Anemia in chronic kidney disease: Clinical guidelines

List of Abbreviations

CKD – chronic kidney disease

HD – hemodialysis

PD – peritoneal dialysis

rhEPO – recombinant human erythropoietin (ATC group: B03XA – other antianemic preparations)

ESAs – erythropoiesis-stimulating agents (ATC group: B03XA – other antianemic preparations)

EPO – erythropoietins (epoetin alfa**, epoetin beta**, darbepoetin alfa**; ATC group: B03XA – other antianemic preparations)

ESAs – erythropoiesis-stimulating agents

PRCA – pure red cell aplasia

TIBC – Total Iron-Binding Capacity

Hb – hemoglobin

HIF-PHI – hypoxia-inducible factor prolyl hydroxylase inhibitor – roxadustat (ATC group: B03XA – other antianemic preparations)

Terms and Definitions

Erythropoiesis-stimulating agents (ESAs) are a group of medications that stimulate the process of red blood cell formation in the bone marrow, used for the treatment of anemias (ATC group B03XA – other antianemic preparations).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Anemia is a syndrome characterized by a decrease in blood hemoglobin concentration, frequently accompanied by a concurrent reduction in the red blood cell count (or total red blood cell volume). An exception is acute anemia associated with bleeding, in which the total blood volume and body hemoglobin content decrease, but the hemoglobin concentration in the blood may remain normal for some time (until hemodilution occurs).

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The development of anemia in chronic kidney disease (CKD) is caused by impaired production of erythropoietin (EPO) in the kidneys. The severity of anemia correlates with the degree of renal dysfunction. Iron deficiency and elevated levels of inflammatory cytokines play a role in the pathogenesis of anemia. Anemia is a predictor of left ventricular hypertrophy development and is associated with impaired quality of life, increased cardiovascular complications, and an increased hospitalization rate. Increased cardiac load due to tachycardia and increased stroke volume caused by anemia induces renal vasoconstriction and fluid retention. Thus, a vicious circle arises in which congestive heart failure, kidney disease, and anemia mutually exacerbate each other.

1.3 Epidemiology of the Disease or Condition

Anemia is a regular complication of chronic kidney disease. Typically, anemia is observed when creatinine clearance drops to 40–60 ml/min, but it may also occur at earlier stages of the disease. The causes of acquired anemia in kidney disease are numerous. Most commonly, anemia in CKD is hyporegenerative due to impaired erythropoietin production in the kidneys. In iron deficiency, anemia is hypochromic, whereas in the absence of iron deficiency, it is normochromic.

1.4 Features of Coding the Disease or Condition

ICD-10 code: D63.8 Anemia in chronic diseases classified elsewhere.

1.5 Classification of the disease or condition

Depending on the severity of the hemoglobin (Hb) concentration reduction, it is generally accepted to distinguish three degrees of anemia severity:

• mild – Hb concentration above 90 g/L;

• moderate: Hb concentration within 90–70 g/L;

• severe: Hb concentration less than 70 g/L.

1.6 Clinical presentation of the disease or condition

Most complaints and symptoms are nonspecific signs of anemia that overlap with the symptoms of the underlying disease.

The most frequent complaints in patients are:

• palpitations, shortness of breath, worsening with physical exertion;

• dizziness, tinnitus;

• weakness, increased fatigue.

Physical examination may reveal the following signs:

• pallor of the skin and visible mucous membranes (jaundice of the skin and mucous membranes in hemolysis);

• tachycardia, tachypnea;

• muffled heart sounds, systolic murmur at the apex of the heart and over large vessels;

• lethargy.

It should be borne in mind that children may be more tolerant to anemia than adults. This is due in part to a greater cardiopulmonary reserve and the absence of coronary artery disease, as well as relatively rapid compensation of the loss of oxygen transport capacity (shifting of the oxygen dissociation curve to the right and a decrease in Hb affinity for oxygen). Thus, compensatory mechanisms of chronic anemia in children ensure tolerance to very low Hb concentrations with few or no symptoms, especially if anemia develops slowly over weeks or months.

Many factors can provoke decompensation in a patient with anemia and lead to life-threatening tissue and organ hypoxia. Decompensation of chronic anemia can be observed in infections and acute blood loss.

Causes of chronic anemia decompensation:

• increased oxygen demand due to infection, pain, fever;

• further decrease in tissue oxygen supply due to acute blood loss, pneumonia.

Early signs of decompensation:

• labored, rapid breathing with intercostal, subcostal, and suprasternal retractions (respiratory distress);

• increased use of abdominal muscles for breathing;

• nasal flaring.

Signs of acute decompensation:

• forced ("groaning") expiration (respiratory distress);

• altered mental status;

• weakened peripheral pulse;

• congestive heart failure;

• hepatomegaly;

• poor peripheral perfusion (capillary refill time greater than 2 seconds).

A patient with these clinical signs urgently requires treatment due to a high risk of death from inadequate oxygen transport capacity.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended methods for diagnosing the disease and related conditions have a limited evidence base (according to the grading systems for levels of evidence certainty (LEC) and levels of recommendation consensus (LRC)) due to the lack of clinical studies devoted to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics, since more effective and proven methods have not yet been developed.

Criteria for establishing a diagnosis: anemia is diagnosed in children with chronic kidney disease (CKD) if the Hb concentration is below 110 g/L in children aged 6 months to 5 years, below 115 g/L in children aged 5–12 years, and below 120 g/L in children aged 12–15 years.

In patients older than 15 years, anemia in CKD is diagnosed when hemoglobin is less than 130 g/L in male patients and less than 120 g/L in female patients.

2.1 Complaints and Anamnesis

• All patients with CKD with suspected anemia are recommended to undergo anamnesis and symptom collection regarding hematopoietic and blood disorders to assess the patient's condition and to rule out other potential causes of anemia [1–6, 37].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: during symptom collection, the patient is questioned about the presence of symptoms of anemia (see section 1.6).

When taking the medical history, attention is paid to potential additional causes of anemia:

• bleeding (acute and chronic);

• hemolysis (autoimmune, microangiopathic);

• intercurrent diseases (chronic infectious and inflammatory diseases);

• iron, folate, and vitamin B12 deficiency (dietary factor, impaired absorption).

2.2 Physical Examination

• All patients with chronic kidney disease with suspected anemia, as well as all patients with a diagnosed condition of anemia in CKD, at every medical appointment are recommended to undergo visual inspection, palpation, and percussion regarding hematopoietic and blood disorders [1–3, 6, 37].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: general examination involves assessing the overall physical condition, symptoms of hemic hypoxia (see section 1.6), and possible signs of anemia syndrome decompensation. During the examination, the physician must assess both objective physical signs of anemia (pallor of the skin and visible mucous membranes, tachycardia, tachypnea) and subjective symptoms of anemia through active, targeted questioning of the patient or (in pediatric practice) their parents.

2.3 Laboratory Diagnostics

The diagnostic trigger for initiating a hematological workup is the detection of anemia in CKD.

A decrease in endogenous EPO production is observed in all cases of anemia associated with CKD; therefore, determining serum EPO levels is not mandatory.

Decreased erythropoietin production, iron deficiency, and inflammatory processes are the main causes of anemia in CKD. However, it should be remembered that inadequate maintenance hemodialysis regimens, infectious complications, chronic blood loss, and secondary hyperparathyroidism are frequent factors worsening anemia. Furthermore, CKD patients may exhibit any other form of anemia, including hemoglobinopathy, autoimmune hemolytic anemia, etc.

• All patients with CKD are recommended to undergo a complete blood count (CBC), hematocrit (Hct) evaluation, red blood cell count, reticulocyte count, differential white blood cell count (leukocyte formula), and platelet count to diagnose and differentiate anemia [1–4, 6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: anemia is diagnosed taking into account age-related norms. Normal values must be adjusted for children living in high-altitude areas.

Hemoglobin levels should be monitored once a week during ESAs dose adjustment and when switching from one ESA to another (ATC: B03XA – other antianemic preparations), then once every 2 weeks, but at least once a month.

In CKD patients who are not undergoing hemodialysis, hemoglobin levels during maintenance ESA therapy should be monitored at least once every 3 months.

In patients undergoing hemodialysis, hemoglobin levels during maintenance ESA therapy should be monitored at least once a month.

• Patients with CKD and anemia are recommended to undergo serum iron testing, transferrin saturation testing, and serum ferritin testing to clarify the nature of anemia and perform differential diagnosis with iron deficiency anemia [1–4].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in CKD, iron metabolism parameters (serum iron, TIBC, transferrin saturation percentage) may be within the normal range, decreased, or elevated. When interpreting ferritin levels, it should be kept in mind that this parameter increases during inflammatory processes.

Since ferritin is an acute-phase protein, its diagnostic value should be assessed differently than in patients without chronic kidney disease. Iron deficiency anemia is diagnosed in CKD patients with a ferritin level below 100 ng/mL.

When ferritin is above 100 ng/mL with a hypochromic red blood cell percentage greater than 6% or transferrin saturation below 20%, functional iron deficiency is diagnosed.

When prescribing ESAs, transferrin saturation and ferritin levels should be determined at least once every 3 months.

More frequent monitoring of transferrin saturation and ferritin concentration may be indicated:

- during the initial period of ESA administration

- when increasing the ESA dose

- if blood loss occurs

- when monitoring the response to intravenous iron therapy

- in any situations where iron deficiency is suspected.

• Patients with hyperchromic (macrocytic) anemia associated with CKD may be recommended to determine blood vitamin B12 (cyanocobalamin) and serum folic acid levels to rule out B12-deficiency or folate-deficiency anemia [1–4, 6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with CKD are recommended to undergo a general clinical blood chemistry panel (determination of creatinine, urea, total protein, ALT, AST) to assess renal and liver function [1–3, 6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with CKD are recommended to undergo a serum C-reactive protein (CRP) test to rule out an inflammatory response [5,19,20,25,26].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• In patients with CKD and anemia who present with clinical and laboratory signs of hemolytic anemia, it is recommended to perform a direct Coombs test to rule out autoimmune hemolysis [14,21].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in cases of intense hemolysis and prior red blood cell transfusions, an indirect Coombs test should also be performed.

• In patients with CKD-related anemia who exhibit resistance to ESA therapy, it is recommended to measure the serum concentration of intact parathyroid hormone to determine the severity of secondary hyperparathyroidism in order to correct it [6, 7,27,28].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• In patients with CKD-related anemia with suspected paraproteinemic hemoblastosis (multiple myeloma, secretory lymphoma) or amyloidosis, it is recommended to perform immunochemical testing of serum and urine to rule out a hematological disorder [10-12].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In patients with CKD-related anemia, when a hematological disorder is suspected, it is recommended to perform a bone marrow examination [13].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comment: the type of bone marrow examination (bone marrow cytologic examination [myelogram]; bone marrow histologic examination [trephine biopsy]) is determined by the suspected hematological disorder and may be combined or supplemented with other bone marrow tests.

2.4 Instrumental Diagnostics

• In patients with CKD-related anemia, if additional indications are present (data on gastrointestinal pathology, suspected occult gastrointestinal bleeding), a detailed clinical evaluation is performed to clarify the cause of anemia, which may include gastrointestinal endoscopic procedures: esophagogastroduodenoscopy, colonoscopy, sigmoidoscopy, video capsule endoscopy, etc. [4, 6,22,23,24]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.5 Other Procedures

No.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

It should be noted that a patient may present with atypical disease manifestations, as well as a combination of a specific disease with other pathologies, which may require the attending physician to modify the algorithm for choosing the optimal diagnostic and treatment strategy. [6, 7, 9]

3.1 Treatment of patients with CKD and anemia

The administration of iron preparations and ESAs helps increase hemoglobin levels in the majority of patients at any stage of CKD. Treatment of anemia in CKD also includes the correction of other treatable causes of hemoglobin reduction, such as vitamin B12 and folic acid deficiency, and treatment of the inflammatory process.

For the majority of adult patients with CKD, the goal of anemia treatment is to increase Hb levels to 100-120 g/L; this applies equally to patients in pre-dialysis stages of CKD, as well as those on dialysis and post-kidney transplantation. When using erythropoiesis-stimulating agents in patients with renal anemia, Hb levels should not exceed 130 g/L. The lower limit of the target Hb level should be reached no later than 4 months after initiating therapy in patients with renal anemia. Upper limit restrictions on Hb levels are established for elderly individuals, patients with diabetes mellitus, patients at high cardiovascular risk, and those with oncological and hematological diseases. Once Hb reaches 130 g/L, erythropoiesis-stimulating agents should be completely discontinued.

• Patients with CKD and anemia are recommended to achieve and maintain hemoglobin within the range of 100-120 g/L. [1,6]

Leveled of Evidence CLevel of Data Reliability 2Level of evidence C (level of data reliability – 2)

Comment: it is recommended to bring Hb closer to the upper limit of the range in low-risk patients (young, without severe cardiovascular disease); in patients with angina pectoris and other manifestations of ischemic heart disease in whom a decrease in Hb leads to exacerbated ischemic symptoms; and in patients preparing for kidney transplantation.

In patients at high risk for vascular complications, particularly those with diabetes mellitus, malignancies, stroke, non-ischemic heart disease, or severe peripheral vascular disease, Hb levels should be kept close to the lower limit of the target range.

• In patients with CKD and anemia with a transferrin saturation below 20% and a ferritin level below 100 ng/mL, it is recommended to prescribe iron preparations to maintain transferrin saturation above 20% and ferritin above 100 ng/mL [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: iron deficiency is a major factor in the development of renal anemia and is a highly prevalent condition in the CKD population. Both relative and absolute iron deficiency are distinguished. Absolute iron deficiency is a total reduction in body iron stores, defined by serum ferritin below 100 mcg/L. Functional iron deficiency (ferritin >100 mg/L with transferrin saturation <20%) manifests as the inability to supply proliferating erythroblasts with an adequate amount of iron despite sufficient total body iron stores. Functional iron deficiency may develop during anemia correction with erythropoiesis-stimulating agents, as well as in inflammatory diseases or when chronic blood loss is underestimated. Iron metabolism parameters (serum ferritin and % transferrin saturation) must be assessed prior to initiating ESA therapy and at least once every 3 months. Optimal iron metabolism parameters that should not be exceeded during iron therapy are: ferritin 200-500 mcg/L, transferrin saturation 30%.

Patients in the pre-dialysis stage of CKD or those on peritoneal dialysis may be prescribed oral iron preparations. However, even before the initiation of renal replacement therapy, anemia is frequently caused by iron deficiency that cannot be compensated for by dietary modifications and oral iron supplementation (in the presence of gastrointestinal disorders or other causes of impaired iron absorption, including uremic progression); in such cases, parenteral iron preparations should be used. An indicator of inadequate iron absorption may be an unsatisfactory response of laboratory iron deficiency parameters to oral iron therapy. The development of iron deficiency during ESA treatment requires prompt correction, which is achievable only via intravenous iron administration. Intramuscular administration of iron preparations is contraindicated in patients with CKD.

Patients on hemodialysis are indicated for intravenous iron preparations.

Iron preparations (ATC group: B03A – Iron preparations) are used in standard dosages determined by safety and tolerability; maintenance doses are determined according to the drug product labeling.

During the intravenous administration of the first dose of iron preparations, the patient must be closely monitored during the infusion and for at least 30 minutes post-infusion. Resuscitation facilities must be available in the event of serious adverse reactions.

The administration of intravenous iron preparations should be avoided in the presence of active systemic infection.

• In patients with CKD and anemia with an Hb below 100 g/L, after ruling out other potential causes of anemia and normalizing iron metabolism parameters, it is recommended to prescribe ESAs to achieve the target Hb level [1–9,30,31].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: prior to initiating treatment, all correctable causes of anemia (including iron deficiency and inflammation) should be excluded.

The decision regarding the necessity and timing of initiating ESA therapy in dialysis patients should be made individually, taking into account the presence of anemia-related symptoms, the risk of blood transfusion requirements, and transplantation prospects.

Currently, ESAs are used to treat renal anemia, most commonly recombinant human erythropoietin (rhEPO) preparations (epoetin alfa**, epoetin beta**, darbepoetin**; ATC group: B03XA – Other antianemic preparations). Prevention and correction of anemia using ESAs prevents and/or reverses left ventricular myocardial hypertrophy and reduces the markedly elevated cardiac output caused by anemia. The use of ESAs in patients prior to the initiation of renal replacement therapy helps increase Hb levels and reduces the need for transfusion therapy.

The choice of the target Hb value and the threshold at which ESA therapy is initiated is individual for each patient and is determined by numerous clinical factors.

In children, the target Hb level ranges from 110 to 120 g/L. Increases in Hb above 120 g/L should be avoided. Higher Hb concentrations may be associated with poorer renal and cardiovascular outcomes.

ESA dosage is selected based on the baseline and target hemoglobin levels, the rate of hemoglobin increase, and the clinical situation.

When prescribing ESAs, the potential benefits (including improved quality of life, school attendance, and avoidance of transfusions) versus potential harms of treatment should be weighed, and potential benefits and risks regarding relatively high or low hemoglobin levels should be discussed with the patient (or parents) to make an informed decision on the target hemoglobin level considering their opinion. ESAs should be prescribed with extreme caution to patients at high risk for stroke (including those with a history of stroke) and patients with malignant neoplasms. ESAs are contraindicated in this group of patients if Hb exceeds 130 g/L.

ESAs are administered intravenously or subcutaneously in hemodialysis patients. In other patients (pre-dialysis stage, peritoneal dialysis), ESAs should be administered subcutaneously.

To treat renal anemia in patients with CKD, all ESAs approved by regulatory authorities of the Russian Federation are permitted (ATC group – B03XA: Other antianemic preparations) short-acting (epoetin alfa**, epoetin beta**), intermediate-acting (darbepoetin alfa**), and long-acting (methoxy polyethylene glycol-epoetin beta**, roxadustat in adult patients, and #methoxy polyethylene glycol-epoetin beta** in children)^[1], which have state registration and are included in the state register of medicines for medical use. The choice of a specific ESA for each patient is individual and determined by clinical factors.

In adult patients with anemia of CKD, along with other ESAs, the possibility of prescribing a new class of ESAs from the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) group – roxadustat (ATC – B03XA: Other antianemic preparations) – should be considered as oral tablets, 3 times a week; the recommended starting dose of roxadustat is 70 mg three times a week for patients with a body weight of less than 100 kg and 100 mg three times a week for patients with a body weight of 100 kg or more [15-18].

Patients with cardiovascular disorders should be monitored particularly closely. Arterial hypertension is not a contraindication to ESA therapy. If an increase in blood pressure is observed during anemia treatment, adequate antihypertensive therapy should be administered.

Use of EPO in children:

In children with chronic kidney disease (CKD), anemia is diagnosed at a hemoglobin concentration of <110 g/L at 0.5–5 years of age; <115 g/L at 5–12 years of age; and <120 g/L at 12–15 years of age [1, 34].

The estimated starting dose of short-acting ESAs (recombinant human EPO – epoetin alfa**, epoetin beta**) is 20–50 IU/kg (single dose) 3 times a week or 100–150 IU/kg/week [1, 34]. After identifying anemia in a CKD patient, all correctable causes of anemia should be corrected before considering erythropoiesis-stimulating agent (ESA) therapy – ruling out vitamin B12 deficiency, folic acid deficiency, and iron deficiency.

When treating children with chronic kidney disease, therapy initiation is recommended when hemoglobin is below 100 g/L; exceeding a rhEPO (epoetin alfa**, epoetin beta**) dose of 10,000 IU per week is not recommended [6]. Target hemoglobin values in patients under 18 years of age with CKD stages G3–G5 are 110–120 g/L [34]. If it is necessary to decrease the hemoglobin concentration, preference should be given to reducing the dose/frequency of the ESA rather than completely discontinuing it [1, 34]. For darbepoetin alfa**, the initial subcutaneous or intravenous dose is 0.45 mcg/kg of body weight once a week; in patients not receiving dialysis, an initial dose of 0.75 mcg/kg subcutaneously once every two weeks may be used.

When switching from rhEPO (epoetin alfa**, epoetin beta**) to darbepoetin alfa**, a conversion factor of 240 is used (the weekly rhEPO dose in international units is divided by 240 to obtain the single weekly dose of darbepoetin alfa** in mcg) [1].

Data from the NAPRTCS registry indicate that younger children require higher doses of ESAs (epoetin alfa**, epoetin beta**) than adults: 275–350 IU/kg/week for infants and 200–250 IU/kg/week for other children [35].

The frequency of ESA administration should be selected individually based on the assessment of CKD stage, other treatment regimens, efficacy, patient preferences, and ESA type.

The target rate of Hb increase is 10 g/L over the first 2 weeks. If the increase in Hb level is not fast enough (less than 10 g/L over a 4-week period), the dose of the drug should be increased by approximately 25%. Dose increases should be made no more often than once every four weeks. In young children, compared to adults, the increase in Hb level may start later. Therefore, the ESA dose is increased if the Hb level does not increase by 20 g/L over 8 weeks or if the hemoglobin level is insufficient to prevent blood transfusions.

The increase in Hb should not exceed 10 g/L over any 2-week period.

A dose reduction is carried out when the Hb level approaches 120 g/L (110 g/L in children under 2 years of age) or when the rate of Hb growth is higher than 10–20 g/L over 2 weeks. The minimum interval between dose adjustments in an outpatient setting is usually two weeks, since the effect of a dose change will not be noticeable over a shorter period.

In hemodialysis CKD patients, rhEPO products (epoetin alfa**, epoetin beta**, darbepoetin alfa**) can be administered intravenously or subcutaneously; in patients receiving peritoneal dialysis or in the pre-dialysis stage of CKD, epoetin alfa**, epoetin beta**, or darbepoetin alfa** are recommended subcutaneously [1]. For short-acting ESAs, the efficacy of subcutaneous administration in hemodialysis patients may be higher than intravenous [36].

Patients with cardiovascular disorders should be monitored particularly closely. Arterial hypertension is not a contraindication to ESA therapy. If an increase in blood pressure is observed during anemia treatment, adequate antihypertensive therapy should be administered. It is recommended to use ESAs with great caution in CKD patients with active malignant neoplasms (especially if the expected outcome is cure) and in patients with a history of stroke.

In the initial phase of ESA therapy, hemoglobin concentration must be measured at least monthly or once every 2 weeks; in the maintenance phase, with a stable hemoglobin level, monitoring is required at least monthly.

In the treatment of chronic anemia, we recommend avoiding red blood cell transfusions where possible to minimize the overall risks associated with their use. In transplant-eligible patients, we especially recommend avoiding where

possible, red blood cell transfusions to minimize the risk of alloimmunization.

Use of EPO in adults:

Anemia treatment with ESAs is carried out in two stages: a correction phase, during which the lower limit of the target Hb level must be achieved in no more than 4 months, followed by a maintenance therapy phase.

In the correction phase, starting doses of rHuEPO are used, which are typically 30% (20–50%) higher than maintenance doses. The initial doses of epoetin alfa** and epoetin beta** are usually 20–50 IU/kg of body weight three times a week. For patients with CKD stage 5 on hemodialysis, hemofiltration, or hemodialysis, either intravenous or subcutaneous administration of ESAs is possible. In patients with non-dialysis CKD and CKD stage 5 on peritoneal dialysis, the subcutaneous route is recommended. Darbepoetin alfa** is usually initiated at a dose of 0.45 mcg/kg of body weight once weekly subcutaneously (s.c.) or intravenously (i.v.), or 0.75 mcg/kg of body weight once every two weeks s.c. The starting dose of methoxy polyethylene glycol-epoetin beta** is 0.6 mcg/kg of body weight every two weeks s.c. or i.v. for non-dialysis and dialysis patients, respectively, or 1.2 mcg/kg of body weight s.c. every 4 weeks for non-dialysis patients. A higher hemoglobin level requires a lower initial dose, except for methoxy polyethylene glycol-epoetin beta**, for which the initial dose remains unchanged. In patients with a history of cardiovascular disease, thromboembolism, and seizures, the initial dose should be reduced. The weekly dose of epoetin alfa** and epoetin beta** can be subsequently increased every 4 weeks by 3 × 20 IU/kg if the hemoglobin increase is insufficient. Dose increases should not occur more frequently than once a month. If the hemoglobin level increases and approaches the upper limit of the target range, the EPO dose should be reduced by approximately 25%. If hemoglobin continues to rise, therapy should be temporarily suspended until hemoglobin begins to decline, at which point therapy should be resumed at a dose approximately 25% lower than the previous dose. If the hemoglobin level has increased by more than 10 g/L over two weeks, or 20 g/L over a month, the EPO dose should be reduced by 25% [1].

3.2 Treatment of patients with ESA resistance

ESA resistance is defined as the failure to achieve an increase in hemoglobin concentration after ESA administration at a standard dose for one month. In adult patients, ESA resistance is currently defined as the need to use more than 20,000 IU/week (300 IU/kg/week s.c. or 450 IU/kg/week i.v.) of epoetin alfa** or epoetin beta**, or more than 1.5 mcg/kg (approximately 100 mcg/week) of darbepoetin alfa**, and more than 2.5 mcg/kg (more than 200 mcg) of methoxy polyethylene glycol-epoetin beta**. This is more than 2.5 times the average effective ESA dose, since the vast majority (more than 90%) of patients without iron deficiency will respond to lower ESA doses. At the same time, the incidence of resistance to ESA therapy is unknown.

• In CKD patients with anemia and ESA resistance, it is not recommended to increase the ESA dose by more than twofold compared to the standard weight-based dosage [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Adult patients with CKD and anemia, presenting with ESA resistance and signs of inflammation (CRP > 5 mg/L) and/or impaired iron reutilization (ferritin elevation above 500 ng/mL with a low transferrin saturation < 20%), may be recommended to discontinue EPO and convert to the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) roxadustat (ATC: B03XA: Other antianemic preparations) in equivalent doses [16, 32, 33].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• Patients with CKD and anemia with ESA resistance are recommended to undergo evaluation to identify the causes and correct treatable causes [1–7, 9].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in patients who remain resistant to ESAs despite the correction of treatable causes, it is recommended to rule out the most common causes of resistance: 1) iron deficiency (absolute or functional) and 2) inflammatory diseases. To monitor the activity of the latter, CRP monitoring is necessary and should be performed regularly, at least every 3 months. If CRP rises above 5 mg/L in patients undergoing hemodialysis, the biocompatibility of dialysis membranes and the quality of dialysis water should be checked.

Conditions that may cause resistance to ESA therapy:

- chronic blood loss;

- secondary and tertiary hyperparathyroidism;

- aluminum intoxication;

- hypovitaminosis (folic acid and vitamin B_{12 deficiency);}

- malignant neoplasms (including oncohematological diseases);

- protein-energy malnutrition;

- inadequate dialysis;

- side effects of certain medications (L01: Antineoplastic agents; L04A: Immunosuppressants; C09A: ACE inhibitors, etc.).

• Patients with CKD and anemia who remain resistant to ESAs despite the correction of treatable causes are recommended to have individualized treatment with the following potential options [1–7, 9]:

- Observation, if an acceptable decrease in hemoglobin level is present

- Continuation of ESA treatment if there is at least a moderate positive effect

- Blood transfusions.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.3 Blood transfusions in patients with CKD and anemia

Blood transfusions in CKD patients should be used only for direct indications: a drop in Hb below 70 g/L or 80 g/L, after surgical procedures in the presence of clear symptoms associated with anemia, in case of resistance to ESA therapy or high risks of ESA therapy, in agreement with a hematologist and/or transfusion specialist.

• In CKD patients with symptoms caused by anemia, to stabilize the patient's condition or in case of preoperative preparation, it is recommended to consider red blood cell transfusion [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: indications for blood transfusion in chronic anemia may arise in cases of ineffectiveness of ESA therapy or in acute conditions (e.g., acute hemorrhage, unstable ischemic heart disease, or concurrent hematological pathology: hemoglobinopathies, pure red cell aplasia, myelodysplasia, hemoblastosis, and other hematological disorders with ESA resistance).

The decision to perform a blood transfusion should be based on the appearance of symptoms caused by anemia, rather than on an arbitrarily chosen critical hemoglobin level.

• In CKD patients with anemia in the absence of anemia symptoms, it is recommended to avoid red blood cell transfusions whenever possible to minimize the risks associated with their use [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: all treatable causes should be ruled out before initiating treatment.

• In CKD patients with anemia who are eligible for transplantation, it is recommended to particularly avoid blood transfusions whenever possible to minimize the risk of alloimmunization [1–6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

^[1] Only in adult patients with anemia in CKD

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific medical rehabilitation for children and adults with anemia in CKD has not been developed.

5. Prevention and Dispensary Observation

Primary prevention includes a balanced diet, timely diagnosis and treatment of iron deficiency, and timely initiation of dialysis. About 47% of patients already require ESA therapy at the predialysis stage. Following the initiation of hemodialysis and peritoneal dialysis, virtually all patients require ESA prescription.

Patients with anemia associated with CKD should be monitored for life.

6. Organization of Medical Care

Considering that anemia is a typical complication of CKD, its correction is carried out as part of the treatment of the underlying disease. Indications for hospitalization include severe anemia (Hb ≤ 70–75 g/L, Ht ≤ 0.25–0.30 L/L) or the presence of symptoms and signs of anemic hypoxia even at higher Hb concentration values.

7. Additional Information

No.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Rumyantsev, Alexander Grigorievich – MD, Academician of the Russian Academy of Sciences, President of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Professor at the Department of Hematology, Oncology and Radiotherapy, Faculty of Pediatrics, Pirogov Russian National Research Medical University

2. Shilov, Evgeny Mikhailovich – MD, Chief freelance nephrologist of the Russian Ministry of Health, Professor at the Department of Internal Professional Diseases and Rheumatology, Institute of Clinical Medicine, Sechenov University

3. Maschan, Alexey Alexandrovich – MD, Corresponding Member of the Russian Academy of Sciences, Deputy General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Professor at the Department of Hematology, Oncology and Radiotherapy, Faculty of Pediatrics, Pirogov Russian National Research Medical University, member of the European Hematology Association

4. Trofimova, Arina Gennadievna – Nephrologist, Head of the Department of Renal Replacement Therapy with a Transplantation Group and Day Hospital, National Medical Research Center for Children's Health of the Russian Ministry of Health

5. Demikhov, Valery Grigorievich – MD, Prof., Director of the Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health

6. Morshchakova, Elena Fedorovna – MD, Professor

7. Lunyakova, Maria Anatolyevna – PhD, Head of the Department of Hematology and Oncology, Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health

8. Skobin, Vladimir Borisovich – PhD, Hematologist at the Department of Hematology and Oncology, Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health

9. Rekhtina, Irina Germanovna – MD, Head of the Chemotherapy Department for Plasma Cell Dyscrasias, National Medical Research Center for Hematology of the Russian Ministry of Health

10. Denisova, Elena Nikolaevna – PhD, Head of the Dialysis Group, Resuscitation and Intensive Care Unit, National Medical Research Center for Hematology of the Russian Ministry of Health

11. Al-Radi, Lyubov Sattarovna – PhD, Senior Researcher at the Department of Diagnostics and Treatment of Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health

12. Kotenko, Oleg Nikolaevich – MD, Chief freelance specialist in nephrology for the city of Moscow, Head of the Moscow City Scientific and Practical Center of Nephrology and Kidney Transplant Pathology, City Clinical Hospital No. 52

13. Shilo, Valery Yuryevich – Associate Professor at the Department of Nephrology, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Chairman of the Supervisory Board of the Association of Medical Organizations for Nephrology and Dialysis

14. Shutov, Evgeny Viktorovich – Head of the Interdistrict Nephrology Center, S.P. Botkin City Clinical Hospital, Head of the Department of Nephrology and Hemodialysis, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Nephrologists

2. Hematologists

3. Pediatricians

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

A3.1 Adverse effects of ESAs

During periods of hemoglobin increase, arterial hypertension may worsen. Patients with CKD may experience hyperkalemia. Headache, arthralgia, influenza-like syndrome, elevated blood platelet count, and allergic reactions are rarely observed. Subcutaneous administration may cause injection site pain. In children under 3 years of age, the use of pharmaceutical forms containing benzyl alcohol as a preservative is contraindicated due to potential toxic effects. ESAs should be prescribed with caution to patients at high cardiovascular risk, patients with active infections, pulmonary hypertension, and a history of thrombosis and malignancies [16].

When prescribing epoetin alfa**, epoetin beta**, and darbepoetin alfa**, the possibility of PRCA development should be considered. PRCA should be ruled out in case of a sudden decrease in hemoglobin concentration by 5-10 g/L per week or an increase in blood transfusion requirements to 1-2 transfusions per week with an absolute reticulocyte count of less than 10,000/µL.

If PRCA is detected, ESA therapy should be discontinued in patients with PRCA developing due to the appearance of autoantibodies.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Anemia frequently accompanies CKD in children and adults, resulting from suppressed erythropoiesis in the bone marrow and iron deficiency.

The main symptoms of anemia include palpitations, dyspnea (worsened by physical exertion), dizziness, tinnitus, weakness, increased fatigue, and pallor of the skin. It should be noted that most symptoms are non-specific signs of anemia that overlap with the symptoms of the underlying disease.

All patients with CKD should undergo laboratory testing to rule out anemia. There are effective methods for correcting anemia using iron preparations and ESAs (B03XA: Other antianemic preparations).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.