Assessment of Erythropoietin Levels in the Diagnosis and Characterization of Chronic Kidney Failure and Anemia in Children

The dissertation is devoted to the assessment of erythropoietin levels in the diagnosis and characterization of chronic kidney failure and anemia in children. The investigation is based on clinical materials from the pediatric nephrology department of the City Clinical Hospital of Nalchik and encompasses children with chronic kidney failure of various etiologies and stages residing in the territory of the Kabardino-Balkarian Republic. In the work, the structure of urinary system disorders as causes of chronic kidney failure has been studied, the frequency of the anemic syndrome has been established, and the correlation between erythropoietin levels, red blood cell parameters, and partial kidney functions at preazotemic and azotemic stages of the disease has been analyzed. Special attention is devoted to the role of erythropoietin as an early diagnostic marker of chronic kidney failure, the influence of congenital urinary system pathology on the course of the disease, and the significance of the infectious factor in the development of anemia.

Relevance of the Topic. Since the mid-1980s, a significant increase in the incidence of urinary system disorders (USD) in children has been noted (Ignatova M.S., Grossman P., 1986; Ignatova M.S., Veltishchev Yu.E., 1989; Tsaregordtsev A.D., 2003). The prevalence of USD, based on official statistics derived from the study of morbidity by healthcare utilization in various regions of the country, ranges from 18 to 48 per 1000 pediatric population, averaging 33‰ (Perepelkina N.Yu., 1995). Simultaneously, an increase in the frequency of congenital and hereditary kidney diseases in the structure of nephrological morbidity is observed. This occurs in parallel with the growth of hereditary and congenital pathology in the structure of morbidity and mortality of the pediatric population (Veltishchev Yu.E., Barashenev Yu.I., 1978; Ignatova M.S. et al., 1984). Congenital and hereditary nephropathies, often having a progressive course, lead to the early formation of chronic kidney failure (CKF) in a child (Ignatova M.S., Grossman P. et al., 1981, 1986; Milenkov S.T. et al., 1981; Tzibisheva A.K. et al., 1982; Papyan A.V., Savenkova N.D., 1997).

Epidemiological and clinical investigations have established that the frequency of CKF development in the presence of congenital and hereditary pathology in children is significantly higher than in acquired kidney and urinary tract diseases (Ignatova M.S., Grossman P., 1986; Ignatova M.S., Veltishchev Yu.E., 1989; Naumova V.I., Papyan A.V., 1991; Papyan A.V., Savenkova N.D., 1997).

At the same time, the prevalence of urinary system disorders in the Kabardino-Balkarian Republic has not been studied. There are also no data on the frequency of chronic kidney failure and one of its main syndromes — anemia in its presence. The contribution of congenital USD pathology to the timing of CKF manifestation and the severity of its course has not been investigated.

The anemic syndrome is one of the characteristic manifestations of CKF of various etiologies (Naumova V.I., Papyan A.V., 1991). As a developmental and growth delay, anemia can be one of the first signs of kidney disease with an indolent-progressive course (Ignatova M.S., Grossman P., 1986).

Many symptoms of CKF are associated with anemia. It is one of the main factors determining the quality of life of patients with CKF (Lashutin S.V., Nikolaev A.Yu., 1997). At the same time, correction of red blood cell parameters leads to improvement of azotemic kidney function (Topchii I.I., 2002) and reduces mortality among patients with CKF (Gafter U. et al., 1994; Xia H. et al., 1999).

According to Van Damme-Lombaerts (1999), treatment of anemia significantly facilitates the course of the disease in the terminal stage of kidney failure in children (163).

The pathogenesis of anemia in CKF is complex and not yet fully understood. The development of anemia has traditionally been associated with three main causes: deficiency of endogenous erythropoietin (EPO), shortened lifespan of erythrocytes, the presence of erythropoiesis inhibitors; significant importance is also attached to enhanced bleeding tendency due to platelet defects (Ermolenko V.M., Ivashchenko M.A., 2002). The main factor in the development of anemia is considered to be a relative or absolute insufficiency of EPO production (Lashutin S.V., Nikolaev A.Yu., 1997; Ermolenko V.M., Ivashchenko M.A., 2002; Rumyantsev A.G., Morshakova E.D., Pavlov A.D., 2002).

In recent years, important data have been obtained regarding the biological properties of EPO, its role in the pathogenesis of renal anemia (Rumyantsev A.G., Morshakova E.D., Pavlov A.D., 2002). Nevertheless, many questions regarding EPO production in CKF remain unclear. Thus, in recent years it has been demonstrated that in some cases, shrunken kidneys in uremia are capable of producing sufficient amounts of EPO (Ermolenko V.M., Ivashchenko M.A., 2002). Some patients with anemia in CKF retain the ability to synthesize EPO in response to acute blood loss and hypoxia (Chandra M. et al., 1988; Topchii I.I., 2002).

The role of erythropoietin not only in the formation of anemia but also in the early diagnosis and characterization of CKF has not yet been investigated.

Renal partial functions are formed during ontogenesis at different time points. The sequence of impairment of individual functions as CKF progresses has been insufficiently studied. Regarding concentrating and diluting capacity, the question is clear; however, impairments of these functions occur upon the death of a significant portion of nephrons, that is, they are not early signs of CKF. The least studied is the dynamics of impairments of secretory kidney functions, in particular EPO production, as interstitial tissue sclerosis and death of producer cells progress.

To expand the understanding of CKF formation at its early stages, a new approach is necessary, in particular, characterization of secretory kidney function. This characterization is especially important for congenital nephrouropathies having structural dysembryogenesis of renal tissue. This is possible by determining the EPO level. All of the above determines the relevance of the chosen topic.

Goal of the Investigation

The goal of the present investigation is to study the level of erythropoietin in chronic kidney failure depending on etiology and stage of development, and to assess the significance of this parameter.

Tasks of the Investigation

1. To study the structure of urinary system disorders as a cause of chronic kidney failure in children residing in the territory of the Kabardino-Balkarian Republic.

2. To determine the frequency of the anemic syndrome in chronic kidney failure depending on etiology and degree of severity.

3. To study the level of erythropoietin in chronic kidney failure depending on etiology and degree of severity.

4. To compare the level of erythropoietin with red blood cell parameters and partial kidney functions at various stages of chronic kidney failure.

5. To determine the contribution of the infectious factor to the development of anemia in chronic kidney failure.

6. To compare the course of chronic kidney failure in children with dysembryogenesis of the urinary system and acquired pathology.

Scientific Novelty of the Work

For the first time:

1. The structure of urinary system disorders as a cause of chronic kidney failure in children of the Kabardino-Balkarian Republic has been studied.

2. The frequency of the anemic syndrome in chronic kidney failure in children of the Kabardino-Balkarian Republic has been established.

3. Features of the course of chronic kidney failure in congenital and acquired forms of urinary system pathology have been identified.

4. A low level of erythropoietin at early stages of chronic kidney failure has been revealed, even in the absence of anemia.

5. The correlation between the level of erythropoietin and the state of partial kidney functions at various stages of chronic kidney failure has been analyzed.

6. A positive influence of anti-infectious therapy on the prevention of anemia at late stages of chronic kidney failure has been established.

Practical Significance of the Work

1. The high frequency of congenital pathology, in particular obstructive uropathies, in the structure of the etiology of chronic kidney failure in children of the Kabardino-Balkarian Republic, constitutes grounds for recommending the introduction of screening ultrasonography of the urinary system for every child in the territory of the Kabardino-Balkarian Republic during the first months of life.

2. The identification of congenital pathology of the urinary system in chronic kidney failure is a prognostically significant sign, as it determines the character of the course of chronic kidney failure.

3. A low level of erythropoietin is an early sign of chronic kidney failure, which makes its use as a diagnostic sign possible.

4. The high significance of the infectious factor in the development of anemia and chronic kidney failure has been substantiated, as has the necessity of prophylactic administration of anti-infectious therapy, especially in cases of dysembryogenesis of the urinary system.

Presentation and Implementation of the Results of the Work in Practice

Based on the materials of the dissertation, 5 publications have been issued. The results of the work were reported at the Congress of Pediatric Nephrologists of Russia (Saint Petersburg, KP 2003), as well as at a sectional meeting of the Union of Pediatricians of the Kabardino-Balkarian Republic. The data of the dissertation investigation are used in seminar and practical sessions for physicians at the Department of Pediatrics, Obstetrics and Gynecology of the Kabardino-Balkarian State University. The results of the investigation have been tested and implemented in the practice of the pediatric nephrology department of the City Clinical Hospital of Nalchik. The dissertation defense took place at the interdepartmental conference of the Department of Pediatric Diseases, Obstetrics and Gynecology, and the Department of Propedeutics of Internal Diseases of the Kabardino-Balkarian State University named after Kh.M. Bербekов on June 25, 2005, and at a meeting of the Department of Pediatrics with courses of perinatology and endocrinology of the FMC and PP of the Saint Petersburg State Pediatric Medical Academy on August 30, 2005.

Positions to be Defended

1. The high frequency of congenital pathology in the structure of causes of CKF in children of the KBR — grounds for examination of all children of early age with the aim of its detection.

2. Congenital pathology of the USD in children of the KBR leads to earlier manifestation of CKF, delay in physical development, and anemia.

3. A low level of EPO is not only a cause of the development of anemia but also a reflection of the degree of impairment of kidney functions, that is, the severity of CKF.

4. Regulation of erythropoiesis by EPO is preserved at early stages of CKF and absent at late stages.

5. Infection is the most important factor in the development of anemia and manifestation of CKF in children with congenital pathology of the urinary system. Prevention of recurrent infection reduces the frequency of anemia in CKF.

Justification of the Dissertation Structure

The structure of the dissertation is determined by the stated goal. The work consists of an introduction, a literature review, a description of materials and methods of investigation, 3 chapters of original research, discussion and conclusion, conclusions, practical recommendations, and a list of references comprising 63 domestic and 105 foreign works. The dissertation is presented on 114 pages of typed text, illustrated with 28 tables, 7 figures, and 3 extracts from medical histories.