Advances in Clinical and Experimental Medicine
2020, vol. 29, nr 5, May, p. 603–609
Publication type: original article
Annexin V in children with idiopathic nephrotic syndrome treated with cyclosporine A
1 Department and Clinic of Pediatric Nephrology, Wroclaw Medical University, Poland
Background. Treatment with cyclosporine A (CsA), a calcineurin inhibitor, is effective in children with difficult idiopathic nephrotic syndrome (INS). Prolonged CsA treatment can result in several adverse effects, the most significant being nephrotoxicity (CsAN). The plasma and urine levels of the proteins annexin V (AnV) and uromodulin (UM) were investigated in order to assess their usefulness as indicators of early-stage CsAN. Uromodulin is considered a distal tubular damage marker. Annnexin V is present in the distal tubules.
Objectives. To measure AnV in children with INS receiving CsA treatment and to assess the usefulness of this biomarker for monitoring CsAN and as an indicator of changes in the distal tubules of the nephron.
Material and Methods. The prospective study included 30 patients with INS and 22 controls. Plasma and urinary AnV levels were measured 3 times: before CsA treatment, and after 6 and 12 months of therapy. The AnV levels were compared to those of UM.
Results. The urinary AnV and UM levels were significantly higher in the INS patients before CsA therapy in comparison to the reference group. A progressive increase of urinary AnV was observed after 6 and 12 months of therapy. Urinary UM only increased after 6 months. No significant correlations were found between plasma and urinary concentrations of the proteins studied.
Conclusion. The increased urinary excretion of AnV in children with INS receiving CsA treatment may suggest its usefulness as an early marker of subclinical CsAN. Annexin V seems to be a more sensitive indicator of tubular damage in the course of CsA therapy than UM, though large, multicenter studies are needed.
children, idiopathic nephrotic syndrome, cyclosporine nephrotoxicity, urine biomarkers
- Zagury A, Oliveira AL, Montalvão JA, et al. Steroid-resistant idiopathic nephrotic syndrome in children: Long-term follow-up and risk factors for end-stage renal disease. J Bras Nefrol. 2013;35(3):191–199.
- Mekahli D, Liutkus A, Ranchin B, et al. Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: A multicenter study. Pediatr Nephrol. 2009;24(8):1525–1532.
- Cattran DC, Rao P. Long-term outcome in children and adults with classic focal segmental glomerulosclerosis. Am J Kidney Dis. 1998;32(1):72–79.
- Kim JS, Bellew CA, Silverstein DM, Aviles DH, Boineau FG, Vehaskari VM. High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int. 2005;68(3):1275–1281.
- Ishikura K, Ikeda M, Hattori S, et al. Effective and safe treatment with cyclosporine in nephrotic children: A prospective, randomized multicenter trial. Kidney Int. 2005;73(10):1167–1173.
- Gerke V, Moss SE. Annexins: From structure to function. Physiol Rev. 2002;82(2):331–371.
- Lizarbe MA, Barrasa JI, Olmo N, Gavilanes F, Turnay J. Annexin–phospholipid interactions: Functional implications. Int J Mol Sci. 2013;14(2):2652–2683.
- Marchewka Z. Low molecular weight biomarkers in the nephrotoxicity. Adv Clin Exp Med. 2006;15(6):1129–1138.
- Wever KE, Wagener FA, Frielink C, et al. Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue. PLoS One. 2011;6(8):e24276. doi:10.1371/journal.pone.0024276
- Bamri-Ezzine S, Ao ZJ, Londoño I, Gingras D, Bendayan M. Apoptosis of tubular epithelial cells in glycogen nephrosis during diabetes. Lab Invest. 2003;83(7):1069–1080.
- Emanuel VL, Mnuskina MM, Smirnov AV, et al. Annexin-5 as a biochemical marker of early vascular disorders under chronic disease of kidneys [in Russian]. Klin Lab Diagn. 2013;4:9–10.
- Meier P, Dayer E, Blanc E, Wauters JP. Early T cell activation correlates with expression of apoptosis markers in patients with end-stage renal disease. J Am Soc Nephrol. 2002;13(1):204–212.
- International Study of Kidney Disease in Children. 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;20(6):765–771.
- Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34(3):571–590.
- Matsuda R, Kaneko N, Horikawa Y, et al. Measurement of urinary annexin V by ELISA and its significance as a new urinary marker of kidney disease. Clin Chim Acta. 2000;298(1–2):29–43.
- Matsuda R, Kaneko N, Horikawa Y, et al. Localization of annexin V in rat normal kidney and experimental glomerulonephritis. Res Exp Med (Berl). 2001;200(2):77–92.
- Tomlinson PA. Low molecular weight proteins in children with renal disease. Pediatr Nephrol. 1992;6(6):565–571.
- Simsek B, Buyukcelik M, Soran M, et al. Urinary annexin V in children with nephrotic syndrome: A new prognostic marker? Pediatr Nephrol. 2008;23(1):79–82.
- Zachwieja J, Dworacki G, Bobkowski W, Dobrowolska-Zachwieja A, Zaniew M, Maciejewski J. Increased apoptosis of peripheral blood lymphocytes in children with nephrotic syndrome. Pediatr Nephrol. 2002;17(3):197–200.
- Sinha A, Bagga A. Nephrotic syndrome. Indian J Pediatr. 2012;79(8):1045–1055.
- Kaneko N, Matsuda R, Hosoda S, Kajita T, Ohta Y. Measurement of plasma annexin V by ELISA in the early detection of acute myocardial infarction. Clin Chim Acta. 1996;251(1):65–80.
- Chugh SS, Clement LC, Macé C. New insights into human minimal change disease: Lessons from animal models. Am J Kidney Dis. 2012;59(2):284–292.
- Zhang S, Audard V, Fan Q, Pawlak A, Lang P, Sahali D. Immunopathogenesis of idiopathic nephrotic syndrome. Contrib Nephrol. 2011;169:94–106.
- Tudpor K, Laínez S, Kwakernaak AJ, et al. Urinary plasmin inhibits TRPV5 in nephrotic-range proteinuria. J Am Soc Nephrol. 2012;23(11):1824–1834.
- Schlaepfer DD, Jones J, Haigler HT. Inhibition of protein kinase C by annexin V. Biochemistry. 1992;31(6):1886–1891.
- Sinha A, Sharma A, Mehta A, et al. Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome. Indian J Nephrol. 2013;23(1):41–46.
- Devuyst O, Dahan K, Pirson Y. Tamm–Horsfall protein or uromodulin: New ideas about an old molecule. Nephrol Dial Transplant. 2005;20(7):1290–1294.