Clinical Significance of Neopterin Determination in Pediatric Kidney Diseases

The dissertation is devoted to the study of the clinical significance of the determination of neopterin — a low-molecular-weight pteridine compound that is a highly sensitive marker of activation of the monocyte link of cellular immunity — at various forms, variants, and stages of chronic glomerulonephritis and non-glomerular kidney pathology in children. In the work, normal reference values of neopterin in serum and its excretion in urine in healthy children have been established for the first time; a comprehensive investigation of neopterin levels in primary chronic glomerulonephritis and non-glomerular kidney diseases has been conducted, with an assessment of the relationship of the indicators with the clinical-laboratory manifestations of the disease, its activity, and the functional state of the kidneys. The obtained data indicate increased neopterin production at all studied kidney diseases, with the greatest increase being characteristic of nephrotic syndrome, especially the steroid-resistant focal segmental glomerulosclerosis, as well as an increase in the neopterin level in the stage of chronic kidney failure, which indicates its involvement in the progression of the pathological process.

According to current concepts, glomerulonephritis (GN) is an immune-mediated disease, the various clinical and morphological variants of which are associated with the activation of different links of the immune system. The course of chronic glomerulonephritis (CGN) depends on a variety of immunopathological and locally cell-mediated reactions that contribute to glomerular damage [11, 17, 42, 43, 49, 65, 131, 151, 156].

Cytokines of inflammatory cells infiltrating renal tissue (monocytes/macrophages, T-lymphocytes), as well as renal glomerular cells and interstitial cells themselves, participate in the mechanisms of development and regulation of pathological processes in glomerulonephritis [1, 11, 42, 70, 96, 103, 111, 117, 154, 168].

Neopterin (NP) is a low-molecular-weight compound belonging to the class of pteridines, which represent a heterogeneous group of substances derived from guanosine triphosphate (GTP). According to current concepts, NP is a non-specific highly sensitive marker of activation of the monocyte link of cellular immunity [25, 26, 178].

The determination of NP in biological fluids of the body represents an alternative approach to the study of immune reactions, which is associated with the quantitative analysis of biochemical changes induced by cytokines [50, 51, 59].

The advantages of NP determination over the study of individual cytokines lie not only in the fact that its level is an integral result of the interaction of individual cytokines, but also in its biological stability, which makes it methodologically more accessible compared with cytokines [26, 52, 71].

In recent years, there has been an exceptionally rapid expansion of the scope of NP use in clinical practice [20, 25, 72, 120].

The determination of NP in biological fluids is used for the diagnosis, prognosis, and also for the assessment of treatment efficacy of a number of diseases [3, 20, 58, 120, 194].

The study of NP is widely used for monitoring the state of cellular immunity in many bacterial, viral [13, 44, 68, 80, 118, 137, 153, 157, 159, 193], systemic, and autoimmune diseases [6, 7, 9, 14, 101, 107, 113, 139, 158], with particular attention being paid to it in transplantology [21, 40, 67, 83, 114, 134, 171].

A high level of neopterin is an indicator of the activity of the immunopathological process and, as a rule, precedes the clinical manifestations of the disease [127, 172, 178].

Nevertheless, despite the proven informativeness of the determination of NP concentration in biological fluids of the body at various immunopathological diseases, there are virtually no studies on the investigation of this indicator at different variants of glomerulonephritis. The role of NP in the pathogenesis of primary CGN has not been clearly formulated, and its significance as a marker of GN activity and a predictor of disease course remains unclear.

The relationship between serum neopterin concentrations, the level of its excretion in urine, and individual indicators of disease activity has not been studied. There is virtually no information on the influence of the functional state of the kidneys on the serum level of NP and its excretion in urine in the preazotemic stage of kidney diseases.

Objective of the work: to establish the clinical significance of the determination of neopterin content in serum and the level of its excretion in urine at various forms, variants, and stages of CGN, as well as in non-glomerular kidney pathology in children.

Research tasks:

1. To study the content of neopterin in serum and the level of its excretion in urine in patients with primary CGN depending on the morphological variant, clinical form, and stage of the disease.

2. To identify the presence of a relationship between changes in neopterin levels in serum and urine and the duration of the disease, individual laboratory indicators of CGN activity, and the functional state of the kidneys.

3. To assess the influence of immunosuppressive therapy on changes in serum neopterin concentrations and the level of its excretion in urine in steroid-resistant and steroid-sensitive nephrotic syndrome.

4. To study the content of neopterin in serum and the level of its excretion in urine in patients with non-glomerular kidney pathology with preserved kidney function and in chronic kidney failure.

Scientific novelty

For the first time, a normal level of neopterin in serum and a normal level of neopterin excretion in urine in healthy children have been established. At the same time, neopterin excretion in urine was assessed based on the ratio of neopterin and creatinine concentrations in urine.

For the first time in domestic pediatrics, a study of serum neopterin and the level of its excretion in urine has been conducted at different forms and stages of primary chronic glomerulonephritis, as well as in children with non-glomerular kidney pathology, and increased production of neopterin has been proven at all studied kidney diseases.

For the first time in pediatric nephrology, under clinical conditions, the significance of neopterin investigation as a marker of cellular immune activation at various forms, variants, and stages of glomerulonephritis has been demonstrated. Evidence of activation of the monocyte link of cellular immunity has been obtained in tubulointerstitial diseases.

It has been established that the content of neopterin in serum and the level of its excretion in urine are closely interrelated with the clinical-laboratory manifestations of glomerulonephritis and undergo significant changes depending on the activity of the pathological process. It has been proven that the involvement of immunocompetent cells persists longer than the clinical manifestations of the disease. The greatest increase in neopterin production is characteristic of nephrotic syndrome (NS) due to T-cell dysfunction, the prognostically unfavorable steroid-resistant type — focal segmental glomerulosclerosis.

For the first time in children with kidney diseases, an increase in serum and urinary neopterin in the stage of chronic kidney failure has been detected, which may indicate the involvement of neopterin in the process of disease progression.

For the first time, it has been shown that in the progression of kidney diseases, neopterin excretion by functioning nephrons increases.

The established increase in NP excretion in urine serves as a basis for studying NP clearance, as a continuation of research, with the aim of establishing an increase in its local renal synthesis.

Practical significance

The established indicators of serum neopterin levels and its excretion in urine in healthy children can be used as reference data when investigating neopterin in children with various pathologies.

The obtained data on differences in the intensity of stimulation of the cellular link of immunity at various forms, variants, and stages of CGN serve as a basis for the differentiation of immunosuppressive therapy at different immunomorphological forms of CGN.

The determination of neopterin content in serum and the level of its excretion in urine in children with steroid-resistant and steroid-sensitive variants of nephrotic syndrome provides the possibility of differential diagnosis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) underlying the corresponding forms of nephrotic syndrome, as well as the prediction of nephrotic syndrome sensitivity to steroid therapy.

The absence of normalization of the serum neopterin level in the stage of clinical-laboratory remission of the steroid-sensitive variant of nephrotic syndrome substantiates the advisability of long-term maintenance courses of immunosuppressive therapy in these patients for the prevention of disease recurrence.

The established influence of cyclosporin A (CsA) on the serum neopterin level serves as a basis for considering an increase in the serum neopterin level as an additional indication for the administration of the drug in nephrotic syndrome.

During dynamic observation, an increase in neopterin in serum or its excretion in urine with unchanged disease activity is prognostically unfavorable and indicates disease progression.