Generic placeholder image

Current Pediatric Reviews


ISSN (Print): 1573-3963
ISSN (Online): 1875-6336

Mini-Review Article

Idiopathic Nephrotic Syndrome in Pediatrics: An Up-to-date

Author(s): Roberta da Silva Filha, Kassia Burini, Laura Gregório Pires, Sérgio Veloso Brant Pinheiro and Ana Cristina Simões e Silva*

Volume 18, Issue 4, 2022

Published on: 21 April, 2022

Page: [251 - 264] Pages: 14

DOI: 10.2174/1573396318666220314142713

Price: $65


Background: Idiopathic or Primary Nephrotic Syndrome (INS) is a common glomerular disease in pediatric population, characterized by proteinuria, edema and hypoalbuminemia with variable findings in renal histopathology.

Objective: This review aims to summarize current data on the etiopathogenesis diagnosis, protocols of treatment and potential therapeutic advances in INS.

Methods: This narrative review searched for articles on histopathology, physiopathology, genetic causes, diagnosis and treatment of INS in pediatric patients. The databases evaluated were PubMed and Scopus.

Results: INS is caused by an alteration in the permeability of the glomerular filtration barrier with unknown etiology. There are several gaps in the etiopathogenesis, response to treatment and clinical course of INS that justify further investigation. Novel advances include the recent understanding of the role of podocytes in INS and the identification of genes associated with the disease. The role of immune system cells and molecules has also been investigated. The diagnosis relies on clinical findings, laboratory exams and renal histology for selected cases. The treatment is primarily based on steroids administration. In case of failure, other medications should be tried. Recent studies have also searched for novel biomarkers for diagnosis and alternative therapeutic approaches.

Conclusion: The therapeutic response to corticosteroids still remains the main predictive factor for the prognosis of the disease. Genetic and pharmacogenomics tools may allow the identification of cases not responsive to immunosuppressive medications.

Keywords: Idiopathic nephrotic syndrome, children, proteinuria, podocyte, steroid therapy, focal segmental glomerulosclerosis.

Graphical Abstract
Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet 2018; 392(10141): 61-74.
[] [PMID: 29910038]
Souto MFO, Teixeira MM, Penido MG, Simões e Silva AC. Physiopathology of nephrotic syndrome in children and adolescents. Arch Latin Nefr Ped 2008; 8(1): 1-10.
Wang CS, Greenbaum LA. Nephrotic syndrome. Pediatr Clin North Am 2019; 66(1): 73-85.
[] [PMID: 30454752]
Chesney R. The changing face of childhood nephrotic syndrome. Kidney Int 2004; 66(3): 1294-302.
[] [PMID: 15327442]
D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med 2011; 365(25): 2398-411.
[] [PMID: 22187987]
Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet 2003; 362(9384): 629-39.
[] [PMID: 12944064]
Dossier C, Sellier-Leclerc AL, Rousseau A, et al. Prevalence of herpesviruses at onset of idiopathic nephrotic syndrome. Pediatr Nephrol 2014; 29(12): 2325-31.
[] [PMID: 24899237]
Soares SF, Donatti TL, Souto FJ. Serological markers of viral, syphilitic and toxoplasmic infection in children and teenagers with nephrotic syndrome: case series from Mato Grosso State, Brazil. Rev Inst Med Trop São Paulo 2014; 56(6): 499-504.
[] [PMID: 25351544]
Ferrara P, Pierri F, Zenzeri L, Vena F, Ianniello F, Chiaretti A. Post-infectious glomerulonephritis with nephrotic syndrome secondary to rotavirus infection. Med Mal Infect 2013; 43(9): 398-400.
[] [PMID: 23978516]
Colucci M, Corpetti G, Emma F, Vivarelli M. Immunology of idiopathic nephrotic syndrome. Pediatr Nephrol 2018; 33(4): 573-84.
[] [PMID: 28451893]
Hinkes BG, Mucha B, Vlangos CN, et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 2007; 119(4): e907-19.
[] [PMID: 17371932]
Preston R, Stuart HM, Lennon R. Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how? Pediatr Nephrol 2019; 34(2): 195-210.
[] [PMID: 29181713]
Lama G, Luongo I, Tirino G, Borriello A, Carangio C, Salsano ME. T-lymphocyte populations and cytokines in childhood nephrotic syndrome. Am J Kidney Dis 2002; 39(5): 958-65.
[] [PMID: 11979339]
Gbadegesin RA, Adeyemo A, Webb NJ, et al. HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J Am Soc Nephrol 2015; 26(7): 1701-10.
[] [PMID: 25349203]
Floege J, Amann K. Primary glomerulonephritides. Lancet 2016; 387(10032): 2036-48.
[] [PMID: 26921911]
International Study of Kidney Disease in Children. Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int 1978; 13(2): 159-65.
[] [PMID: 713276]
Kim SH, Park SJ, Han KH, et al. Pathogenesis of minimal change nephrotic syndrome: an immunological concept. Korean J Pediatr 2016; 59(5): 205-11.
[] [PMID: 27279884]
Guimarães FTL, Melo GEBA, Cordeiro TM, et al. T-lymphocyte-expressing inflammatory cytokines underlie persistence of proteinuria in children with idiopathic nephrotic syndrome. J Pediatr (Rio J) 2018; 94(5): 546-53.
[] [PMID: 28963877]
Zhao L, Cheng J, Zhou J, Wu C, Chen J. Enhanced steroid therapy in adult MCNS: a systematic review and meta-analysis. Intern Med 2015; 54(17): 2101-8.
[] [PMID: 26328632]
Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Goldstein SL. Pediatr Nephrol. 7th ed. New York: Springer 2016; pp. 1055-77.
Elie V, Fakhoury M, Deschênes G, Jacqz-Aigrain E. Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. Pediatr Nephrol 2012; 27(8): 1249-56.
[] [PMID: 21710250]
Pereira WdeF, Brito-Melo GEA, Guimarães FTL, Carvalho TGR, Mateo EC, Simões e Silva AC. The role of the immune system in idiopathic nephrotic syndrome: a review of clinical and experimental studies. Inflamm Res 2014; 63(1): 1-12.
[] [PMID: 24121975]
Schönenberger E, Ehrich JH, Haller H, Schiffer M. The podocyte as a direct target of immunosuppressive agents. Nephrol Dial Transplant 2011; 26(1): 18-24.
[] [PMID: 20937691]
Shimada M, Araya C, Rivard C, Ishimoto T, Johnson RJ, Garin EH. Minimal change disease: a “two-hit” podocyte immune disorder? Pediatr Nephrol 2011; 26(4): 645-9.
[] [PMID: 21052729]
Kopp JB, Anders HJ, Susztak K, et al. Podocytopathies. Nat Rev Dis Primers 2020; 6(1): 68.
[] [PMID: 32792490]
Goldwich A, Burkard M, Olke M, et al. Podocytes are nonhematopoietic professional antigen-presenting cells. J Am Soc Nephrol 2013; 24(6): 906-16.
[] [PMID: 23539760]
Novelli R, Benigni A, Remuzzi G. The role of B7-1 in proteinuria of glomerular origin. Nat Rev Nephrol 2018; 14(9): 589-96.
[] [PMID: 29959373]
Reiser J, Mundel P. Danger signaling by glomerular podocytes defines a novel function of inducible B7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol 2004; 15(9): 2246-8.
[] [PMID: 15339973]
Krummey SM, Ford ML. Braking bad: novel mechanisms of CTLA-4 inhibition of T cell responses. Am J Transplant 2014; 14(12): 2685-90.
[] [PMID: 25387592]
Karp AM, Gbadegesin RA. Genetics of childhood steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2017; 32(9): 1481-8.
[] [PMID: 27470160]
Guimarães FTL, Ferreira RN, Brito-Melo GEA, 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: 114.
[] [PMID: 31001501]
Bertelli R, Bonanni A, Di Donato A, Cioni M, Ravani P, Ghiggeri GM. Regulatory T cells and minimal change nephropathy: in the midst of a complex network. Clin Exp Immunol 2016; 183(2): 166-74.
[] [PMID: 26147676]
Eroglu FK, Orhan D, İnözü M, et al. CD 80 expression and infiltrating regulatory T cells in idiopathic nephrotic syndrome of childhood. Pediatr Int 2019; 61(12): 1250-6.
[] [PMID: 31513327]
Garin EH, Reiser J, Cara-Fuentes G, et al. Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 2015; 30(3): 469-77.
[] [PMID: 25239302]
Hansrivijit P, Puthenpura MM, Ghahramani N. Efficacy of abatacept treatment for focal segmental glomerulosclerosis and minimal change disease: A systematic review of case reports, case series, and observational studies
. Clin Nephrol 2020; 94(3): 117-26.
[] [PMID: 32589135]
Shalaby SA, Al-Edressi HM, El-Tarhouny SA, Fath El-Bab M, Zolaly MA. Type 1/type 2 cytokine serum levels and role of interleukin-18 in children with steroid-sensitive nephrotic syndrome. Arab J Nephrol Transplant 2013; 6(2): 83-8.
[PMID: 23656401]
Davin JC. The glomerular permeability factors in idiopathic nephrotic syndrome. Pediatr Nephrol 2016; 31(2): 207-15.
[] [PMID: 25925039]
Simões E Silva AC, Lanza K, Palmeira VA, Costa LB, Flynn JT. 2020 update on the renin–angiotensin–aldosterone system in pediatric kidney disease and its interactions with coronavirus. Pediatr Nephrol 2021; 36(6): 1407-26.
[] [PMID: 32995920]
Filha RDS, Pinheiro SVB, Macedo e Cordeiro T, et al. Evidence for a role of angiotensin converting enzyme 2 in proteinuria of idiopathic nephrotic syndrome. Biosci Rep 2019; 39(1): BSR20181361.
[] [PMID: 30514826]
Rheault MN, Gbadegesin RA. The genetics of nephrotic syndrome. J Pediatr Genet 2016; 5(1): 15-24.
[PMID: 27617138]
Rood IM, Deegens JK, Wetzels JF. Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Nephrol Dial Transplant 2012; 27(3): 882-90.
[] [PMID: 22334613]
Laurin LP, Lu M, Mottl AK, Blyth ER, Poulton CJ, Weck KE. Podocyte-associated gene mutation screening in a heterogeneous cohort of patients with sporadic focal segmental glomerulosclerosis. Nephrol Dial Transplant 2014; 29(11): 2062-9.
[] [PMID: 24500309]
Kitzler TM, Kachurina N, Bitzan MM, Torban E, Goodyer PR. Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2018; 33(10): 1741-50.
[] [PMID: 29982877]
Świerczewska M, Ostalska-Nowicka D, Kempisty B, Nowicki M, Zabel M. Molecular basis of mechanisms of steroid resistance in children with nephrotic syndrome. Acta Biochim Pol 2013; 60(3): 339-44.
[] [PMID: 24020059]
Bierzynska A, McCarthy HJ, Soderquest K, et al. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 2017; 91(4): 937-47.
[] [PMID: 28117080]
Cil O, Perwad F. Monogenic causes of proteinuria in children. Front Med (Lausanne) 2018; 5: 55.
[] [PMID: 29594119]
Nagano C, Yamamura T, Horinouchi T, et al. Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. Sci Rep 2020; 10(1): 270.
[] [PMID: 31937884]
Rheault MN, Zhang L, Selewski DT, et al. AKI in children hospitalized with neprhotic syndrome. Clin J Am Soc Nephrol 2015; 10(12): 2110-8.
[] [PMID: 26450933]
Rumana J, Hanif M, Muinuddin G, Maruf-Ul-Quader M. Correlation of fractional excretion of magnesium with steroid responsiveness in children with nephrotic syndrome. Saudi J Kidney Dis Transpl 2014; 25(4): 830-6.
[] [PMID: 24969196]
Mendonça AC, Oliveira EA, Fróes BP, et al. A predictive model of progressive chronic kidney disease in idiopathic nephrotic syndrome. Pediatr Nephrol 2015; 30(11): 2011-20.
[] [PMID: 26084617]
Kidney Disease: Improving Global Outcomes (KDIGO). Chapter 2: General principles in the management of glomerular disease. In KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012; 2: 156-62.
Hahn D, Hodson EM, Willis NS, Craig JC, Hodson EM. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2015; 8(3): CD001533.
[] [PMID: 25785660]
Larkins NG, Liu ID, Willis NS, Craig JC, Hodson EM. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev 2020; 4: CD002290.
[] [PMID: 32297308]
McCarthy HJ, Bierzynska A, Wherlock M, et al. Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2013; 8(4): 637-48.
[] [PMID: 23349334]
Kidney Disease: Improving Global Outcomes (KDIGO). Chapter 4: Steroid-resistant nephrotic syndrome in children. In KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012; 2: 72-176.
Kuppe C, van Roeyen C, Leuchtle K, et al. Investigations of glucocorticoid action in GN. J Am Soc Nephrol 2017; 28(5): 1408-20.
[] [PMID: 27895155]
van den Broek M, Smeets B, Schreuder MF, Jansen J. The podocyte as a direct target of glucocorticoids in nephrotic syndrome. Nephrol Dial Transplant 2021.: gfab016.
[] [PMID: 33515261]
Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008; 14(9): 931-8.
[] [PMID: 18724379]
Yoshikawa N, Nakanishi K, Sako M, et al. A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment. Kidney Int 2015; 87(1): 225-32.
[] [PMID: 25054775]
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.
[] [PMID: 29549463]
Hodson EM, Wong SC, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2016; 10: CD003594.
[] [PMID: 27726125]
van Husen M, Kemper MJ. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol 2011; 26(6): 881-92.
[] [PMID: 21229269]
Yamazaki M, Fukusumi Y, Kayaba M, et al. Possible role for glomerular-derived angiotensinogen in nephrotic syndrome. J Renin Angiotensin Aldosterone Syst 2016; 17(4): 1-8.
[] [PMID: 27932705]
Yi Z, Li Z, Wu XC, He QN, Dang XQ, He XJ. Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol 2006; 21(7): 967-72.
[] [PMID: 16773409]
Gipson DS, Chin H, Presler TP, et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol 2006; 21(3): 344-9.
[] [PMID: 16395603]
Hilgers KF, Dötsch J, Rascher W, Mann JF. Treatment strategies in patients with chronic renal disease: ACE inhibitors, angiotensin receptor antagonists, or both? Pediatr Nephrol 2004; 19(9): 956-61.
[] [PMID: 15278690]
Bagga A, Mudigoudar BD, Hari P, Vasudev V. Enalapril dosage in steroid-resistant nephrotic syndrome. Pediatr Nephrol 2004; 19(1): 45-50.
[] [PMID: 14648339]
Hosseiniyan Khatibi SM, Ardalan M, Abediazar S, Zununi Vahed S. The impact of steroids on the injured podocytes in nephrotic syndrome. J Steroid Biochem Mol Biol 2020; 196(Suppl. 1).: 105490.
[] [PMID: 31586640]
Fakhouri F, Bocquet N, Taupin P, et al. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am J Kidney Dis 2003; 41(3): 550-7.
[] [PMID: 12612977]
Zhang H, Wang Z, Dong LQ, Guo YN. Children with steroid-resistant nephrotic syndrome: long-term outcomes of sequential steroid therapy. Biomed Environ Sci 2016; 29(9): 650-5.
[PMID: 27806747]
Zotta F, Vivarelli M, Emma F. Update on the treatment of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2022; 37(2): 303-14.
[] [PMID: 33665752]
Mühlig AK, Lee JY, Kemper MJ, et al. Levamisole in children with idiopathic nephrotic syndrome: clinical efficacy and pathophysiological aspects. J Clin Med 2019; 8(6): 860.
[] [PMID: 31208104]
Srinivas NR. Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data. Biopharm Drug Dispos 2015; 36(9): 575-86.
[] [PMID: 26224332]
Kahan BD, Welsh M, Rutzky LP. Challenges in cyclosporine therapy: the role of therapeutic monitoring by area under the curve monitoring. Ther Drug Monit 1995; 17(6): 621-4.
[] [PMID: 8588231]
David-Neto E, Araujo LM, Brito ZM, et al. Sampling strategy to calculate the cyclosporin-A area under the time-concentration curve. Am J Transplant 2002; 2(6): 546-50.
[] [PMID: 12118899]
Iijima K, Sako M, Oba MS, et al. Cyclosporine C2 monitoring for the treatment of frequently relapsing nephrotic syndrome in children: a multicenter randomized phase II trial. Clin J Am Soc Nephrol 2014; 9(2): 271-8.
[] [PMID: 24262503]
Nishino T, Takahashi K, Tomori S, Ono S, Mimaki M. Cyclosporine A C1.5 monitoring reflects the area under the curve in children with nephrotic syndrome: a single-center experience. Clin Exp Nephrol 2022; 26(2): 154-61.
[] [PMID: 34559341]
Liu ID, Willis NS, Craig JC, Hodson EM. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2019; 2019(11): 1-32.
[] [PMID: 31749142]
Arslansoyu Camlar S, Soylu A, Kavukçu S. Cyclosporine in pediatric nephrology. Iran J Kidney Dis 2018; 12(6): 319-30.
[PMID: 30595561]
Barletta G-M, Smoyer WE, Bunchman TE, Flynn JT, Kershaw DB. Use of mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome. Pediatr Nephrol 2003; 18(8): 833-7.
[] [PMID: 12774223]
Iijima K, Sako M, Nozu K. Rituximab for nephrotic syndrome in children. Clin Exp Nephrol 2017; 21(2): 193-202.
[] [PMID: 27422620]
Chan EY, Tullus K. Rituximab in children with steroid sensitive nephrotic syndrome: in quest of the optimal regimen. Pediatr Nephrol 2021; 36(6): 1397-405.
[] [PMID: 32577808]
Prytuła A, Iijima K, Kamei K, et al. Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 2010; 25(3): 461-8.
[] [PMID: 20033225]
Larkins N, Kim S, Craig J, Hodson E. Steroid-sensitive nephrotic syndrome: an evidence-based update of immunosuppressive treatment in children. Arch Dis Child 2016; 101(4): 404-8.
[] [PMID: 26289063]
Bagga A, Sinha A, Moudgil A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 2007; 356(26): 2751-2.
[] [PMID: 17596616]
Greenbaum LA, Benndorf R, Smoyer WE. Childhood nephrotic syndrome--current and future therapies. Nat Rev Nephrol 2012; 8(8): 445-58.
[] [PMID: 22688744]
Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 2011; 3(85): 85ra46.
[] [PMID: 21632984]
Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients’ management. Nat Rev Nephrol 2013; 9(3): 154-69.
[] [PMID: 23338210]
Kara A, Gurgoze MK, Serin HM, Aydin M. Cerebral arterial thrombosis in a child with nephrotic syndrome. Niger J Clin Pract 2018; 21(7): 945-8.
[PMID: 29984731]
Gera DN, Yadav DK, Kute VB, Patil SB, Trivedi HL. Cerebral venous sinus thrombosis in children with nephrotic syndrome. Indian J Nephrol 2012; 22(6): 455-8.
[] [PMID: 23439670]
Lee JM, Kronbichler A, Shin JI, Oh J. Current understandings in treating children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2021; 36(4)(Suppl. 1): 747-61.
[] [PMID: 32086590]
Braun DA, Rao J, Mollet G, et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet 2017; 49(10): 1529-38.
[] [PMID: 28805828]
Becherucci F, Mazzinghi B, Provenzano A, Murer L, Giglio S, Romagnani P. Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome? J Nephrol 2016; 29(4): 543-50.
[] [PMID: 27209298]
Lovric S, Ashraf S, Tan W, Hildebrandt F. Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrol Dial Transplant 2016; 31(11): 1802-13.
[] [PMID: 26507970]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy