A multicenter observational study on predictive factors of immunosuppressive therapy efficacy in membranous nephropathy

Background and Aims: The attempt to identify the most suitable therapies and their appropriate dose is at the base of tailored medicine approach. We decided to analyze the renal outcomes of patients affected by primary membranous nephropathy (MN) referring to University Hospital G. Martino in Messina (Italy) Spedali Civili in Brescia (Italy), from January 2005 to December 2020, treated with conservative or immunosuppressive therapy, searching for any predictive factor of therapeutic response. Method: We performed a retrospective analysis of 87 MN patients (M 28, F 59), checking anti PLA2R status, kidney biopsy and comorbidities. All patients underwent a quarterly control for 1 year, evaluating blood pressure, body mass index (BMI), biochemistry, urinalysis and 24h proteinuria. Variables distribution was evaluated with Kolgomorov-Smirnov test and data expressed as median [IQR range] or mean ± SD. Basal features were analyzed with T-student test for independent variables, Mann-Whitney test for continue variables, and Pearson’s Chi-Square analysis for dummy variables. Trend analysis were computed with a Linear Mixed Model for repeated analysis. Results: We performed 435 repeated measurement, with mean age at diagnosis of 54±18 years-old; median eGFR an proteinuria were, respectively, 75 ml/min/1.73m2 [IQR 51-104 ml/min/1.73m2] and 4.9 g/day [IQR 2.4-8.0 g/day]. We divided the patients according to their basal proteinuria/BMI ratio being lower or higher than the whole cohort median value. Significant association were found between the proteinuria/BMI ratio and sex (Rho= -0.23, P=0.06), baseline serum albumin (Rho: -0.68, P<0.01). Prevalence of hypertension (30% vs 16%, P=0.23), higher levels of LDL-c (174±64 mg/dl vs 159±61 mg/dl, P=0.55) and triglycerides (190±123 mg/dl vs 181±85 mg/dl, P=0.76) in the subgroup with lower proteinuria/BMI ratio represented a trend without reaching a statistical significance. The unadjusted model proved a negative association in longitudinal follow-up between eGFR and both proteinuria/BMI ratio (β:-9.05, P=0.07, 95% CI:-18.85/-0.76), confirmed in the adjusted model (β:-11.57, P=0.04, 95% CI=-22.96/-0.19). Age was related to a reduction of eGFR (adjβ:-0.99, 95%CI: -1.29/-0.70, P=0.001), as well as the conservative treatment compared to Ponticelli regimen (adjβ:-8.52, 95%CI -17.43/0.38, P=0.06). Conclusion: According to a registry study Yonekura et al, a higher BSA increases the podocytes’ damage and consequently accelerated disease progression, with particular impact on MN and minimal change disease patients. Increased fat mass stimulates mesangial expression, elevating kidney metabolic request and promoting hyperfiltration. Moreover dyslipidemia results in lipotoxicity, stimulating tubular epithelial cell apoptosis and progressive tubulointerstitial fibrosis. In our analysis, patients treated exclusively with optimized conservative approach (RAASi at maximum tolerated dose) experienced a higher eGFR slope during follow-up compared to patients treated with Ponticelli regimen, despite being classified as low-risk. Conversely, no differences in efficacy were found between Ponticelli regimen and rituximab, as it is actually stated by literature. We analyzed the proteinuria/BMI ratio in the three group of patients undergoing each treatment, and patients with supportive therapy had a lower proteinuria/BMI ratio than the other two groups, without significant differences in BMI. This result allows us to speculate that the amount of proteinuria should also be related to BMI to better stratify the risk of disease progression. Although larger studies are needed and should be encouraged to confirm our results, we can speculate that the proteinuria/BMI ratio, which can be considered as the proteinuria for each unit of BMI, impairs per se renal outcomes, as well as higher BMI levels up to obesity are associated with elevated risk for renal function loss over time when longitudinally evaluated.