Characteristics of the Development of Nutritional Insufficiency in Patients Treated with Chronic Haemodialysis

The dissertation is devoted to the study of the characteristics of the development of nutritional insufficiency in patients with terminal renal failure treated with chronic haemodialysis. The research aims to clarify the pathogenetic role of protein-energy insufficiency, hyperleptinaemia, and pro-inflammatory cytokines in the formation of impaired nutritional status in this group of patients. The work compares caliperometry and bioimpedance analysis as methods for assessing body composition and evaluates the diagnostic significance of determining serum levels of leptin, interleukin-6, and interleukin-8. The data obtained expand the understanding of the mechanisms underlying the development of nutritional insufficiency during chronic haemodialysis and may be used to improve the diagnosis and correction of nutritional status disorders in haemodialysis patients.

Relevance of the problem.

One of the topical problems of contemporary nephrology is the development of nutritional insufficiency (NI) in patients treated with chronic haemodialysis (HD) [Cooper L., 2001; Carvalho K.T. et al., 2004]. After five years of HD therapy, the proportion of patients with NI amounts to 40–50% and continues to increase thereafter [Walser M., 1999]. Nutritional status is one of the independent prognostic factors of morbidity and mortality in haemodialysis patients [Lowrie E.G. et al., 1994; Beto J.A. et al., 1999]. Despite the relevance of this problem, there is still no unified view on the mechanisms of the development of NI in such patients. The principal factors in the development of NI include: a decrease in the intake of basic nutrients due to various causes, which leads to the development of protein-energy insufficiency (PEI) in haemodialysis patients; metabolic disturbances inherent in terminal renal failure itself, in particular, an increase in the level of "potential uraemic toxins" normally eliminated by the kidneys; and also the influence of factors associated with the HD procedure [Kopple J.D., 2001]. Equally important is the role of chronic inflammation in the development of NI in this group of patients [Stenvinkel P. et al., 2000; Kopple J.D., 2001].

Among the "potential uraemic toxins," the hormone leptin, discovered in 1994, is of particular interest in connection with the development of NI in HD patients. Leptin is an anorexigenic hormone that is secreted by adipocytes into the blood and controls the mass of adipose tissue by stimulating lipid metabolism in the body. The principal property of leptin is the restriction of the volume of food products consumed and the maintenance of lipid metabolism at a normal level [Pankov Yu.A., 2003] by reducing the main orexigenic neurotransmitters on the one hand and inducing anorexigenic neurotransmitters on the other. In patients treated with HD, both men and women, the level of circulating leptin is higher than in healthy individuals [Plata-Salaman C.R., 2004; Mak R.H. et al., 2006]. Given that leptin suppresses appetite and increases energy expenditure, it has been suggested that hyperleptinaemia in HD patients may be one of the factors mediating the development of NI in this patient population [Stenvinkel P. et al., 2000; Cheung W. et al., 2005; Mak R.H. et al., 2006].

Recent studies have shown that in patients with terminal renal failure (TRF) treated with HD, there is an elevation of inflammatory markers in serum, in particular of a number of pro-inflammatory cytokines [Don B.R., Kaysen G.A., 2000; Bayes B. et al., 2003]. In chronic inflammation, pro-inflammatory cytokines exert an active influence on metabolism, leading to the development of anorexia, protein catabolism, impairment of the function of the main anabolic hormones, increased energy expenditure, and a reduction in body fat content [Kershaw E.E., Flier J.S., 2004]. These effects of chronic inflammation resemble the metabolic disturbances that lead to the development of NI observed in haemodialysis patients. Moreover, chronic inflammation and NI are widespread in patients treated with HD and tend to coexist [Kaysen G.A., 2000; Bayes B. et al., 2003]. In this regard, a hypothesis has emerged that chronic inflammation is one of the causative factors in the development of NI in this group of patients [Stenvinkel P. et al., 2000; Pupim L.B., Ikizler T.A., 2003; Yao Q. et al., 2004].

The high prognostic significance of nutritional insufficiency in haemodialysis patients explains the need for timely and accurate diagnosis of this condition. However, at present there are certain difficulties in assessing a number of nutritional status parameters in this category of patients, which considerably complicates the detection of nutritional insufficiency.

Aim of the study: to clarify the pathogenetic significance of protein-energy insufficiency, leptin, and pro-inflammatory cytokines in the development of nutritional insufficiency in patients with terminal renal failure treated with chronic haemodialysis.

Research objectives:

In patients with terminal renal failure treated with chronic haemodialysis:

1. To compare caliperometry and bioimpedance analysis in order to identify the optimal approach to determining body composition.

2. To clarify changes in serum levels of leptin and pro-inflammatory cytokines.

3. To trace the relationships between serum levels of leptin and pro-inflammatory cytokines and the parameters of nutritional insufficiency.

4. To evaluate the contribution of protein-energy insufficiency to the development of nutritional insufficiency.

5. To refine the indications for determining the concentrations of leptin and pro-inflammatory cytokines in serum.

Scientific novelty of the study.

For the first time, the possibility of the onset of nutritional insufficiency has been demonstrated and the mechanisms of its development in haemodialysis patients have been clarified, even with adequate haemodialysis and sufficient intake of basic nutrients.

The pathogenetic role of hyperleptinaemia in the development of nutritional insufficiency in patients treated with chronic haemodialysis has been substantiated, due to the direct suppressive effect of leptin on lean body mass, especially in the early period of haemodialysis therapy and in patients with excess body weight.

By applying the method of multiplex analysis of the content of pro-inflammatory cytokines in the serum of patients with terminal renal failure treated with chronic haemodialysis, a relationship has been established between elevated levels of pro-inflammatory cytokines and the development of nutritional insufficiency in haemodialysis patients. It has been shown that an increase in the duration of treatment is accompanied by an intensification of the signs of chronic inflammation.

The advantage of bioimpedance analysis over caliperometry for determining fat and muscle mass in patients treated with chronic haemodialysis has been demonstrated.

Practical significance of the work.

The diagnostic significance of determining serum leptin levels in patients treated with chronic haemodialysis has been demonstrated in the early stages of haemodialysis therapy with the aim of clarifying the genesis of nutritional insufficiency, which will enable timely and adequate correction of nutritional insufficiency in this group of patients.

It has been established that, for monitoring nutritional insufficiency, the most informative of the pro-inflammatory cytokines are interleukin-6 and interleukin-8 in serum. An increase in their concentration above the norm, in the absence of active foci of chronic inflammation, requires therapeutic measures aimed at correcting the severity of the inflammatory process.

It has been established that in the assessment of body composition, bioimpedance analysis has advantages over caliperometry, as it allows a more accurate determination of fat mass and provides more accurate indicators of muscle mass, both in absolute and relative terms.

Statements defended:

1. Nutritional insufficiency is widespread in patients with terminal renal failure treated with chronic haemodialysis, even with sufficient intake of basic nutrients and adequate haemodialysis therapy.

2. Hyperleptinaemia and elevated serum levels of pro-inflammatory cytokines (interleukin-6, interleukin-8) have a pathogenetic significance in the development of nutritional insufficiency in haemodialysis patients.

3. A staged influence of non-nutritional factors on the development of nutritional insufficiency in haemodialysis patients is observed.

4. The addition of bioimpedance analysis and the determination of serum levels of leptin, interleukin-6, and interleukin-8 to the generally accepted methods significantly improves the quality of diagnosis of impaired nutritional status in patients treated with chronic haemodialysis.

Personal contribution of the author to the study.

The collection of material was carried out personally by the author, who studied the primary medical documentation, conducted clinical and anthropometric examinations of patients, performed the collection and preparation of samples for biochemical analysis, hormonal study, and multiplex analysis of pro-inflammatory cytokine content, and maintained the developed electronic database.

The initial processing of the results was also carried out personally by the author, which served as the basis for subsequent analysis using, among other methods, multivariate statistics.

Approval of the dissertation.

The results of the dissertation were reported at the meetings of the Problem Commission on Nephrology of SPbGMU named after Academician I.P. Pavlov (2006, 2007), at joint meetings of the Department of Propaedeutics of Internal Diseases and the Research Institute of Nephrology of SPbGMU named after Academician I.P. Pavlov (2005, 2006, 2007). The main provisions of the dissertation research were also reported at the VI Interregional Scientific and Practical Conference "Artificial Nutrition and Infusion Therapy of Patients in Critical Care Medicine" (Saint Petersburg, 2006), the 10th All-Russian Medical and Biological Conference of Young Researchers "Man and His Health" (Saint Petersburg, 2007), the II International Youth Medical Congress "Saint Petersburg Scientific Readings-2007" (Saint Petersburg, 2007), and at a meeting of the Nephrology Section of the Saint Petersburg Society of Therapists named after S.P. Botkin (Saint Petersburg, 2007).

Implementation of research results into practice.

The results of the dissertation work have been implemented into the practice of patient management at the Department of Chronic Haemodialysis of the Clinic of Propaedeutics of Internal Diseases of SPbGMU named after Academician I.P. Pavlov, and are also used in the training of specialists at the Department of Nephrology and Dialysis of the Faculty of Postgraduate Education of SPbGMU named after Academician I.P. Pavlov.

Publications.

On the topic of the dissertation research, 7 printed works have been published, including 5 articles in scientific journals recommended by the Higher Attestation Commission of the Russian Federation.

Scope and structure of the dissertation.

The dissertation is set out on 114 pages of typewritten text and consists of an introduction, a review of the literature, a description of patients and research methods, the author's own data, a discussion of the results obtained, conclusions, practical recommendations, and a bibliography. The work contains 9 figures and 19 tables. The bibliography includes 234 literary sources, of which 11 are in Russian and 223 in foreign languages.