B7–1 Blockade Does Not Improve Post–Transplant Nephrotic Syndrome Caused by Recurrent FSGS

Delville, Marianne; Baye, Emilie; Dürrbach, Antoine; Audard, Vincent; Kofman, Tomek; Braun, Laura; Olagne, Jérôme; Nguyen, Claire; Deschênes, Georges; Moulin, Anne‐Marie; Delahousse, Michel; Kesler-Roussey, Gwenaëlle; Beaudreuil, Séverine; Martinez, Frank; Rabant, Marion; Grimbert, Philippe; Gallazzini, Morgan; Terzi, Fabiola; Legendre, Christophe; Canaud, Guillaume

doi:10.1681/asn.2015091002

Cited by 78 publications

(63 citation statements)

References 15 publications

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“…One potential target of T cells on the podocyte is CD80 (also known as B7-1), a T cell costimulatory molecule expressed on antigen-presenting cells and B cells, which has been found in the urine of patients with MCD during disease relapse (35). Recently, however, the presence of CD80 on human podocytes during renal disease, including MCD and FSGS, as well as in experimental models of the diseases, has been excluded and the efficacy of recombinant CTLA4-Ig (abatacept and belatacept, which downregulate CD80) in reducing proteinuria was not confirmed (36). These results suggest caution and the need for thorough validation of preclinical results before passing from bench to bedside.…”

Section: Pathogenesismentioning

confidence: 99%

Minimal Change Disease

Vivarelli

Massella

Ruggiero

et al. 2016

CJASN

417

383

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Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.

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Section: Pathogenesismentioning

confidence: 99%

Minimal Change Disease

Vivarelli

Massella

Ruggiero

et al. 2016

CJASN

417

383

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“…However, the excitement was dampened by subsequent studies, as several groups faced problems trying to reproduce previous data. First, following a thorough experimental design, B7-1 expression by podocytes was not confirmed in human or murine diabetic nephropathy [14,15,16], nor in focal segmental glomerulosclerosis, either primary or recurrent post-transplantation [14,17,18,19,20,21], while multiple artifacts due to non-specific staining obtained with immunofluorescence (IF) analyses were described [14,15,17,18]. Second, the efficacy of B7-1 blockers, abatacept and belatacept, in inducing proteinuria remission was challenged in patients with FSGS, either primary or recurrent post-transplantation [11,19,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Another Piece of the Puzzle of Podocyte B7-1 Expression: Lupus Nephritis

Novelli

Gagliardini²,

Ruggiero

et al. 2016

Nephron

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Background/Aims: Lupus nephritis (LN) is a frequent complication and a major predictor of poor prognosis of systemic lupus erythematosus. Immune complex deposition and T cell infiltration are crucial events in LN pathogenesis. B7-1 (CD80), normally expressed by antigen-presenting cells, is one of the major co-stimulators of T-cell activation through the binding with its counter-receptors CD28 and cytotoxic T-lymphocyte antigen-4. Unexpectedly, B7-1 induction was described at the podocyte level in patients affected by different renal diseases, including LN. These observations suggested a novel exciting function for B7-1 as a biomarker of podocyte injury, and hence that B7-1 inhibitory drugs could serve as podocyte-targeted treatment of intractable renal diseases. However, subsequent studies hardly questioned the reliability of B7-1 detection assays and the therapeutic efficacy of B7-1 blockade in proteinuric patients, casting doubts on B7-1 expression by podocytes. Here, we thoroughly investigated whether B7-1 was indeed expressed by podocytes in LN, before even considering employing B7-1 blockade in patients with severe manifestations of LN and unfavourable prognosis. Methods: Applying different immunohistochemical assays with 4 primary antibodies, we analysed kidney biopsies from 42 LN patients at different stages of the disease, and from NZB/NZW mice, an LN model. Results: B7-1 was not induced in podocytes in human and murine LN; instead its expression was confined to infiltrating inflammatory cells. Conclusion: B7-1 is not expressed by podocytes in LN. A renoprotective effect of B7-1 blockade in LN patients cannot be ruled out but, if confirmed, cannot be the result of an effect on podocyte B7-1.

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“…IAds were stopped for our patient during the abatacept infusions, although it soon became apparent that the proteinuria increased and reached nephrotic levels, thus confirming IAds‐dependency. Inefficacy of abatacept with post‐transplantation SRNS was reported recently …”

Section: Discussionmentioning

confidence: 90%

Ofatumumab in post‐transplantation recurrence of a pediatric steroid‐resistant idiopathic nephrotic syndrome

Bernard

Bruel

Allain-Launay

et al. 2018

Pediatric Transplantation

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Treatment of SRNS is a challenge. Antiproliferative agents and depleting antibodies have been reported to be effective. However, these agents are not always successful, and use of ofatumumab could provide a different treatment option. Our patient was diagnosed with a SRNS at 5 years of age. She developed ESRD, with FSGS. This was cause for a first renal transplantation. The NS relapsed, leading to loss of the graft, and a second renal transplantation was performed. Due to the recurrence of the NS, IAds were initiated and led to a complete remission. Our patient remained dependent on IAds, however, despite treatments with calcineurin inhibitors, corticosteroids, rituximab, and abatacept. Ofatumumab was introduced and led to a remission, thus allowing cessation of the IAd treatment. Another infusion of ofatumumab was administered 8 months after the last one, due to the recurrence of the NS and a renewed increase in B cells. Although it did not result in a complete remission, the proteinuria was stabilized in the absence of IAds. Ofatumumab may be an alternative treatment for post-transplantation rituximab-resistant SRNS, although this needs to be confirmed by further studies.

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B7–1 Blockade Does Not Improve Post–Transplant Nephrotic Syndrome Caused by Recurrent FSGS

Cited by 78 publications

References 15 publications

Minimal Change Disease

Minimal Change Disease

Another Piece of the Puzzle of Podocyte B7-1 Expression: Lupus Nephritis

Ofatumumab in post‐transplantation recurrence of a pediatric steroid‐resistant idiopathic nephrotic syndrome

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