Vargas-Brochero, Maria J.

Abstract Background and Aims Malignancy is commonly seen in patients with membranous Nephropathy (MN) with a prevalence up to 22%. M-type phospholipase A2 receptor (PLA2R) antigen and its associated antibody account for up to 80% of the cases but its association with malignancy is less clear. To date, no study has specifically evaluated cancer incidence and risk factors in patients with PLA2R associated MN as most studies were conducted in an era before many MN antigens were identified. Here, we report cancer incidence, types of cancer, and effect of immunosuppressive therapy and clinical parameters in a cohort of patients with PLA2R-associated MN. Method A single center retrospective cohort study in adults with diagnosis of PLA2R associated MN from 1/1/1996 to 12/31/2021. Follow-up was defined as the time from MN diagnosis to the last follow-up or if the patient initiated dialysis or underwent transplantation. The primary outcome in this study was the incidence of cancer events reported as cancer incidence/1000 patients/year. The cancer events were compared to the age-adjusted United States (U.S.) general population using Centers for Disease Control (C.D.C) data. The standardized incidence ratio (SIR) was calculated by dividing the cancer rates in our cohort to the cancer rates in general population. Time-to-event analysis was conducted using the Kaplan-Meier method. The log-rank test compared age, sex, smoking habits, hypertension, diabetes, body mass index (BMI), previous immunosuppression (IS), remission of the MN, PLA2R titers at the time of diagnosis. Cox proportional hazards regression was used to evaluate the associations between baseline characteristics and cancer incidence. For the multivariate model of cancer incidence, we evaluated variables clinically relevant for the outcome. Results We identified 239 patients with PLA2R-associated MN, with mean (±SD) age of 52 (±13) years, with 72.8% male (n = 174), median [IQR] BMI of 29.8 [26.3, 33.6] kg/m2, median eGFR of 68 [45, 94] ml/min, median proteinuria of 8.2 [5.1, 11.2] g/24h, and median PLA2R titers of 38 [9, 122] RU/ml. Common comorbidities included hypertension (60.2%), and diabetes (17.1%). Majority of patients drank alcohol (90.7%) and 32.6% were smokers (active or former). Of 239 patients, 15 had a history of cancer before the MN diagnosis. But in all these patients, cancer had been treated and was considered to be in full remission. A diagnosis of cancer was made in 37 patients (15.4%) during a median follow-up of 60 [27.5, 145.5] months. Incidence of cancer in our cohort was 22.6 [95% CI, 15.9 to 31.1] per 1000 persons/year. In comparison, age adjusted U.S. general population has a lower cancer incidence of 15.9 [95% CI, 15.9 to 16.1] cases per 1000 person/year. The resulting SIR of cancer in our cohort was 1.42. This SIR is lower than the one reported by Bjørneklett and al. (2007) in a Norwegian cohort that included all patients with MN and was not limited to PLA2R-positive MN. The cumulative incidence of cancer diagnosis is shown in Fig. 1. Mean age at cancer diagnosis was 66 (±10.2) years old. Prostate cancer was the most common (n = 11) type of cancer, followed by skin cancer (n = 9), followed by cancer of the urinary tract (n = 5). In univariate and multivariate analysis (Table 1), only older age (>65 years) and tobacco use were associated with statistically significant increased risk of cancer. Other clinical parameters such as sex, eGFR, baseline proteinuria, BMI, hypertension, diabetes, alcohol use, anti-PLA2R antibody titer, type of immunosuppression, remission status (partial, complete, no response) were not associated with a significant increased risk of cancer. Conclusion Patients with PLA2R associated MN are at increased risk of developing cancer following diagnosis compared to general population and routine age-appropriate cancer screening in this population is essential. The increased incidence of cancer is independent of IS therapy, response to therapy or other comorbidities. These data suggests that there are likely mechanisms beyond the traditional risk factors at play that may be unique to the presence of PLA2R antibodies.

Abstract Background and Aims Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are emerging as an essential part of the new standard of care for proteinuria, alongside renin-angiotensin system (RAS) inhibitors in patients with proteinuric chronic kidney disease (CKD). Subgroup analysis of EMPA-KIDNEY and DAPA-CKD trials done in patients with glomerular diseases [IgA Nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS)] showed these agents are less effective in reducing proteinuria compared to other agents like Sparsentan, or Double RAS Blockade. Also, the antiproteinuric effects of SGLT2i in patients with glomerular diseases is not well understood. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2i in non-diabetic patients with glomerular diseases. Method Single-center retrospective cohort study. Inclusion criteria (1) adult patients with a biopsy-proven glomerular disease or genetic diagnosis [i.e., Collagen IV mutations] from January 1st, 2019, to December 31st, 2023, (2) no Diabetes Mellitus, (3) proteinuria more than 0.75 g/24 h at the time of initiation of treatment despite optimized blood pressure control with renin-angiotensin system (RAS) inhibition at maximum tolerated dose (5) no concomitant use of induction immunosuppression therapy—stable maintenance immunosuppression was allowed. Patients with active neoplasia, no follow-up available after initiation of therapy or kidney transplant were excluded. Baseline was defined as the time of the initiation of SGLT2i. Laboratory values, including proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR), were obtained at baseline and 6 months. Changes in laboratory values over time were analyzed using the paired t-test and the signed-rank test, depending on the distribution. Weight status was classified based on BMI in three categories: regular (BMI < 25 kg/m2), overweight (25–29.9 kg/m2), and obese (>30 kg/m2). Results We identified 115 non-diabetic patients with glomerular diseases. Median age [IQR] at the time of SGLT2i initiation was 49.1 [35.4, 61.5] years; 74 (64.3%) patients were male, and 96 (83.5%) patients were white, with the second most common ethnicity being Asian with 10 (8.7%) patients. Median BMI for the entire cohort was 28.2 [26.0, 33.1] Kg/m2. Fifty-three (46.1%) patients had IgAN, 22 (19.1%) had secondary FSGS (sFSGS), 3 (2.6%) primary FSGS (pFSGS), and 12 (10.4%) genetic FSGS (gFSGS), with collagen IV mutations as the most common cause of gFSGS. Kidney function and proteinuria over time are presented in Table 1. Significant declines in eGFR [−1.77 ml/min/1.73m2 95% CI: (−4.2, −1.19)] and proteinuria [−0.58 g/24h 95% CI (−0.91, −0.44)] were observed at 6 months in the entire cohort compared to baseline. However, in the subgroup analysis by BMI strata, i.e., <25, 25-29.9, ≥30, the reduction in proteinuria was statistically significant only in overweight and obese patients. The expected early drop in eGFR was not observed in patients with a normal BMI. However, the decline in eGFR progressively increased and was statistically significant in the obese group (Fig. 1). Conclusion The principal finding of the present study is the lack of significant proteinuria reduction in patients with BMI<25 kg/m², which contrasts with the significant reductions observed in overweight and obese patients. SGLT2i's main antiproteinuric mechanism of action involves reducing glomerular hyperfiltration, which is commonly seen in patients with diabetes and obesity. In non-diabetic patients with glomerulopathies, proteinuria may be sustained by mechanisms not dependent on glomerular hyperfiltration, especially in those patients with normal BMI. These findings are crucial to advocate a personalized approach to treatment, challenging the “one-size-fits-all” strategy.

ABSTRACT Background Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are emerging as an essential part of the standard of care for proteinuria in patients with chronic kidney disease. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2is. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2is in non-diabetic patients with glomerular diseases. Methods This is a retrospective, multicentre, international observational cohort study that included non-diabetic patients with biopsy-proven glomerular disease and proteinuria >0.5 g/24 h who received SGLT2is between 2016 and 2023. Laboratory values, including proteinuria and estimated glomerular filtration rate (eGFR), were obtained at baseline and after 3–6 months. Changes in laboratory values over time were analysed using the paired signed-rank test. Results A total of 300 patients met the inclusion criteria. The median age was 51.82 years [interquartile range (IQR) 41–62.65], 64.7% were male and 92.7% were white. The most common glomerular disease was immunoglobulin A nephropathy (40.3%). The median eGFR was 52.26 ml/min/1.73 m2 (IQR 36.41–74.01), the median proteinuria was 1.60 g/24 h (IQR 1.15–2.91) and the median serum albumin was 4.08 g/dl (IQR 3.80–4.30). Proteinuria reduction after SGLT2i initiation was significant only in overweight and obese patients (P < .001 versus 0.18). Patients with normal BMI did not experience the expected early decrease in eGFR (P = .16). Conclusions SGLT2is are ineffective in proteinuria reduction in patients with a BMI <25 kg/m2, which contrasts with the significant proteinuria reduction in overweight and obese patients with glomerulopathies.

ABSTRACT Background Up to 20% of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) and kidney involvement progress to end-stage kidney disease (ESKD) despite therapy. The role of monoclonal gammopathy (MG) in disease progression in patients with AAV is not well understood. Methods We conducted a retrospective study to identify patients diagnosed with AAV and renal involvement who had undergone monoclonal protein testing between November 1999 and December 2023. A total of 167 patients were included in the renal survival analysis and were categorized into monoclonal positive (n = 34) and monoclonal negative (n = 133) groups. For the mortality analysis, we expanded the cohort to include an additional 26 patients who were dialysis-dependent at baseline and remained on dialysis throughout follow-up, resulting in a total of 193 patients. We performed multivariate Cox analysis to identify predictors of adverse renal events [>40% decline in estimated glomerular filtration rate (eGFR) or ESKD (eGFR <15 mL/min/1.73 m², need for dialysis or transplantation)] and mortality. Results Median age of the cohort was 68 (58.5–74.5) years, with 50.8% males, 65.8% MPO positive, and 64.6% receiving rituximab as induction therapy. After adjusting for baseline proteinuria, sclerotic Berden class and induction therapy, MG was associated with adverse renal events [hazard ratio (HR) 3.29 (95% confidence interval 1.12–9.68), P = .03]. MG at baseline was not associated with mortality [HR 1.65 (0.87–3.12), P = .12], however patients with persistent MG at 6 months had higher mortality compared with those without MG or those whose MG was not sustained [HR 3.95 (1.10–14.21), P = .035]. Conclusions Patients with AAV and renal involvement who have MG are at significantly increased risk of adverse renal events even after adjusting for factors such as eGFR and degree of chronicity (known predictors of poor renal outcome). The exact mechanism by which MG portends poor outcomes is poorly understood, and additional research is required.

Key Points Our study found a high prevalence of monoclonal gammopathy (MG) in patients diagnosed with ANCA-negative pauci-immune crescentic GN. Patients with MG showed a higher degree of fibrosis on kidney biopsy than those without MG with higher mortality rate. Our data suggest an association between MG and ANCA-negative pauci-immune crescentic GN, emphasizing this population's need for MG testing and monitoring. Background In a small subset of patients with pauci-immune crescentic GN (PICGN), ANCA are not identified, and patients are referred to as having ANCA-negative vasculitis. The cause of the disease in this subset of patients has remained elusive. We explored the role of monoclonal gammopathy (MG) in those with ANCA-negative PICGN. Methods We conducted a retrospective study and identified patients with PICGN who had undergone ANCA and monoclonal testing. Those positive for ANCA were excluded. Results We identified 14 patients with ANCA-negative vasculitis, of whom eight (57%) tested positive for MG with a mean age of 60.3±12.2 years, 75% were female, and with a mean serum creatinine of 4.3±1.92 mg/dl. The most common monoclonal proteins were IgG ( n =4, 50%) and kappa ( n =4, 50%). One patient had diagnosis of multiple myeloma. Most common extra-renal manifestations were skin rash (leukocytoclastic vasculitis) and neuropathy. Kidney biopsy showed a higher degree of interstitial fibrosis and tubular atrophy compared with those without MG. The median follow-up time was 3.2 years, with 50% mortality in those with MG. Conclusions More than 50% of the patients with ANCA-negative PICGN have MG, and patients present with more evidence of fibrosis on kidney biopsy, with higher mortality rate observed in our cohort. Monoclonal proteins may trigger the development of PICGN; their specific role in the pathogenesis of this disease needs further investigation.