**1. Introduction**

Chronic kidney disease (CKD) is a multi-symptomatic syndrome resulting from a reduction in the number of active nephrons. The diagnosis of CKD is based on anatomical and/or functional renal abnormalities as well as glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 [1]. Although the prevalence of CKD in children is much lower than in adults, the disease is a significant clinical problem in the child population. Indeed, mortality in CKD children remains high and is about 30 times higher than the expected mortality at any given age [2]. The most common causes of CKD in children are urological defects, glomerulopathies, congenital nephropathies, and kidney dysplasia [2,3]. Their effect is the reduction of active nephrons, leading to intraglomerular hypertension in the

remaining nephrons and their hypertrophy. This also leads to proteinuria, progressive hardening of the glomeruli as well as fibrosis of the renal interstitial tissue [1,4]. However, CKD complications can affect just about every organ [1]. These include cardiovascular disease (hypertrophy of the left ventricle, coronary heart disease), respiratory system (pulmonary edema, "uremic lung"), endocrine disorders (glucose intolerance, dyslipidemia), hematological (normochromic anemia, hemorrhagic diathesis) or mineral and bone disorders (vitamin D deficiency, hypoparathyroidism) [1,4]. In the CKD pathogenesis, the key role of oxidative stress has recently been stressed [5–7].

The increased production of free radicals in CKD leads to oxidative stress which initiates oxidative damage to proteins and lipids. This increases the accumulation of oxidized proteins in the kidney parenchyma and leads to a progressive impairment of its function [5–7]. It has been proven that the advanced oxidation protein products (AOPP) and advanced glycation end products (AGE) intensify the RAAS (renin–angiotensin–aldosterone system) activation, increase the expression of NF-κB (nuclear factor-κB) pathway and impair nitric oxide (NO) production [8,9]. The oxidation protein products increase synthesis of collagen and fibronectin in the mesangial cells, activate the NADPH oxidase (NOX) through the protein kinase C dependent pathway, enhance the activity of caspase-3, the expression of the p58 protein and Bax. Therefore, the protein oxidation products play a critical role in proteinuria and thickening of the renal glomeruli progression, decreasing the number of podocytes through apoptosis [10–13]. Moreover, as a result of peroxidation of kidney lipids, the activity of membrane enzymes and transporting proteins is inhibited, which disturbs the integrity of cell membranes [5–7]. Nevertheless, it is suggested that the accumulation of oxidized proteins and lipids may also disrupt other organs [5–7].

A number of systemic diseases affect the function of salivary glands. Reduced saliva production, disturbances of protein secretion into saliva as well as xerostomia (subjective dryness of oral mucosa) were observed in patients with diabetes, obesity, hypertension, psoriasis, and rheumatoid arthritis [14–18]. It is suggested that oxidative stress may play a key role in the pathogenesis of salivary hypofunction. In fact, the oral cavity is the only place in the body exposed to so many environmental factors such as food, stimulants (alcohol, tobacco smoke), air pollution, medicines, or dental materials [19]. Although all of them can generate oxygen free radicals, patients with systemic diseases are particularly predisposed to salivary oxidative stress [14–17]. Indeed, in a situation of reduced antioxidant capacity, systemic oxidative stress can affect the oxidative-reductive balance of the oral cavity. Products of protein/lipid oxidation can aggregate and accumulate in the salivary glands leading to damage of secretory cells. Protein oxidation products can also increase reactive oxygen species (ROS) formation (by activating NOX and NF-κB signaling), which, on a positive feedback, enhances local oxidative stress [20,21].

In our earlier studies we have shown that oxidative stress in CKD children affects not only the kidneys but also the oral cavity [3,22,23]. Indeed, we have shown disturbances of the enzymatic and non-enzymatic antioxidant barrier and increased oxidative damage to salivary proteins [3]. Moreover, salivary FRAP (ferric ion reducing antioxidant power) with high sensitivity (100%) and specificity (100%) differentiates children with mildly to moderately decreased kidney function from those with severe renal impairment [22]. Additionally, CKD patients are much more likely to develop oral diseases such as dental caries, candidiasis or tooth erosion [24]. However, still little is known about salivary gland function in children with CKD. We suppose that as in other oxidative stress-related diseases, CKD causes a decrease in saliva production and disturbances of protein secretion into saliva [20,25–27]. This may be due to the accumulation of protein oxidation products in the salivary glands, which damage their parenchyma and lead to hyposalivation. As in obesity, insulin resistance or psoriasis, salivary gland hypofunction may also result from the impairment of NO bioavailability and the damaging effect of nitrosative stress mediators (especially peroxynitrite) [20,25,26]. Therefore, our study is the first to evaluate salivary glycooxidation products, oxidative damage to lipids and nitrosative stress biomarkers in CKD children with normal and decreased saliva secretion. In addition to the non-stimulated and stimulated salivary flow, we also assessed other indicators of salivary gland

function, such as salivary amylase activity and total protein content. An important part of our study is also the assessment of salivary-blood correlation of the analyzed redox biomarkers.
