sechenovSechenov Medical JournalСеченовский вестник2218-73322658-3348Сеченовский Университет10.47093/2218-7332.2025.16.1.34-44sechenov-1256Research ArticlePATHOLOGICAL PHYSIOLOGYПАТОЛОГИЧЕСКАЯ ФИЗИОЛОГИЯBone turnover markers in oral and gingival crevicular fluid in children with end-stage chronic kidney diseaseМаркеры ремоделирования костной ткани в ротовой и зубодесневой жидкостях у детей с терминальной стадией хронической болезни почекhttps://orcid.org/0000-0002-0275-6261ЕловскаяА. А.ElovskayaA. A.

Еловская Алина Алексеевна - ассистент кафедры детской, профилактической стоматологии и ортодонтии Института стоматологии им. Е.В. Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Alina A. Elovskaya - Assistant Professor, Pediatric, Preventive dentistry and Orthodontics Department in E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

elovskaya_a_a@staff.sechenov.ruhttps://orcid.org/0000-0002-6875-9377МасликоваЕ. С.MaslikovaE. A.

Масликова Екатерина Андреевна - ассистент кафедры детской, профилактической стоматологии и ортодонтии Института стоматологии им. Е.В. Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Ekaterina A. Maslikova - Assistant Professor, Pediatric, Preventive dentistry and Orthodontics Department in E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0000-0002-6453-1615МорозоваН. С.MorozovaN. S.

Морозова Наталия Сергеевна - д.м.н., профессор кафедры пропедевтики стоматологических заболеваний Института стоматологии им. Е.В. Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Natalia S. Morozova - Dr. of Sci. (Medicine), Professor of the Department of Dental Diseases Propaedeutics in E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0000-0001-9410-2240ЗахароваН. Б.ZakharovaN. B.

Захарова Наталия Борисовна - д.м.н., профессор кафедры клинической лабораторной диагностики.

Ул. Большая Казачья, д. 112, г. Саратов, 410012

Natalia B. Zakharova - Dr. of Sci. (Medicine), Professor, Department of Clinical Laboratory Diagnostics.

112, Bolshaya Kazachia str., Saratov, 410012

https://orcid.org/0000-0002-4380-4522МальцеваЛ. Д.MaltsevaL. D.

Мальцева Лариса Дмитриевна, канд. мед. наук, доцент кафедры патологической физиологии.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Larisa D. Maltseva - Cand. of Sci. (Medicine), Associate Professor, Pathophysiology Department, Sechenov First.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0000-0001-9079-872XДаниловаЕ. Ю.DanilovaE. Yu.

Данилова Елена Юрьевна - младший научный сотрудник лаборатории молекулярного моделирования и химии природных соединений Института молекулярной тераностики научно-технологического парка медицины.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Elena Y. Danilova - Junior research assistant of the Laboratory of Molecular Modeling and Chemistry of Natural Compounds of the Institute of Molecular Theranostics of the Science and Technology Park of Medicine.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0009-0001-7452-2907ШайхаттароваИ. И.ShaikhattarovaI. I.

Шайхаттарова Ильсияр Ильнуровна - студентка Института стоматологии им. Е.В. Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Ilsiiar I. Shaikhattarova - student, E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0009-0007-1029-3432ШиринаА. А.ShirinaA. A.

Ширина Ангелина Александровна - студентка Института стоматологии им. Е.В. Боровского Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Angelina А. Shirina - student, E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0009-0009-1661-1862ШустоваВ. А.ShustovaV. A.

Шустова Виолетта Александровна - студентка Института стоматологии им. Е.В. Боровского.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Violetta A. Shustova - student, E.V. Borovsky Institute of Dentistry.

8/2, Trubetskaya str., Moscow, 119048

https://orcid.org/0000-0003-2453-1319МорозоваО. Л.MorozovaO. L.

Морозова Ольга Леонидовна - д.м.н., профессор кафедры патологической физиологии.

Ул. Трубецкая, д. 8, стр. 2, г. Москва, 119048

Olga L. Morozova - Dr. of Sci. (Medicine), Professor, Pathophysiology Department.

8/2, Trubetskaya str., Moscow, 119048

ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова» Минздрава России (Сеченовский университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian FederationФГБОУ ВО «Саратовский государственный медицинский университет им. В.И. Разумовского» Минздрава РоссииРоссияSaratov State Medical University named after V.I. RazumovskyRussian Federation2025190520251613444Copyright © Elovskaya A.A., Maslikova E.A., Morozova N.S., Zakharova N.B., Maltseva L.D., Danilova E.Y., Shaikhattarova I.I., Shirina A.A., Shustova V.A., Morozova O.L., 20252025Еловская А.А., Масликова Е.С., Морозова Н.С., Захарова Н.Б., Мальцева Л.Д., Данилова Е.Ю., Шайхаттарова И.И., Ширина А.А., Шустова В.А., Морозова О.Л.Elovskaya A.A., Maslikova E.A., Morozova N.S., Zakharova N.B., Maltseva L.D., Danilova E.Y., Shaikhattarova I.I., Shirina A.A., Shustova V.A., Morozova O.L.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sechenovmedj.com/jour/article/view/1256Objective

Objective. To study bone turnover markers in biological fluids (urine, blood serum, oral fluid (OF) and gingival crevicular fluid (GCF)) at the stage of planning an orthodontic strategy in children with end-stage chronic kidney disease (ESKD).

Materials and methods

Materials and methods. Pilot, cross-sectional, multicenter study was conducted. A total of 48 children aged 7 to 17 years were examined and divided into three groups: 14 children with ESCKD, 14 children with renal transplant dysfunction (RTD), 20 almost healthy children. Bone turnover markers were assessed by changes in osteocalcin (OC) in the OF, GCF and blood serum, urinary deoxypyridinoline (DPD), levels of total, ionized calcium and phosphorus in blood and pH of OF. Bone tissue mineral density was assessed by cone-beam computerized tomography according to the C. Mish classification.

Results

Results. All groups of children were comparable by gender and age. All patients had no significant mineral and bone disorders. Total and ionized calcium did not demonstrate statistically significant differences between the study groups. Serum phosphorus level was higher in ESCKD children compared to RTD children and control group. Urinary DPD, OC in GCF and OF pH were higher in children with CKD compared to healthy children. However, there were no statistically significant changes between the ESCKD group and the RTD group. In the posterior maxilla, the Hounsfield index was higher in the group with RTD compared to the ESCKD group (p < 0.01), and similar to the control group. In the anterior maxilla, as well as in the anterior and posterior mandibular regions, the Hounsfield index was higher in the control group than in the ESCKD and RTD groups.

Conclusion

Conclusion. The most prominent changes of bone turnover markers were found in children with ESCKD. Urinary DPD and OC in GCF were associated with the decrease in kidney function and jawbone mineral density.

Цель исследования

Цель исследования. Изучить маркеры ремоделирования костной ткани в биологических жидкостях (моче, сыворотке крови, ротовой жидкости (РЖ) и зубодесневой жидкости (ЗДЖ)) на этапе планирования ортодонтической стратегии у детей с терминальной стадией хронической болезни почек (тХБП).

Материалы и методы

Материалы и методы. Проведено пилотное одномоментное многоцентровое исследование. Обследованы 48 детей в возрасте от 7 до 17 лет, разделенных на три группы: 14 – с тХБП, 14 – с дисфункцией трансплантата почки (ДТП), 20 практически здоровых детей. Определяли маркеры ремоделирования кости: остеокальцин (ОК) в РЖ, ЗДЖ и сыворотке крови, дезоксипиридинолин (ДПИД) в моче, уровень общего, ионизированного кальция и фосфора в крови и pH РЖ. Минеральную плотность костной ткани оценивали по данным конуснолучевой компьютерной томограммы по классификации С. Mish.

Результаты

Результаты. Группы детей были сопоставимы по возрасту и полу. Все пациенты были без выраженных минерально-костных нарушений. Уровни общего и ионизированного кальция в крови не различались между исследуемыми группами. Уровень фосфора в крови был выше в группе тХБП по сравнению с группой ДТП и группой контроля. Концентрации ДПИД в моче и OК в ЗДЖ, а также уровень pH РЖ были выше в группах детей с ХБП по сравнению с контрольной группой, при этом статистически значимых различий между группами тХБП и ДТП не выявлено. В заднем отделе верхней челюсти индекс Хаунсфилда был выше в группе с ДТП по сравнению с группой тХБП (p < 0,01) и сопоставим с контрольной группой. В переднем отделе верхней челюсти, а также в переднем и заднем отделах нижней челюсти индекс Хаунсфилда был выше в контрольной группе, чем в группах тХБП и ДТП.

Заключение

Заключение. Наиболее выраженные изменения маркеров ремоделирования кости выявлены у детей с тХБП. Уровни ДПИД в моче и ОК в ЗДЖ ассоциированы со степенью снижения функции почек и минеральной плотностью челюстных костей.

дисфункция трансплантата почкиминерально-костные нарушения при хронической болезни почекостеокальциндезоксипиридинолинортодонтическое лечениеrenal transplant dysfunctionmineral and bone disorders in chronic kidney diseaseosteocalcindeoxypyridinolineorthodontic treatmentИсследование не имело спонсорской поддержки (собственные ресурсы)The study had no sponsorship (own resources)

Chronic kidney disease (CKD) is a persistent organ damage for three months or more due to various etiologic factors. The pathologic basis of the disease is the process of replacement of normal anatomical structures by fibrosis, which leads to organ dysfunction. CKD is evidenced by a decrease in estimated glomerular filtration rate (eGFR) and/or albuminuria and other markers of kidney damage [1]. The prevalence of CKD in the world population is more than 800 million people [2]. The global mortality from CKD reached 1.2 million in 2017 and is projected to increase [3].

In the world pediatric population, the prevalence of CKD reaches 18.5–58.3 cases per 1 million children [4]. In Russia since 2012, the overall incidence of CKD in children continues to grow [3]. Approaches to CKD diagnosis are unified for both children and adults. However, due to the predominance of non-glomerular etiology of CKD in children, albuminuria is detected less frequently than in adults [5]. According to the European Pediatric Registry, congenital anomalies of the kidney and urinary tract and genetic diseases are the leading etiologic factors of CKD in children, accounting for 40–60% and 20–30% of detected cases, respectively; glomerulonephritis makes an etiologic contribution in less than 10% of cases [5].

End-stage kidney disease (ESCKD) requires renal replacement therapy (hemodialysis, peritoneal dialysis or renal transplant). ESCKD is associated with life quality decline and unfavorable outcomes [6]. Moreover, ESCKD in children is accompanied by significant mineral and bone disorders (CKD-MBD) [7–9], arising as a result of hyperparathyroidism and impaired calcium-phosphorus (Ca-P) metabolism [10][11]. In CKD-MBD children are observed with a decrease in growth [12], a high tendency to fractures [13][14], as well as multiple structural changes in bone tissue, including cortical loss, demineralization, bone trabeculae rarefaction, which are associated with increased osteoclast activity [13].

Bone turnover markers in CKD-MBD are deoxypyridinoline (DPD) and osteocalcin (OC) [15]. DPD is a compound formed during collagen breakdown, it is released into the bloodstream, and then excreted in the urine. DPD reflects osteoclasts activity; DPD level increasing directly correlates to the severity of renal dysfunction in experimental study on rats [16]. OC is a vitamin K-dependent protein synthesized by osteoblasts, reflects impaired bone mineralization in CKD-associated hyperparathyroidism [17][18].

CKD patients are prone to various maxillofacial bone changes such as decreased density of cortical bone and increased jawbone porosity [19], shortened mandible branches, increased gonial angle, decreased posterior facial height [8][20][21], structural and functional temporomandibular joint changes [22][23], along with a significant slowdown in teething [22]. These changes require a personalized approach to orthodontic treatment in CKD children and objective markers for making a medical decision.

Today there are still some open questions about optimal timing for initiating orthodontic treatment and its types in CKD children, and monitoring bone remodeling during this treatment. Thus, searching for biomarkers reflecting specific bone changes including maxillofacial bones in CKD patients remains in demand.

Study objective: to investigate bone turnover markers in different biological fluids (urine, blood serum, oral fluid (OF) and gingival crevicular fluid (GCF) at the stage of planning an orthodontic strategy in children with end-stage chronic kidney disease (ESCKD).

MATERIALS AND METHODS

This pilot cross-sectional multicenter study based on Russian Federal Law No. 323-FZ dated 21.11.2021 “On the Fundamentals of Public Health Protection in the Russian Federation”, (Legislation Bulletin of the Russian Federation, 2011, No. 48, Art. 6724). The required number of patients in groups was determined before the study. The sample size was sufficient given the power of 80%.

Patient enrollment

The study was conducted from March 1 to June 30, 2024, at the following clinical centers: E.V. Borovsky Institute of Dentistry, Sechenov University; Surgical Department No. 1, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation. A continuous recruitment of patients was carried out from those who applied to the above-mentioned medical institutions.

Inclusion criteria:

Non-inclusion criteria:

– endocrine and metabolic diseases (n = 10),

– autoimmune diseases (n = 2),

– genetic diseases (n = 4),

– oncological diseases (n = 1),

– diseases of the gastrointestinal tract (n = 3);

– chronic liver diseases (n = 7),

– drug-induced disorders of bone metabolism (n = 5).

A total of 65 children and adolescents were assessed for participation in the study. Exclusion criteria were identified in 37 patients (Fig.). The study included 28 CKD children, who were divided into two groups: Group 1 – 14 ESCKD patients with eGFR according to CKiD U25 with a constant creatinine coefficient ≤ 25 ml/min/1.73m2; Group 2 – 14 patients with kidney graft dysfunction (RTD) with eGFR according to the CKiD U25 with a constant creatinine coefficient > 25 ml/min/1.73 m2.

FIG. Study flowchart.

Note: ESCKD – end-stage kidney disease, DAA – dentoalveolar anomalies, RRT – renal replacement therapy, RTD – renal transplant dysfunction, eGFR – estimated glomerular filtration rate (CKiD U25).

https://cdn.elpub.ru/assets/journals/sechenov/2025/1/dfAY2pL6oNSGpcGnk2YmdmCKAhnPl7SgwV0IYGUe.png

The control group consisted of 20 practically healthy children and adolescents with no general medical pathology, matched by sex and age to the group of children with CKD, who underwent dental examination at the Department of Pediatric, Preventive Dentistry and Orthodontics in E.V. Borovsky Institute of Dentistry during the study period.

Determination of bone metabolism biomarkers

Biological fluids from patients were taken once in the morning before the breakfast and diagnostic and therapeutic procedures. Blood samples of 5 mL each were collected from cubital vein or from the hand back veins, stabilized with heparin (25 IU/ml), urine sample of 50 mL each, oral fluid sample at least 5 mL.

Biochemical blood analysis was performed by photocolorimetric methods to determine the level of total (Ca) and ionized (Ca2+) calcium, phosphorus (P). Calculation of total blood plasma calcium with correction for albumin was performed according to the formula: measured plasma calcium level (mmol/L) + 0.02*(40 – measured plasma albumin level (g/L).

Urinary DPD was measured by solid-phase chemiluminescent immunoassay.

OC in serum, GCF and OF was measured by using commercial Osteocalcin ELISA kits for solid-phase enzyme-linked immunosorbent assay (BioVendor, USA).

The Milwaukee PH56 (Milwaukee Instruments, USA) device was used to determine oral pH.

Bone density was assessed using cone-beam computed tomography (CBCT), expressed in Hounsfield units (HU) according to C. Mish classification [24], based on the mathematical reconstruction of X-ray attenuation coefficients assigned to each pixel. The X-ray assessment was performed in four sections: the anterior and posterior sections of the upper jaw; the anterior and posterior sections of the lower jaw.

Statistical analysis

Quantitative features are presented as median and interquartile range, qualitative ones – as proportion. The studied features of patient groups were tested for normal distribution using Shapiro-Wilk test and for homogeneity of variances using Levene test. Variables corresponding to normal distribution and having homogeneous variances are presented as mean values and standard deviation, mean values were compared using one-way analysis of variance (ANOVA). Other variables are presented as median and interquartile range (25th; 75th percentiles), for their comparison the Kruskal–Wallis method was used. For post-hoc analysis the Tukey test was used. The results of statistical analysis were considered significant at p < 0.05. The experimental results were processed using Prism 8.0.1 (GraphPad Software, USA) and R language. 4.4.2 in the R-Studio software environment.

RESULTS

The study included patients without pronounced clinical manifestations of CKD-MBD and osteoporosis. The main characteristics of the study groups are presented in Table 1.

Mean age in study groups were 12.7 ± 2.9 years and girls’ number in RTD group was lower than in ESCKD group and control, but the differences were not statistically significant (Table 1).

Serum creatinine in ESCKD group was significantly higher and eGFR was lower compared to RTD group and control. ESCKD patients received hemodialysis or peritoneal dialysis treatment for an average from 6 months to 3 years.

Total and ionized serum calcium did not differ between the study groups (Table 1). Serum P was significantly higher in ESCKD group compared to RTD group and control. While there were not found any statistically significant differences in phosphorus levels in RTD group and control (Table 1).

Summarized markers results in studied groups are presented in Table 2.

Urinary DPD concentration was higher in CKD groups compared to control (Table 2). However, no statistically significant differences were found between urinary DPD concentration in ESCKD and RTD patients.

Serum OC concentration was increased in ESCKD patients compared to control (p < 0.05) and did not differ from RTD group. OC in GCF was higher in control compared to ESCKD (p < 0.001) and RTD (p < 0.001) groups. Meanwhile salivary OC was comparable in all groups (Table 2).

OF pH was statistically significantly higher in both ESCKD and RTD children compared to control (Table 2). Moreover, there were no differences between oral pH in RTD and ESCKD groups, thus oral acidity was similar in these two groups.

Bone density radiographical assessment shows that Hounsfield Index of posterior maxilla was higher in RTD group compared to ESCKD group (p < 0.01), and there was no difference with control. Hounsfield Index of anterior maxilla in control was higher than in ESCKD and in RTD groups. A similar pattern was found in Hounsfield index of both anterior and posterior mandible where the control group levels were statistically significantly higher than in ESCKD and RTD patients (Table 2).

Table 1. Characteristics of study patient groups

Note: RTD – renal transplant dysfunction; eGFR – estimated glomerular filtration rate; ESCKD – end-stage chronic kidney disease; a – p < 0.05 when comparing ESCKD and control groups; b – p < 0.05 when comparing RTD and control groups; c – p < 0.05 when comparing RTD and ESCKD.

FeatureChronic kidney diseaseControl group (n = 20)p value (ANOVA)
ESCKD (n = 14)RTD (n = 14)
Age, years12.1 ± 2.413.4 ± 3.012.6 ± 3.4n.s.
Girls, n (%)11 (79)6 (43)13 (65)n.s.
eGFR ml/min/1.73 m²10.51 ± 3.25 a,c56.73 ± 15.31 b,c90.01 ± 10.26 a,b<0.0001
Creatinine in serum, µmol/L477.8 (403.1; 571.6) a,c85.7 (73.2; 131.9) b,c63.0 (50.35; 71.68) a,b<0.0001
Calcium total in serum, mmol/L2.40 (2.14; 2.62)2.42 (2.34; 2.46)2.40 (2.27; 2.49)<0.01
Total serum calcium adjusted for albumin, mmol/L2.34 ± 0.282.39 ± 0.132.37 ± 0.14n.s.
Calcium ionized in serum, mmol/L1.16 (0.96; 1.21)1.18 (1.10; 1.23)1.21 (1.17; 1.24)<0.01
Phosphorus in serum, mmol/L1.751 ± 0.490 a,c1.342 ± 0.266 s1.436 ± 0.195 a<0.005

Table 2. Bone turnover markers

Note: DPD – deoxypyridinoline; RTD – renal transplant dysfunction; ESCKD – end-stage chronic kidney disease; OC – osteocalcin; max – maxilla; man – mandible; a – p < 0.05 when comparing ESCKD and control groups; b – p < 0.05 when comparing RTD and control groups; c – p < 0.05 when comparing RTD and ESCKD.

FeatureChronic kidney diseaseControl group (n = 20)p value (ANOVA)
ESCKD (n = 14)RTD (n = 14)
Urinary DPD, nmol/mmolCreat15.80 (12.68; 27.90) a15.08 (10.27; 24.61) b4.90 (2.95; 11.98) a,b<0.001
Serum OC, ng/mL213.1 ± 55.01 a173.7 ± 86.78153.9 ± 56.15 a<0.05
Salivary OC, ng/mL11.78 ± 1.9312.94 ± 1.7613.46 ± 3.73n.s.
ОС in gingival crevicular fluid, ng/mL13.11 ± 3.98 a11.92 ± 3.10 b20.08 ± 4.69 a,b<0.0001
Oral fluid рН7.080 (6.375; 8.153) a7.240 (6.875; 7.593) b6.250 (5.575; 6.800) a.b<0.001
Hounsfield Index of anterior maxilla482.5 (394.5; 554.3) a439.0 (396.3; 503.0) b681.5 (449.0; 766.8) a.b<0.0001
Hounsfield Index of posterior maxilla203.0 (194.8; 238.8) a.c363.0 (248.3; 485.0) c420.0 (329.0; 539.0) a<0.01
Hounsfield Index of anterior mandible1059 (951; 1451) a1670 (1083; 1985) b3098 (1985; 3538) a.b<0.0001
Hounsfield Index of posterior mandible824.4 ± 111.0 a826.5 ± 89.5 b1735 ± 377.2 a.b<0.0001
DISCUSSION

Study results demonstrated CBCT changes in bone turnover markers and bone density were the most pronounced in ESCKD children. Urinary DPD increase, a decrease in serum and GCF OC and a decrease in the Hounsfield index in both anterior and posterior regions of the maxilla and mandible were revealed. Similar changes were noted in RTD patients, but OC level was reduced only in GCF. Bone density assessment had no significant differences between ESCKD and RTD groups, except Hounsfield index in posterior maxilla.

Kidneys play a crucial role in Ca-P metabolism by almost complete tubular reabsorption of these ions. Ca-P homeostasis in CKD patients is disrupted, so serum P in ESCKD patients had been increasing with eGFR decreasing in our study. It’s important to check serum P in CKD-MBD patients for maintaining bone homeostasis, and our results are consistent with Rastogi A. et al. [25]. Serum P in KDG group was close to control group, and inversely correlates with a higher eGFR level, because of kidney filtration improvement after transplantation, but due graft dysfunction P level remained high. These trends are consistent with other studies data on mineral metabolism effect on bone remodeling in patients after kidney transplantation [26][27].

Our study results showed that serum Ca does not statistically differ between the groups, which indicates the stability of this marker regardless of kidney and graft function. However, ESCKD markers are less homogeneous and it still has a greater spread. No expressed calcium metabolism disorders were detected as well as in Liu J. et al. and Hasanzamani B. et al. studies [28][29]. It should be noted that the levels of parathyroid hormone and bone fraction of alkaline phosphatase were not taken into account.

Urinary DPD was found as highly sensitive marker of bone metabolism disorders in ESCKD and RTD patients. Thus, we found clear and significant differences in this marker between the study groups. DPD increase in CKD children compared to control may indicate high osteoclast activity and bone resorption activation. DPD changes were recorded simultaneously with a Hounsfield index decrease in jawbones. It indicates bone collagen breakdown, type I mainly, the end products of bone metabolism excretion with urine and it confirms persistent bone metabolism changes in CKD children. However, literary data did not confirm that urinary DPD can reflect bone metabolism in CKD-MBD patients [30]. On the other hand, DPD level is known as one of the leading biochemical markers of bone remodeling and is used in osteoporosis early diagnosis [31]. Thus, urinary DPD determination in CKD patients may become promising for assessing osteoclasts activity and bone resorption and requires further study on a larger CKD patient sample.

Presented study results convincingly demonstrate that OC is an informative marker of osteoblast activity in ESCKD and RTD children, and GCF is the best biological fluid for its determination, since the most significant OC changes are registered in GCF, despite the limited sample. OC decrease in GCF was found in ESCKD and RTD children compared to control, which indicates a violation of bone metabolism. Serum OC increase was detected only in ESCKD group probably due to the limited sample. OC in OF did not statistically significantly differ between three groups possibly due to high protease activity in OF [32]. We didn’t find any information about OC measurement in GCF in CKD patients in the reviewed literature. However, Fadli N. et al. used GCF for the assessment of OC and proinflammatory markers [33]. Interest in GCF exertion as a fluid for various markers detection in patients with systemic diseases, including CKD, is growing due to its sufficient informativeness and minimally invasive nature.

OF pH increase with its alkaline tendency may be associated with a disturbance in general metabolism, including a change in the acid-base balance in ESCKD patients [34].

In addition, the obtained data indicate significant disturbances in bone structure in ESCKD and RTD children, which is manifested in a significant decrease in Hounsfield index compared to control, especially in the anterior and posterior mandible. These changes are consistent with previous studies [23], confirming disturbances in bone metabolism and decreased bone mineralization in patients with renal dysfunction.

Limitations and directions for future research

Result interpretations have several limitations due to pilot study design: small sample size, one observation point. The levels of parathyroid hormone and bone fraction of alkaline phosphatase were not taken into account when assessing CKD-MBD. Perhaps due to insufficient study power, there were no statistically significant differences in total serum calcium adjusted for albumin, as well as OC in oral fluid. To draw conclusions on these markers, it is necessary to conduct longitudinal studies on large samples using probability selection of observation units.

AUTHOR CONTRIBUTIONS

Olga L. Morozova and Natalia S. Morozova developed study concept and design and edited the article. Ilsiiar I. Shaykhattarova, Angelina A. Shirina and Violetta A. Shustova performed the scientific literature search. Alina A. Elovskaya and Ekaterina A. Maslikova examined patients, selected and analyzed biomaterial, and wrote the main part of the final version of the article. Natalia B. Zakharova carried out laboratory tests. Larisa D. Maltseva interpreted laboratory data. Elena Yu. Danilova performed statistical analysis. All authors approved the final version of the article.

Ethics statements. This study using biological material was conducted in accordance with the World Medical Association's Declaration of Helsinki on Ethical Principles of Biomedical Research. The study was conducted in accordance with the permission of the Local Ethics Committee of I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), No. 01-22 dated January 20, 2022. Informed voluntary consent for inclusion in the study was obtained from one of the patient's parents or other legal representative.

Data access. The data that support the findings of this study are available from the corresponding authors upon reasonable request. The data and statistical methods presented in the article have been statistically reviewed by the journal editor, a certified biostatistician.

Conflict of interest. The authors declare that there is no conflict of interest.

Financing. The study had no sponsorship (own resources).

1 International Classification of Diseases, 10th revision (ICD-10). Access date: 10.01.2025 . https://mkb-10.com

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The authors declare that there are no conflicts of interest present.