease, advanced age); acute worsening of anemia due to blood loss (haemorrhage or surgery) or haemolysis; severe resistance or failure to respond to EPO treatment due to hematologic disease or severe systemic inflammatory disease. Since EPO treatment must be initiated early, blood transfusions should only be necessary in patients with acute bleeding, acute hemolysis, or severe inflammation and only in the emergency setting. When EPO treatment is not available, it is usual to accept low Hb concentrations of the order of 8 g / dl.

Conclusion:

Among the current data concerning anemia of CKD, two important points should be highlighted:

• The treatment with EPO theoretically allows a total correction of the anemia. However, the results of intervention studies on survival, ventricular hypertrophy and quality of life have shown no benefit in having an Hb level greater than 12 g / dl;

• the mechanisms of CKD anemia do not only involve a deficiency of EPO but also and mainly an abnormality in the production of EPO in response to anemia and resistance to EPO. A better knowledge of these mechanisms should allow in the future a better management of the anemia and an optimization of the treatment by EPO.

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