Fervenza, Fernando C

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 We describe a case of immunoglobulin A nephropathy (IgAN) treated with targeted-release budesonide (Nefecon) that resulted in notable systemic adverse effects. The patient developed cushingoid features, weight gain, hyperglycaemia and leucocytosis within 3 months of therapy. During dose tapering he experienced symptomatic adrenal insufficiency confirmed by low morning cortisol, requiring hydrocortisone replacement. Despite Nefecon’s design for terminal ileum absorption, and hence assumed minimal systemic exposure, this case demonstrates clinically significant adverse effects and adrenal suppression. These findings underscore the need for careful monitoring and patient education when initiating and tapering Nefecon in IgAN management.

Key Points Baseline kidney function and chronic structural injury strongly predicted both renal recovery and long-term clinical outcomes. Tubulointerstitial nephritis was the predominant lesion in Sjögren syndrome with renal involvement. Early detection and management of renal involvement in Sjögren syndrome are critical to preventing irreversible kidney damage. Background Renal involvement in primary Sjögren syndrome (SS) is uncommon but clinically consequential. Previous studies have been limited by small samples and incomplete biopsy data. We evaluated a large biopsy-confirmed cohort to characterize clinicopathologic features of SS with renal involvement and identify predictors of renal recovery and long-term outcomes. Methods We retrospectively identified adults with SS and kidney biopsy at Mayo Clinic (2012–2025). Clinical, laboratory, and histologic data were extracted. Predictors of complete renal recovery within 6 months, defined as serum creatinine (sCr) returning to within 25% of baseline or <1.4 mg/dl if baseline was unknown, were evaluated using logistic regression. Cox regression assessed long-term risk of a composite end point: newly developed or progressive CKD, ESKD, or all-cause mortality. Results Fifty-six patients were included (median age 57 years; 91% female). Extraglandular manifestations occurred in 76% and baseline CKD in 65%. The median sCr at baseline and biopsy was 1.3 and 1.6 mg/dl, respectively. Anti-Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein was positive in 80%. Low C3 occurred in 14% and low C4 in 25%. Tubulointerstitial nephritis was the predominant lesion (71%). Moderate/severe interstitial fibrosis/tubular atrophy and arteriosclerosis were present in 36% and 41%, respectively. Immunosuppressive therapy was applied in 84%. Complete recovery occurred in 67%. Over a median 3.9 years (interquartile range, 1.4–7.2), 43% reached the composite end point. Baseline sCr ≥2 mg/dl, 24-hour proteinuria ≥1 g, and presence of segmental glomerulosclerosis were associated with lower odds of recovery (odds ratio=0.16, 0.13 and 0.11, P = 0.02, 0.001 and 0.008, respectively) and higher long-term risk (hazard ratio=4.51, 2.92 and 3.52; P = 0.002, 0.01 and 0.02, respectively). Moderate/severe arteriosclerosis also increased long-term risk (hazard ratio=2.56; P = 0.03). Conclusions In biopsy-confirmed SS-related renal involvement, the severity of kidney dysfunction and the extent of chronic glomerular and vascular injury strongly predict renal prognosis. Early detection and targeted management of high-risk features may improve long-term renal outcomes.

ABSTRACT Immunoglobulin A nephropathy (IgAN) is an immune-mediated disease of B-cell origin and the most common primary glomerulonephritis worldwide, which often progresses to kidney failure within 10–20 years of diagnosis. Microscopic hematuria is frequently observed in IgAN; it is thought to result from damage to the glomerular filtration barrier caused by pathogenic immune complex deposits, allowing red blood cells to leak into the urinary space. Emerging evidence suggests that microscopic hematuria in IgAN may be linked to active glomerular inflammation, poorer disease prognosis and progressive kidney function decline. Despite this, it remains an underutilized biomarker for IgAN because of a lack of standardization (which can lead to preanalytical errors), challenging logistical considerations in large multicenter trials and non-glomerular hematuria as a confounding factor. The “proteinuria-centric” approach by the nephrology community may overlook that active forms of glomerulonephritis manifest with both proteinuria and hematuria, in contrast to primary podocytopathies where proteinuria is the main feature. When properly assessed, microscopic hematuria is a prognostically relevant biomarker in IgAN that may improve risk stratification and assessment of therapeutic response when evaluated alongside traditional biomarkers. This review evaluates the methods of assessment, pathophysiology and clinical utility of microscopic hematuria in IgAN.

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 &gt;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 &lt; .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 &lt;25 kg/m2, which contrasts with the significant proteinuria reduction in overweight and obese patients with glomerulopathies.

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.

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 &lt; 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&lt;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 &lt; 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 &lt; .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 &lt; 15 ml/min/1.73 m2 between groups.