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Volume: 15 Issue: 5 October 2017

FULL TEXT

REVIEW
Pre- and Posttransplant Refractory Idiopathic Membranous Glomerulonephritis: The Forgotten Potential Culprit

Idiopathic membranous nephropathy has been recently recognized as an autoimmune disease that may recur or develop de novo posttransplant, whereby specific auto- or alloantibodies are directed against recently recognized podocyte structures such as the phospholipase receptor PLAR2 and the throm-bo-spondin receptor THSD7A. The observed inconsistencies in therapeutic responses with all presently recognized therapies irrespective of immuno-suppressive regimen used and the superiority of complete and sustained remission rates in recurrent disease after kidney transplant compared with native disease imply the existence of different immunopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of membranous nephropathy. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help com-ponent and distinct auto- and alloantibody-secreting mechanisms involving different B cells. These pathways are present in separate compartments such as in CD20+-activated B cells found in spleen and lymph nodes, CD19+/CD20- plasmablasts and short-lived plasma cells in the blood, and CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney. These latter nonproliferating plasma cells lacking CD19 and CD20 markers would be resistant to in vivo B-cell depletion by anti-CD20 monoclonal therapies. They produce considerable amounts of immunoglobulin G (IgG) autoantibodies and alloantibodies and provide the basis for humoral memory and refractory autoimmune diseases. This may explain the limited rate of sustained complete remission, which, as observed in most studies, does not exceed a rate of 20% in all rituximab-treated patients despite total B-cell eradication. There is an important need for the development of new biomarkers to help identify and predict therapeutic responses. Potential new therapeutic targets against plasma cells such as proteasome inhibitors, anti-CD38 monoclonal antibodies, and autoreactive pathogenic B-cell-specific depleting regimens, as well as new anti-CD20 monoclonal antibodies, may help tailor therapy to the individual need for optimal outcome.


Key words : Autoimmune disease, Plasma cell, Proteasome inhibitors

Introduction

In patients with idiopathic membranous glomeru-lonephritis (iMGN), therapeutic responses to con-ventional therapies such as alkylating agents and steroids, T-cell-targeted therapies such as calcineurin inhibitors, and B-cell-directed therapies such as mycop-henolate mofetil and the recently introduced anti-CD20 monoclonal antibody (MAb) as rescue therapy in cases of primary resistance or partial disease remission or as first-line treatment, irres-pective of immunosuppressive regimen used, have been inconsistent.1 These inconsistencies coupled with the superior complete and sustained remission rates in recurrent disease after kidney transplant versus rates of complete and partial remission, relapse, and resistance in the native kidney with iMGN2 implies the existence of different immu-nopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of iMGN. These pathogenic mechan-isms involve primarily B-cell-mediated pathways with a T-cell help component3,4 and distinct autoantibody- and alloantibody-secreting mechanisms involving different B-cell lineages present in separate compartments. These compartments include a CD20+-activated B cell compartment found in spleen and lymph nodes, which generate the circulating CD19+/CD20- plas-mablasts, and short-lived plasma cells (SLMPC) in the blood, as well as a second compartment that consists of CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells (LLMPC) niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney (Figure 1 and Table 1). The non-proliferating LLMPCs are known to provide the basis for humoral memory and refractory autoimmune diseases.5-9

Recent evidence has suggested the existence of 2 independent plasma cell (CD19+/CD20+ and CD38+/CD138+) compartments that contribute to autoantibody and alloantibody production.5,6 As expected, LLMPCs that lack CD20 markers5-7 would be refractory to a CD20+-targeting immunosup-pressive therapy (Figure 1).6 This may partly explain the limited rate of complete remission (which does not exceed 20% in all treated patients) and the rates of relapse, partial response, or no response (nearly 80% of all patients) observed in most studies using the anti-CD20 MAb rituximab, as rescue or a first-line therapy in native iMGN. This was recently shown in the French GEMRITUX trial8 and in a large observational study involving 132 patients.9 Interest-ingly, GEMRITUX, the first multicenter randomized controlled trial comparing nonimmunosuppressive antiproteinuric therapy with combined antipro-teinuric therapy using rituximab in patients with iMGN, failed to reach its primary endpoint. Only 35% of patients in the rituximab group achieved combined complete-partial remission during the study period versus 21% in the control group. Interestingly, only 19% of the treatment group attained complete remission. Moreover, it is well known that rituximab does not prevent later regeneration of CD20+ cells, which could also explain the frequent relapses following its discontinuation. Furthermore, available data on B-cell depletion and recovery in relation to remission and relapse of the nephrotic syndrome associated with iMGN, in which CD19 was used as a marker of B-cell dynamic monitoring, suggested no clear relation.8,10

In contrast to regenerating activated CD20+ B cells, SLMPCs and mainly LLMPCs (nonproliferating B cells niched in the bone marrow and inflamed organs), which produce considerable amounts of IgG autoantibodies and alloantibodies, lack both CD20 and CD19 markers.5-7 Consequently, these cells would be resistant to in vivo B-cell depletion by anti-CD20 MAb therapies, as recently reported in patients with rheumatoid arthritis6 and in patients with iMGN.8 This may explain the frequently observed relapses or primary resistance of patients with iMGN to anti-CD20 therapy despite ongoing B-cell depletion defined by eradication of CD19+ and CD20+ cells.8,10

Proteasome inhibitors (PIs), known plasma cell-depleting agents,11 may offer a novel therapeutic alternative, at least in patients with persistent recurrent nephrotic syndrome following anti-CD20 MAb discontinuation or in patients primarily refractory or partially responsive to combined conventional or conservative rituximab therapy despite total CD20+ cell ablation. For these patients, rituximab fails to induce complete remission despite achieving the same depleting effect on circulating B cells that is observed in rituximab-sensitive patients.8,10 This was also reported in a recent case of a 50-year-old male patient with early recurrent iMGN after deceased-donor kidney transplant (Figure 2).12 The patient received induction therapy with rabbit antithymocyte globulin (ATG Fresenius, Grafalon; Neovii, Waltham, MA, USA) and was discharged with a serum creatinine level of 0.78 mg/dL on triple maintenance immunosuppressive therapy that included tacrolimus (Prograf; Astellas Pharma, Tokyo, Japan), mycophenolate mofetil (Cellcept; Hoffmann-La Roche, Basel, Switzerland), and prednisone. At 7 months after transplant, graft biopsy for new-onset isolated proteinuria (2.7 g/day reaching a peak of about 9 g/day) revealed stage II recurrent iMGN posttransplant despite triple renin-angiotensin-aldosterone blockade with ramipril (Tritace; Sanofi-Aventis, Paris, France), irbesartan (Aprovel, Sanofi-Aventis), and spironolactone (Aldactone; Konoshima Chemical, Osaka, Japan).

In the face of partial remission with persistent proteinuria (5 g/day) despite total CD20+ cell eradication after combined antiproteinuric and rituximab (Mabthera; Roche, Basel, Switzerland) therapy (4 consecutive doses of 0.5 g each) over several months, stable ideal body weight, and well-controlled arterial blood pressure (100-120/70-80 mm Hg), the PI bortezomib (Velcade; Takeda Oncology, Cambridge, MA, USA) was introduced as a rescue therapy at a single cycle (4 doses of 1.6 mg each over 2 weeks). This treatment resulted in a substantial decline in proteinuria within several months and its subsequent disappearance a few months later that was preceded by a considerable drop in plasma CD138+ cell count, a marker of memory plasma cells, from baseline and a simultaneous reappearance of CD20+ cells in the blood. The patient has maintained complete remission for the past 24 months and is free of any adverse effects (Figure 2). These preliminary observations indicated that different B-cell subtypes play a central role in the immunopathogenesis of recurrent posttransplant iMGN involving CD20+-activated B cells and CD19-/CD20-/CD38+/CD138+ LLMPCs, belonging to 2 separate compartments.4-7

The LLMPC autoreactive or alloreactive B cells produce autoantibodies and alloantibodies in an independent fashion from the activated CD20+ B cells. They are refractory to conventional immuno-suppressive drugs and to therapeutic approaches that target CD20+ B cells6 and may be partially depleted by the PI bortezomib.5,11-13 Moreover, these findings highlight the lack of association between B-cell depletion/recovery and the evolution of nephrotic syndrome. To my knowledge, the case described above is the first to report the successful use of a PI in a patient with recurrent iMGN post-transplant refractory to a combined conservative rituximab therapy (antiproteinuric, tacrolimus, mycophenolate mofetil, and rituximab).

In a similar case, a 35-year-old Egyptian male patient with rejection-free recurrent iMGN after renal transplant who was refractory to combined conservative rituximab plus conventional treatment was recently treated with bortezomib (unpublished data from Dr. Rashad Barsoum, oral communication). Pretreatment protein-to-creatinine ratio was 3 with a serum creatinine level of 2.2 mg/dL. After completion of 2 × 4 dose cycles of bortezomib, his protein-to-creatinine ratio dropped to 1.7 mg/mg and serum creatinine decreased to 1.4 mg/dL. Seven months later, proteinuria spontaneously dropped to a protein/creatinine ratio of 0.85. Unfortunately, no immunologic monitoring was performed.

Rituximab-resistant or partially responsive iMGN or recurrent iMGN posttransplant may benefit from a PI-based therapy. Proteasome inhibitors target survival factors, cell homing, and surface molecules and deplete the whole memory plasma cell pool, a nonproliferating cell and a major producer of antibodies, mainly of the IgG type,5-7,11-13 which are involved in the pathogenesis of iMGN and other autoimmune diseases. In addition to its B-cell-depleting effect, bortezomib induces apoptosis of T cells through the inhibition of proteolytic proteasome activity and the translocation of nuclear factor-κB to the nucleus, leading to inhibition of antibody production by B cells and to the down-regulation of the production of proinflammatory cytokines such as interleukin 6 and interferon-γ by activated T cells. Bortezomib also activates the mitochondrial pathway of apoptosis in activated CD4+ T cells by disrupting the equilibrium of proapoptotic and antiapoptotic proteins at the outer mitochondrial membrane, resulting in the breakdown of mitochondrial membrane potential.11

Accumulating evidence highlights the utility of bortezomib and its relative safety profile as a new player in the pretransplant desensitization process in hypersensitized transplant patients and in the setting of posttransplant antibody-mediated humoral rejection refractory to combined anti-T-cell and anti-B-cell-depleting therapies in addition to alloantibody removal and neutralization through plasmapheresis or immunoadsorption and intravenous immuno-globulin, respectively.11,13,14

Given its pathophysiologic (in situ immune complex subepithelial deposits with either com-plement activation or direct autoantibody or alloantibody cytotoxicity irrespective of complement activation),15 immunologic (circulating antipodocyte autoantibodies or alloantibodies such as the anti-phospholipase PLAR2 and the antithrombospondin THSD7A receptor antibodies),8,9 and histologic (colocalization of podocyte antigen, IgG and C4d in a global granular pattern along the glomerular basal membrane)12,16 features, recurrent iMGN post-transplant may be considered as slowly progressing antibody-mediated rejection directed against one or more alloantigen expressed on the surface of the glomerular epithelial cell, the podocyte.12 This process leads to a cascade of intracellular events, causing new cellular proteins to be released and thereby inducing the production of new circulating autoantibodies or alloantibodies directed against these proteins that could be nephritogenic and therefore responsible for the perpetuation of the disease and the ultimate loss of the graft if untreated.15

Ofatumumab and obinutuzumab, new second- and third-generation anti-CD20 MAbs that bind to epitopes on the B-cell surface different from those of rituximab, may further the paradigm shift in the treatment of iMGN.17 Whether these can maintain a higher rate of complete remission remains to be determined; however, importantly, these would not resolve the issue of the growing potential role of LLMPCs (CD19-/CD20-/CD38+/CD138+) in the production of autoantigen- and alloantigen-specific nephritogenic autoantibodies and alloantibodies (Figure 1). These nonproliferating cells are involved in the pathogenesis of many autoimmune diseases, including iMGN,5 and could be responsible for anti-CD20 MAb-resistant or relapsing nephrotic syn-drome and the inability to reach sustained complete remission in nearly 50% of patients with recurrent iMGN after kidney transplant2 and 80% of patients with iMGN in the native kidney,8 irrespective of the immunosuppressive regimen. Moreover, the better complete remission rates (52%)2 in patients with recurrent iMGN posttransplant versus 13.6% (as reported in the largest observational study where rituximab was used as rescue or first-line therapy9) to 19% (first randomized controlled trial where rituximab was added to a conservative antipro-teinuric nonimmunosuppressive therapy8) in the native kidney setting highlight the important role of T-cell-targeted therapies, which seem to play an important role in autoimmune kidney diseases3 and may add value to anti-CD20 MAb treatment by increasing the rate of remission in patients with recurrent disease posttransplant versus those with native iMGN. Surprisingly, the new-generation anti-CD20 MAb ofatumumab failed to demonstrate superiority over rituximab as a salvage chemo-immunotherapy in relapsed or refractory diffuse large B-cell lymphoma, as shown in a recent randomized controlled trial involving 447 patients.18 It should be noted that there are considerable differences between the in vitro and in vivo effects of specific drugs, where biologic and environmental factors may considerably differ between exper-imental (in vitro) and clinical (in vivo) conditions and therefore explain the obvious discrepancy and variability in therapeutic efficacy.

Given the existence of different potential immu-nopathogenic signatures that may be operational in the pathogenesis of iMGN, there is an important need for the development of immunologic or other biomarkers to help identify patients who are likely to successfully respond to T-cell-targeted therapy,3 B-lymphocyte depletion,5 or ultimately a combi-nation of both.12 Furthermore, in addition to the measurement of already known nephritogenic autoantibodies or alloantibodies in iMGN, such as anti-PLA2R and anti-THSD7A antibodies and those yet to be identified, which may have diagnostic and prognostic importance8,9; immunologic monitoring should be introduced in order to assess not only CD19 and CD20 markers6-10 but also CD138 and CD34 markers of short- and long-lived memory plasma cells, mainly in patients with relapsed and resistant disease.3-7,12

Potential therapeutic targets against plasma cells in the bone marrow niche are emerging (Figure 3).5 Depleting plasma cells could eliminate pathogenic alloantibody- or autoantibody-producing B cells and interrupt cellular functions of B cells that enhance pathogenic T-cell activation. However, nonselective pan-depletion of B cells can also remove protective autoantibodies and potentially lead to unnecessary immunologic and infectious adverse events. Instead, targeting B cells to remove specific pathogenic auto-reactive or alloreactive B-cell clones while sparing others through autoantigen-specific plasma cell depletion using an affinity matrix would prevent undesired immune activation or immune deficiency. Plasma cells secreting antibodies that are not directed against the autoantigen of interest would be preserved.5

Two ongoing trials (“MEmbranous Nephropathy Trial Of Rituximab” [MENTOR], ClinicalTrials.gov identifier NCT01180036; and “Sequential therapy with TAcrolimus–Rituximab versus steroids plus cyclo-phosphamide in patients with primary MEmbranous Nephropathy” [STARMEN], ClinicalTrials.gov iden-tifier NCT01955187)19,20 will assess whether a B-cell-depleting regimen (rituximab) may have a better risk-benefit profile than a T-cell-based therapy (such as cyclosporine A) and whether combined anti-B-cell plus T-cell therapies (rituximab combined with tacrolimus) versus conventional Ponticelli regimen may reduce disease recurrence after withdrawal of calcineurin inhibitor therapy. The commonly en-countered inadequate clinical responses with the different therapeutic regimens used in iMGN and recurrent posttransplant iMGN, the probable distinct immunologic signatures associated with the disease, the recently emerging data on the crucial pathogenic role of plasma cells in providing the basis for humoral memory and refractory autoimmune diseases, the well-established PIs dual B-cell and T-cell therapeutic effects, and the recent clinical observations on the beneficial effects of bortezomib in inducing complete and sustained disease remis-sion in recurrent posttransplant iMGN12 should prompt investigators to introduce bortezomib and the new generation of PIs as part of the therapeutic armamentarium in iMGN. In addition, new anti-CD38 MAbs (daratumumab and isatuximab) are being developed that kill malignant plasma cells; these will also be studied in future comparative interventional trials with both T-cell-based and B-cell-depleting therapeutic regimens. Other poten-tial beneficial effects of these plasma cell-targeted therapies may be their introduction as desensitizing agents before transplant to prevent iMGN recurrence posttransplant. This option would be mainly in high-risk transplant recipients with increased peritransplant levels of alloantigen-specific or autoantigen-specific alloantibodies or autoantibodies and those with previous death-censored graft loss due to disease recurrence.2,21

Future studies aimed at pathogenesis-based therapeutic perspectives and disease-specific under-standing of how autoreactive or alloreactive pathogenic B cells arise could facilitate both the development of novel selective therapies such anti-CD38 MAb and autoreactive pathogenic B-cell-specific-depleting regimens. These options could potentially tailor treatment to individual needs and further the optimal use of existing therapies, such as rituximab, new-generation anti-CD20 agents, and plasma cell-depleting agents for best outcomes.


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Volume : 15
Issue : 5
Pages : 483 - 489
DOI : 10.6002/ect.2017.0185


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From the Department of Internal Medicine and the Renal Tranplant Unit, Rafik Hariri University Hospital, Bir Hassan, Beirut, Lebanon
Acknowledgements: The author has no sources of funding for this study and no conflicts of interest to declare.
Corresponding author: Antoine Barbari, Lebanese Faculty of Medical Sciences, Department of Internal Medicine, and the Renal Transplant Unit, Rafik Hariri University Hospital, Bir Hassan, Beirut, Lebanon
Phone: +961 3326556, +961 1832040
E-mail: barbariantoine@gmail.com