A Cross-Sectional Study of Urinary Neutrophil Gelatinase-Associated Lipocalin and its Association with Steroid Responsiveness in Iraqi Children with Idiopathic Nephrotic Syndrome

Ali Mohammed Abd Al Ridha; Dheyaa Jabbar Kadhim; Ayad Hussein Ali  Alkhazrajy

doi:10.32007/jfacmedbagdad.2049

Authors

Ali Mohammed Abd Al Ridha University of Kufa - Faculty of Pharmacy https://orcid.org/0000-0002-5580-9849
Dheyaa Jabbar Kadhim Faculty of Pharmacy - University of Baghdad https://orcid.org/0000-0002-2654-1441
Ayad Hussein Ali Alkhazrajy Babylon Hospital for Maternity and Pediatrics https://orcid.org/0000-0003-2525-5117

DOI:

https://doi.org/10.32007/jfacmedbagdad.2049

Keywords:

Nephrotic syndrome, biomarker, steroid-resistant nephrotic syndrome, Neutrophil gelatinase-associated lipocalin, Steroid-sensitive nephrotic syndrome

Abstract

Background: Steroid-resistant nephrotic syndrome (SRNS)is associated with serious complications and financial burdens. Studies reported increased urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels in children with idiopathic nephrotic syndrome (INS).

Objectives: This study aimed to evaluate the uNGAL potential to distinguish SRNS from steroid-sensitive nephrotic syndrome (SSNS) in Iraqi children.

Patients and Methods: Children with SRNS (n=31) and SSNS (n=32) were recruited from Babylon Hospital for Maternity and Pediatrics from March to June 2022. Patients' data included demographics, clinical characteristics, and urinary lab tests. The uNGAL concentrations were measured via a commercially available ELISA kit.

Results: A significantly higher uNGAL median (p-value<0.001) was noted in the SRNS group (median [IQR] = 131.512 [30.28] ng/mL) than in the SSNS group (88.45 [41.6] ng/mL). The correlation between uNGAL levels and estimated glomerular filtration rate (eGFR) was negative (Spearman's rho coefficient = − 0.599, p<0.001). The discriminatory power ofuNGAL to discern SRNS from SSNS was significantly high (AUC=0.899, p<0.0001) with a sensitivity of 87.1% and specificity of 87.5% at an optimal cut-off value of 111.091 ng/mL.

Conclusion: uNGAL is associated with a reliable discriminatory strength to distinguish, noninvasively, children with SRNS from those with SSNS.

Received: Jan. 2023

Accepted: Jul, 2023

Published: Oct.2023

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References

Eddy AA, Symons JM. Nephrotic syndrome in childhood. The Lancet. 2003 Aug 23;362(9384):629-39.https://doi.org/10.1016/S0140-6736(03)14184-0.

Olowu WA, Ademola A, Ajite AB, Saad YM. Childhood nephrotic syndrome in tropical Africa: then and now. Paediatr Int Child Health. 2017 Nov;37(4):259-68.

https://doi.org/10.1080/20469047.2017.1374002.

Arif MK, Arif M, Amjad N. A histopathological outlook on nephrotic syndrome: A pediatric perspective. Indian J Nephrol. 2016 Jun;26(3):188-91.https://doi.org/10.4103/0971-4065.159555.

Ahmed NF, Ibrahim R. Childhood nephritic syndrome Clinical manifestations and histopathological spectrum. J Fac Med Baghdad. 2007 Oct 1;49(3):304-6.

Azat NFA, hameed NN, Sahib OA. Pediatric Glomerular Diseases (Review of histopathological subtypes). J Fac Med Baghdad. 2010 Apr 4;52(1):1-2.

Hjorten R, Anwar Z, Reidy KJ. Long-term Outcomes of Childhood Onset Nephrotic Syndrome. Front Pediatr. 2016;4:53. https://doi.org/10.3389/fped.2016.00053.

Gipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol Berl Ger. 2006 Mar;21(3):344-9.

https://doi.org/10.1007/s00467-005-2097-0.

Frankul FM, Fahmi N, Ahmed L. Hypertension in Children with Nephrotic Syndrome. J Fac Med Baghdad. 2005 Apr 3;47(1):5-8.

Banaszak B, Banaszak P. The increasing incidence of initial steroid resistance in childhood nephrotic syndrome. Pediatr Nephrol Berl Ger. 2012 Jun;27(6):927-32.https://doi.org/10.1007/s00467-011-2083-7.

Nandlal L, Naicker T, Bhimma R. Nephrotic Syndrome in South African Children: Changing Perspectives in the New Millennium. Kidney Int Rep. 2019 Apr;4(4):522-34. https://doi.org/10.1016/j.ekir.2019.01.019.

Mohammed TF, Al-Badri AA, Abd Al-Latteef A, Abdulhussain RMH. Trends of Histopathology in Childhood Nephrotic Syndrom. Iraqi Postgrad Med J. 2009;1(1):47-55.

Kumar J, Sarwar B, Kishan J, Khan AR, Abdullah MA, Shah SS. Changing Histopathological Trends in Idiopathic Steroid Resistant Nephrotic Syndrome in Pediatric Population. Ann Pak Inst Med Sci. 2021 May 19;17(2):146-50.https://doi.org/10.48036/apims.v17i2.456.

Gipson PE, Gipson DS. CHAPTER 27 - Focal segmental glomerulosclerosis. In: Lerma EV, Sparks MA, TOPF JM, editors. Nephrology Secrets (Fourth Edition) [Internet]. Elsevier; 2019. p. 186-91. Available from: https://www.sciencedirect.com/science/article/pii/B9780323478717000368https://doi.org/10.1016/B978-0-323-47871-7.00036-8.

Pelletier JH, Kumar KR, Engen R, Bensimhon A, Varner JD, Rheault MN, et al. Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings. Pediatr Nephrol Berl Ger. 2018 Oct;33(10):1773-80.https://doi.org/10.1007/s00467-018-3994-3.

Francis A, Trnka P, McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol CJASN. 2016 Nov 7;11(11):2041-6. https://doi.org/10.2215/CJN.03060316.

Ahmed NF, Hussain HH. Chronic Renal Failure in Children Admitted to Children Welfare Teaching Hospital. Iraqi Postgrad Med J. 2008 Jan 1;7(1):12-7.

Tullus K, Webb H, Bagga A. Management of steroid-resistant nephrotic syndrome in children and adolescents. Lancet Child Adolesc Health. 2018 Dec;2(12):880-90. https://doi.org/10.1016/S2352-4642(18)30283-9.

Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol Berl Ger. 2020 Aug;35(8):1529-61. https://doi.org/10.1007/s00467-020-045191.

Glassock RJ. Con: kidney biopsy: an irreplaceable tool for patient management in nephrology. Nephrol Dial Transplant. 2015 Apr;30(4):528-31. https://doi.org/10.1093/ndt/gfv044.

Stone H, Magella B, Bennett MR. The Search for Biomarkers to Aid in Diagnosis, Differentiation, and Prognosis of Childhood Idiopathic Nephrotic Syndrome. Front Pediatr [Internet]. 2019;7. Available from: https://www.frontiersin.org/articles/10.3389/fped.2019.00404https://doi.org/10.3389/fped.2019.00404.

Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008 Sep;52(3):595-605.

https://doi.org/10.1053/j.ajkd.2008.01.020.

Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol CJASN. 2009 Feb;4(2):337-44. https://doi.org/10.2215/CJN.03530708.

Bennett MR, Piyaphanee N, Czech K, Mitsnefes M, Devarajan P. NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome. Pediatr Nephrol Berl Ger. 2012 May;27(5):807-12.

https://doi.org/10.1007/s00467-011-2075-7.

Choudhary A, Mohanraj PS, Krishnamurthy S, Rajappa M. Association of Urinary Vitamin D Binding Protein and Neutrophil Gelatinase-Associated Lipocalin with Steroid Responsiveness in Idiopathic Nephrotic Syndrome of Childhood. Saudi J Kidney Dis Transplant. 2020 Oct;31(5):946-56.

https://doi.org/10.4103/1319-2442.301201.

Ochocińska A, Jarmużek W, Janas R, Grenda R. Response to corticosteroid therapy is not related to serum and urine NGAL concentration in nephrotic children. Pediatr Pol - Pol J Paediatr. 2018;93(3):245-50.https://doi.org/10.5114/polp.2018.77439.

Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct 1;100(4):S1-276.

https://doi.org/10.1016/j.kint.2021.05.021.

Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982 Apr;143(1):29-36.https://doi.org/10.1148/radiology.143.1.7063747.

Patel ML, Sachan R, Misra R, Kamal R, Shyam R, Sachan P. Prognostic significance of urinary NGAL in chronic kidney disease. Int J Nephrol Renov Dis. 2015;8:139-44. https://doi.org/10.2147/IJNRD.S87423.

Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 2007 May;71(10):967-70. https://doi.org/10.1038/sj.ki.5002165.

Nickolas TL, Forster CS, Sise ME, 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 Sep;82(6):718-22. https://doi.org/10.1038/ki.2012.195.

Bolignano D, Coppolino G, Lacquaniti A, Nicocia G, Buemi M. Pathological and prognostic value of urinary neutrophil gelatinase-associated lipocalin in macroproteinuric patients with worsening renal function. Kidney Blood Press Res. 2008;31(4):274-9. https://doi.org/10.1159/000151665.

Wasilewska A, Zoch-Zwierz W, Taranta-Janusz K, Michaluk-Skutnik J. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity? Pediatr Nephrol Berl Ger. 2010 May;25(5):889-97. https://doi.org/10.1007/s00467-009-1397-1.

Khurana M, Traum AZ, Aivado M, Wells MP, Guerrero M, Grall F, et al. Urine proteomic profiling of pediatric nephrotic syndrome. Pediatr Nephrol Berl Ger. 2006 Sep;21(9):1257-65.

https://doi.org/10.1007/s00467-006-0165-8.

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 Jun;5(5-6):334-42. https://doi.org/10.1002/prca.201000110.

Woroniecki RP, Shatat IF, Supe K, Du Z, Kaskel FJ. Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood. Am J Nephrol. 2008;28(1):83-90.

https://doi.org/10.1159/000109396.

Ahmed HM, botrous OE, khattab R, Abdallah AM. Urinary Interleukin-8 as a Biomarker for Steroid Resistance in Childhood Onset Nephrotic Syndrome. GEGET. 2019;14(1):90-5.

https://doi.org/10.21608/geget.2019.38030.