Case Reports

Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature

Fed Pract. 2024 August;41(8):250-255 | doi:10.12788/fp.0506

References

1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.

2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL

3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014

4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2

5. 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):1207-1215. doi:10.1093/ckj/sfaa247

6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.

7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420

8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850

9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121

10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6

11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x

12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616

13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002

14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910

15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125

16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98

17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348

18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.

19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441

20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1

21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055

22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963

23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018

24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5

25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023

26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp

27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.^23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.²³ Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m², or ≤ 40 mg every other week.²⁴ Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.²⁴

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.²⁵ The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.²⁵

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.²⁶ Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.^25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

References

1. Arif E, Nihalani D. Glomerular filtration barrier assembly: an insight. Postdoc J. 2013;1(4):33-45.

2. Garg PA. Review of podocyte biology. Am J Nephrol. 2018;47(suppl 1):3-13. doi:10.1159/000481633SUPPL

3. Warady BA, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. doi:10.1016/j.xkme.2020.05.014

4. Angioi A, Pani A. FSGS: from pathogenesis to the histological lesion. J Nephrol. 2016;29(4):517-523. doi:10.1007/s40620-016-0333-2

5. 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):1207-1215. doi:10.1093/ckj/sfaa247

6. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal change disease. Clin J Am Soc Nephrol. 2017;12(2):332-345.

7. Medjeral-Thomas NR, Lawrence C, Condon M, et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with De Novo minimal change disease: a multicenter, randomized, controlled trial. Clin J Am Soc Nephrol. 2020;15(2):209-218. doi:10.2215/CJN.06290420

8. Ye Q, Lan B, Liu H, Persson PB, Lai EY, Mao J. A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies. Acta Physiol (Oxf). 2022;235(4):e13850. doi:10.1111/apha.13850

9. Trautmann A, Schnaidt S, Lipska-Ziμtkiewicz BS, et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol. 2017;28:3055-3065. doi:10.1681/ASN.2016101121

10. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021;36(3):711-719. doi:10.1007/s00467-020-04819-6

11. Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64(4):1169-78. doi:10.1046/j.1523-1755.2003.00234.x

12. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017; 12(3):502-517. doi:10.2215/CJN.05960616

13. Savige J. Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant? Kidney Int Rep. 2018;3(6):1239-1241. doi:10.1016/j.ekir.2018.08.002

14. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol. 2011;6(7):1626-1634. doi:10.2215/CJN.07830910

15. Saurus P, Kuusela S, Lehtonen E, et al. Podocyte apoptosis is prevented by blocking the toll-like receptor pathway. Cell Death Dis. 2015;6(5):e1752. doi:10.1038/cddis.2015.125

16. Baud L, Oudinet JP, Bens M, et al. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111-1118. doi:10.1038/ki.1989.98

17. White S, Lin L, Hu K. NF-κB and tPA signaling in kidney and other diseases. Cells. 2020;9(6):1348. doi:10.3390/cells9061348

18. Tesch GH, Lan HY, Atkins RC, Nikolic-Paterson DJ. Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. Am J Pathol. 1997;151(1):141-150.

19. Lai KN, Leung JCK, Chan LYY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA Nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. doi:10.1093/ndt/gfn441

20. Saleem MA, Kobayashi Y. Cell biology and genetics of minimal change disease. F1000 Res. 2016;5: F1000 Faculty Rev-412. doi:10.12688/f1000research.7300.1

21. Kim KP, Williams CE, Lemmon CA. Cell-matrix interactions in renal fibrosis. Kidney Dial. 2022;2(4):607-624. doi:10.3390/kidneydial2040055

22. Zvaifler NJ. Relevance of the stroma and epithelial-mesenchymal transition (EMT) for the rheumatic diseases. Arthritis Res Ther. 2006;8(3):210. doi:10.1186/ar1963

23. Angeletti A, Magnasco A, Trivelli A, et al. Refractory minimal change disease and focal segmental glomerular sclerosis treated with Anakinra. Kidney Int Rep. 2021;7(1):121-124. doi:10.1016/j.ekir.2021.10.018

24. Trachtman H, Vento S, Herreshoff E, et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16:111. doi:10.1186/s12882-015-0094-5

25. Mariani LH, Eddy S, AlAkwaa FM, et al. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int. 2023;103(3):565-579. doi:10.1016/j.kint.2022.10.023

26. Korshak L, Washington DL, Powell J, Nylen E, Kokkinos P. Kidney Disease in Veterans. US Dept of Veterans Affairs, Office of Health Equity. Updated May 13, 2020. Accessed June 28, 2024. https://www.va.gov/HEALTHEQUITY/Kidney_Disease_In_Veterans.asp

27. Malone AF, Phelan PJ, Hall G, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-1259. doi:10.1038/ki.2014.305

Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature

References

Literature Review

Conclusions

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