Autoantibodies against thrombospondin type 1 domain–containing 7A induce membranous nephropathy

IntroductionClinical course of membranous nephropathy (MN) is difficult to predict. Measurement of circulating anti-PLA2R autoantibodies (PLA2R-Ab) and detection in immune deposits of PLA2R antigen (PLA2R-Ag) are major advances in disease understanding. We evaluated the clinical significance of these biomarkers.MethodsIn this 14-year retrospective study, we collected data from 108 MN patients and assessed the relationship between clinical course, PLA2R-Ab and PLA2R-Ag. We also assessed THSD7A status.ResultsEighty-five patients suffered from primary MN (PMN) and 23 patients from a secondary form. The median follow-up was 30.4 months [interquartile range, 17.7;56.7]. Among the 77 patients with PMN and available serum and/or biopsy, 69 (89.6%) had PLA2R-related disease as shown by anti-PLA2R-Ab and/or PLA2R-Ag, while 8 patients (8/77, 10.4%) were negative for both. There was no significant difference between these two groups in age at diagnosis and outcome assessed by proteinuria, serum albumin level and eGFR. Two of the 8 negative patients were positive for THSD7A. In patients with PLA2R related PMN, younger age, lower proteinuria, higher eGFR, and lower PLA2R-Ab level at baseline and after 6 months were associated with remission of proteinuria. Initial PLA2R-Ab titer ≤ 97.6 RU/mL and complete depletion of PLA2R-Ab within 6-months were significantly associated with spontaneous remission at the end of follow-up. In rituximab treated patients, lower PLA2R-Ab titer at initiation of treatment, and absence of PLA2R-Ab and higher serum albumin level at 3 months were significantly associated with remission. Noticeably, 81.8% of the patients who achieved remission completely cleared PLA2R-Ab. Depletion of PLA2R-Ab and increase of serum albumin level preceded the decrease of proteinuria.ConclusionAssessment of PLA2R autoimmunity is essential for patient management. Combination of PLA2R-Ab and PLA2R-Ag increases diagnosis sensitivity. PLA2R-Ab titer is a biomarker of disease severity at initial assessment, and the kinetics of the antibody are significantly correlated to disease evolution.

show abstract

“…There is some indication that patients with anti-THSD7A antibody may have a higher risk of cancer [21]. …”

Section: Introductionmentioning

confidence: 99%

Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years

et al. 2017

View full text Add to dashboard Cite

show abstract

“…There is only limited knowledge of the role of THSD7A in human disease. Besides the involvement in the pathogenesis of MN there is evidence for participation in angiogenesis as well as an association with obesity …”

Section: Introductionmentioning

confidence: 99%

THSD7A expression in human cancer

Stahl

Hoxha

Wiech

et al. 2017

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

We recently described a case of a Thrombospondin Type-1 Domain containing 7A (THSD7A) associated membranous nephropathy in a female patient who was synchronously suffering from a THSD7A-positive malignancy. We here investigated the role of THSD7A as a new potential tumor antigen by evaluating over 20 000 tissue spots in more than 70 different tumor entities by immunohistochemistry using tissue microarrays. THSD7A expression was highly variable in different neoplasias with differing staining patterns. Both gain and loss of THSD7A expression compared to expression status in non-tumor tissue were linked to tumor-specific markers in the different tumor entities and were of prognostic value. The potential role of THSD7A in tumor development and therapy needs further investigation.

show abstract

“…Unlike PLA2R, THSD7A is expressed on murine podocytes, and MN was induced in mice by injection of anti‐THSD7A, thereby establishing a causative role for these antibodies . These antibodies also induced cytoskeletal reorganization in human podocytes …”

Section: Membranous Nephropathy In the Native Kidneymentioning

confidence: 99%

Membranous nephropathy in the kidney allograft

Filippone

Farber

2016

Clinical Transplantation

View full text Add to dashboard Cite

Membranous nephropathy (MN) may occur in a kidney transplant as recurrence of the original disease (rMN) or as a de novo MN (dnMN). rMN often occurs early, within the first year, and often in a mild or subclinical fashion. Recurrence cannot be predicted by clinical features at the time of transplantation. The natural history is increasing proteinuria over time, with less chance for spontaneous remission compared to primary MN (pMN). Antiphospholipase A2 receptor (PLA2R) antibodies should be evaluated in all patients with pMN at the time of transplantation and serially. If titers persist or rise, biopsy is indicated. Irrespective of PLA2R status, any case with proteinuria reaching 1 g/day should be biopsied. No randomized controlled trials have been published regarding treatment of rMN. Observational data support use of rituximab. Given the progressive nature of rMN and lack of spontaneous remissions, a period of observation does not seem justifiable. dnMN occurs with about equal frequency as rMN and shares features of secondary MN in native kidneys. Causes include viral infections (e.g., hepatitis B or C), which should be treated. In some cases, dnMN may represent an atypical alloimmune response. The role of rituximab in dnMN is undefined.

show abstract

Autoantibodies against thrombospondin type 1 domain–containing 7A induce membranous nephropathy

Cited by 203 publications

References 32 publications

Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years

Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years

THSD7A expression in human cancer

Membranous nephropathy in the kidney allograft

Contact Info

Product

Resources

About