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The role of B7-1 in proteinuria of glomerular origin

Nature Reviews Nephrology volume 14, pages 589–596 (2018)Cite this article

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Abstract

The damage and loss of podocytes is a primary hallmark of nephrotic syndrome. In the pursuit of targetable molecules that are involved in podocyte pathophysiology, some studies have identified B7-1 (also known as CD80) as a potential biomarker. Furthermore, B7-1 blockade has been proposed as a podocyte-specific treatment for patients with nephrotic syndrome who have limited therapeutic options, such as those with focal segmental glomerulosclerosis, minimal change disease, diabetic nephropathy and lupus nephritis. In this Perspectives article, we describe and compare supporting and contradicting data on the role of podocyte B7-1 in the pathogenesis of various podocytopathies. Moreover, we highlight crucial issues that should be addressed urgently — such as standardization of sample processing time, material conservation and antibody usage in immunohistochemical protocols — as a clinical trial that is investigating the efficacy of B7-1 blockade in treatment-resistant nephrotic syndrome is ongoing.

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Fig. 1: B7-1 is a transmembrane protein that is normally expressed by antigen-presenting cells.

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References

  1. Goldwich, A. et al. Podocytes are nonhematopoietic professional antigen-presenting cells. J. Am. Soc. Nephrol. 24, 906–916 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Reiser, J. et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Mundel, P. Podocytes and the quest for precision medicines for kidney diseases. Pflugers Arch. 469, 1029–1037 (2017).

    Article  CAS  Google Scholar 

  4. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02592798 (2018).

  5. Collins, M., Ling, V. & Carreno, B. M. The B7 family of immune-regulatory ligands. Genome Biol. 6, 223 (2005).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Sansom, D. M. CD28, CTLA-4 and their ligands: who does what and to whom? Immunology 101, 169–177 (2000).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Rau, F. C., Dieter, J., Luo, Z., Priest, S. O. & Baumgarth, N. B7-1/2 (CD80/CD86) direct signaling to B cells enhances IgG secretion. J. Immunol. 183, 7661–7671 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Alegre, M. L. & Fallarino, F. Mechanisms of CTLA-4-Ig in tolerance induction. Curr. Pharm. Des. 12, 149–160 (2006).

    Article  CAS  Google Scholar 

  9. Mease, P. et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 63, 939–948 (2011).

    Article  CAS  Google Scholar 

  10. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 3077–3087 (2010).

    Article  CAS  Google Scholar 

  11. Gardner, D., Jeffery, L. E. & Sansom, D. M. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. Am. J. Transplant. 14, 1985–1991 (2014).

    Article  CAS  Google Scholar 

  12. Larsen, C. P., Knechtle, S. J., Adams, A., Pearson, T. & Kirk, A. D. A new look at blockade of T cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Am. J. Transplant. 6, 876–883 (2006).

    Article  CAS  Google Scholar 

  13. Larsen, C. P. et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 5, 443–453 (2005).

    Article  CAS  Google Scholar 

  14. Novelli, R., Gagliardini, E., Ruggiero, B., Benigni, A. & Remuzzi, G. Another piece of the puzzle of podocyte B7-1 expression: lupus nephritis. Nephron 133, 129–138 (2016).

    Article  CAS  Google Scholar 

  15. Delville, M. et al. B7-1 blockade does not improve post-transplant nephrotic syndrome caused by recurrent FSGS. J. Am. Soc. Nephrol. 27, 2520–2527 (2016).

    Article  Google Scholar 

  16. Baye, E. et al. The costimulatory receptor B7-1 is not induced in injured podocytes. Kidney Int. 90, 1037–1044 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Salant, D. J. Podocyte expression of B7-1/CD80: is it a reliable biomarker for the treatment of proteinuric kidney diseases with abatacept? J. Am. Soc. Nephrol. 27, 963–965 (2016).

    Article  CAS  Google Scholar 

  18. Maas, R. J., Deegens, J. K., Smeets, B., Moeller, M. J. & Wetzels, J. F. Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat. Rev. Nephrol. 12, 768–776 (2016).

    Article  Google Scholar 

  19. Garin, E. H. et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J. Am. Soc. Nephrol. 20, 260–266 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Garin, E. H. et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int. 78, 296–302 (2010).

    Article  CAS  Google Scholar 

  21. Ishimoto, T. et al. Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol. Dial. Transplant. 28, 1439–1446 (2013).

    Article  CAS  Google Scholar 

  22. Ling, C. et al. Urinary CD80 levels as a diagnostic biomarker of minimal change disease. Pediatr. Nephrol. 30, 309–316 (2015).

    Article  Google Scholar 

  23. Yu, C. C. et al. Abatacept in B7-1-positive proteinuric kidney disease. N. Engl. J. Med. 369, 2416–2423 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lennon, R., Randles, M. J. & Humphries, M. J. The importance of podocyte adhesion for a healthy glomerulus. Front. Endocrinol. (Lausanne) 5, 160 (2014).

    Google Scholar 

  25. He, F. F., Chen, S., Su, H., Meng, X. F. & Zhang, C. Actin-associated proteins in the pathogenesis of podocyte injury. Curr. Genomics 14, 477–484 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  27. Larsen, C. P., Messias, N. C. & Walker, P. D. B7-1 immunostaining in proteinuric kidney disease. Am. J. Kidney Dis. 64, 1001–1003 (2014).

    Article  Google Scholar 

  28. Appel, G. B. Therapy: new data do not support use of abatacept in diabetic nephropathy. Nat. Rev. Nephrol. 11, 692–694 (2015).

    Article  CAS  Google Scholar 

  29. Laszik, Z., Dobi, S. & Vincenti, F. B7-1/CD80 is not a reliable immunophenotypical marker of focal segmental glomerulosclerosis, membranous nephropathy, and diabetic nephropathy [abstract]. J. Am. Soc. Nephrol. Abstract Suppl. 25, TH-OR074 (2014).

  30. Novelli, R., Gagliardini, E., Ruggiero, B., Benigni, A. & Remuzzi, G. Any value of podocyte B7-1 as a biomarker in human MCD and FSGS? Am. J. Physiol. Renal Physiol. 310, F335–F341 (2016).

    Article  CAS  Google Scholar 

  31. Lee, S. W. et al. Tubular B7-1 expression parallels proteinuria levels, but not clinical outcomes in adult minimal change disease patients. Sci. Rep. 7, 41859 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  33. Garin, E. H. et al. Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr. Nephrol. 30, 469–477 (2015).

    Article  Google Scholar 

  34. Grellier, J. et al. Belatacept in recurrent focal segmental glomerulosclerosis after kidney transplantation. Transpl. Int. 28, 1109–1110 (2015).

    Article  Google Scholar 

  35. Reiser, J. & Alachkar, N. Proteinuria: abate or applaud abatacept in proteinuric kidney disease? Nat. Rev. Nephrol. 10, 128–130 (2014).

    Article  CAS  Google Scholar 

  36. Ueda, H. et al. Association of the T cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    Article  CAS  Google Scholar 

  37. Fiorina, P. et al. Role of podocyte B7-1 in diabetic nephropathy. J. Am. Soc. Nephrol. 25, 1415–1429 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Perico, N. et al. Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J. Am. Soc. Nephrol. 5, 1139–1146 (1994).

    CAS  Google Scholar 

  39. Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    Article  CAS  Google Scholar 

  40. Gagliardini, E. et al. B7-1 is not induced in podocytes of human and experimental diabetic nephropathy. J. Am. Soc. Nephrol. 27, 999–1005 (2016).

    Article  CAS  Google Scholar 

  41. Tervaert, T. W. et al. Pathologic classification of diabetic nephropathy. J. Am. Soc. Nephrol. 21, 556–563 (2010).

    Article  Google Scholar 

  42. Herrera, M. et al. Inhibition of T cell activation by the CTLA4-Fc abatacept is sufficient to ameliorate proteinuric kidney disease. Am. J. Physiol. Renal Physiol. 312, F748–F759 (2017).

    Article  CAS  Google Scholar 

  43. Norlin, J., Nielsen Fink, L., Helding Kvist, P., Douglas Galsgaard, E. & Coppieters, K. Abatacept treatment does not preserve renal function in the streptozocin-induced model of diabetic nephropathy. PLoS ONE 11, e0152315 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Kinoshita, K. et al. Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice. J. Immunol. 164, 6046–6056 (2000).

    Article  CAS  Google Scholar 

  45. Huang, L. et al. Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway. Mol. Med. Rep. 12, 4187–4195 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 66, 379–389 (2014).

    Article  CAS  Google Scholar 

  47. ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the abatacept and cyclophosphamide combination efficacy and safety study. Arthritis Rheumatol. 66, 3096–3104 (2014).

    Article  CAS  Google Scholar 

  48. Mundel, P. Podocyte-targeted treatment for proteinuric kidney disease. Semin. Nephrol. 36, 459–462 (2016).

    Article  Google Scholar 

  49. Mundel, P. & Greka, A. Developing therapeutic ‘arrows’ with the precision of William Tell: the time has come for targeted therapies in kidney disease. Curr. Opin. Nephrol. Hypertens. 24, 388–392 (2015).

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Trachtman, H. et al. Randomized clinical trial design to assess abatacept in resistant nephrotic syndrome. Kidney Int. Rep. 3, 115–121 (2018).

    Article  Google Scholar 

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Acknowledgements

The authors thank K. Mierke, IRCCS–Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy, for editing the manuscript before submission. R.N. is a recipient of a fellowship from ‘Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR)’, Bergamo, Italy.

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Authors and Affiliations

  1. IRCCS–Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy

    Rubina Novelli, Ariela Benigni & Giuseppe Remuzzi

  2. Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy

    Giuseppe Remuzzi

  3. ‘L. Sacco’ Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy

    Giuseppe Remuzzi

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  1. Rubina Novelli
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R.N. and G.R. wrote the manuscript; A.B. and G.R. critically revised the paper. All authors reviewed and approved the final manuscript.

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Correspondence to Giuseppe Remuzzi.

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Glossary

CTLA4-immunoglobulin fusion protein

(CTLA4-Ig). A soluble protein chimaera that consists of the extracellular domain of CTLA4 fused to the crystallizable fragment (Fc) portion of human IgG1.

Microbead-mediated crosslinking

A laboratory technique that uses uniform polymer particles to bind and isolate specific targets.

MRL-Faslpr mice

Lupus-prone mice that develop a systemic autoimmune syndrome that shares many features with human systemic lupus erythematosus.

Polyinosinic:polycytidylic acid

(polyIC). Toll-like receptor 3 (TLR3) ligand that has structural similarities with double-stranded DNA. polyIC is used for the induction of podocytopathy and proteinuria.

Synaptopodin

Actin-associated protein that is expressed by renal podocytes.

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Novelli, R., Benigni, A. & Remuzzi, G. The role of B7-1 in proteinuria of glomerular origin. Nat Rev Nephrol 14, 589–596 (2018). https://doi.org/10.1038/s41581-018-0037-z

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