Anti-phospholipase A2 Receptor Research Articles

Comparison of obinutuzumab and rituximab for treating primary membranous nephropathy.

This study compared the effectiveness and safety profiles of obinutuzumab and rituximab in the treatment of patients with primary membranous nephropathy. Patients with primary membranous nephropathy who had urine protein ≥ 3.5 g/24 hours and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 despite six months of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and treatment with obinutuzumab or rituximab were included and matched by propensity score (ratio: 1:2) based on age, sex, urine protein, eGFR, and titers of Anti-Phospholipase A2 receptor (PLA2R) antibody. The primary outcome was defined as a combination of partial or complete remission at 12 months. Logistic regression models, Kaplan Meier curves, and absolute risk differences were employed to compare the therapeutic effectiveness and safety profiles of obinutuzumab and rituximab. Sixty-three patients with primary membranous nephropathy were included in the study, with 21 patients receiving obinutuzumab and 42 patients receiving rituximab. At 12 months, the primary outcome was achieved in 20 of 21 patients in the obinutuzumab group and 28 of 42 patients in the rituximab group (obinutuzumab vs. rituximab: 95% vs. 67%; odds ratio (OR): 10.00, 95% confidence intervals (CI):1.21-82.35, P=0.03). Moreover, patients in the obinutuzumab group acquired more complete remission (obinutuzumab vs. rituximab: 38% vs. 14%; OR: 3.69, 95% CI:1.08-12.68, P=0.04). In PLA2R-associated primary membranous nephropathy subgroup analyses, patients in obinutuzumab group sustained lower CD19 B cell counts (CD19 B cell counts: median (IQR) 0 (0-6) cells/ul vs. 20 (3-58) cells/ul, P=0.002) and were more prone to achieve immunological remission (defined as PLA2R antibody <2 RU/ml) at six months [obinutuzumab vs. rituximab: 92% (12 out of 13) vs. 64% (16 out of 25), P=0.06] than rituximab. Both treatment regimens were well tolerated. Our study demonstrated that obinutuzumab is associated with higher odds of clinical remission compared to rituximab at 12 months which may be due to higher immunological remission at six months with a similar safety profile in patients with primary membranous nephropathy.

The correlation between anti-phospholipase A2 receptor antibodies and hypercoagulability in patients with idiopathic membranous nephropathy

Background Patients with idiopathic membranous nephropathy (IMN) are more likely to be complicated by venous thromboembolism (VTE). The aim of the study was to investigate the potential association between anti-phospholipase A2 receptor (PLA2R) antibodies and hypercoagulability in patients with IMN. Methods A total of 168 patients with biopsy-proven IMN and 36 patients with biopsy-proven minimal change disease (MCD) were enrolled in this study. The clinical data, serum anti-PLA2R antibodies and coagulation-related indices of the patients were retrospectively analyzed. Results Patients with IMN were categorized into glomerular PLA2R staining-positive (GAg+) IMN group and glomerular PLA2R staining-negative (GAg-) IMN group in the study. Patients with IMN who were GAg + had lower PT, APTT and R time than patients with IMN who were GAg-, while the CI value was higher in patients with IMN who were GAg+. Patients with IMN who were GAg + were divided into the SAb+/GAg + group and the SAb-/GAg + group. Patients with IMN who were SAb+/GAg + had higher Fib and MA values than patients with IMN who were SAb-/GAg+. Correlation analysis showed that serum anti-PLA2R antibodies were positively correlated with fibrinogen, D-dimer, K time, CI value, α-angle, and MA value. Multiple linear regression analysis indicated that anti-PLA2R antibodies were independently correlated with fibrinogen and MA value. Conclusion Our study provides a new perspective on the underlying mechanisms of hypercoagulability in patients with IMN. Anti-PLA2R antibodies are associated with hypercoagulability in patients with IMN and may affect coagulation in patients with IMN by affecting platelet aggregation function and fibrinogen counts.

Effect of cyclophosphamide combined with glucocorticoid therapy on idiopathic membranous nephropathy: A multicenter open-label randomized controlled trial.

We aimed to evaluate the effect of cyclophosphamide combined with glucocorticoid therapy on idiopathic membranous nephropathy through a multicenter open-label randomized controlled trial. 92 patients with idiopathic membranous nephropathy admitted from March 2020 to September 2022 were included and assigned to a control group (n=46) and a research group (n=46) using a random number table. The control group was given glucocorticoid, and the research group was given cyclophosphamide combined with glucocorticoid. Clinical efficacy, renal function-related indicators (serum creatinine, blood urea nitrogen and albumin, and 24-hour urine protein quantification), inflammatory factors (interleukin (IL)-6, IL-18, transforming growth factor-β, and tumor necrosis factor-α), immune function-related indicators (anti-phospholipase A2 receptor antibody, and T-lymphocyte subsets), oxidative stress-related indicators (heme oxygenase-1, superoxide dismutase, malondialdehyde, and nitric oxide), blood lipid-related indicators (total cholesterol, triacylglycerol, and low-density lipoprotein), and adverse reactions were compared. The overall remission rate of the research group was higher than that of the control group (93.48 vs. 78.26%, p<0.05). After treatment, the research group had lower levels of 24-hour urine protein quantification, serum creatinine, blood urea nitrogen, IL-6, IL-18, transforming growth factor-β, tumor necrosis factor-α, heme oxygenase-1, malondialdehyde, anti-phospholipase A2 receptor antibody, CD8+, total cholesterol, triacylglycerol and low-density lipoprotein, higher levels of albumin, superoxide dismutase, nitric oxide, and CD4+ and a higher CD4+/CD8+ ratio than the control group (p<0.05). Cyclophosphamide combined with glucocorticoid therapy is effective for improving the overall remission rate and can suppress inflammatory responses and oxidative stress in patients with idiopathic membranous nephropathy.

Macrocarpal B blocks the binding between the phospholipase A2 receptor and its antibodies

The pathogenic role of anti-phospholipase A2 receptor (PLA2R) antibodies in primary membranous nephropathy (MN) has been well-established. This study aimed to identify potential small-molecule inhibitors against the PLA2R-antibody interaction, offering potential therapeutic benefits. A comprehensive screening of over 4000 small-molecule compounds was conducted by ELISA to assess their inhibitory effects on the binding between the immobilized full-length extracellular PLA2R and its antibodies. The affinity of anti-PLA2R IgG from MN patients and the inhibitory efficacy of each compound were evaluated via surface plasmon resonance (SPR). Human podocyte injuries were analyzed using CCK-8 assay, wound healing assay, western blot analysis, and immunofluorescence, after exposure to MN plasma +/- blocking compound. Fifteen compounds were identified as potential inhibitors, demonstrating inhibition rates >20 % for the PLA2R-antibody interaction. Anti-PLA2R IgG exhibited a consistent affinity among patients (KD = 10−8 M). Macrocarpal B emerged as the most potent inhibitor, reducing the antigen–antibody interaction by nearly 30 % in a dose-dependent manner, comparable to the performance of the 31-mer peptide from the CysR domain. Macrocarpal B bound to the immobilized PLA2R with an affinity of 1.47 × 10−6 M, while showing no binding to anti-PLA2R IgG. Human podocytes exposed to MN plasma showed decreased podocin expression, impaired migration function, and reduced cell viability. Macrocarpal B inhibited the binding of anti-PLA2R IgG to podocytes and reduced the cellular injuries.

Anti-Phospholipase A2 Receptor Antibody (Anti-PLA2R) Testing to the Rescue

Serological testing for M-type anti-phospholipase A2 receptor antibodies (antiPLA2R Ab) has abrogated the need for kidney biopsy to diagnose membranous nephropathy in the appropriate clinical setting. We report a case of a 63-year-old hypertensive male who presented with nephrotic syndrome associated with autosomal dominant polycystic kidney disease which was effectively diagnosed with the use of antiPLA2R Ab test. He achieved complete remission upon treatment with Rituximab. Hitherto, all anecdotal case reports of this uncommon association were diagnosed only by kidney biopsy. We highlight the usefulness of PLA2RAb especially in such cases of difficult-to-biopsy kidneys.

Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody–Positive Primary Membranous Nephropathy

IntroductionPrimary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN. MethodsPatients with PMN that was newly diagnosed or relapsed (Cohort 1 [C1]; n=18) or refractory to immunosuppressive therapy (Cohort 2 [C2]; n=13) received nine infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary endpoint was the incidence and severity of treatment-emergent adverse events (TEAEs). ResultsThirty-one patients were enrolled and received felzartamab. Twenty-seven (87.1%) patients had TEAEs, including infusion-related reactions (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five (16.1%) patients had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20/26 (76.9%) efficacy-evaluable patients (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (UPCR reduction ≥50%, UPCR <3.0 g/g, and stable eGFR) was achieved by 9/26 (34.6%) patients (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20/26 (76.9%) patients (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]). ConclusionIn this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.

#514 Efficacy of continues low dose rituximab in PLA2R-associated primary membranous nephropathy

Abstract Background and Aims We reported that rituximab 100 mg monthly showed an effective regimen for low anti-phospholipase A2 receptor (anti-PLA2R) primary membranous nephropathy (PMN), especially for those elderly and susceptible PMN. Here we attempted to compare effect of the rituximab (RTX) 100 mg monthly vs traditional corticosteroid-cyclophosphamide (GC-Cy) for the treatment of PLA2R-associated PMN in our hospital. Method All the included PMN patients were treated in our hospital between June 2017 and June 2022 and were retrospectively analyzed. The inclusion criteria:(1) age &amp;gt;18 years old, (2) biopsy-proven PMN, (3) anti-PLA2R titers &amp;gt;20 RU/ml, (4) nephrotic syndrome (NS, both proteinuria &amp;gt;3.5 g/24 and serum albumin &amp;lt;30 g/L), (5) eGFR &amp;gt;30 ml/ min. 1.73 m2, (6) followed up at least 12 months. Patients were stratified into the RTX and GC-Cy groups according to their received treatment. In the RTX group, patients received RTX 100 mg monthly until the NS was remission or at least serum anti-PLA2R less than 2 RU/ml. In the GC-Cy group, patients received prednisolone (0.5-1.0 mg/kg/day) or methylprednisolone (similar dose) orally for 1-2 months, then dosage was reduced gradually, and the total duration about one year; meanwhile received intravenous cyclophosphamide (0.6-1.0 g every month), total doses 6-12 g. Results The baseline parameters (included age, gender, anti-PLA2R antibody, urinary protein, serum albumin, and eGFR) did not differ significantly between the two groups (see Table 1). Total RTX dosed were 819 ± 240 (400-1200 mg) in the RTX group. After different treatment, anti-PLA2R antibody was significantly higher in rituximab group than in the GC-Cy group at 3 months (P &amp;lt; 0.05), but were not significantly different between the two groups at 6, 9, and 12 months (P &amp;gt; 0.05, see Fig. 1A); urinary proteins were significantly higher in RTX group than in the GC-Cy group at 3, 6, and 9 months (P &amp;lt; 0.001), but were not significantly different between the two groups at 12 months (P &amp;gt; 0.05, see Fig. 1B); serum albumin were significantly lower in RTX group than in the GC-Cy group at 3, 6, 9 and 12 months (P &amp;lt; 0.01, see Fig. 1C). The total remission rate was not significantly different between the two groups at 12 months (P &amp;gt; 0.05, see Fig. 1D). Conclusion Compared to traditional GC-Cy treatment, RTX 100 mg monthly appeared as a weak but lasting effective regimen for anti-PLA2R-associated PMN.

#2388 Relevance of anti-PLA2R levels in therapy decision and prediction of therapy outcome in patients with membranous nephropathy

Abstract Background and Aims Detection of anti-phospholipase A2 receptor (PLA2R) antibodies in patients with primary membranous nephropathy (MN) supports diagnosis as well as disease monitoring. An individualised therapy approach was introduced for anti-PLA2R positive MN patients at the Radboud University Medical Center. Immunosuppressive treatment (cyclophosphamide combined with steroids) was stopped when anti-PLA2R results by indirect immunofluorescence testing (IIFT) became negative. Here, we evaluated the relevance of anti-PLA2R levels for therapeutic decisions and the outcome of MN, comparing qualitative and quantitative detection methods. Method Stored serum samples were retrieved for beginning of treatment (baseline), decision point, and follow-up. Anti-PLA2R levels were determined qualitatively by IIFT as well as quantitatively by enzyme-linked immunosorbent assay (ELISA) and chemiluminescence immunoassay (ChLIA) at baseline as well as after treatment and correlated to immunological remission and persistence. Results For an evaluation of the relevance of anti-PLA2R levels at the start of therapy, serum samples of 60 patients were available. Patients sampled at the beginning of the therapy were grouped according to tertiles of anti-PLA2R levels determined by ChLIA (n[lowest tertile] = 20, n[middle tertile] = 20, n[highest tertile] = 20). Lower anti-PLA2R levels were seen in patients with relapsing disease. Higher anti-PLA2R levels were associated with more severe proteinuria. Patients in the lowest tertile of anti-PLA2R were more likely to develop immunological remission after 8 weeks of therapy. In total, 90% vs 75% vs 45% of patients in the tertiles turned anti-PLA2R negative after being treated for 8 weeks. Moreover, in this subgroup of patients who showed immunological remission after 8 weeks of therapy, only 11% of the patients in the lowest tertile needed renewed immunosuppressive therapy, while this percentage increased in the middle and highest tertiles (11% vs 53% vs 33%, p=0.033). For the assessment of anti-PLA2R levels before and after therapy, samples at baseline and week 8 of treatment were examined. At baseline, 50/50 (100%) tested positive in IIFT and ChLIA as well as 48/50 (94%) in ELISA. After 8 weeks on treatment, immunological remission based on IIFT was found in 37/51 (73%) patients. At this point, the overall agreement compared to IIFT was 92% for ChLIA and 82% for ELISA. Yet the availability of quantitative levels provided further insight into this group of patients in whom treatment was discontinued. With ChLIA, anti-PLA2R titers &amp;gt;5 RU/mL after 8 weeks of therapy were found in 4% of IIFT negative patients with persistent remission, vs 55% of IIFT negative patients with early relapse (p=0.006). Conclusion Individualised treatment of MN patients with cyclophosphamide and steroids has been recently introduced. In this respect, the quantitative determination of anti-PLA2R levels adds further value. Of the examined quantitative methods, ChLIA demonstrated the highest agreement with IIFT. Additional studies are needed to evaluate the impact on clinical decision making and outcome.

Obinutuzumab as Initial or Second-Line Therapy in Patients With Primary Membranous Nephropathy

IntroductionB-cell lymphocytes have been demonstrated to play a key role in the pathogenesis underlying membranous nephropathy (MN). The aim of this study was to evaluate the therapeutic efficacy and safety of obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody in individuals with MN. MethodsWe retrospectively analysed data from 59 consecutive patients with primary MN who provided consent to receive obinutuzumab and were followed for at least 6 months. The primary outcomes were complete (proteinuria <0.3 g/d) or partial (proteinuria <3.5 g/d with ≥ 50% reduction) remission of proteinuria. ResultsTwenty patients received obinutuzumab as initial therapy and 39 patients were previously treated with at least one immunosuppressant (second-line therapy). Fifty patients (84.7%) achieved complete or partial remission of proteinuria during the median follow-up of 9.4 months. The likelihood of remission was significantly higher when obinutuzumab was used as initial therapy than as second line therapy after adjusting for the baseline estimated glomerular filtration rate, 24-hour urinary protein levels, and anti-phospholipase A2 receptor (PLA2R) status (adjusted HR, 4.5; 95%CI 2.1 to 9.5, P <0.001). Circulating CD19+ B-cell count decreased to <5 cells/μL in all patients within 2 weeks after infusion. Serum anti-PLA2R concentrations decreased to <14 relative units/mL in 43 out of 48 patients with PLA2R–related MN. Following Obinutuzumab administration, a significant reduction in 24-hour urine protein and increase in serum albumin were observed. No serious adverse events were observed. ConclusionObinutuzumab may represent a promising and well-tolerated therapeutic option for individuals with primary MN. The potential of obinutuzumab was highlighted as an initial therapy for primary MN.

Preference for anti-phospholipase A2 receptor antibody assay in patients with suspected membranous nephropathy: a survey study on medical practice after publication of Japanese Guidelines for Nephrotic Syndrome 2020.

International practice guidelines advocate for the use of anti-phospholipase A2 receptor (PLA2R) antibody testing to diagnose primary membranous nephropathy (pMN). This study aimed to clarify the current status of anti-PLA2R antibody testing in the diagnosis of pMN in Japan and to scrutinize the factors associated with the implementation of this antibody test. Utilizing a web-based questionnaire for nephrologists, responses were collected from 306 facilities and 427 nephrologists between November 2021 and December 2021. Preference for anti-PLA2R antibody testing was also investigated. Factors related to the experience of quantifying anti-PLA2R antibodies were estimated by generalized estimating equations using a robust analysis of variance with clusters of facilities of affiliation. Of the 427 respondents, 140 (32.8%) had previous measurement experience at their current workplace and 165 (38.6%) had previous measurement experience overall. In pMN-suspected cases without contraindications to renal biopsy, 147 (34.4%) of the respondents opted to request anti-PLA2R antibody testing. The respondents' experience with anti-PLA2R antibody quantification at their current place of work was generally higher in university hospitals and increased with the annual number of kidney biopsies and the number of years since graduation. The results of this study suggest that a significant proportion of nephrologists in Japan have no experience in performing anti-PLA2R antibody assays, and that the assays may be hampered by the limited capabilities of the current workplace and the financial burden on facilities and patients.

Comparison of the efficacy of steroid-free versus classic steroid-containing regimens in primary membranous nephropathy.

Objective: To compare the efficacy of a steroid-free regimen with steroid-based treatment in managing primary membranous nephropathy (PMN) and investigate the potential benefits of steroid-free regimens in PMN therapy. Methods: This was a single-centre prospective cohort study. A total of 81 patients were divided into two groups according to their medication regimen: a rituximab (RTX)/tacrolimus (TAC) group (low-dose RTX combined with low-dose TAC group, without steroids, n = 31) and a prednisone (P)/TAC group (P combined with TAC group, n = 61). The changes in 24-h urine protein quantification, levels of blood albumin, blood creatinine, total cholesterol, triglyceride and fasting blood glucose as well as anti-phospholipase A2 receptor antibody titres were observed in both groups before treatment and after 1, 3, 6 and 12months of treatment. Clinical remission (complete and partial remission), serological remission and recurrence were assessed in both groups after treatment, and the occurrence of adverse reactions was observed. Results: 1) Before treatment, there was no significant difference in baseline values between the two groups (p > 0.05). 2) After 12months of treatment, the 24-h proteinuria and total cholesterol levels in the RTX/TAC group were significantly lower than those in the P/TAC group (p < 0.05). 3) After 6months of treatment, the clinical remission rate of the RTX/TAC group was significantly higher than that of the P/TAC group (p < 0.05). After 12months of treatment, the clinical remission rate of the RTX/TAC group was significantly higher than that of the P/TAC group (p < 0.05). (4) After 3, 6 and 12months of treatment, serological remission rates in the RTX/TAC group were significantly higher than those in the P/TAC group (p < 0.05). During treatment, the anti-PLA2R antibody titres in the RTX/TAC group remained lower than those in the P/TAC group (p < 0.05). Conclusion: The low-dose RTX combined with low-dose TAC steroid-free regimen induces serological remission in patients with PMN earlier than the classic regimen of P combined with TAC, and there was no significant difference in adverse effects between the two groups. Besides, the long-term clinical remission effect of low-dose RTX combined with low-dose TAC is better than that of P combined with TAC.

Diagnostic value of renal biopsy in anti-phospholipase A2 receptor antibody-positive patients with proteinuria in China

Renal biopsy remains the gold standard for diagnosing membranous nephropathy (MN). Recent studies have suggested that renal biopsy can be replaced with the serum phospholipase A2 receptor (PLA2R) antibody test for MN diagnosis in patients with nephrotic syndrome. However, this test has not been validated in the Chinese population. In this study, we investigated whether renal biopsy provides additional diagnostic information on patients with proteinuria who are seropositive for PLA2R antibodies (SAb +). We retrospectively reviewed the clinicopathological characteristics of SAb + adult patients (aged ≥ 18 years) with proteinuria (≥ 0.5 g/24 h) assessed at the Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, from June 2021 to March 2022. Among a total of 801 SAb + patients who received renal biopsy, those with incomplete pathological data, diabetes or any potential cause of secondary MN were excluded. Among the 491 remaining patients, 474 had primary MN (PMN), 16 had atypical MN (AMN, 9 patients with “full house” and 2 patients with HBsAg + /HBcAg + immunofluorescence results), and 1 had focal segmental glomerulosclerosis. In patients with an eGFR of ≥ 60 mL/min/1.73 m2 (n = 451), 436 had PMN, and 71 (16.3%) exhibited additional biopsy findings, with obesity-related glomerulopathy being the most common. In patients with an impaired eGFR (n = 40), 38 had PMN, and 31 (81.6%) showed additional findings, with acute tubular injury being the most common. In conclusion, anti-PLA2R antibody positivity is highly predictive of PMN in Chinese adults but often coexists with other pathological diagnoses. The advantages of renal biopsy for detecting other pathologies should be weighed against the potential risks of the biopsy procedure.

Anti–Phospholipase A2 Receptor 1 and Anti–Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study

Rationale & ObjectiveProteinuria and anti-phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. Study DesignProspective cohort study. Setting & ParticipantsOne-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for >6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by ELISA), and clinical outcomes. ExposureRituximab. OutcomesComplete (proteinuria <0.3 g/24h) or partial (proteinuria >0.3 g/24h and <3.0 g/24h with >50% reduction vs. basal) NS remission. Analytical ApproachUnivariable and multivariable Cox regression analyses. ResultsAll patients had anti-CysR antibodies; 62 (54.9%) were multi-domain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (p<0.001, r=0.934), 6 months (p<0.001, r=0.964), and 12 months (p<0.001, r=0.944). During a median (IQR) follow-up of 37.1 (20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 [HR (95% CI): 0.997 (0.996-0.999), p=0.002) and anti-CysR [HR (95% CI): 0.996 (0.993-0.998), p=0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (p<0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (p<0.05 for all comparisons). LimitationsObservational design. ConclusionsIn PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy, independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary.

Serum anti-phospholipase A2 receptor antibody in pathological diagnosis of type 2 diabetes mellitus patients with proteinuria

Patients with diabetes mellitus complicated with proteinuria can be diabetic nephropathy (DN), diabetic complicated with non-diabetic kidney disease (NDKD), or DN with NDKD. Among these membranous nephropathy accounted for a large proportion of DN with NDRD. At present, serum anti-phospholipase A2 receptor (PLA2R) antibody is widely used in the diagnosis and evaluation of therapy in idiopathic membranous nephropathy, our study aimed to investigate the diagnostic significance of anti-PLA2R antibody in type 2 diabetes mellitus (T2DM) patients with proteinuria, providing a method for patients with contraindications of kidney biopsy. Eighty-seven T2DM patients with proteinuria who went on kidney biopsy were divided into the DN group, idiopathic membranous nephropathy (IMN) group, and others group according to their pathological results. In our study, 52.87% and 28.74% of patients were found to have IMN and diabetic nephropathy respectively. The levels of anti-PLA2R antibody, total cholesterol, triglyceride, and estimated glomerular filtration rate (eGFR) were higher in the IMN group, while the prevalence of diabetic retinopathy (DR), systolic blood pressure (SBP) and HbA1c were higher in the DN group. For T2DM patients with proteinuria, anti-PLA2R antibody (AUC = 0.904, 95%CI 0.838–0.970) has a high diagnostic value for IMN. The duration of diabetes (OR = 0.798, P = 0.030), eGFR level (OR = 1.030, P = 0.024), and positive anti-PLA2R antibody (OR = 72.727, P < 0.001) favor the diagnosis of IMN, while DR (OR = 50.234, P < 0.001), SBP (OR = 1.041, P = 0.030), and negative anti-PLA2R antibody (OR = 0.008, P = 0.001) is beneficial to the diagnosis of DN. Our study found that NDKD is not uncommon in patients with T2DM and proteinuria, and IMN was the main pathological type. Positive anti-PLA2R antibody has a strong accuracy in the diagnosis of IMN in patients with T2DM and proteinuria.

Prognostic prediction of idiopathic membranous nephropathy using interpretable machine learning

Background Established prognostic models of idiopathic membranous nephropathy (IMN) were limited to traditional modeling methods and did not comprehensively consider clinical and pathological patient data. Based on the electronic medical record (EMR) system, machine learning (ML) was used to construct a risk prediction model for the prognosis of IMN. Methods Data from 418 patients with IMN were diagnosed by renal biopsy at the Fifth Clinical Medical College of Shanxi Medical University. Fifty-nine medical features of the patients could be obtained from EMR, and prediction models were established based on five ML algorithms. The area under the curve, recall rate, accuracy, and F1 were used to evaluate and compare the performances of the models. Shapley additive explanation (SHAP) was used to explain the results of the best-performing model. Results One hundred and seventeen patients (28.0%) with IMN experienced adverse events, 28 of them had compound outcomes (ESRD or double serum creatinine (SCr)), and 89 had relapsed. The gradient boosting machine (LightGBM) model had the best performance, with the highest AUC (0.892 ± 0.052, 95% CI 0.840–0.945), accuracy (0.909 ± 0.016), recall (0.741 ± 0.092), precision (0.906 ± 0.027), and F1 (0.905 ± 0.020). Recursive feature elimination with random forest and SHAP plots based on LightGBM showed that anti-phospholipase A2 receptor (anti-PLA2R), immunohistochemical immunoglobulin G4 (IHC IgG4), D-dimer (D-DIMER), triglyceride (TG), serum albumin (ALB), aspartate transaminase (AST), β2-microglobulin (BMG), SCr, and fasting plasma glucose (FPG) were important risk factors for the prognosis of IMN. Increased risk of adverse events in IMN patients was correlated with high anti-PLA2R and low IHC IgG4. Conclusions This study established a risk prediction model for the prognosis of IMN using ML based on clinical and pathological patient data. The LightGBM model may become a tool for personalized management of IMN patients.

The cutoff value and prognosis of anti-PLA2R antibody for idiopathic membranous nephropathy: a single-center retrospective study in China

Serum anti-phospholipase A2 receptor (anti-PLA2R) antibody is used for the noninvasive diagnosis of idiopathic membranous nephropathy (IMN). However, the cutoff value of anti-PLA2R antibodies in IMN patients is debatable. This study aimed to investigate the cutoff value of anti-PLA2R antibodies for diagnosing IMN and the correlation of anti-PLA2R antibodies with clinical parameters and prognosis. A total of 252 IMN patients and 521 non-IMN patients with both renal biopsy and serum anti-PLA2R antibody data from April 2017 to November 2019 were enrolled. Anti-PLA2R antibody was detected by an enzyme-linked immunosorbent assay. The anti-PLA2R antibody titer was higher in the IMN group than in the non-IMN group (153.1 ± 22.4 vs. 2.0 ± 0.2 RU/mL, p < 0.001). The optimal anti-PLA2R antibody cutoff value for diagnosing IMN was 2.5 RU/mL, with a sensitivity, specificity, and Youden index of 85.7%, 88.3%, and 0.740, respectively. There was a significant positive correlation between anti-PLA2R antibody and 24-h urinary protein levels (r = 0.341, p < 0.001), and a significant negative correlation between anti-PLA2R antibody and serum albumin levels (r=−0.274, p < 0.001) in patients with IMN. The remission rates positively correlated with the immunosuppressive usage rates and increased from the low- to the high-titer subgroup. Multivariable Cox regression analysis showed that immunosuppressive therapy (adjusted HR = 4.656; 95% confidence interval [CI], 1.461–14.839; p = 0.009) was associated with a higher remission rate in patients with IMN. The optimal Anti-PLA2R antibody cutoff value for diagnosing IMN was 2.5 RU/mL, which was much lower than that indicated by the manufacturer. If IMN is actively treated, patients can have much better prognoses. Trial registration: retrospectively registered.

Immune-related acute kidney injury in Australian non-small cell lung cancer patients: Real-world results

BackgroundThe use of immune checkpoint inhibitors has altered therapeutic paradigms in NSCLC. However, they may cause immune-related toxicities, including acute kidney injury (irAKI), especially when combined with nephrotoxic agents. We investigated the incidence, management and outcomes of AKI in Australian NSCLC patients. MethodsMedical records from a cancer centre registry were reviewed. AKI was defined and graded on absolute creatinine rise, or rise above baseline. Fishers exact test compared proportions. The Kaplan-Meier method estimated survival, and multiple logistic regression tested for risk factors. ResultsOf 449 patients who underwent immunotherapy from 2013 to 2021, the median age was 65 years and 61% were male. Metastatic disease was present in 68% at diagnosis, the remainder had stage Ia-III disease; 70% had adenocarcinoma; and 17% had EGFR mutations.AKI was identified in 65 patients (14.5%) of which 19 were irAKI (4.2%). Within irAKI patients, eleven (58%) had other immune-related adverse events. Median time to irAKI onset was 4 months (IQR 4–6). Seventeen (89%) patients had AKI stage 1 or 2; two had stage 3. Eleven patients developed chronic kidney disease; none required renal replacement therapy. Kidney biopsies demonstrated acute interstitial nephritis (n = 3), acute tubular necrosis (n = 1) and anti-phospholipase A2 receptor negative membranous glomerulonephritis (n = 1). Five patients were rechallenged with immunotherapy; two had recurrent irAKI.The median overall survival for those with irAKI was not reached versus 12 months with no irAKI (HR 0.35, 95 %CI 0.20–0.60, p = 0.01). Risk factors for irAKI included having an additional, non-renal irAE (OR 6.21, 95 %CI 2.35–17.26, p ≤ 0.01); immunotherapy combined with other cancer therapies (OR 5.62, 95 %CI 2.08–16.20, p ≤ 0.01); and ECOG performance status > 1 (OR 4.39 (95 %CI 1.11–14.90, p = 0.02) ConclusionsThe incidence of irAKI was similar to the published literature. Renal recovery was poor, however survival was not compromised. Improved diagnostic and therapeutic strategies for irAKI would benefit this population.

Comparison of performance and clinical utility of different methods for detecting anti-PLA2R antibody

ObjectivesThis study aimed to compare the performance of enzyme-linked immunosorbent assay (ELISA) and magnetic particle chemiluminescence immunoassay (MP-CLIA) for detecting anti-phospholipase A2 receptor (PLA2R) antibody and their clinical significance in idiopathic membranous nephropathy (IMN) patients. MethodsSerum samples from 448 patients with different types of nephropathy, including 222 with IMN, were tested using both methods. Sensitivity, specificity, and prognostic significance of PLA2R antibody levels were evaluated. ResultsSimilar sensitivity and specificity of ELISA and MP-CLIA in identifying IMN patients was found. However, MP-CLIA performed better than ELISA in predicting the prognosis of IMN patients. Adjusting the cutoff value reduced the false-negative rate in both methods. Logistic regression analysis identified six variables, including MP-CLIA-PLA2R levels, eGFR, lymphocyte count, B lymphocyte count, NK cell count, and complement 4, as predictors of renal function outcomes in IMN patients. ConclusionsBoth ELISA and MP-CLIA are reliable methods for detecting anti-PLA2R antibodies in IMN patients. However, MP-CLIA is more accurate in predicting the prognosis of IMN. Combining MP-CLIA-PLA2R with other variables can help predict renal function outcomes in IMN patients. Our study emphasizes the importance of considering both analytical performance and clinical utility when selecting a PLA2R antibody assay kit.

Anti-phospholipase A2 receptor positive membranous nephropathy: investigating the link between electron microscopy stages and clinical outcome

ABSTRACT This retrospective, observational study sought to examine the relationship between Ehrenreich-Churg electron microscopy (EM) stages and long-term outcomes in anti-PLA2R membranous nephropathy (MN). Seventy-one patients with anti-PLA2R MN (median titer 185.7RU/mL) were followed for a median of 46 months, with end-stage kidney disease (ESKD) as the primary endpoint, and response to treatment as a secondary endpoint. Patients were grouped into stages I-II (41 patients) and stages III-IV (30 patients) for analytical purposes. Notably, the III-IV group demonstrated a lower eGFR, lower anti-PLA2R titer, but a higher chronicity score. Kaplan-Meier analysis showed shorter mean kidney survival time in stages III-IV compared to I-II (p 0.03). However, multivariate analysis using Cox regression indicated that Ehrenreich-Churg stages did not significantly influence kidney survival, but lower eGFR at diagnosis and higher histopathological chronicity score did. Remission was achieved by 64% of patients and no relationship between Ehrenreich-Churg stages and treatment response was found. The only identified risk factor for not achieving remission was the severity of hyposerinemia at diagnosis. In conclusion, while EM stages III-IV are associated with more chronic lesions and stages I-II with more active immunologic disease, the histological chronicity score seems to be a stronger predictor of long-term outcomes.

Pharmacogenetic testing improves treatment responses in patients with PLA2R-related membranous nephropathy

To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients. A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment. Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05). Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.