S.L. MOROZOV ^{1, 2}, V.V. DLIN¹

 ¹Scientific-research Clinical Institute of Pediatrics named after Academician Yu.E. Veltishchev, Moscow

²Russian National Research Medical University named after N.I. Pirogov, Moscow

 Contact details:

Morozov S.L. — PhD (medicine), Senior Researcher of the Department of Hereditary and Acquired Kidney Diseases, Associate Professor of the Department of Hospital Pediatrics No. 2

Address: 2 Taldomskaya St., Moscow, Russian Federation, 125412, tel.: +7-903-138-77-32, e-mail: mser@list.ru

The global task of the recent decade is to search for clinical and laboratory markers accurately showing a patient’s reaction to steroid therapy and other immunosuppressive drugs. It is important the applied methods and tests to be non-invasive and simple to use. The article considers various biomarkers used to verify the type of nephrotic syndrome depending on the sensitivity to steroid therapy. Besides the common markers, which are used in clinical practice or have shown a significant result, the work highlights the molecular-genetic markers of resistance to steroid therapy, which are of special clinical importance today. Also, the article presents authors’ own results in diagnosing the steroid resistance of the primary nephrotic syndrome.

Key words: children, nephrotic syndrome, resistance markers, steroid resistant nephrotic syndrome, steroid sensitive nephrotic syndrome, мутация, primary nephrotic syndrome.

REFERENCES

1. Eddy A.A., Symons J.M. Nephrotic syndrome in childhood. Lancet, 2003, vol. 362 (9384), pp. 629–639. DOI: 10.1016/S0140-6736(03)14184-0
2. Stone H., Magella B., Bennett M.R. The Search for Biomarkers to Aid in Diagnosis, Differentiation, and Prognosis of Childhood Idiopathic Nephrotic Syndrome. Front Pediatr, 2019, vol. 7, p. 404. DOI: 10.3389/fped.2019.00404
3. Noone D.G., Iijima K., Parekh R. Idiopathic nephrotic syndrome in children. Lancet, 2018, vol. 392 (10141), pp. 61–74. DOI:10.1016/S0140-6736(18)30536-1
4. Pasini A., Benetti E., Conti G., Ghio L., Lepore M., Massella L. et al. The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I — Diagnosis and treatment of the first episode and the first relapse. Ital J Pediatr, 2017, vol. 43 (1), p. 41. DOI: 10.1186/s13052-017-0356-x
5. Morozov S.L., Voronkova A.S., Dlin V.V. Significance of ABCB1 gene expression in children with idiopathic nephrotic syndrome. Nefrologiya, 2021, no. 25 (1), pp. 83–89 (in Russ.). DOI: 10.36485/1561-6274-2021-25-1-83-89
6. Ignatova M.S., Dlin V.V. Nephrotic syndrome: past, present and future. Rossiyskiy vestnik perinatologii i pediatrii, 2017, no. 62 (6) (in Russ.). DOI: 10.21508/1027-4065-2017-62-5-29-44
7. Kim J.S., Bellew C.A., Silverstein D.M., Aviles D.H., Boineau F.G., Vehaskari V.M. High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int, 2005, vol. 68 (3), pp. 1275–1281. DOI: 10.1111/j.1523-1755.2005.00524.x
8. Bierzynska A., McCarthy H.J., Soderquest K., Sen E.S., Colby E., Ding W.Y. et al. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int, 2017, vol. 91 (4), pp. 937–947. DOI: 10.1016/j.kint.2016.10.013
9. Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int, 1981, vol. 20 (6), pp. 765–771. DOI: 10.1038/ki.1981.209
10. Nickolas T.L., Forster C.S., Sise M.E., Barasch N., Solá-Del Valle D., Viltard M. et al. NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease. Kidney Int, 2012, vol. 82 (6), pp. 718–722. DOI: 10.1038/ki.2012.195
11. Eremeeva A.V., Dlin V.V., Korsunskiy A.A., Zaykova N.M., Bondarenko E.D. Clinical significance of neutrophil gelatinase-associated lipocalin-2 determination in patients with chronic kidney disease, 2018, no. 22 (4), pp. 50–56 (in Russ.). DOI: 10.24884/1561-6274-2018-22-4-50-56
12. Bennett M.R., Piyaphanee N., Czech K., Mitsnefes M., Devarajan P. NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome. Pediatr Nephrol, 2012, vol. 27 (5), pp. 807–812. DOI: 10.1007/s00467-011-2075-7
13. Bertelli R., Bonanni A., Caridi G., Canepa A., Ghiggeri G.M. Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease. Front Med (Lausanne), 2018, vol. 5, p. 170. DOI: 10.3389/fmed.2018.00170
14. Garin E.H., Diaz L.N., Mu W., Wasserfall C., Araya C., Segal M. et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol, 2009, vol. 20 (2), pp. 260–266. DOI: 10.1681/ASN.2007080836
15. Bennett M.R., Pleasant L., Haffner C., Ma Q., Haffey W.D., Ying J. et al. A Novel Biomarker Panel to Identify Steroid Resistance in Childhood Idiopathic Nephrotic Syndrome. Biomark Insights, 2017, vol. 12. DOI: 10.1177/1177271917695832
16. Gallon L., Leventhal J., Skaro A., Kanwar Y., Alvarado A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med, 2012, vol. 366 (17), pp. 1648–1649. DOI: 10.1056/NEJMc1202500
17. Zimmerman S.W. Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol., 1984, vol. 22 (1), pp. 32–38.
18. Bakker W.W., Borghuis T., Harmsen M.C., van den Berg A., Kema I.P., Niezen K.E. et al. Protease activity of plasma hemopexin. Kidney Int, 2005, vol. 68 (2), pp. 603–610. DOI: 10.1111/j.1523-1755.2005.00438.x
19. Bakker W.W., van Dael C.M.L., Pierik L.J.W.M., van Wijk J.A.E., Nauta J., Borghuis T. et al. Altered activity of plasma hemopexin in patients with minimal change disease in relapse. Pediatr Nephrol, 2005, vol. 20 (10), pp. 1410–1415. DOI: 10.1007/s00467-005-1936-3
20. Desmedt S., Desmedt V., Delanghe J.R., Speeckaert R., Speeckaert M.M. The intriguing role of soluble urokinase receptor in inflammatory diseases. Crit Rev Clin Lab Sci., 2017, vol. 54 (2), pp. 117–133. DOI: 10.1080/10408363.2016.1269310
21. Xu Y., Berrou J., Chen X., Fouqueray B., Callard P., Sraer J.D. et al. Induction of urokinase receptor expression in nephrotoxic nephritis. Exp Nephrol, 2001, vol. 9 (6), pp. 397–404. DOI: 10.1159/000052638
22. Wei C., Möller C.C., Altintas M.M., Li J., Schwarz K., Zacchigna S. et al. Modification of kidney barrier function by the urokinase receptor. Nat Med, 2008, vol. 14 (1), pp. 55–63. DOI: 10.1038/nm1696
23. Wei C., Trachtman H., Li J., Dong C., Friedman A.L., Gassman J.J. et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol, 2012, vol. 23 (12), pp. 2051–2059. DOI: 10.1681/ASN.2012030302
24. Piyaphanee N., Ma Q., Kremen O., Czech K., Greis K., Mitsnefes M. et al. Discovery and initial validation of α 1-B glycoprotein fragmentation as a differential urinary biomarker in pediatric steroid-resistant nephrotic syndrome. Proteomics Clin Appl, 2011, vol. 5 (5–6), pp. 334–342. DOI: 10.1002/prca.201000110
25. McCarthy E.T., Sharma M., Savin V.J. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol, 2010, vol. 5 (11), pp. 2115–2121. DOI: 10.2215/CJN.03800609
26. Doublier S., Zennaro C., Musante L., Spatola T., Candiano G., Bruschi M. et al. Soluble CD40 ligand directly alters glomerular permeability and may act as a circulating permeability factor in FSGS. PLoS One, 2017, vol. 12 (11), pp. e0188045. DOI: 10.1371/journal.pone.0188045
27. Warejko J.K., Tan W., Daga A., Schapiro D., Lawson J.A., Shril S. et al. Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol, 2018, vol. 13 (1), pp. 53–62. DOI: 10.2215/CJN.04120417
28. Morozov S.L., Dlin V.V., Sadykov A.R., Voronkova A.S., Sukhorukov V.S. Mechanisms of resistance to immunosuppressive therapy in patients with nephrotic syndrome. Rossiyskiy vestnik perinatologii i pediatrii, 2017, no. 62 (4), pp. 19–24 (in Russ.). DOI: 10.21508/1027-4065-2017-62-4-19-24
29. Pätäri-Sampo A., Ihalmo P., Holthöfer H. Molecular basis of the glomerular filtration: nephrin and the emerging protein complex at the podocyte slit diaphragm. Ann Med, 2006, vol. 38 (7), pp. 483–492. DOI: 10.1080/07853890600978149
30. Duma D., Jewell C.M., Cidlowski J.A. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol, 2006, vol. 102 (1–5), pp. 11–21. DOI: 10.1016/j.jsbmb.2006.09.009
31. Zhou J., Cidlowski J.A. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids, 2005, vol. 70 (5–7), pp. 407–417. DOI: 10.1016/j.steroids.2005.02.006
32. Bauer B., Hartz A.M.S., Pekcec A., Toellner K., Miller D.S., Potschka H. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol, 2008, vol. 73 (5), pp. 1444–1453. DOI: 10.1124/mol.107.041210
33. Youssef D.M., Elbehidy R.M., Abdelhalim H.S., Amr G.E. Soluble interleukine-2 receptor and MDR1 gene expression levels as inflammatory biomarkers for prediction of steroid response in children with nephrotic syndrome. Iran J Kidney Dis, 2011, vol. 5 (3), pp. 154–161.
34. Crettol S., Venetz J-P., Fontana M., Aubert J-D, Ansermot N., Fathi M. et al. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet Genomics, 2008, vol. 18 (4), pp. 307–315. DOI: 10.1097/FPC.0b013e3282f7046f
35. Morozov S.L., Aksenova M.E. Primary nephrotic syndrome in children. Prospects for personalized therapy. Prakticheskaya meditsina, 2018, no. 8, pp. 39–42 (in Russ.).