The value of ABCB1 gene expression in children with idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome is the most common childhood glomerulopathy. Despite modern advances in medicine, idiopathic NS is still a big problem, this is due to the fact that the mechanisms of pathogenesis are not fully understood, and the lack of unified approaches to drug therapy are the main obstacles to improving care for children. Approximately 20% of patients with nephrotic syndrome are resistant to standard glucocorticosteroid therapy, the so-called steroid-resistant nephrotic syndrome. In recent years, the issue of the role of the multidrug resistance gene ABCB1 in the formation of steroid resistance in children with primary nephrotic syndrome has been discussed. This article presents our own data on the study of ABCB1 gene expression in children with idiopathic nephrotic syndrome. A change in ABCB1 gene expression was demonstrated depending on the response to steroid therapy. Thus, ABCB1 gene expression is higher in patients with steroid-resistant nephrotic syndrome than in patients who responded to steroid therapy. At the same time, there are significant differences in ABCB1 expression between SZNS and SNNS. In clinical practice, patients with steroid-dependent nephrotic syndrome have relapses of the disease against the background of withdrawal of prednisolone, which is most likely due to the rapid elimination of prednisolone and further requires a revision of the prednisolone reduction scheme. The data obtained indicate the need for a personal approach to the management of patients with idiopathic nephrotic syndrome, taking into account the molecular genetic characteristics.

1. Savenkova ND. Treatment strategy for onset, recurrent and often recurrent hormone-sensitive and hormone-dependent nephrotic syndrome with minimal changes in children. Nefrologija 2013;17(3):17-25. doi: 10.24884/1561-6274-2013-17-3-17-25

2. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet 2003;362(9384):629-639. doi: 10.1016/S0140-6736(03)14184-0

3. Bagga A, Mantan M. Nephrotic syndrome in children. Indian J Med Res 2005;122(1):13-28

4. Niaudet P, Boyer O. Idiopathic Nephrotic Syndrome in Children: Clinical Aspects. Pediatric Nephrology, Seventh Edition, 2016:840-869. doi: 10.1007/978-3-662-43596-0_24

5. Gipson DS, Massengill SF, Yao L et al. Management of childhood onset nephrotic syndrome. Pediatrics 2009;124(2):747-757. doi: 10.1542/peds.2008-1559

6. Savenkova ND, Papajan AV, Batrakova IV. Nefroticheskij sin-drom s minimal'nymi izmenenijami u detej. V knige: Klinicheskaja nefrologija detskogo vozrasta. AV Papajan, ND Savenkova. Ruko-vodstvo dlja vrachej. Sankt-Peterburg, 2008. S. 279-303

7. Schijvens AM, ter Heine R, de Wildt SN, Schreuder MF. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome. Pediatr Nephrol 2019;34(3):389-403. doi: 10.1007/s00467-018-3929-z

8. Tan L, Li S, Yang H et al. Efficacy and acceptability of immunosuppressive agents for pediatric frequently-relapsing and steroid-dependent nephrotic syndrome: A network metaanalysis of randomized controlled trials. Medicine (Baltimore) 2019;98(22):e15927. doi: 10.1097/MD.0000000000015927

9. Wang F, Zhang Y, Mao J et al. Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2017;32(7):1181-1192. doi: 10.1007/s00467-017-3590-y

10. Lane BM, Cason R, Esezobor CI, Gbadegesin RA. Genetics of Childhood Steroid Sensitive Nephrotic Syndrome: An Update. Front Pediatr 2019;7:8. doi: 10.3389/fped.2019.00008

11. Swierczewska M, Ostalska-Nowicka D, Kempisty B et al. Molecular basis of mechanisms of steroid resistance in children with nephrotic syndrome. Acta Biochim Pol 2013;60(3):339-344

12. Che R, Zhang A. Mechanisms of glucocorticoid resistance in idiopathic nephrotic syndrome. Kidney Blood Press Res 2013;37(4-5):360-378. doi: 10.1159/000350163

13. Bauer B, Hartz AMS, Pekcec A et al. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol 2008;73(5):1444-1453. doi: 10.1124/mol.107.041210

14. Bauer B, Hartz AMS, Fricker G, Miller DS. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol 2004;66(3):413-419. doi: 10.1124/mol.66.3

15. Leopoldo M, Nardulli P, Contino M et al. An updated patent review on P-glycoprotein inhibitors (2011-2018). Expert Opinion on Therapeutic Patents 2019;29(6):455-461. doi: 10.1080/13543776.2019.1618273

16. Wasilewska A, Zoch-Zwierz W, Pietruczuk M. Expression of multidrug resistance P-glycoprotein on lymphocytes from nephrotic children treated with cyclosporine A and ACE-inhibitor. Eur J Pediatr 2007;166(5):447-452. doi: 10.1007/s00431-006-0256-3

17. Wasilewska A, Zoch-Zwierz W, Pietruczuk M, Zalewski G. Expression of P-glycoprotein in lymphocytes from children with nephrotic syndrome, depending on their steroid response. Pediatr Nephrol 2006;21(9):1274-1280. doi: 10.1007/s00467-006-0187-2

18. Prasad N, Jaiswal AK, Agarwal V et al. Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: A longitudinal study. Cytokine 2015;72(2):190-196. doi: 10.1016/j.cyto.2014.12.028

19. Singh H, Agarwal V, Chaturvedi S et al. Reciprocal Relationship Between HDAC2 and P-Glycoprotein/MRP-1 and Their Role in Steroid Resistance in Childhood Nephrotic Syndrome. Front Pharmacol 2019;10:558. doi: 10.3389/fphar.2019.00558

20. Morozov SL, Voronkova AS, Dlin VV et al. Analysis of gene expression using Ncounter Nanostring technology in medical research: experience in use in children with nephrotic syndrome. Rossijskij vestnik perinatologii i pediatrii 2019;64(1):110-115. doi: 10.21508/1027-4065-2019-64-1-110-115

21. Morozov SL, Dlin VV, Suhorukov VS, Voronkova AS. Molecular nephropathology: new possibilities for the diagnosis of kidney disease. Rossijskij vestnik perinatologii i pediatrii 2017;62(3):32-36. doi: 10.21508/1027-4065-2017-62-3-32-36