Childhood Kidney Diseases

Korean Society of Pediatric Nephrology (대한소아신장학회)
권호 표지
DOI QR코드

DOI QR Code

Recent key advances in the understanding of the pathogenesis of childhood minimal change disease

  • Zhengyu Zhou (Department of Nephrology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine) ;
  • Lei Yin (Department of Nephrology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine)
  • Received : 2026.02.24
  • Accepted : 2026.06.08
  • Published : 2026.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Minimal change disease (MCD) is the leading cause of idiopathic nephrotic syndrome in children, accounting for >85% of cases in those aged 1-12 years. Although 80%-90% of patients achieve initial remission with glucocorticoids, steroid dependence or frequent relapses occur in 55%-60% of cases, necessitating prolonged immunosuppression. Long-term steroid exposure in children is associated with severe age-specific adverse events, including growth retardation, skeletal dysplasia, cataracts, and impaired vaccine responses from immunosuppression. Steroid resistance and chronic kidney disease may also develop in some patients. Recent clinical evidence and literature (2015-2025) have transformed our understanding of MCD from the traditional "single T cell-driven" hypothesis to a multidimensional interactive regulatory network. This network is based on coordinated T- and B-cell dysregulation, mediated by defined podocyte injury pathways and modulated by genetic and environmental factors. Distinct pediatric traits stem from immature immune system development and pediatric podocyte plasticity. In this review, we synthesize recent advances in these pediatric pathogenic mechanisms, delineate age-dependent differences between childhood and adult MCD, and propose a precision medicine framework for disease subtyping, noninvasive biomarker development, and targeted therapies. This work addresses critical unmet clinical needs in the long-term management of pediatric MCD.

Keywords

Acknowledgement

The authors thank all the researchers whose work has been cited in this review. The DeepSeek large language model (DeepSeek-V2, developed by DeepSeek Inc., Hangzhou, China) was used for initial manuscript drafting and language polishing. All content in the manuscript has been critically reviewed, extensively revised, and verified for academic accuracy, clinical relevance, and originality by the authors. The authors take full responsibility for the content of this manuscript.

References

  1. Vivarelli M, Gibson K, Sinha A, Boyer O. Childhood nephrotic syndrome. Lancet 2023;402:809-24.
  2. Kidney Disease: Improving Global Outcomes (KDIGO) Nephrotic Syndrome in Children Work Group; Floege J, Gibson KL, Vivarelli M, Liew A, Radhakrishnan J, et al. KDIGO 2025 clinical practice guideline for themanagementofnephrotic syndrome inchildren.Kidney Int 2025;107:S241-89.
  3. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet 2018;392:61-74.
  4. Tsuji S, Akagawa S, Akagawa Y, Yamaguchi T, Kino J, Yamanouchi S, et al.Idiopathicnephrotic syndrome inchildren: role of regulatory T cells andgutmicrobiota.PediatrRes 2021;89:1185-91.
  5. Braun F, Mandel AM, Blomberg L, Wong MN, Chatzinikolaou G, Meyer DH, et al. Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage. JCI Insight 2025;10:e172370.
  6. Yang X, Man C, Tang X, Li T, Yang X, Wang M, et al. The disturbance and clinical significance of B cell and circulating follicular helper T cell subsets in children with primary nephrotic syndrome. Immunol Lett 2021;238:32-9.
  7. Zhong S, Wang N, Zhang C. Podocyte death in diabetic kidney disease:potentialmolecularmechanisms andtherapeutic targets.IntJ MolSci 2024;25:9035.
  8. LiaoY,HuH,WanQ,SongH.The role ofBlymphocyte subsets innephrotic syndrome:functions,mechanisms, clinical significance and futureperspectives.FrontImmunol 2025;16:1598197.
  9. Kajio Y, Suzuki T, Kobayashi K, Kanazawa N, Iyoda M, Honda H, et al. Activation of the inflammasome and pyroptosis cascade in podocytes of patients with minimal change disease. Clin Kidney J 2024;17:sfae216.
  10. Li S, Hu M, He C, Sun Y, Huang W, Lei F, et al. A multicenter study investigating the genetic analysis of childhood steroid-resistant nephrotic syndrome: variants in COL4A5 may not be coincidental. PLoSOne 2024;19:e0304864.
  11. Chen G, Zeng M, Liu Z, Zhou M, Zha J, Zhang L, et al. The kinetics of mTORC1 activation associates with FOXP3 expression pattern of CD4+ T cells and outcome of steroid-sensitive minimal change disease.IntImmunopharmacol 2023;122:110589.
  12. Barry A, McNulty MT,JiaX, GuptaY, DebiecH, LuoY, et al. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.NatCommun2023;14:2481.
  13. Colucci M, Angeletti A, Zotta F, Carsetti R, Lugani F, Rava L, et al. Age and memory B cells at baseline are associated with risk of relapse and memory B-cell reappearance following anti-CD20 treatment in pediatric frequently-relapsing/steroid-dependent nephrotic syndrome.Kidney Int 2023;104:577-86.
  14. Chan CY, Teo S, Lu L, Chan YH, Lau PY, Than M, et al. Low regulatory T-cells: a distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy. TranslRes 2021;235:48-61.
  15. ZhuH, SunJ,YanY, LiuP,HuangY.Immune podocyte injury inautoimmune glomerulardiseases.FrontImmunol 2026;17:1804416.
  16. TaniguchiT.The roleoffollicularhelperTcells inthepathogenesisof allergic disease-related minimal change nephrotic syndrome. CEN CaseRep2024;13:74-5.
  17. Saleh MA, Shaaban AA, Talaat IM, Elmougy A, Adra SF, Ahmad F, et al.RhoA/ROCKinhibitionattenuates endothelin-1-inducedglomerulopathy inthe rats. LifeSci 2023;323:121687.
  18. Tsuji S, Yamaguchi T, Akagawa Y, Akagawa S, Yamanouchi S, Kimata T, et al. Significance of regulatory T cells in children with idiopathic nephrotic syndrome.JNephrol 2022;35:711-3.
  19. Kaczmarski M. Allergy to cow's milk proteins and other allergens: an unrecognized co-factor of idiopathic nephrotic syndrome in children or a factor interferingwith the treatment ofthis disease?: a case report.Reports (MDPI) 2023;6:25.
  20. Nell D, Wolf R, Podgorny PM, Kuschnereit T, Kuschnereit R, Dabers T, et al. Complement activation in nephrotic glomerular diseases. Biomedicines 2024;12:455.
  21. Raglianti V, Angelotti ML, Cirillo L, Ravaglia F, Landini S, Palazzo V, et al. Anti-slit diaphragm antibodies on kidney biopsy identify pediatric patients with steroid-resistant nephrotic syndrome responsive tosecond-line immunosuppressants.Kidney Int 2024;106:1124-34.
  22. Watts AJ, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol 2022;33:238-52.
  23. Hengel FE, Dehde S, Lasse M, Zahner G, Seifert L, Schnarre A, et al. Autoantibodies targeting nephrin in podocytopathies. N Engl J Med 2024;391:422-33.
  24. Ichikawa Y, Sakakibara N, Aoyama S, Kimura Y, Inoki Y, Tanaka Y, et al. Co-localization of IgG with nephrin in immune-mediated idiopathicnephrotic syndrome.ClinExpNephrol 2025;29:1821-8.
  25. Shirai Y, Miura K, Ishizuka K, Ando T, Kanda S, Hashimoto J, et al. A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.Kidney Int 2024;105:608-17.
  26. Chan EY, Yu EL, Angeletti A, Arslan Z, Basu B, Boyer O, et al. Longterm efficacy and safety of repeated rituximab to maintain remission in idiopathic childhood nephrotic syndrome: an international study.JAmSocNephrol 2022;33:1193-207.
  27. Chen Q, Jiang H, Ding R, Zhong J, Li L, Wan J, et al. Cell-type-specific molecular characterization of cells from circulation and kidney in IgA nephropathy with nephrotic syndrome. Front Immunol 2023;14:1231937.
  28. Kim SH, Park SJ, Han KH, Kronbichler A, Saleem MA, Oh J, et al. Pathogenesisofminimal changenephrotic syndrome: animmunological concept.KoreanJPediatr 2016;59:205-11.
  29. Kanazawa N, Iyoda M, Suzuki T, Tachibana S, Nagashima R, Honda H. Exploring the significance of interleukin-33/ST2 axis in minimal changedisease.SciRep2023;13:18776.
  30. Katafuchi E, Hisano S, Kurata S, Muta K, Uesugi N, Miyamoto T, et al. Aberrant localization of b1 integrin in podocyte cytoplasm of primaryFSGSwithcellular lesion.VirchowsArch2025;486:1049-59.
  31. Liu L, Li Q, Zhang G. Systemic inflammation accelerates the development of focal segmental glomerulosclerosis in a mouse model of adriamycininducednephrosis.SciRep2025;15:14304.
  32. Shen X, Wang H, Weng C, He Y, Shao X, Le J, et al. Angiopoietin-like 4 exacerbates renal tubular epithelial cell pyroptosis in acute kidney injury via integrin b5/FAK signaling pathway. Kidney Int 2025;108:1073-87.
  33. Sever S. Role of actin cytoskeleton in podocytes. Pediatr Nephrol 2021;36:2607-14.
  34. Liang T, Qi C, Lai Y, Xie J, Wang H, Zhang L, et al. HDAC6-mediated a-tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy. J Cell Mol Med 2020;24:11558-72.
  35. HuH, LiangW, DingG.Podocytemetabolic reprogramming andtargetedtherapy.JAmSocNephrol 2026;37:619-33.
  36. Nishimura Y. Podocytes in health and disease:from developmentto regeneration.HumCell 2025;38:169.
  37. Hayashi K. Targeting DNA methylation in podocytes to overcome chronickidneydisease.KeioJMed2023;72:67-76.
  38. Trachtman H, Laskowski J, Lee C, Renner B, Feemster A, Parikh S, et al. Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome. Am J Physiol Renal Physiol 2021;321:F505-16.
  39. Robinson GA, Peng J, Peckham H, Butler G, Pineda-Torra I, Ciurtin C, et al. Investigating sex differences in T regulatory cells from cisgender and transgender healthy individuals and patients with autoimmune inflammatory disease: a cross-sectional study. Lancet Rheumatol 2022;4:e710-24.
  40. Faghihi T, Assadi F. Sex differences on the pharmacokinetics of drugs for children with chronic kidney disease: a narrative review. AdvPharmBull 2024;14:537-42.
  41. Hayashi K. Altered DNA methylation in kidney disease: useful markers andtherapeutic targets.ClinExpNephrol 2022;26:309-15.
  42. Hayward S, Parmesar K, Welsh GI, Suderman M, Saleem MA. Epigenetic mechanisms and nephrotic syndrome: a systematic review. Biomedicines 2023;11:514.
  43. Kaneko K. Gut dysbiosis as a susceptibility factor in childhood idiopathicnephrotic syndrome.PediatrNeonatol 2025;66Suppl 1:S2-7.
  44. Uy N, Graf L, Lemley KV, Kaskel F. Effects of gluten-free, dairy-free diet on childhood nephrotic syndrome and gut microbiota. Pediatr Res 2015;77:252-5.