Advanced oxidation protein products in development of glomerulonephritis in children

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State University of Medicine and Pharmacy “Nicolae Testemiюanu” of the Republic of Moldova

ADVANCED OXIDATION PROTEIN PRODUCTS IN THE DEVELOPMENT OF GLOMERULONEPHRITIS IN CHILDREN

Сiuntu A.O.

MD, associate professor

Аннотация

Представлены результаты определения концентрации продуктов глубокого окисления белков (ПГОБ) в моче у 50 детей с различными формами первичного гломерулонефрита. Концентрация ПГОБ в моче была выше в группе больных с стероид-резистентным нефротическим синдромом (СРНС) в фазе клинических проявлений по сравнению с пациентами с стероид-чувствительным нефротическим синдромом (СЧНС). При этом, уровень ПГОБ в моче увеличился в 2,5 раза в группе пациентов с СЧНС и в 3,7 раза в группе пациентов с СРНС по сравнению с контрольной группой. В период ремиссии концентрация ПГОБ в моче была по-прежнему высокой в группе больных с СРНС. У больных со смешанной формой хронического гломерулонефрита (ХГН) в период обострения концентрация ПГОБ в моче увеличилась в 2,3 раза и оставалась высокой в период ремиссии, превышая почти в 1,7 раза уровень таковой в контрольной группе. Определение концентрации ПГОБ в моче является надежным маркером для оценки степени белково-опосредованных окислительных повреждений у больных с гломерулонефритом, а также для оценки эффективности терапевтических стратегий, направленных на снижение уровня окислительного стресса у этих больных.

Ключевые слова: продукты глубокого окисления белков (ПГОБ), гломерулонефрит, нефротический синдром, дети.

Annotation

The article considers the results of evaluation of the concentration of advanced oxidation protein products (AOPPs) in the urine of 50 children with various types of primary glomerulonephritis. The AOPPs concentration in urine was higher in patients with steroid-resistant nephrotic syndrome (SRNS) exacerbation in comparison with patients with steroid-sensitive nephrotic syndrome (SSNS). Thus, the level of AOPPs in the urine increased 2.5 fold in the group of patients with SSNS and by 3.7 fold in SRNS compared with the control group. AOPPs concentration in the urine during remission was still high in patients with SRNS. Patients with mixed type of chronic glomerulonephritis (CGN) during exacerbation showed 2.3 fold greater concentrations of AOPPs in urine and remained high in the period of remission, exceeding almost 1.7 fold the level of control group. Evaluation of AOPPs urine concentration is a reliable marker for evaluating the degree of protein-mediated oxidative damage in patients with glomerulonephritis as well as to assess the efficacy of the therapeutic strategies aimed to reduce the oxidative stress in these patients.

Keywords: Advanced oxidation protein products (AOPPs), glomerulonephritis, nephrotic syndrome, children.

Introduction

glomerulonephritis oxidation protein oxidative

Witko-Sarsat was the first to mention advanced oxidation protein products (AOPPs) in 1996. AOPPs are formed in the plasma during the oxidative stress through the action of the chlorure oxidants and particularly by the activity of hypochlorous acid and chloramines (produced by myeloperoxidase in activated neutrophils) in patients with chronic uremia [14, P.1304]. They seem to have similar structure as AGE-proteins and perform related biological activities i.e. AGEs, inducing synthesis of proinflammatory cytokines and cell adhesion. Patients with impaired renal function show increased levels of these products in the plasma, but the highest values are identified in patients with renal replacement therapy [14, P.1304]. The processes of plasma proteins oxidation and accumulation, in particular of the albumin, result in elevation of AOPPs levels in patients with kidney injury. Assessment of AOPPs values allows estimating the amount of proteins that have passed through a considerable oxidation processes, especially of albumin [7, P.87], [10, P.1115].

Clinical and in vitro studies showed that AOPPs have an important contribution by redox-dependent pathway to renal structural alterations with interstitial fibrosis, nephropaties like glomerulosclerosis, and tubular atrophy. Results from the latest researches indicate AOPPs as a new pathogenic agent in the advancement of chronic kidney diseases (CKD) [14, P.1304]. Although a large number of studies were performed in this field, they present incomplete data on AOPPs role in glomerular disease in children at different stages of the disease. In this connection, new investigations on the AOPPs negative effect in children with different types of glomerulonephritis are of great importance.

The aim of this study was to assess the AOPPs accumulation in the urine of children with different clinical stages of glomerulonephritis.

Methods and materials

50 children with primary glomerulonephritis were enrolled in our study group, including 25 patients with steroid-sensitive nephrotic syndrome (SSNS), 15 patients with steroid-resistant nephrotic syndrome (SRNS), and 10 children with chronic glomerulonephritis (CGN) mixed type. Other 20 healthy children were selected as the control group. Nephrotic syndrome (NS) was diagnosed based on edema, massive proteinuria (< 40 mg²/h or the ratio protein/urinary creatinine > 2.0 mg/mg) and hypoalbuminemia (> 2.5 g/d L). A complete remission within first 4 weeks, seldom 8 weeks of corticosteroid therapy was achieved in children with steroid-sensitive nephrotic syndrome (SSNS). Children with steroid-resistant nephrotic syndrome (SRNS) presented proteinuria up to 3 g/d L during 6-8 weeks of treatment with prednisolone in a dosage of 2 mg/kg/24 hours (maximum 60 mg/24h) with subsequently pulse therapy with prenisolone in a dosage of 20-30 mg/kg/24h N3 (maximum 1 g for treatment course) [6, P.139].

Complete remission of nephrotic syndrome has been established in children with total resolution of edema, with stabilization of serum albumin up to 3.5 g/dl and decrease of proteinuria below 4 mg/m²/hour (100 mg/m²/24 h) in three consecutive urinalysis. Recurrences were outlined as a relapse of massive proteinuria (>40 mg/m²/h or the ratio of protein/urinary creatinine > 2.0 mg/mg or ? 2 mg/mg + albuminuria) within 3 successive days, mostly with recurrence of edema [6, P.139].

Spectrophotometric method was used to assess AOPP urine concentration [14, P.1304]. These investigations were performed in the laboratory of Institute for Maternal and Child Healthcare and in the Laboratory of Biochemistry of State University of Medicine and Pharmacy “Nicolae Testemiюanu”, grounded on biological patterns collected on the modern investigation standards, admitted by the Committee of Ethics of Research from State University of Medicine and Pharmacy “Nicolae Testemiюanu” Republic of Moldova (approbative referral of 13.05.2015, No. 55).

The results of the study were processed by statistical methods with evaluation of arithmetic mean [X], deviation mean, and mean squared error [±m]. Also have been used nonparametric statistical test “Mann-Whitney U” and the threshold of significance p<0.05 (StatsDirect statistical software, version 1.9.5, 2001).

Results

The average age of nephrotic syndrome and mixed type of CGN onset in children enrolled in the study was 6.4 ± 0.50 years and 9.1 ± 0.99 years respectively. The average length of disease was 2.9 ± 0.47 years. Clinical signs and laboratory indices identified in urinalysis of children with SN were: edema (92.5 ± 2.9%), anasarca (60.0 ± 5.5%), hypoproteinemia (52.9 ± 0.9 g/l), serum albumin (34.0 ± 2.8 g/l), and severe disorders of lipid metabolism with total lipid (9.5 ± 1.0 mmol/l), cholesterol (8.5 ±0.4 mmol/l), в-lipoproteids (99.4 ± 2.8 arbitrary units); serum urea (6.2 ± 0.5 mmol/l), creatinine (0.06 ± 0.04 mmol/l), proteinuria (5.5 ± 0.7 g/l). The level of endogenous creatinine clearance constituted > 90 ml/min/1.73 m².

The levels of urinary AOPPs in children with primary glomerulonephritis are shown in the table 1.The results showed important increase of AOPPs levels in all patients with GN from study group in comparison with control. Children with steroid-resistant NS during exacerbation had significantly higher urinary levels of AOPPs compared to patients with steroid-sensitive NS. It was proved that urinary AOPPs concentration in acute phase of disease in children with steroid-sensitive NS were 2.5 and 3.7 fold greater in steroid-resistant NS compared to the reference values from the control group. Urinary AOPPs concentration during remission in steroid-sensitive NS significantly decreased compared to exacerbation period and the difference with the reference values were found to be statistically.

The AOPPs level also significantly decreased during remission in steroid-resistant NS compared the acute phase of disease, but exceeded almost twice the reference values from controls. The urinary AOPPs during exacerbation increased by 2.3 fold in children with mixed type of chronic GN, and remained high, exceeding 1.7 fold, in remission period in comparison to the control group.

Table 1

The urinary concentration of AOPPs in children with different clinical types of primary glomerulonephritis

Note: AGN - acute glomerulonephritis, CGN - chronic glomerulonephritis, statistically significant difference compared to control group values: * p <0.05; ** p<0.01; *** p <0.001; p₁ authenticity compared with the respective index recorded exacerbations; p₂ - AGN authenticity compared with the SSNS.

Discussion

Children with different types of GN showed significantly increased levels of AOPPs concentration in the urine during exacerbations and remission, the highest values being recorded in children with SNSR. Other studies from this field reported similar results. AOPPs accumulation in plasma was detected in patients with CKD and coronary heart disease [9, P.750].

Recent studies have shown that plasma levels of AOPPs significantly increased with renal failure progression in patients with CKD and in patients with diabetes [12, P.10]. These surveys have proved that AOPPs conglomerations have emerged in result of podocyte apoptosis and their exposure to intracellular oxidative stress. Zhou L.L., et al. research by using co-immune precipitation and immune fluorescence methods, found that AOPPs is localized and interconnected with the receptor of advanced glycation end products (RAGE) on podocytes. It was possible to secure the podocytes from AOPPs induced apoptosis both in vitro and in vivo and to improve albuminuria in AOPPs experimental mice by blocking the RAGE with anti-RAGE immunoglobulin G or its reticence by siRNA. Otherwise, AOPPs associate with RAGE will cause podocyte apoptosis and in result might lead to chronic kidney disease progression [16, P.759].

A large cohort survey have proved that high levels of AOPP in plasma at the onset of IgAN is one of the most important self-sufficient risk factor for advanced renal failure and for the need of dialysis [3, P.1606]. The results of these studies recommends that the high level of AOPPs may be used as a marker for a poor prognosis in IgAN, and that more aggressive treatment may be needed in patients with increased plasma level of AOPPs at the initial stage of the disease.

The most important injuries of the AOPPs activity was noticed on renal cells by the activation of renin-angiotensin system (RAS) in tubular cells [1, P.19]. An additional effect of AOPPs is the expression of fibronectin and collagen I in the mesangial cells cultures mediated by NADPH oxidase-dependent O₂production [13, P.427]. The pro-inflammatory mediators such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 are released following the stimulation of renal endothelial cells by AOPPs [4, P.1699]. The outcome of harmful impact on renal cells caused by AOPPs is renal function loss with increased urinary protein excretion, decreased creatinine clearance, and rapid progression of glomerulosclerosis and interstitial fibrosis [8, P.528], [11, P.1829].

The pro-inflammatory role of AOPPs is in vitro monocyte activation, triggering both respiratory burst and TNF-б synthesis in them [15, P. 82].

The latest researches have proven progressive renal injury with extensive tubular fibrosis and glomerulosclerosis, severe proteinuria, and impaired renal function in patients with increased AOPPs plasma levels. Pathogenesis of renal failure has been confirmed by increase of urinary protein excretion in sham-operated rats that received AOPPs, but without renal fibrosis and altered function. The outcomes of these studies suggested that AOPPs might be the causative factor of renal hypertrophy and fibrotic remodeling in the remnant kidney [5, P. 528].

AOPP-modified proteins in target tissues and the biological outcomes have raised the need to search for cellular surface molecules that will detect AOPPs and will activate the cellular response. The first identified receptor for AOPP-modified albumin was the receptor for advanced glycation end products (RAGE) on the surface of endothelial cells [4, P.1699].

All the evidences stand for the AOPPs importance as a new class of renal pathogenic mediator in the progression and poor outcome of CKD. Most of clinical surveys have proven the association between increased AOPPs levels and kidney damage. This connection allowed them to recommend the assessment of AOPPs levels as a prognostic predictor of kidney disease [4, P.1699], [17, P.1148]. Future treatments of CKD have to target AOPPs, and more studies are needed to develop new therapeutic strategies for the prevention of AOPP-associated renal injury in CKD patients [2, P.102].

Conclusions

The assessment of urinary AOPPs concentration is a reliable marker for rating the degree of protein-mediated oxidative injury in patients with glomerulonephritis and for evaluation of the effectiveness of the therapeutic strategies aimed to reduce oxidative stress.

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