Soler, María José

ABSTRACT C3 glomerulonephritis (C3GN) is a rare kidney disease driven by dysregulation of the alternative complement pathway. We report two challenging cases of patients with C3GN in whom various immunosuppressant therapies have failed to achieve complete remission, prompting treatment with eculizumab, an anti-C5 humanized monoclonal antibody that inhibits the terminal complement pathway. Although transient improvement in kidney function was observed, both patients eventually experienced worsening renal parameters, with increasing proteinuria and hematuria, culminating in progression to end-stage kidney disease. Repeated kidney biopsies following eculizumab therapy demonstrated persistent, granular mesangial and capillary wall C3 (3+) staining on immunofluorescence studies, indicating ongoing complement activation upstream of the C5 blockade and the perpetuation of C3 deposits in the glomeruli. These cases underscore the limited efficacy of terminal complement inhibition in halting disease progression in C3GN.

ABSTRACT Background Although kidney biopsy remains the gold standard for diagnosing immune checkpoint inhibitors–associated acute interstitial nephritis (ICI-AIN), several promising urinary biomarkers have emerged as potential non-invasive diagnostics. Notably, recent studies have highlighted tumor necrosis factor alpha (TNF-α), CXC motif chemokine ligand 9 (CXCL-9) and others as potential biomarkers to help distinguish ICI-AIN from other causes of acute kidney injury (AKI). However, a direct systematic comparison between these two biomarkers in a cohort of patients undergoing immunotherapy has not been performed. Methods We prospectively enrolled a cohort of ICI-treated cancer patients who developed AKI (including both ICI-AIN and ICI-Non-AIN AKI), as well as those without AKI, referred to as the internal validation cohort. Urinary CXCL-9 and TNF-α were measured across all groups using the human Quantikine ELISA Kit. We externally validated our findings in a cohort of biopsy proven ICI-AIN patients from Spain, referred to as the external validation cohort. Results Urinary CXCL-9 levels were significantly higher in ICI-AIN patients from Mayo (n = 40) compared with those with ICI-Non-AIN AKI (n = 36) and ICI-treated patients without AKI (n = 16) (both P ≤ .0001); these findings were confirmed in the validation cohort from Spain (n = 19) with P-values of .0008 and <.0001, respectively. The area under the curve (AUC) for urinary CXCL-9 distinguishing ICI-AIN biopsy proven (combined from both cohorts, n = 45) from ICI-Non-AIN AKI was 0.83 (95% confidence interval 0.74–0.92), while for urinary TNF-α the AUC was 0.63 (0.51–0.75). Conclusions Increased urinary CXCL-9 was superior to TNF-α as a biomarker for the non-invasive diagnosis of ICI-AIN, even after prior corticosteroid exposure, highlighting its promise as clinical diagnostic tool.

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 The impact of sex in the clinical presentation and outcomes of patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) has not been studied, particularly in patients with severe kidney involvement at presentation (eGFR < 15 ml/min/1.73 m2). Methods A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and eGFR<15 ml/min/1.73 m2 or end-stage kidney disease (ESKD) at presentation. Clinical presentation and renal outcomes were analyzed according to sex. Results We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR < 15 ml/min/1.7 3m2 at the time of diagnosis: 78 (47%) were females and 88 (53%) were males. Hypertension was more frequently present in males (85.2% vs 70.5%, P = .022). Median serum creatinine (SCr) was higher in males when compared with females [5.2 (IQR 4.2–7.4) vs 3.6 (IQR 2.8–5.1) mg/dl, P < .001]. Males started dialysis within 4 weeks more frequently than female (p = .003) although the median percentage of crescents was similar between groups (35.7% in males versus 36.4% in females, P = .0873). However, the rate of dialysis initiation or progression to ESKD in the first 12 months was not different between males (15, 62.5%) versus females (29, 61.7%) at 12 months. By multivariable logistic regression, factors related with dialysis initiation within the first 4 weeks in our cohort were SCr, alveolar hemorrhage, and PR3-ANCA adjusted for sex. Conclusion In our cohort, male patients presented with higher serum creatinine (SCr), and dialysis was started within the first 4 weeks more frequently (53.4% vs 30.7%). There were no differences in outcomes of kidney recovery, overall dialysis rates, and progression to ESKD within 12 months in patients with AAV-GN and eGFR < 15 ml/min/1.73 m2 between groups.

ABSTRACT Background Membranous nephropathy (MN) associated with phospholipase A2 receptor (PLA2R) antibodies is the most common cause of nephrotic syndrome in non-diabetic adult patients. This study investigated the relationship between clinical phenotypes and renal outcomes in this population, emphasizing the potential for phenotype-based treatment stratification. Methods We conducted a retrospective, multi-center cohort study of PLA2R-positive MN. Unsupervised cluster analysis grouped patients based on clinicopathological characteristics. Primary outcomes included complete or partial remission within 2 years of biopsy and end-stage kidney disease (ESKD) or death during follow-up. Results Among 178 patients, three distinct clusters emerged (n = 89, 70, and 19). Within 2 years of biopsy, 102 patients (57%) achieved complete or partial remission. Cluster 1, characterized by the mildest disease markers, including the lowest body mass index, serum anti-PLA2R titer, serum creatinine, proteinuria, and triglycerides, had the highest remission rate of 72%, compared with 50% in cluster 2 and 54% in cluster 3. Cluster 2 had significantly lower remission compared to cluster 1 (HR 0.64, 95% CI 0.42–0.96, P = .03); results were similar in cluster 3, albeit not statistically significant (HR 0.50, 95% CI 0.23–1.09, P = .08). Elevated anti-PLA2R levels (>100 U/ml) and proteinuria (>8 g/24-hour) predicted reduced remission (HR 0.56, 95% CI 0.36–0.88, P = .01; HR 0.43, 95% CI 0.26–0.73, P = .002, respectively), while high high-density lipoprotein levels were protective (HR 1.01, 95% CI 1.00–1.02, P = .048). Overall, 21 patients (12%) developed ESKD or died. ESKD-free survival differed significantly across clusters (log-rank test P = .04). Conclusions Unsupervised clustering identified distinct clinical phenotypes in PLA2R-positive MN, each associated with different renal prognoses. Phenotype-based risk stratification could enhance treatment precision, improve patient outcomes, and potentially reduce treatment-related adverse effects.