INTRODUCTION:The number of kidney biopsies performed in patients with diabetes has increased rapidly over the last two decades. However, the overall value of the biopsy has been questioned because any coexisting non-diabetic kidney disease (NDKD) is not identified in many patients. Here, we quantify the frequency of identifying NDKD and examine clinical indications, demographic factors, and histologic parameters that increase the odds of finding NDKD and the impact on developing end stage kidney disease. METHODS:A retrospective analysis of clinical and pathologic parameters of 49,075 biopsied patients with diabetes with and without diabetic nephropathy (DN) from 2001-2024 was performed. Data from the United States Renal Data Service were examined to determine the impact of a NDKD on disease progression to end stage kidney disease. RESULTS:NDKD was found in 58.8% of patients with diabetes who underwent kidney biopsy, including 35.9% without concurrent DN and 22.9% as a second diagnosis in DN. Acute kidney injury and acute nephritic syndrome had greater odds of a NDKD diagnosis in patients with DN. The youngest (under 30 years) and oldest (60 years and older) patients had a higher prevalence of NDKD. Higher chronicity on biopsy was associated with a lower prevalence of NDKD diagnosis. Patients with NDKD were 2.56-fold less likely to develop end stage kidney disease compared to patients with DN alone. CONCLUSIONS:This is the largest analysis examining prevalence of a NDKD in patients with diabetes and the impact of biopsy indication on finding a second diagnosis in biopsy-proven DN. The objective is to provide nephrologists with guidance in when to perform a biopsy based on the odds of finding a NDKD related to the patient's clinical indication. Given the high prevalence of NDKD, our study shows that kidney biopsy remains a critical tool in the care of diabetic patients.

ABSTRACT Introduction C3 glomerulopathy (C3G) is driven by fluid-phase alternative complement pathway dysregulation, with emerging evidence linking glomerular neutrophil infiltration to disease severity. Neutrophil extracellular traps (NETs) are implicated in other forms of glomerulonephritis. However, their participation in the pathogenesis of C3G remains undefined. Methods Kidney biopsies from 33 patients with C3G (15 with dense deposit disease [DDD] and 18 with C3 glomerulonephritis [C3GN]) were compared with 15 anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) biopsies as a neutrophil-rich disease control in this retrospective cross-sectional study. Glomerular neutrophils and NETs were identified using immunofluorescence, staining for myeloperoxidase, citrullinated histone H3, peptidyl arginine deiminase-4, and DNA. Supervised machine learning was used to quantify glomerular NET formation, and the data were correlated with kidney function at time of biopsy using linear regression. Results Intraglomerular NETs were abundant and detected in the majority of glomeruli in C3G biopsies. Compared with AAV, C3G showed a significantly higher fraction of neutrophils forming NETs, despite similar neutrophil counts per glomerulus. NET abundance was similar in DDD and C3GN. In exploratory analyses, a greater proportion of glomeruli containing NETs was associated with lower kidney function (estimated glomerular filtration rate) at biopsy, and this association remained significant after adjustment for age, C3G subtype, and interstitial fibrosis. Conclusions These observations demonstrate that intraglomerular NETs are a common and prominent observation in C3G and are associated with reduced kidney function at biopsy. These findings raise the possibility that NET deposition in glomeruli is a previously unrecognized driver of glomerular injury in C3G. TRANSLATIONAL STATEMENT Targeted complement inhibitors have expanded treatment options for C3 glomerulopathy, but treatment responses remain incomplete and the cellular processes accompanying active intrarenal injury remain incompletely defined. We examined renal biopsies of C3G patients for neutrophil infiltration / recruitment and release of neutrophil extracellular traps (NETs) and found that these structures were highly abundant in glomeruli. Greater glomerular NET burden was associated with lower estimated glomerular filtration rate at biopsy. Our observations identify NETs as a candidate component of the pathogenesis of glomerular pathology in C3G and support the investigation of NET-targeting interventions in addition to complement inhibition in C3G patients.

C3 glomerulopathy-primary immune complex membranoproliferative glomerulonephritis (C3G/IC-MPGN) is an ultrarare disease spectrum associated with a significant health burden and for which there is a huge unmet need for safe and effective treatment. The underlying pathophysiology is dysregulation and overactivation of the alternative complement pathway. Two new therapeutic agents, iptacoplan and pegcetacoplan, that target proximal steps in the cascade, have demonstrated to be effective and have been approved for use in patients with C3G alone and with C3G/IC-MPGN, respectively. A key challenge to the nephrology community is how to incorporate these disease-modifying drugs into clinical practice in a timely and equitable manner. This report summarizes the deliberations and recommendations that emerged from the SEISMIC (Addressing access issues in diagnosis and treatment of C3G nephropathy and IC-MPGN) summit in July 2025. The meeting assembled a broad panel of experts and patients and addressed the following three aims: 1) define issues in proper and timely diagnosis of this complex disease spectrum, 2) assess management strategies in light of the availability of this new class of therapeutic agents, and 3) identify barriers to access to care and treatment with these new therapeutic agents and design strategies to surmount them.

Aims C3 glomerulopathy (C3G) and primary immune complex-membranoproliferative glomerulonephritis (IC-MPGN) are complement-mediated diseases driven by C3 dysregulation with excessive accumulation of C3 breakdown products in the kidney. Pegcetacoplan (PEG) a C3/C3b inhibitor, targets the central components of the complement pathway, directly inhibiting C3 overactivation and preventing further deposition of C3 breakdown products in the glomeruli. VALIANT (NCT05067127) is the first Phase 3 trial investigating PEG in a broad cohort, including adolescents (≥12 yrs) and adults with native or post-transplant recurrent C3G or primary IC-MPGN. Methods: VALIANT is a randomized, multicenter, double-blind, placebo (PBO)-controlled trial evaluating PEG efficacy and safety. 124 pts were randomized to PEG (n = 63) (twice weekly subcutaneous infusion) or PBO (n = 61) for 26 weeks (wks). The primary endpoint was log-transformed UPCR ratio at wk 26 vs baseline, assessing proteinuria reduction vs PBO. Key secondary endpoints at wk 26 were a composite renal endpoint (proportion of pts achieving ≥50% UPCR and ≤15% eGFR decline), proportion of patients achieving ≥50% UPCR reduction, C3G histologic index activity score change (adjusted LS mean change), reduced C3c renal biopsy staining of ≥2 OOM, eGFR change, (LS mean change), mL/min/1.73 m2. Safety was assessed by treatment-emergent adverse events (TEAE) frequency and severity. Results: The primary endpoint was met, with PEG demonstrating a 68.1% (95% CI: –76.2, –57.3) mean UPCR reduction vs. PBO at wk 26 (p < 0.0001). Results were consistent across disease type, age, and transplant status subgroups. PEG also led to robust reductions in C3c staining and clinically meaningful eGFR stabilization vs PBO. Treatment-emergent AE frequency and severity were similar between arms. None of the 4 serious infections (3 PEG; 1 PBO) were attributed to encapsulated bacteria. Conclusion: PEG is the first therapy to achieve significant and clinically meaningful reductions in proteinuria (68.1% vs. PBO), C3c staining and eGFR stabilization in pts ≥12 yrs with C3G or primary IC-MPGN. PEG was well tolerated with no new safety signals observed.

BACKGROUND:C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear. METHODS:We conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline. RESULTS:A total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, -67.2% [95% confidence interval {CI}, -74.9 to -57.2] vs. 2.9% [95% CI, -8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred. CONCLUSIONS:Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.).

Diabetic kidney disease (DKD) is the leading cause of progressive chronic kidney disease in adults in the United States. However, the impact of preterm birth on the progression of DKD has not been studied. The goal of this project was to determine the effect of preterm birth on kidney health after exposure to hyperglycemia. CD-1 pups born preterm (19 days post conception (dpc)) and term (20 dpc) were studied, and outcomes of the male mice were reported. Preterm and term mice were treated with streptozotocin at six weeks to induce hyperglycemia. Body weight and blood sugar were monitored. Histologic, molecular, and imaging techniques were used to characterize the mice at 18 weeks. The preterm mice with diabetes had a lower podocyte density, lower proximal tubular fraction, and more atubular glomeruli compared to the term mice without diabetes. The preterm mice with diabetes also had a lower podocyte density and lower renin expression compared to term mice with diabetes. Based on single-cell RNA sequencing, the preterm mice with diabetes had increased expression of genes related to the angiogenesis migration pathway-related in endothelial cells and increased expression of genes in the actin adhesion pathway in podocytes compared to term mice with diabetes. Furthermore, the preterm mice with diabetes exhibited a weaker endothelial cell-podocyte interaction compared to term mice with diabetes. These data suggest that preterm birth increases susceptibility to glomerular and tubular damage after a brief "second hit" of hyperglycemia. In conclusion, preterm birth disrupts endothelial-podocyte crosstalk and increases susceptibility to kidney injury induced by hyperglycemia.

Introduction:Complement 3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) have high risks for disease recurrence and allograft loss in transplant kidneys. Pegcetacoplan (targeted complement 3 [C3]/C3b inhibitor) may prevent excessive deposition of C3 and complement 5 [C5] breakdown products and associated renal damage. Methods:NOBLE (NCT04572854) is a prospective, phase 2, multicenter, open-label, randomized controlled trial evaluating the efficacy and safety of pegcetacoplan in posttransplant patients with recurrent C3G or IC-MPGN. The primary end point was reduction in C3c staining on renal biopsy at week 12 for patients who received either pegcetacoplan 1080 mg twice weekly by subcutaneous infusion plus standard-of-care (SOC) or SOC only. Results:Ten patients received pegcetacoplan and 3 received SOC only through week 12. At week 12, 5 of 10 pegcetacoplan-treated patients (50%) achieved ≥2 orders of magnitude (OOM) reduction in C3 staining (4 of these 5 had 0 staining and absent electron microscopy deposits) and 8 of 10 (80%) achieved ≥1 OOM reduction; 1 of 3 (33%) SOC-only patients showed staining reduction. Mean C3G histology activity score decreased by >54% in 8 of 10 pegcetacoplan-treated patients (80.0%). Pegcetacoplan-treated patients with baseline urine protein-to-creatinine ratio (uPCR) ≥1000 mg/g showed a median (interquartile range [IQR]) 54.4% (-56.33 to -53.95) reduction in proteinuria at week 12. In addition, pegcetacoplan-treated patients showed stable estimated glomerular filtration rate (eGFR), reduced plasma sC5b-9, and increased serum C3. Pegcetacoplan was well-tolerated and most adverse events were mild/moderate. No discontinuations, treatment withdrawals, or deaths were reported. Conclusion:NOBLE demonstrated efficacy, safety, and tolerability of pegcetacoplan for patients with posttransplant recurrent C3G and primary IC-MPGN.

Extrapulmonary complications of cystic fibrosis (CF) occur in nearly all adults living with the disease and renal manifestations are no exception. Data from the Cystic Fibrosis Foundation registry showed that chronic kidney disease (CKD) increases with age in patients with CF, nearly doubling every decade and impacting nearly 20% of adults with CF at 50 years 1. Risk factors include long-term and repeat exposures to anti-microbial therapies and other nephrotoxic drugs, infections, episodes of volume depletion related to malabsorption, development of diabetes mellitus due to pancreatic insufficiency, and impairment in calcium phosphate metabolism.

Rationale & Objective: Few data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics and correlates of histological disease severity in adults with FSGS who underwent a clinical kidney biopsy. Study Design: Real-world cohort study with data derived from health records. Setting & Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories from January 1, 2016 to May 31, 2020. Exposure: Race, chronic kidney disease stage, nephrotic proteinuria, age, sex, and hypertension. Outcomes: Severe histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical Approach: Demographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed using multiple logistic regression. Results: Among 2,011 patients with FSGS, 40.6% were White, and 23.6% Black. White patients were older (52.8 vs 45.5 years, P < 0.001) with a higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 vs 43.1 mL/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% vs 14.6%, P < 0.001) or IFTA >50% (34.6% vs 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (OR, 2.46; 95% CI, 1.59-3.79; P < 0.001). A higher proportion of patients with nephrotic than nonnephrotic proteinuria exhibited diffuse foot process effacement. Limitations: Unequal representation across United States regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. Conclusions: Black patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications. Plain-Language Summary: Focal segmental glomerulosclerosis (FSGS) accounts for around one-quarter of diagnoses derived from clinical kidney biopsies in the United States. Limited data are available regarding the classes and distribution of histological features at FSGS diagnosis among diverse real-world populations. Analyzing data from US patients who underwent kidney biopsy and were diagnosed with FSGS, we showed that up to half of patients had features of severe histological disease. Of this overall population, Black patients were more frequently diagnosed at a younger age but with more severe histological disease than White patients. The work highlights the need for timelier diagnosis of FSGS to enable intervention at an earlier disease stage.

Immunoglobulin A (IgA) vasculitis, or Henoch-Schonlein purpura, is the most common systemic vasculitis in children, clinically presenting as palpable purpura in combination with arthritis, gastrointestinal involvement, or kidney injury. Subcutaneous edema is reported in patients with IgA vasculitis, and it commonly affects the lower extremities, especially around joints. Here, we report a case of IgA vasculitis with a rare presentation of edema isolated to the periorbital area in a 7-year-old boy, who subsequently developed crescentic glomerulonephritis with nephrotic range proteinuria. Isolated periorbital edema is an uncommon cutaneous feature of IgA vasculitis.