The interplay of oxidative stress and inflammation in pediatric patients with nephrotic syndrome

  • Yonas Mulat Simachew University of Belgrade
  • Marija Mihajlović
  • Tamara Antonić
  • Gordana Miloševski-Lomić
  • Amira Peco-Antić
  • Dragana Jovanović
  • Dušan Paripović
  • Aleksandra Stefanović
Keywords: Nephrotic syndrome; Oxidative stress; Inflammation; Hypertension; Pentraxin 3; Advanced oxidation protein products

Abstract


Summary

Background: The pathophysiological mechanisms crucial in the development of nephrotic syndrome (NS) in the pediatric population are still not fully understood. This study aims to investigate the synergistic interaction of oxidative stress and inflammation in the pathogenesis of NS. Additionally, one of the objectives of this study is to examine the relationship between hypertension and the degree of oxidative stress and inflammation in patients during the acute phase of the disease.

Methods: The study included 33 children, aged 2 to 9 years, with NS. Blood samples were collected during the acute phase and remission. Parameters of oxidative status were determined, including total oxidative status (TOS), advanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB), sulfhydryl groups (-SH), paraoxonase 1 (PON1), and total antioxidant status (TAS) in serum, measured spectrophotometrically. Inflammatory parameters such as pentraxin 3 (PTX3), leptin, programmed cell death ligand 1 (PD-L1), and E-cadherin were determined using enzyme-linked immunosorbent assay (ELISA).

Results: Patients with NS and hypertension had significantly higher levels of AOPP and TOS (p=0.029 and p=0.003, respectively). During the acute phase of the disease, lower activity of -SH and PON1 was observed compared to remission (p<0.001, for both). PTX3 levels were higher, while leptin levels were lower during the acute phase (p<0.001, for both). PTX3 correlated with AOPP and TAS during the acute phase but not in remission (rs=0.42, p=0.027 and rs=0.43, p=0.025, respectively). A negative correlation between AOPP and leptin was observed during the acute phase, which disappeared in remission (rs=-0.42, p=0.028).

 

Conclusions: Results of this study show that hypertension influences oxidative stress markers, and decreased antioxidant capacity may contribute to NS development. PTX 3 appears as a potential disease activity marker, indicating a dynamic connection between inflammation and oxidative stress. Leptin may also play a role in oxidative stress in NS. 

List of abbreviations: AOPP, advanced oxidation protein products; BMI, body mass index; DBP, diastolic blood pressure; ELISA, enzyme-linked immunosorbent assay; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;  total antioxidant status; PAB, prooxidant-antioxidant balance; -SH, sulfhydryl group; SBP, systolic blood pressure; PON 1, paraoxonase; PTX 3, pentraxin 3; PD-L1, programmed cell death ligand 1; TC, total cholesterol; TG, triglyceride; TAS, total antioxidant status; TOS, total oxidation status.

 

References

References


1.Mishra OP, Gupta AK, Prasad R, Ali Z, Upadhyay RS, Mishra SP, et al. Antioxidant status of children with idiopathic nephrotic syndrome. Pediatr Nephrol. 2011;26(2):251–6.


2.Mihaela Busuioc R, Mircescu G. Nephrotic Syndrome Complications-New and Old. Part 2. Mædica J Clin Med. 2022; 17(2): 404-14


3.Ashoor IF, Mansfield SA, O’Shaughnessy MM, Parekh RS, Zee J, Vasylyeva TL, et al. Prevalence of Cardiovascular Disease Risk Factors in Childhood Glomerular Diseases. J Am Heart Assoc. 2019;8(14): e012143.


4.Shatat IF, Becton LJ, Woroniecki RP. Hypertension in childhood nephrotic syndrome. Front. Pediatr. 2019; 7:287.


5.Zhang Z, Zhao L, Zhou X, Meng X, Zhou X. Role of inflammation, immunity, and oxidative stress in hypertension: New insights and potential therapeutic targets. Front. Immunol. 2023;13: 1098725


6.Demirci Ş, Şekeroǧlu MR, Noyan T, Köçeroǧlu R, Soyoral YU, Dülger H, et al. The importance of oxidative stress in patients with chronic renal failure whose hypertension is treated with peritoneal dialysis. Cell Biochem Funct. 2011;29(3):249–54.


7.Bakr A, Abul Hassan S, Shoker M, Zaki M, Hassan R. Oxidant stress in primary nephrotic syndrome: Does it modulate the response to corticosteroids? Pediatr Nephrol. 2009;24(12):2375–80.


 


8.Figueroa SM, Araos P, Reyes J, Gravez B, Barrera-Chimal J, Amador CA. Oxidized albumin as a mediator of kidney disease. Antioxidants. 2021; 10:1–13.


9.Fan A, Jiang X, Mo Y, Tan H, Jiang M, Li J. Plasma levels of oxidative stress in children with steroid-sensitive nephrotic syndrome and their predictive value for relapse frequency. Pediatr Nephrol. 2016;31(1):83–8.


10.Mao S, Zhang A, Huang S. Serum levels of malondialdehyde, vitamin C and e in idiopathic nephrotic syndrome: A meta-analysis. Ren Fail. 2014;36(6):994–9.


11.Duni A, Liakopoulos V, Roumeliotis S, Peschos D, Dounousi E. Oxidative stress in the pathogenesis and evolution of chronic kidney disease: Untangling ariadne’s thread. Int J Mol Sci. 2019;20(15):1–17.


12.Kotur-Stevuljević J, Vekić J, Stefanović A, Zeljković A, Ninić A, Ivanišević J, et al. Paraoxonase 1 and atherosclerosis-related diseases. Biofactors. 2020;46(2):193–205.


13.Bourgonje AR, Abdulle AE, Bourgonje MF, Binnenmars SH, Gordijn SJ, Bulthuis MLC, et al. Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population. Redox Biol. 2021; 48:102211.


14.Alamdari DH, Paletas K, Pegiou T, Sarigianni M, Befani C, Koliakos G. A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin Biochem. 2007;40(3–4):248–54.


15.Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004;37(4):277–85.


16.Erel O. A new automated colorimetric method for measuring total oxidant status. 2005; 38:1103–11.


17.Camici M. The Nephrotic Syndrome is an immunoinflammatory disorder. Med Hypotheses. 2007;68(4):900–5.


18.Roca N, Martinez C, Jatem E, Madrid A, Lopez M, Segarra A. Activation of the acute inflammatory phase response in idiopathic nephrotic syndrome: association with clinicopathological phenotypes and with response to corticosteroids. Clin Kidney J. 2021;14(4):1207–15.


19.Speeckaert MM, Speeckaert R, Carrero JJ, Vanholder R, Delanghe JR. Biology of human pentraxin 3 (PTX3) in acute and chronic kidney disease. J Clin Immunol. 2013;33(5):881–90.


20.Sjöberg B, Qureshi AR, Heimbürger O, Stenvinkel P, Lind L, Larsson A, et al. Association between levels of pentraxin 3 and incidence of chronic kidney disease in the elderly. J Intern Med. 2016;279(2):173–9.


21.Magrini E, Mantovani A, Garlanda C. The Dual Complexity of PTX3 in Health and Disease: A Balancing Act? Trends Mol Med. 2016; 22(6): 497–510.


22.Korczynska J, Czumaj A, Chmielewski M, Swierczynski J, Sledzinski T. The Causes and Potential Injurious Effects of Elevated Serum Leptin Levels in Chronic Kidney Disease Patients. Int J Mol Sci. 2021; 22(9):4685.


23.Wasilewska A, Tomaszewska B, Biernacka WZ zwierz A. Serum and urine leptin concentration in children with nephrotic syndrome. Pediatr Nephrol. 20(5):597-602.


24.Ece A, Atamer Y, Gürkan F, Bilici M, Koçyiǧt Y. Anti-oxidant status in relation to lipoproteins, leptin and pro-inflammatory cytokines in children with steroid-sensitive nephrotic syndrome. Nephrology. 2004;9(6):366–73.


25.Buyan N, Özkaya O, Bideci A, Sevim C, Kalman S, Bakkalog S. Leptin, soluble leptin receptor, and transforming growth factor- β 1 levels in minimal change nephrotic syndrome. Pediatr Nephrol. 2003;18(10):1009-14.


26.Varal IG, Civilibal M, Duru NS, Elevli M. A prospective study of serum concentrations of leptin, homocysteine and insulin resistance in children with steroid-sensitive nephrotic syndrome. Exp Biomed Res. 2020;3(2):79–89.


27.Wei Y, Jiang Z. The role of programed death-ligand 1 in renal diseases. J Recept Signal Transduct. 2020;40(4):295–300.


28.Grywalska E, Smarz-Widelska I, Krasowska-Zajac E, Korona-Glowniak I, Zaluska-Patel K, Mielnik M, et al. The PD-1/PD-L1 Inhibitory Pathway is Altered in Primary Glomerulonephritides. Arch Immunol Ther Exp. 2018;66(2):133–43.


29.Pippin JW, Kaverina N, Wang Y, Eng DG, Zeng Y, Tran U, et al. Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease. J Clin Invest. 2022;132(16): e156250


30.Van Den Bossche J, Malissen B, Mantovani A, De Baetselier P, Van Ginderachter JA. Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood. 2012;119(7):1623–33.


31.Andersen RF, Palmfeldt J, Jespersen B, Gregersen N, Rittig S. Plasma and urine proteomic profiles in childhood idiopathic nephrotic syndrome. Proteomics Clin Appl. 2012;6(7–8):382–93.


32.Cattran DC, Feehally J, Cook HT, Liu ZH, Fervenza FC, Mezzano SA, et al. Kidney disease: Improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int. 2012;2 Suppl 2:139–274.


33.Friedewald WT, Levy RI, Fredrickson DS. Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clin chem.1972;18(6):499-502.


34.Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, et al. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int. 1996;49(5):1304–13.


35.Richter RJ, Furlong CE. Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics. 1999;9(6):745-53.


36.Ellman GL. Tissue Sulfhydryl Groups. Arch Biochem Biophys. 1959;82(1):70-7


37.Karthikeyan K, Sinha I, Prabhu K, Bhaskaranand N, Rao A. Plasma protein thiols and total antioxidant power in pediatric nephrotic syndrome. Nephron Clin Pract. 2008;110(1):10-4.


38.Karadag A, Ozcelik B, Saner S. Review of methods to determine antioxidant capacities. Food Anal Methods. 2009;2(1):41–60.


39.Kniazewska MH, Obuchowicz AK, Wielkoszyński T, Zmudzińska-Kitczak J, Urban K, Hyla-Klekot L. Evaluation of certain constituents of antioxidant defense in youth treated in the past for steroid-sensitive idiopathic nephrotic syndrome. Pediatr Nephrol. 2009;24(11):2187–92.


40.Ece A, Atamer Y, Gürkan F, Davutoǧlu M, Koçyiǧit Y, Tutanç M. Paraoxonase, total antioxidant response, and peroxide levels in children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol. 2005;20(9):1279–84.


41.El-Melegy NT, Mohamed NA, Sayed MM. Oxidative modification of low-density lipoprotein in relation to dyslipidemia and oxidant status in children with steroid sensitive nephrotic syndrome. Pediatr Res. 2008;63(4):404–9.


42.Lee HH, Kim SY, Na JC, Yoon YE, Han WK. Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury. PLoS One. 2018;13(4):1–15.


43.Xiao Y, Yang N, Zhang Q, Wang Y, Yang S, Liu Z. Pentraxin 3 Inhibits Acute Renal Injury-Induced Interstitial Fibrosis Through Suppression of IL-6/Stat3 Pathway. Inflammation. 2014;37(5):1895–901.


44.Chen X, Luo J, Wu M, Pan Z, Xie Y, Wang H, et al. Study on association of pentraxin 3 and diabetic nephropathy in a rat model. J Diabetes Res. 2018;2018.


45.Divella C, Stasi A, Franzin R, Rossini M, Pontrelli P, Sallustio F, et al. Pentraxin-3-mediated complement activation in a swine model of renal ischemia/reperfusion injury. Aging. 2021;13(8):10920–33.


46.Miljković M, Stefanović A, Bogavac-Stanojević N, Simić-Ogrizović S, Dumić J, Černe D, et al. Association of pentraxin-3, galectin-3 and matrix metalloproteinase-9/TIMP-1 with cardiovascular risk in renal disease patients. Acta Clin Croat. 2017;56(4):673–80.


47.Zlibut A, Bocsan IC, Agoston-Coldea L. Pentraxin-3 and endothelial dysfunction. Adv Clin Chem. 2019;91: 163–179


48.Ou H, Huang Z, Mo Z, Xiao J. The Characteristics and Roles of Advanced Oxidation Protein Products in Atherosclerosis. Cardiovasc Toxicol. 2017;17(1):1–12.


49.Miljkovic M, Stefanovic A, Simic-Ogrizovic S, Vekic J, Bogavac-Stanojevic N, Cerne D, et al. Association of Dyslipidemia, Oxidative Stress, and Inflammation with Redox Status in VLDL, LDL, and HDL Lipoproteins in Patients with Renal Disease. Angiology. 2018;69(10):861–70.


50.Balci YI, Nuray E, Polat A, Enli Y, Ozgurler F, Akin M. Pentraxin-3 levels in beta Thalassemia major and minor patients and its relationship with antioxidant capacity and total oxidant stress. J Pediatr Hematol Oncol. 2016;38(1):12–6.


51.Wang L, Cano M, Datta S, Wei H, Ebrahimi KB, Gorashi Y, et al. Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation. J Pathol. 2016;240(4):495–506.


52.Guimarães FTL, Ferreira RN, Brito-Melo GEA, Rocha-Vieira E, Pereira W de F, Pinheiro SVB, et al. Pediatric patients with steroid-sensitive nephrotic syndrome have higher expression of T regulatory lymphocytes in comparison to steroid-resistant disease. Front Pediatr. 2019; 7:1–9.


53.Tsuji S, Kimata T, Yamanouchi S, Kitao T, Kino J, Suruda C, et al. Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome. Pediatr Int. 2017;59(5):643–6.


54.Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science. 2019;364(6440):558-566.


55.Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, et al. PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways. Immunity. 2019;51(6):1059-1073.


56.Kaneko K. Molecular mechanisms in the pathogenesis of idiopathic nephrotic syndrome. 1st ed. Tokyo: Springer; 2016. 1–240 pp.


57.Maeda N, Maruhashi T, Sugiura D, Shimizu K, Okazaki IM, Okazaki T. Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells. Journal of Biological Chemistry. 2019;294(52):19896–906.


58.Deng Y, Xia X, Zhao Y, Zhao Z, Martinez C, Yin W, et al. Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance. Nat Commun. 2021;12(1): 7041


59.Koziolek M, Mueller GA, Dihazi GH, Jung K, Altubar C, Wallbach M, et al. Urine E-cadherin: A marker for early detection of kidney injury in diabetic patients. J Clin Med. 2020;9(3):639


60.Yang J, Xiong Y, Zhou L, Huang Y, Chen W, Wang B. Soluble E-cadherin is associated with oxidative stress in patients with chronic HBV infection. J Med Virol. 2020;92(1):34–44.


61.Dinleyici M, Yildiz B, Çetin N, Kural N, Alatas O. Serum and urinary leptin and ghrelin in children with nephrotic syndrome. Neuro Endocrinol Lett. 2013;34(5):388–94.


62.Schroth M, Gro M, Do HG, Blum WF, Rascher W, Do È. Renal loss of leptin in patients with nephrotic syndrome. Eur J Endocrinol. 2001;145(4):463-8


63.Zhou J, Shi F, Xun W. Leptin, hs-CRP, IL-18 and urinary protein before and after treatment of children with nephrotic syndrome. Exp Ther Med. 2018; 15(5):4426–30


64.Conti G, Caccamo D, Siligato R, Gembillo G, Satta E, Pazzano D, et al. Association of higher advanced oxidation protein products (AOPPs) levels in patients with diabetic and hypertensive nephropathy. Medicina. 2019;55(10): 675


65.Xu H, Cabezas-Rodriguez I, Qureshi AR, Heimburger O, Barany P, Snaedal S, et al. Increased levels of modified advanced oxidation protein products are associated with central and peripheral blood pressure in peritoneal dialysis patients. Perit Dial Int. 2015;35(4):460–70.

Published
2023/12/26
Section
Original paper