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Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis

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Abstract

Background

Minimal Change Disease (MCD) in relapse is associated with increased podocyte CD80 expression and elevated urinary CD80 excretion, whereas focal segmental glomerulosclerosis (FSGS) has mild or absent CD80 podocyte expression and normal urinary CD80 excretion.

Methods

One patient with MCD, one patient with primary FSGS and three patients with recurrent FSGS after transplantation received CD80 blocking antibodies (abatacept or belatacept). Urinary CD80 and CTLA-4 levels were measured by ELISA. Glomeruli were stained for CD80.

Results

After abatacept therapy, urinary CD80 became undetectable with a concomitant transient resolution of proteinuria in the MCD patient. In contrast, proteinuria remained unchanged after abatacept or belatacept therapy in the one patient with primary FSGS and in two of the three patients with recurrent FSGS despite the presence of mild CD80 glomerular expression but normal urinary CD80 excretion. The third patient with recurrent FSGS after transplantation had elevated urinary CD80 excretion immediately after surgery which fell spontaneously before the initiation of abatacept therapy; after abatacept therapy, his proteinuria remained unchanged for 5 days despite normal urinary CD80 excretion.

Conclusion

These observations are consistent with a role of podocyte CD80 in the development of proteinuria in MCD. In contrast, CD80 may not play a role in recurrent FSGS since the urinary CD80 of our three patients with recurrent FSGS was only increased transiently after surgery and normalization of urinary CD80 did not result in resolution of proteinuria.

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References

  1. Habib R, Kleinknecht C (1971) The primary nephrotic syndrome in childhood: Classification and clinicopathologic study of 406 cases. Pathol Annu 6:417–474

    CAS  PubMed  Google Scholar 

  2. [No authors listed] (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of kidney Disease in Children. J Pediatr 98:561-564

  3. Davison AM, Cameron SJ, Grünfeld JP (2005) Textbook of Clinical Nephrology, 3rd edn. Oxford University Press, New York, pp 439–469

    Google Scholar 

  4. Barisoni L, Schnaper HW, Kopp JB (2007) A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol 2:529–542

    Article  PubMed  Google Scholar 

  5. Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, Johnson RJ (2009) Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 20:260–266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, Johnson RJ (2010) Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 78:296–302

    Article  CAS  PubMed  Google Scholar 

  7. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113:1390–1397

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878–883

    Article  CAS  PubMed  Google Scholar 

  9. Savin VJ, McCarthy ET, Sharma R, Reddy S, Dong J, Hess S, Kopp J (2008) Cardiotrophin-like cytokine-1: Candidate for the focal glomerulosclerosis permeability factor (abstract). J Am Soc Nephrol 19:59A

    Article  Google Scholar 

  10. Wei C, Möller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J (2008) Modification of kidney barrier function by the urokinase receptor. Nat Med 14:55–63

    Article  CAS  PubMed  Google Scholar 

  11. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17:952–960

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, McMahan JL, Radeva M, Heil KM, Trautmann A, Anarat A, Emre S, Ghiggeri GM, Ozaltin F, Haffner D, Gipson DS, Kaskel F, Fischer DC, Schaefer F, Reiser J, PodoNet and FSGS CT Study Consortia (2012) Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 23:2051–2059

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ishimoto T, Shimada M, Gabriela G, Kosugi T, Sato W, Lee PY, Lanaspa MA, Rivard C, Maruyama S, Garin EH, Johnson RJ (2013) Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol Dial Transplant 28:1439–1446

    Article  CAS  PubMed  Google Scholar 

  14. Shimada M, Araya C, Rivard C, Ishimoto T, Johnson RJ, Garin EH (2011) Minimal Change Disease: A “Two hit” podocyte immune disorder? Pediatr Nephrol 26:645–649

    Article  PubMed  Google Scholar 

  15. International Study of Kidney Disease in Children (1981) Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int 20:765-771

  16. Oaks MK, Hallet KM (2000) Cutting edge: A soluble form of CTLA-4 in patients with autoimmune thyroid disease. J Immunol 164:5015–5018

    Article  CAS  PubMed  Google Scholar 

  17. Fiorina P, Vergani A, Bassi R, Niewczas MA, Altintas MM, Pezzolesi MG, D’Addio F, Chin M, Tezza S, Ben Nasr M, Mattinzoli D, Ikehata M, Corradi D, Schumacher V, Buvall L, Yu CC, Chang JM, La Rosa S, Finzi G, Solini A, Vincenti F, Rastaldi MP, Reiser J, Krolewski AS, Mundel PH, Sayegh MH (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415–1429

    Article  CAS  PubMed  Google Scholar 

  18. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA (1991) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561–569

    Article  CAS  PubMed  Google Scholar 

  19. Cara-Fuentes G, Wasserfall CH, Wang H, Johnson RJ, Garin EH (2014) Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? Pediatr Nephrol. doi:10.1007/s00467-014-2874-8

    Google Scholar 

  20. Spink C, Stege G, Tenbrock K, Harendza S (2013) The CTLA-4 + 49GG genotype is associated with susceptibility for nephrotic kidney diseases. Nephrol Dial Transplant 28:2800–2805

    Article  CAS  PubMed  Google Scholar 

  21. Ohl K, Spink C, Wagner N, Zahn K, Wagner N, Eggermann T, Kemper MJ, Querfeld U, Hoppe B, Harendza S, Tenbrock K (2014) CTLA4 polymorphism in minimal change nephrotic syndrome in children: A case-control study. Am J Kidney Dis 63:1074–1075

    Article  CAS  PubMed  Google Scholar 

  22. Chang JM, Hwang DY, Chen SC, Kuo MC, Hung CC, Hwang SJ, Tsai JC, Chen HC (2013) B7-1 expression regulates the hypoxia-driven cytoskeleton rearrangement in glomerular podocytes. Am J Physiol Ren Physiol 304:F127–F136

    Article  Google Scholar 

  23. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, Burke GW 3rd, Mundel P (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369:2416–2423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Cochat P, Kassir A, Colon S, Glastre C, Tourniaire B, Parchoux B, Martin X, David L (1993) Recurrent nephrotic syndrome after transplantation: early treatment with plasmapheresis and cyclophosphamide. Pediatr Nephrol 7:50–54

    Article  CAS  PubMed  Google Scholar 

  25. Pradhan M, Petro J, Palmer J, Meyers K, Baluarte HJ (2003) Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr Nephrol 18:934–938

    Article  PubMed  Google Scholar 

  26. Canaud G, Zuber J, Sberro R, Royale V, Anglicheau D, Snanoudj R, Gaha K, Thervet E, Lefrère F, Cavazzana-Calvo M, Noël LH, Méjean A, Legendre C, Martinez F (2009) Intensive and prolonged treatment of focal and segmental glomerulosclerosis recurrence in adult kidney transplant recipients: a pilot study. Am J Transplant 9:1081–1086

    Article  CAS  PubMed  Google Scholar 

  27. Alachkar N, Carter-Monroe N, Reiser J (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1263–1264

    PubMed  Google Scholar 

  28. Benigni A, Gagliardini E, Remuzzi G (2014) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 370:1261–1263

    Article  CAS  PubMed  Google Scholar 

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Support

This study was supported by NIH R01DK080764 to EHG. and RJJ and in part by grants from the National Institutes of Health DK073495 and DK089394 to RJJ. JR is supported by grants from the National Institute of Health (DK073495, DK089394 and DK101350).

Financial disclosures

Jochen Reiser has pending or issued patents in the area of novel therapeutics for renal diseases. He stands to gain royalties from their future commercialization.

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Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, 1600 SW Archer Rd., HD214, Gainesville, FL, 32610, USA

    Eduardo H. Garin, Gabriel Cara-Fuentes & Heiman Wang

  2. Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA

    Jochen Reiser & Changli Wei

  3. Division of Nephrology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, USA

    Dany Matar & Nada Alachkar

  4. Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA

    Richard J. Johnson

Authors
  1. Eduardo H. Garin
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  2. Jochen Reiser
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  3. Gabriel Cara-Fuentes
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  4. Changli Wei
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  5. Dany Matar
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  6. Heiman Wang
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  7. Nada Alachkar
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  8. Richard J. Johnson
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Correspondence to Eduardo H. Garin.

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Garin, E.H., Reiser, J., Cara-Fuentes, G. et al. Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30, 469–477 (2015). https://doi.org/10.1007/s00467-014-2957-6

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  • DOI: https://doi.org/10.1007/s00467-014-2957-6

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