Molecular-genetic causes of nephrocalcinosis in Russian children and their impact on the renal and extrarenal phenotypes

Introduction. Nephrocalcinosis (NC) is defined as the deposition of calcium oxalate or calcium phosphate in the intratubular lumen and/or kidney interstitium. Recent studies have reported that NC might be a specific sign of hereditary kidney diseases with various phenotypic manifestations. The rate of genetic mutation as a rule was higher in children with earlier onset and positive family history.

Purpose. To study the causes, characterize the genotype and phenotype in Russian children with NC.

Materials and methods. A single-center retrospective-prospective cohort study included 91 patient under the age of 18 years, 57 (62.6%) boys and 34 (37.4%) girls with bilateral NC. We analyzed the phenotype and kidney function in NC children classified into 3 groups according to etiology: 1) primary tubulopathies; 2) tubulopathies due to metabolic and endocrine disorders; 3) NC, unconfirmed by molecular genetic research.

Results. Pathogenic nucleotide variants were identified in 51 (56%) children with a predominance in the genes CLCN5, CYP24A1, AGXT, HPRT1 described in patients with Dent disease (OMIM 300009), primary hyperoxaluria type 1 (OMIM 259900), idiopathic infantile hypercalcemia type 1 (OMIM 143880), Lesh–Nihan syndrome (OMIM 300322) respectively. The median age of detection of NC was 16 years, 4 [3.9; 52.2 months, among which 42 (46.1%) children were under the age of 1 year, 44 (48.4%) aged 1 to 10 years, 5 (5.5%) older than 10 years. Various bone deformities prevailed among the extrarenal manifestations (19 (20.4%)). Over 3 years of follow-up (n = 51) the average GFR changed from 102.5 ± 26.0 ml/min/1.73 m² to 94.5 ± 21.9 ml/min/1.73 m² (p = 0.002); over 5 years of follow-up (n = 31) from 104.7 ± 23.9 ml/min/1.73 m² to 89.6 ± 25.1 ml/min/1.73 m² (p = 0.002), that was statistically significant in the group of primary tubulopathies (p = 0.030; p = 0.002). At baseline, the average GFR value was lower in NC stages 2 and 3.

Conclusion. Conducting a molecular genetic study in NC children, in addition to early diagnosis of diseases with variable renal prognosis and will also help to achieve effectiveness in the timely prescription of pathogenetic and symptomatic therapy.

Compliance with ethical standards. The study was approved by the local independent ethical committee of the National Medical Research Center for Children’s Health (protocol No. 11 of November 25, 2021).

For correspondence: Rasita A. Nikolaeva, pediatrician, postgraduate student of the National Medical Research Center for Children’s Health, Moscow, 119991, Russian Federation. E-mail: nikolaevarasita@mail.ru

Contribution:
Nikolaeva R.A. — material collection and data processing, statistical data processing, text writing;
Maltseva V.V. — statistical data processing, text editing;
Ananin P.V. — statistical data processing, text editing;
Milovanova A.M. — statistical data processing, text editing;
Vashurina T.V. — consept and design of the review, text editing;
Zrobok O.I. — consept and design of the review, text editing;
Tsygina E.N. — consept and design of the review, text editing;
Zhanin I.S. — conducting molecular genetic diagnostics, analysis and processing of the results;
Pushkov A.A. — conducting molecular genetic diagnostics, analysis and processing of the results;
Savostyanov K.V. — analysis of the results of molecular genetic diagnostics, text editing;
Tsygin A.N. — consept and design of the review, text editing.
All co-authors are responsible for theintegrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: July 15, 2024
Accepted: August 2, 2024
Published: October 30, 2024

1. Loimann E., Tsygin A.N., Sarkisyan A.A., eds. Paediatric Nephrology: Practical Guide [Detskaya nefrologia: prakticheskoe rukovodstvo]. Moscow: LitTera; 2010. (in Russian)

2. Wrong O. Nephrocalcinosis. In: Davison A.M., Cameron J.S., Grünfeld J., eds. Oxford Textbook of Clinical Nephrology. Oxford: Oxford University Press; 2005.

3. Oliveira B., Kleta R., Bockenhauer D., Walsh S.B. Genetic, pathophysiological, and clinical aspects of nephrocalcinosis. Am. J. Physiol. Renal. Physiol. 2016; 311(6): F1243–52. https://doi.org/10.1152/ajprenal.00211.2016

4. Ammenti A., Pelizzoni A., Cecconi M., Molinari P.P., Montini G. Nephrocalcinosis in children: a retrospective multi-centre study. Acta Paediatr. 2009; 98(10): 1628–31. https://doi.org/10.1111/j.1651-2227.2009.01401.x

5. Rönnefarth G., Misselwitz J. Nephrocalcinosis in children: a retrospective survey. Members of the Arbeitsgemeinschaft für pädiatrische Nephrologie. Pediatr. Nephrol. 2000; 14(10-11): 1016–21. https://doi.org/10.1007/s004670050065

6. Mantan M., Bagga A., Virdi V.S., Menon S., Hari P. Etiology of nephrocalcinosis in northern Indian children. Pediatr. Nephrol. 2007; 22(6): 829–33. https://doi.org/10.1007/s00467-006-0425-7

7. Halbritter J., Baum M., Hynes A.M., Rice S.J., Thwaites D.T., Gucev Z.S., et al. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J. Am. Soc. Nephrol. 2015; 26(3): 543–51. https://doi.org/10.1681/ASN.2014040388

8. Braun D.A., Lawson J.A., Gee H.Y., Halbritter J., Shril S., Tan W., et al. Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin. J. Am. Soc. Nephrol. 2016; 11(4): 664–72. https://doi.org/10.2215/CJN.07540715

9. Daga A., Majmundar A.J., Braun D.A., Gee H.Y., Lawson J.A., Shril S., et al. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int. 2018; 93(1): 204–13. https://doi.org/10.1016/j.kint.2017.06.025

10. Habbig S., Beck B.B., Hoppe B. Nephrocalcinosis and urolithiasis in children. Kidney Int. 2011; 80(12): 1278–91. https://doi.org/10.1038/ki.2011.336

11. Fayard J., Pradat P., Lorthois S., Bacchetta J., Picaud J.C. Nephrocalcinosis in very low birth weight infants: incidence, associated factors, and natural course. Pediatr. Nephrol. 2022; 37(12): 3093–104. https://doi.org/10.1007/s00467-021-05417-w

12. Schell-Feith E.A., Kist-van Holthe J.E., van der Heijden A.J. Nephrocalcinosis in preterm neonates. Pediatr. Nephrol. 2010; 25(2): 221–30. https://doi.org/10.1007/s00467-008-0908-9

13. Savost’yanov K.V. Modern Algorithms for the Genetic Diagnosis of Rare Hereditary Diseases in Russian Patients [Sovremennye algoritmy geneticheskoi diagnostiki redkikh nasledstvennykh boleznei u rossiiskikh patsientov]. Moscow: Poligrafist i izdatel’; 2022. https://elibrary.ru/rduzgh (in Russian)

14. Milovanova A.M., Pushkov A.V., Savost’yanov K.V., Zrobok O.I., Vashurina T.V., Anan’in P.V., et al. A study of genetic causes of congenital and infantile nephrotic syndrome in children of Russian Federation. Nefrologiya i dializ. 2021; 23(1): 57–72. https://elibrary.ru/kvqirq (in Russian)

15. Oestreich A.E., Deeg K.H., Hofmann V., Hoyer P.F., eds. Ultraschalldiagnostik in Pädiatrie und Kinderchirurgie [Ultrasound Diagnosis in Pediatrics and Pediatric Surgery]. Pediatr. Radiol. 2015; 45: 300–1. https://doi.org/10.1007/s00247-014-3229-0 (in German)

16. Selistre L., De Souza V., Cochat P., Antonello I.C., Hadj-Aissa A., Ranchin B., et al. GFR estimation in adolescents and young adults. J. Am. Soc. Nephrol. 2012; 23(6): 989–96. https://doi.org/10.1681/ASN.2011070705

17. Emma F., Goldstein S.L., Bagga A., Bates C.M. Rukshana Shroff: Pediatric Nephrology. Philadelphia: Springer; 2022.

18. Joung J., Cho H. Etiology and prognosis of nephrocalcinosis according to gestational age in Korean children. BMC Pediatr. 2023; 23(1): 451. https://doi.org/10.1186/s12887-023-04293-7

19. Bota S., Andrade J.V., Francisco T., Santos R. Nephrocalcinosis in a Portuguese pediatric population. Port. J. Nephrol. Hypert. 2019; 33(1): 14–8. https://doi.org/10.32932/pjnh.2019.04.005

20. Shavit L., Jaeger P., Unwin R.J. What is nephrocalcinosis? Kidney Int. 2015; 88(1): 35–43. https://doi.org/10.1038/ki.2015.76

21. Doğan C.S., Uslu-Gökçeoğlu A., Comak E., Alimoğlu E., Koyun M., Akman S. Renal function and linear growth of children with nephrocalcinosis: a retrospective single-center study. Turk. J. Pediatr. 2013; 55(1): 58–62.

22. Ramya K., Krishnamurthy S., Sivamurukan P. Etiological profile of nephrocalcinosis in children from Southern India. Indian Pediatr. 2020; 57(5): 415–9.

23. Döven S.S., Tülpar S., Baştuğ F., Yıldırım Z.N.Y., Yılmaz E.K., Çiçek N., et al. A nationwide retrospective study in Turkish children with nephrocalcinosis. Turk. J. Med. Sci. 2021; 51(5): 2564–9. https://doi.org/10.3906/sag-2103-347

24. Woo H.A., Lee H., Choi Y.H., Min J., Kang H.G., Ahn Y.H., et al. Clinical outcomes of nephrocalcinosis in preschool-age children: association between nephrocalcinosis improvement and long-term kidney function. Front. Pediatr. 2023; 11: 1214704. https://doi.org/10.3389/fped.2023.1214704

25. Pournasiri Z., Madani A., Ghaemi A., Adl Z., Salehpour S. Long-term effect of nephrocalcinosis on renal function and body growth index in children: a retrospective single center study. Iran. J. Pediatr. 2018; 28(4): e22029. https://doi.org/10.5812/ijp.22029