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0NEPHROGENIC ANEMIA: ETIOPATHOGENESIS OF ANEMIA IN CHRONIC KIDNEY DISEASE IN CHILDREN (LITERATURE
REVIEW)
Baymuratova G.A.
Medical Institute of Karakalpakstan https://doi.org/10.5281/zenodo.13144967
Abstract. The literature review summarizes the etiology, mechanisms of development and course of anemia syndrome in chronic kidney disease in children. Also there are presented data on epidemiology and risk factors for chronic kidney disease due to anemia in the development of which the leading role is played by erythropoietin and iron deficiency.
Keywords: chronic kidney disease, anemia syndrome, erythropoietin, children.
The relevance of this issue lies in the fact that anemia is one of the characteristic manifestations of chronic kidney disease (CKD) in children, detected by measuring hemoglobin (Hb) levels. Low hemoglobin levels (below 99 g/L; p < 0.05) in children with CKD are associated with a high mortality rate [3, 4]. It is known that the frequency and severity of anemia increase with the deterioration of kidney function, specifically depending on the stage of CKD [15, 24].
In the development of anemia in chronic kidney disease (CKD), a key role is played by the reduction in the production of erythropoietin, which is produced by the kidneys. In addition to this, other factors contribute to the development of anemia, such as a shortened lifespan of red blood cells, chronic blood loss, iron or folic acid deficiency, secondary hyperparathyroidism, chronic inflammation, and others [6, 14].
The objective of this literature review is to summarize the existing knowledge on the etiology, mechanisms of development, and progression of anemia syndrome in chronic kidney disease (CKD) in children.
Nephrogenic anemia, according to the criteria set by The National Institute for Health and Clinical Excellence (NICE), is defined as a hemoglobin level below 110 g/L in adults and children over 2 years old, and below 105 g/L in children under 2 years old with confirmed CKD (glomerular filtration rate less than 60 ml/min/1.73 m2) or the presence of symptoms characteristic of anemia (such as fatigue, shortness of breath, weakness, and rapid heartbeat) [12].
Currently, there are several different criteria for diagnosing anemia in patients with kidney pathology. The modern criteria recommended in various guidelines, such as the EBPG (Revised European Best Practice Guidelines for the Management of Anemia in Patients with Chronic Renal Failure, 2004) and NKF-K/DOQI (K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease), closely align with the definition of anemia proposed by the World Health Organization (WHO) [1].
The primary pathogenetic mechanism of renal anemia is the disruption of the normal inverse relationship between hematocrit levels and erythropoietin production. Under normal conditions, a decrease in hematocrit levels is accompanied by an increase in erythropoietin production. When hemoglobin levels drop due to reduced partial pressure of oxygen, autoregulatory mechanisms are activated to promote the dimerization of hypoxia-inducible factor
HIF1. The activated HIF1 complex stimulates the transcription of the erythropoietin gene, leading to increased production of erythropoietin [4, 5, 7].
It is known from the literature that uncorrected anemia accelerates the progression of chronic kidney disease (CKD) and can lead to its terminal stage. Recent studies conducted over the past decade have revealed a significantly increased risk of hospitalization in children with CKD who had reduced hemoglobin (Hb) levels [3, 18]. Effective correction of anemia can slow the progression of renal failure and, therefore, plays an important role in the overall management of patients with CKD [2, 25].
Research by M.A. Atkinson has identified racial differences in hemoglobin levels among children in the terminal stages of CKD [13, 31]. According to the study, African American children exhibit lower hemoglobin levels in CKD compared to white children. The most significant differences in hemoglobin levels are found at the lower boundaries of the distribution within each of these populations [7, 11, 26].
Anemia in chronic kidney disease (CKD) can develop at any stage of the disease but most commonly manifests in stage 3, which is considered the initial stage of chronic renal failure (CRF). The primary cause of anemia in CKD is erythropoietin deficiency, along with other contributing factors such as reduced erythrocyte lifespan caused by metabolic acidosis and iron deficiency [8, 16]. The standard treatment for anemia in CKD is the use of erythropoietin (EPO) drugs, which can be short-acting (e.g., epoetin) or long-acting (e.g., darbepoetin). However, in some cases, even the maximum doses of EPO fail to achieve the target hemoglobin levels, leading to EPO resistance. EPO resistance is often due to either absolute or relative (functional) iron deficiency. In relative iron deficiency, the increased iron demand during EPO therapy cannot be fully met by the available stores, exacerbated by declining kidney function and reduced synthesis of erythrocyte growth hormone in the peritubular cells of the proximal nephron [6, 9].
According to M. Nangaku et al. (2007), the activation of the erythropoietin transcription gene occurs when HIF binds to the hypoxia-responsive element (HRE) [17]. The synthesis of erythropoietin is induced through the activation of erythron precursor cells via interaction with the erythropoietin receptor (EPOR). The signaling pathway is regulated by factors that control signal transduction and transcription activation [10].
The severity and duration of anemia in CKD affect the intensity of asthenic syndrome, exercise tolerance, susceptibility to infections, and the risk of cardiovascular complications. Early-stage CKD anemia correction with iron supplements improves the quality of life and reduces the risk of cardiovascular mortality [6, 30]. The primary diagnostic criterion for anemia in CKD patients is a hemoglobin concentration two standard deviations below the mean for age and sex: less than 11.5 g/dL for adult women, less than 13.5 g/dL for adult men, and less than 12.0 g/dL for elderly men (over 70 years old) [22].
In their 2012 study, E.A. Hamed and colleagues investigated the impact of hypoxia and oxidative stress biomarkers in children undergoing hemodialysis for chronic kidney disease (CKD) [15, 19]. The study included 40 CKD patients on hemodialysis and 20 healthy children as a control group. Hypoxia-inducible factor (HIF-1a) and vascular endothelial growth factor (VEGF) were measured in blood using specialized ELISA kits through an enzyme-linked immunosorbent assay (ELISA). Total antioxidant capacity (TAC), total peroxidase capacity (TPC), pyruvate, and lactate were studied using enzymatic/chemical colorimetric methods. The oxidative stress index (OSI) and lactate/pyruvate (L/P) ratios were calculated using appropriate formulas. The results showed
that total antioxidant capacity (TAC) was significantly reduced both before and after dialysis in patients compared to healthy children [14, 21].
Patients with chronic renal failure (CRF) also face iron metabolism disorders, including decreased iron transport to erythroid cells due to reduced transferrin levels, as well as impaired iron release from stores in hepatocytes and reticuloendothelial system cells [10, 29].
These findings underline the complexity of managing anemia in CKD patients, as the interplay of hypoxia, oxidative stress, and iron metabolism disorders necessitates a comprehensive approach to treatment. Regular monitoring and targeted therapies aimed at addressing these underlying issues are crucial for improving patient outcomes and quality of life.
Hyporegenerative anemias, associated with decreased erythrocyte production, include various forms of impaired heme synthesis. These encompass anemias due to iron deficiency (iron deficiency anemia), iron retention in the body's reticuloendothelial system (RES) with disrupted erythropoietin regulation of bone marrow production (anemia of chronic disease - ACD, anemia of inflammation), erythropoietin deficiency (chronic kidney disease - CKD), and endocrinopathies [4, 6, 28, 30].
According to the PAERI (Prevalence of Anemia in Early Renal Insufficiency) study, the overall prevalence of anemia in chronic kidney disease (CKD) is 47%. This prevalence varies across different stages of CKD: 26.7% among patients with stage I CKD and 75.5% among those diagnosed with stage V CKD. By the time renal replacement therapy begins, approximately two-thirds of CKD patients have a hematocrit (Hct) level below 30% [31].
Addressing the issues of primary prevention of urinary system diseases, based on the early identification of risk factors at individual, family, and population levels, remains crucial. In recent years, there has been an increase in the proportion of kidney pathologies among children within the structure of chronic diseases, especially those related to urinary system disorders [4, 5]. These diseases are typically diagnosed at advanced stages, where significant kidney function impairments have already occurred, often leading to early disability and fatal outcomes [2].
With the increased overall frequency of urinary system pathologies, significant changes in its structure have been observed. The proportion of glomerulonephritis has risen from 1.3% to 4.6%, and tubulointerstitial nephritis from 1.6% to 2.8% (p <0.01). Simultaneously, there has been a sharp increase in dysmetabolic nephropathies from 9.6% to 16.8% and congenital malformations of the urinary system from 14.6% to 26.1% (p <0.0001). An important indicator describing the epidemiological situation is the morbidity rate, which includes microbial-inflammatory processes, dysmetabolic nephropathies, and congenital malformations of the urinary system, collectively accounting for more than 90% of all nephrological diseases [10, 23].
A retrospective analysis by F. Artunc and T. Risler involving 500 patients revealed a certain relationship between hemoglobin levels and serum EPO concentration. Patients were stratified based on the presence or absence of CKD, with adjustments made for anemia severity. EPO levels were reflected in percentiles. In patients without CKD, a clear parametric dependence between anemia severity and increased EPO levels was found. However, with the onset of CKD, this relationship weakens and is completely lost by stages IV-V of the disease. When determining relative EPO deficiency as a drop below the 25th percentile, relative EPO deficiency with hemoglobin levels below 110 g/l was found in 38% of cases at stage I CKD, 67% at stage II, 93% at stage III, and 100% at stages IV and V CKD [32].
Recent studies highlight the multifactorial nature of anemia development in CKD patients [5, 27]. Despite having the same level of renal function, patients with CKD exhibit significant individual variations in hemoglobin levels. This phenomenon may be due to the diverse factors in the pathogenesis of renal anemia. Modern perspectives emphasize the importance of reduced erythropoietin production by the kidneys and the antiproliferative effects of uremic toxins on bone marrow erythroid progenitors. However, it is also noted that inflammation, infection leading to anemia of chronic disease, comorbid conditions, neoplasms, medications, and nutritional deficiencies such as iron, vitamin B12, folic acid, and protein-energy malnutrition can influence anemia development [1, 4, 32].
Thus, for the diagnosis and monitoring of anemia in CKD patients, the following are recommended: measuring hemoglobin levels to determine the severity of anemia, and analyzing red blood cell indices such as mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) to assess the type of anemia. A reticulocyte count is also performed. For determining tissue iron stores and the type of anemia, it is not sufficient to only evaluate serum iron and total iron-binding capacity (TIBC); ferritin levels and transferrin saturation should also be measured [6, 21, 27, 31].
In conclusion, the literature review underscores the pivotal role of erythropoietin and iron deficiency in the development of anemia syndrome in children with chronic kidney disease (CKD). A significant number of patients with renal pathology exhibit the formation of anemia, which manifests as early as the initial stages of CKD. The progression of CKD is associated with both erythropoietin levels and iron metabolism. The development and persistence of anemia in CKD patients not only indicate kidney dysfunction but also hold significant pathophysiological implications.
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