Clinical significance of IgM and C3 deposition in children with primary immunoglobulin A nephropathy

Xiong, Limei; Liu, Li‐Li; Tao, Yuhong; Hui, Guo

doi:10.1007/s40620-023-01724-7

Cited by 7 publications

(3 citation statements)

References 26 publications

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“…Furthermore, both C3 and C4 levels were found to be negatively correlated with serum IgM, pointing a role for IgM that deserves to be further investigation. This observation aligns with a recent study on 116 pediatric IgAN patients, which showed that mesangial IgM deposition at biopsy seems to be an independent risk factor for poor renal prognosis 45 .…”

Section: Discussionsupporting

confidence: 92%

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

Tringali,

Vetrano,

Tondolo

et al. 2024

Sci Rep

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IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.

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Section: Discussionsupporting

confidence: 92%

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

Tringali,

Vetrano,

Tondolo

et al. 2024

Sci Rep

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“…In this study, we have demonstrated that mesangial IgM deposition is an independent risk factor for ESKD in patients with IgAN. Mesangial IgM deposition has been reported in varying frequencies, ranging from 22 to 70% in previous studies, and similarly, in our cohort, IgM was present in 70% of the patients [ 10–12 , 19 ]. Our study indicates that despite the usual association of IgM deposition in segmental sclerosis with a higher grade of chronicity in the kidney, we did not observe a relationship between the presence or intensity of mesangial IgM deposits and the Oxford MEST-C classes.…”

Section: Discussionsupporting

confidence: 86%

Prognostic role of mesangial IgM deposition in IgA nephropathy: a long-term cohort study

Stefan,

Stancu,

Zugravu

et al. 2024

Renal Failure

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Background The clinical significance of mesangial immunoglobulin (Ig) M deposition in IgA nephropathy (IgAN) has been less explored and remains a topic of debate. Therefore, our study aimed to investigate the prognostic value of mesangial IgM deposition in a long-term follow-up cohort of IgAN patients. Methods A unicentric retrospective study was conducted on 93 consecutive IgAN patients (median age 41 years, 68% male, eGFR 48.7 mL/min, proteinuria 1.1 g/g) from 2010 to 2015. They were followed until end-stage kidney disease (ESKD), death, or until the end of the study in January 2021, with a median follow-up of 7 years. An independent pathologist evaluated the IgM immunofluorescence pattern, Oxford MEST-C score, and transmission electron microscopy (TEM) lesions following a comprehensive protocol. Results In our cohort, 70% had mesangial IgM-positive deposits, while 30% were IgM-negative. Both groups were similar in age, sex, prevalence of arterial hypertension, Charlson comorbidity scores, kidney function (eGFR and proteinuria), pathology findings (Oxford MEST-C score, IgG and C3 immune deposition), and TEM analysis. Treatment with RASI and immunosuppression, and death rates were also comparable. However, 37% of IgM-positive patients progressed to ESKD, significantly higher than the 11% in the IgM-negative group. Univariate and multivariate Cox proportional hazards regression analyses identified lower eGFR, higher Oxford MEST-C score, and mesangial IgM deposits as independent factors associated with shorter kidney survival. Conclusions Our study highlights mesangial IgM deposition as a potential risk factor for ESKD in patients with advanced IgAN, laying a foundation for further research in this area.

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“…In order to assess possible relationship between serum complement and other baseline variables linear regression was performed, highlighting a positive correlation between C3 and C4 as previously described by Bi et colleagues, supporting the hypothesis of systemic complement consumption in complement-driven IgAN [13]. Furthermore, both C3 and C4 levels were found negatively correlated with serum IgM, pointing to a role for IgM that deserves to be further elucidated in future, as recently studied in a cohort of 116 pediatric patients by Xiong et al were mesangial IgM deposition has been found an independent risk factor for poor renal prognosis [45].…”

Section: Discussionsupporting

confidence: 81%

#1486 Looking for a new role of known players: the additional value of plasmatic C3 and C4 in predicting IgA Nephropathy prognosis, an observational study

Tringali,

Vetrano,

Tondolo

et al. 2024

Nephrology Dialysis Transplantation

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Background and Aims IgA Nephropathy (IgAN) is the most common glomerular disease worldwide [1]. Complement system activation through the alternative and lectin pathways is crucial in its pathogenesis and leads to worse outcome, eliciting the need for (new) biomarkers to assess risk of disease progression and potential response to new targeted treatments [2, 3]. Only few works have correlated serum C3 and C4 with disease activity and prognosis [4, 5]. Our work explores the potential advantages of incorporating serum C3 and C4 levels into a standardized prognostic model to assess kidney outcome in IgAN. Method This retrospective study, conducted at Sant'Orsola University Hospital in Bologna, investigated the prognostic value of serum complement C3 and C4 in patients with IgAN. The primary outcome was defined as a 40% decline in eGFR or the onset of kidney failure. The study aimed to evaluate whether the addition of serum C3 and C4 to an established predictive model, incorporating variables from the International IgA Prediction Tool (IntIgAPT), enhances the accuracy of outcome prediction. We computed the measures of goodness of fit for each model: Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), Nagelkerke R2 test (NR2) that depicts the% explained variation of the outcome based on the set of variables included, and Likelihood Ratio Test (LRT); discrimination with the c-index. Furthermore, we aimed to evaluate the characteristics of patients stratified by baseline serum C3 levels (Low <90 mg/dl, Medium 90-140 mg/dl, High >140 mg/dl). Results 101 patients were included in the cohort. 90% were Caucasian and 65.3% were male with a mean age of 42.6 years. As reported in Table 1, mean eGFR and median proteinuria levels at baseline were 70.4 ml/min/1.73 m² and 1.04 g/24 h respectively. Mean serum C3 was 114.9 mg/dL. The Low group had lower values of eGFR at baseline (47.0 vs 75.67 and 68.64 ml/min/1.73 m², p = 0.015), while the Medium group had lower values of uProt (0.75 vs 1.81 and 1.46 g/24 h, p = 0.004). During a median 54.28 months follow-up, the Low group exhibited significantly higher primary outcome incidence (16.3 events vs 2.9 and 1.7 events x 100 pts/year, p = 0.003). We computed a first model (M1) based upon IntIgAPT variables and then a second model (M2) as the same of M1 plus serum C3 and C4 at baseline (Table 2). C3 showed a negative association with outcome (OR 0.88, CI 0.78 to 0.99, p = 0.05) whereas C4 had a positive one (OR 1.21, CI 1.02 to 1.48, p = 0.05). M2 had an improved prediction accuracy than M1, as evidenced by lower AIC (49.1 vs 53.8), higher c-index (0.74 vs 0.65), and NR2 (0.76 vs 0.65). Likelihood ratio test was significant between the two (p = 0.008). Conclusion The inclusion of serum C3 and C4 in a validated prognostic model enhances prediction accuracy and improves the percentage of events explained, highlighting complement's inherent informativeness. In our population lower C3 and higher C4 levels were associated with poorer prognosis in IgAN, characterizing a more ‘Complement-Pathic’ subset of patients. This result expands the current evidence, for the first time to our knowledge, in a Caucasian-prevalent study population.

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Clinical significance of IgM and C3 deposition in children with primary immunoglobulin A nephropathy

Cited by 7 publications

References 26 publications

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

Prognostic role of mesangial IgM deposition in IgA nephropathy: a long-term cohort study

#1486 Looking for a new role of known players: the additional value of plasmatic C3 and C4 in predicting IgA Nephropathy prognosis, an observational study

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