Chronic transplant glomerulopathy: New insights into pathogenesis

Gokhale, Avantee; Chancay, Jorge; Shapiro, Ron; Randhawa, Parmjeet; Menon, Madhav C.

doi:10.1111/ctr.14214

Cited by 5 publications

(4 citation statements)

References 64 publications

(83 reference statements)

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“…To minimize relevant imbalances between trial arms, patients will undergo stratified randomization to reduce center bias and weight for ABMR phenotype (active versus chronic active ABMR). Stratification for the presence or absence of chronic injury (most prominently transplant glomerulopathy) was chosen to account for potential variability regarding the extent of chronic injury, which is well established to be a major predictor of graft outcome, critically influencing responsiveness to treatment [ 43 ]. Even with the use of surrogate endpoints, such as eGFR slope, which may effectively predict transplant survival, larger samples would be needed.…”

Section: Discussionmentioning

confidence: 99%

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Mayer

Budde

Halloran

et al. 2022

Trials

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Background Antibody-mediated rejection (ABMR) is a cardinal cause of renal allograft loss. This rejection type, which may occur at any time after transplantation, commonly presents as a continuum of microvascular inflammation (MVI) culminating in chronic tissue injury. While the clinical relevance of ABMR is well recognized, its treatment, particularly a long time after transplantation, has remained a big challenge. A promising strategy to counteract ABMR may be the use of CD38-directed treatment to deplete alloantibody-producing plasma cells (PC) and natural killer (NK) cells. Methods This investigator-initiated trial is planned as a randomized, placebo-controlled, double-blind, parallel-group, multi-center phase 2 trial designed to assess the safety and tolerability (primary endpoint), pharmacokinetics, immunogenicity, and efficacy of the fully human CD38 monoclonal antibody felzartamab (MOR202) in late ABMR. The trial will include 20 anti-HLA donor-specific antibody (DSA)-positive renal allograft recipients diagnosed with active or chronic active ABMR ≥ 180 days post-transplantation. Subjects will be randomized 1:1 to receive felzartamab (16 mg/kg per infusion) or placebo for a period of 6 months (intravenous administration on day 0, and after 1, 2, 3, 4, 8, 12, 16, and 20 weeks). Two follow-up allograft biopsies will be performed at weeks 24 and 52. Secondary endpoints (preliminary assessment) will include morphologic and molecular rejection activity in renal biopsies, immunologic biomarkers in the blood and urine, and surrogate parameters predicting the progression to allograft failure (slope of renal function; iBOX prediction score). Discussion Based on the hypothesis that felzartamab is able to halt the progression of ABMR via targeting antibody-producing PC and NK cells, we believe that our trial could potentially provide the first proof of concept of a new treatment in ABMR based on a prospective randomized clinical trial. Trial registration EU Clinical Trials Register (EudraCT) 2021-000545-40. Registered on 23 June 2021. ClinicalTrials.gov NCT05021484. Registered on 25 August 2021

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Section: Discussionmentioning

confidence: 99%

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Mayer

Budde

Halloran

et al. 2022

Trials

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“…The pathology of kidney biopsy can indicate non-specific features such as chronic immune damage, interstitial fibrosis or renal tubular atrophy ( Sayin et al, 2017 ). With the advancement of matching technology, surgical technology and the use of immunosuppressive agents, short-term outcome of kidney transplantation has been improved, but long-term outcome still remains a challenge ( Gokhale et al, 2021 ). How to reduce the occurrence of CAN is currently the most concerned issue.…”

Section: Clinical Applications and Mechanisms Of Twhf And Its Prepara...mentioning

confidence: 99%

Applications and Mechanisms of Tripterygium Wilfordii Hook. F. and its Preparations in Kidney Diseases

Xue

Qiao

Yang³

et al. 2022

Front. Pharmacol.

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Tripterygium wilfordii Hook. f. (TwHF) is a Chinese botanical drug containing a large number of metabolites. The discovered and recognized anti-inflammatory and immune-regulating effects have made it attract more and more attentions in trials and clinical researches. The extraction and processing of TwHF for pharmaceuticals is a manifestation of the role of traditional Chinese medicine. However, TwHF is toxic. Optimization of TwHF preparations has become a requirement for the development of TwHF pharmaceuticals. Our article introduces the main preparations of TwHF on the Chinese market and their characteristics. In particular, we summarize the clinical applications and influential mechanisms of TwHF and its preparations in kidney diseases. Considering that nephropathy is closely related to immune inflammation and TwHF is a botanical drug with a high number of metabolites, the application of TwHF in kidney diseases may be much more complicated. By revealing the role and mechanisms of TwHF in kidney diseases, this study aims to provide more insights to basic and clinical studies about nephropathy.

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“…It will be important to understand the pathobiology of xenograft failure to achieve the best possible outcomes. In renal allotransplantation, the most common cause of late graft failure is transplant glomerulopathy secondary to chronic AMR 9,10 …”

Section: Introductionmentioning

confidence: 99%

Late graft failure of pig‐to‐rhesus renal xenografts has features of glomerulopathy and recipients have anti‐swine leukocyte antigen class I and class II antibodies

Ladowski,

Tector,

Martens

et al. 2024

Xenotransplantation

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Prolonged survival in preclinical renal xenotransplantation demonstrates that early antibody mediated rejection (AMR) can be overcome. It is now critical to evaluate and understand the pathobiology of late graft failure and devise new means to improve post xenograft outcomes. In renal allotransplantation the most common cause of late renal graft failure is transplant glomerulopathy—largely due to anti‐donor MHC antibodies, particularly anti‐HLA DQ antibodies. We evaluated the pig renal xenograft pathology of four long‐surviving (>300 days) rhesus monkeys. We also evaluated the terminal serum for the presence of anti‐SLA class I and specifically anti‐SLA DQ antibodies. All four recipients had transplant glomerulopathy and expressed anti‐SLA DQ antibodies. In one recipient tested for anti‐SLA I antibodies, the recipient had antibodies specifically reacting with two of three SLA I alleles tested. These results suggest that similar to allotransplantation, anti‐MHC antibodies, particularly anti‐SLA DQ, may be a barrier to improved long‐term xenograft outcomes.

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Chronic transplant glomerulopathy: New insights into pathogenesis

Cited by 5 publications

References 64 publications

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial

Applications and Mechanisms of Tripterygium Wilfordii Hook. F. and its Preparations in Kidney Diseases

Late graft failure of pig‐to‐rhesus renal xenografts has features of glomerulopathy and recipients have anti‐swine leukocyte antigen class I and class II antibodies

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