Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02199145 |
| Other study ID # |
14-AOI-05 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 17, 2015 |
| Est. completion date |
June 4, 2020 |
Study information
| Verified date |
November 2023 |
| Source |
Centre Hospitalier Universitaire de Nice |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic
syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%
undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major
auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase
of MN. Predictors of disease progression include high titers of anti-PLA2R1 autoantibodies
and serum creatinine levels at presentation, as well as decline in renal function during the
first six months of follow-up. Investigators identified new prognostic factors in a cohort of
41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1 autoantibodies at the time
of presentation. During a follow-up of at least 36 months, 21 patients had a persistent
nephrotic syndrome (group A) and 20 showed partial or total remission (group R). We first
measured the cross-reactivity of their sera at the time of presentation to human, rabbit and
mouse recombinant PLA2R1 by western blot. All patients exhibited reactivity against human and
rabbit PLA2R1, but only some of them did against mouse PLA2R1. These results suggest the
presence of distinct epitopes that are differentially conserved among PLA2R1
orthologs.Investigators then set-up three parallel ELISAs using human, rabbit and mouse
recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs at
presentation but only 32 of them (78%) in mouse ELISA.They finally analyzed the association
between anti-PLA2R1 titers at presentation in the different ELISAs and the subsequent
clinical outcome. The mean anti-PLA2R1 activity was significantly different between group A
and R in mouse ELISA but not in human and rabbit ELISA. Patients with anti-mouse PLA2R1
activity over 605 RU (relative unit)/ml showed a significantly lower survival without
doubling of serum creatinine or ESKD , but patients in the highest tertile of anti-PLA2R1
activity in rabbit and human ELISA did not show a significant increased risk of renal failure
progression. The results suggest that the specific detection of particular anti-PLA2R1
autoantibodies using the novel anti-mouse PLA2R1 ELISA can identify MN patients at risk for
ESKD. The aim is to confirm these result on a prospective cohort.
Description:
Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic
syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%
undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major
auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase
of MN [2,3]. Predictors of disease progression include high titers of anti-PLA2R1
autoantibodies and serum creatinine levels at presentation, as well as decline in renal
function during the first six months of follow-up. Investigators identified new prognostic
factors in a cohort of 41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1
autoantibodies at the time of presentation. During a follow-up of at least 36 months, 21
patients had a persistent nephrotic syndrome (group A) and 20 showed partial or total
remission (group R). We first measured the cross-reactivity of their sera at the time of
presentation to human, rabbit and mouse recombinant PLA2R1 by western blot. All patients
exhibited reactivity against human and rabbit PLA2R1, but only some of them did against mouse
PLA2R1. These results suggest the presence of distinct epitopes that are differentially
conserved among PLA2R1 orthologs. We then set-up three parallel ELISAs using human, rabbit
and mouse recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs
at presentation but only 32 of them (78%) in mouse ELISA.
Investigators finally analyzed the association between anti-PLA2R1 titers at presentation in
the different ELISAs and the subsequent clinical outcome. The mean anti-PLA2R1 activity was
significantly different between group A and R in mouse ELISA in both univariate and
multivariate analyses (p =0.006 and p =0.02, respectively) but not in human and rabbit
ELISAs. An analysis of the mouse ELISA titers defines a threshold of 605 RU/ml above which
100% of patients had a poor prognosis, but no such threshold could be defined in rabbit and
human ELISA. Patients with anti-mouse PLA2R1 activity over 605 RU/ml showed a significantly
lower survival without doubling of serum creatinine or ESKD (p=0.002 using the log-rank
test), but patients in the highest tertile of anti-PLA2R1 activity in rabbit and human ELISAs
did not show a significant increased risk of renal failure progression. The results suggest
that the specific detection of particular anti-PLA2R1 autoantibodies using the novel
anti-mouse PLA2R1 ELISA can identify MN patients at risk for ESKD. The aim is to confirm
these result on a prospective cohort.We propose to measure on a prospective cohort at the
time of MN diagnosis if high titer of anti-mPLA2R1 Ab (anti-mouse phospholipase A2 receptor1
antibodies) is associated with nephrotic proteinuria (over 3.5 g/g) or increased of
creatininemia over 30% at month 6, 12 and 18. An ancillary study will try to characterised
the nephrogenic epitope conserved between human, rabbit and mouse.
Each patient with nephrotic syndrome should benefit of a kidney biopsy. For each patient we
will conserved 2 dry tubes frozen at the time of biopsy. If we confirm the diagnosis of MN
with anti-PLA2R1 Ab, we propose to the patient to be included in this study. He will have a
visit every months for the first three months and every three months after, with collection
of the following: blood pressure, weight, creatinine, albumin, blood electrolytes,
proteinuria / creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and
mouse) In case of persistent refractory nephrotic syndrome after 6 months, or the appearance
of a 30% increase in serum creatinine, treatment with rituximab (2 × 1 g IV 15 days) will be
proposed. Clinical and biological monitoring will be continued every 3 months for 18 months.
