Validity of spot urine samples for estimating systemic fluoride exposure in children across diverse fluoridation modalities.

Non-diabetic kidney disease (NDKD) is a major contributor to chronic kidney disease (CKD) worldwide. Although renin-angiotensin system inhibitors (RASi) remain standard therapy, sodium-glucose cotransporter-2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (non-steroidal MRA), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are now recommended in clinical guidelines. However, direct comparative evidence to guide their prioritization in NDKD is limited. We performed a systematic review and Bayesian network meta-analysis of randomized controlled trials enrolling adults with NDKD. The primary endpoint was the annualized change in estimated glomerular filtration rate (eGFR) slope; secondary endpoints included urine protein-to-creatinine ratio (UPCR), blood pressure, and biochemical safety parameters. Eighteen trials were included. SGLT2i, as add-on to RASi, produced the greatest preservation of kidney function compared with RASi alone (mean difference [MD] 12.1 mL/min/1.73 m²/year; 95% credible interval [CrI] 3.9 to 20.4). non-steroidal MRA achieved the largest reduction in proteinuria versus RASi (UPCR MD -0.4 g/g; 95% CrI -1.0 to -0.2). SGLT2i also yielded the greatest systolic blood pressure reduction versus RASi (MD -9.1 mmHg vs RASi; 95% CrI -11.7 to -6.5). Surface under the cumulative ranking (SUCRA) probabilities identified SGLT2i as most effective for eGFR slope preservation (99.8%) and non-steroidal MRA as most effective for proteinuria reduction (98.8%). Safety analyses showed a mild, expected hemoglobin decrease with SGLT2i and a non-significant creatinine rise with non-steroidal MRA. SGLT2i and non-steroidal MRA confer distinct renal benefits in NDKD-SGLT2i primarily preserve kidney function, whereas non-steroidal MRA most effectively reduce proteinuria. These results support a phenotype-driven therapeutic framework and highlight the need for head-to-head trials to validate precision-guided treatment strategies in NDKD.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines involved in B-cell activation and survival, contributing to the pathogenesis of IgAN. This meta-analysis aimed to evaluate the efficacy, safety, and biomarkers of BAFF- or APRIL-targeted therapies in patients with IgAN. We searched PubMed, Scopus, and the Cochrane Library for randomized controlled trials (RCTs) comparing BAFF- or APRIL-targeted drugs with placebo in adults with IgAN, published up to December 2024 and written in English. Efficacy outcomes were the mean percent change in the 24-hour urine protein-to-creatinine ratio (UPCR) and the mean change in the estimated glomerular filtration rate (eGFR) from baseline. Safety included the incidence of adverse events. The biomarkers we used were changes in serum Gd-IgA1, IgG, IgA, and IgM from baseline. The risk of bias and the certainty of evidence were assessed using RoB v2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). We used the R software version 4.2.1 for statistics. Four Phase II RCTs, including 331 patients, were included, with three studies having a low risk of bias, while there were some concerns regarding one study. Compared to placebo, BAFF- or APRIL-targeted drugs significantly reduced 24-hour UPCR (mean difference [MD] -38.94%; 95% confidence interval [CI] -58.98 to -18.90; P = 0.0001; I² = 0%) and significantly improved the eGFR (MD 7.05 mL/min/1.73 m²; 95% CI 3.83 to 10.27; P < 0.0001; I² = 0%). Adverse events did not significantly differ between the study groups. BAFF- or APRIL-targeted drugs significantly decreased serum Gd-IgA1, IgG, IgA, and IgM compared with placebo, indicating lower immune complex formation and response to treatment. BAFF- or APRIL-targeted therapies appear to be effective and safe in reducing proteinuria in patients with IgAN. CRD42024598157.

Objectives: Primary hyperoxaluria type III (PH3) causes kidney stones in children and adults. Gas chromatography/mass spectrometry (GC/MS)-based metabolomics has been applied to study patients with primary hyperoxaluria types I and II, 2,8-dihydroxyadenine lithiasis, and xanthinuria types I to III. This study was performed to verify the usefulness of this technique for the diagnosis of PH3. Specifically, we evaluated an 8-month-old infant with recurrent kidney stones. Methods: GC/MS-based metabolomics was performed on spot urine samples using initial urease pretreatment without fractionation. Results: Metabolomics revealed increased levels of 2,4-dihydroxyglutarate and 4-hydroxyglutamate. No simultaneous elevations of these two critical biomarkers were observed in other patients, except for one case of PH3 confirmed by the identification of HOGA1 mutations. A moderate increase in 4-hydroxyglutamate has been observed only in cases of primary hyperammonemia, in which analytes such as orotate, uridine, glutamine, or proline, but not 2,4-dihydroxyglutarate, are biomarkers, thus distinguishing PH3 from primary hyperammonemia. Conclusions: GC/MS-based urine metabolomics enables the rapid screening and chemical diagnosis of PH3 and other congenital anomalies that cause urolithiasis. This technique can also be used to monitor disease progression, as patients with PH3 benefit from long-term follow-up, particularly when transitioning from childhood to adulthood. The timely identification of patients with hereditary urolithiasis is crucial. To address this, a discussion was had about the current diagnostic criteria.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and endothelin receptor antagonists (ERAs) can reduce proteinuria and may slow kidney progression in IgA nephropathy. Their potential synergistic efficacy and safety are unclear. This open-label randomized crossover trial enrolled adults with immunoglobulin A nephropathy (IgA nephropathy), estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2, and 24-hour urine protein-creatinine ratio (UPCR) ≥0.44 g/g or 24-hour urine protein ≥0.5 g despite maximal renin-angiotensin system blockade. Treatments were given in random order (ambrisentan 5 mg/day, henagliflozin 10 mg/day, and combination), each for 4 weeks followed by a 4-week washout. Primary endpoint was correlation between treatments in 24-hour UPCR changes. Secondary endpoints included eGFR change. Safety endpoints included fluid retention (body weight change). Sixty-five patients were enrolled, with a mean baseline eGFR of 69 ml/min/1.73 m2 (SD=23) and a median 24-hour UPCR of 0.8 g/g (0.6-1.3). No correlation was found in 24-hour UPCR reduction between single-agent therapy and combination therapy (ambrisentan, r =0.13, P =0.97; henagliflozin, r =0.04, P =1.00). After treatment, the mean reduction in 24-hour UPCR was -44% with combination therapy (95% confidence interval [CI], -52 to -34), which was similar to ambrisentan alone (-48%; 95% CI, -56 to -39) but significantly superior to henagliflozin alone (-21%; 95% CI, -33 to -6). Mean reduction in eGFR from baseline was -4.7 ml/min/1.73 m2 (95% CI, -6.9 to -2.6) with combination therapy, which was significantly greater than with ambrisentan (-0.5 ml/min/1.73 m2; 95% CI, -2.8 to 1.9) but comparable with henagliflozin (-3.5 ml/min/1.73 m2; 95% CI, -5.8 to -1.2). Less fluid retention occurred with combination treatment versus ambrisentan alone. Combining an ERA with an SGLT2 inhibitor further reduced proteinuria versus SGLT2 inhibitor alone, with less fluid retention than ERA alone.

Systemic sclerosis (SSc) and renal involvement most frequently present as scleroderma renal crisis (SRC). Immune complex-mediated glomerulonephritis (GN) is an exceptionally rare renal manifestation in SSc and may complicate timely diagnosis and management. We report the case of a 40-year-old woman with a history of hypertension and Raynaud's phenomenon who presented with progressive dyspnea, bilateral lower limb edema, and oliguria. Laboratory investigations demonstrated rapidly deteriorating renal function (serum urea/creatinine - 71/6.44 mg/dL rising to 82/7.35 mg/dL within 24 h), nephrotic-range proteinuria (urine protein-creatinine ratio ≈ 11.6), hematuria (25-30 red blood cells/high-power field), and borderline low complement C3 (80.3 mg/dL). Autoimmune analysis revealed a speckled antinuclear antibody pattern (1:100) with Scl-70 positivity. Ultrasound showed enlarged kidneys with increased cortical echogenicity, and two-dimensional echocardiography confirmed moderate pulmonary arterial hypertension. Renal biopsy demonstrated diffuse proliferative GN with neutrophilic exudation, immunoglobulin G (IgG) and C3 immune complex deposition on immunofluorescence, and acute tubular injury, without thrombotic microangiopathy, thereby excluding SRC. The patient underwent hemodialysis and was initiated on low-dose corticosteroids. She was lost to follow-up after discharge. This case underscores an atypical and rare renal presentation of SSc, emphasizing the necessity of considering alternative diagnoses when renal dysfunction occurs without features of SRC. Early renal biopsy is essential to guide appropriate and individualized therapy in such cases.

Objective: To compare the outcomes of linagliptin plus insulin versus insulin alone among patients with type II diabetes mellitus with chronic kidney disease. Study Design: Randomized clinical trial studyPlace and Duration of Study: This study was conducted at the Department of Medicine, Fauji Foundation Hospital, Rawalpindi, Pakistan, from October 2025 to December 2025. Methods: A total of 284 patients with type II diabetes mellitus and chronic kidney disease were included in the study and randomly allocated into two equal groups. Group A received linagliptin 5 mg once daily in addition to insulin therapy, while Group B received insulin therapy alone. Patients aged 18–75 years with eGFR between 15–45 ml/min and HbA1c &gt;6.5% were enrolled. Baseline demographic and clinical parameters including age, gender, BMI, duration of diabetes, CKD grade, HbA1c, and urine protein-creatinine ratio (UPCR) were recorded. Patients were followed for three months and post-treatment HbA1c and UPCR were measured. Data were analyzed using SPSS version 25. Independent sample t-test was applied to compare outcomes between the groups, with p ≤0.05 considered statistically significant. Results: The mean age of the participants was 54.3 ± 10.7 years, with 158 (55.6%) males and 126 (44.4%) females. The mean BMI was 27.6 ± 4.2 kg/m². After three months of treatment, the mean HbA1c was significantly lower in the linagliptin plus insulin group (7.2 ± 0.6%) compared with the insulin-only group (7.6 ± 0.8%) (p = 0.001). Similarly, renal outcomes measured through urine protein-creatinine ratio improved in the combination therapy group (0.82 ± 0.14 mg/g) compared with the insulin-only group (0.91 ± 0.16 mg/g) (p = 0.003). Stratified analysis showed consistent improvement across different age groups and genders. Conclusion: Linagliptin combined with insulin demonstrated significantly better glycaemic control and improvement in proteinuria compared with insulin monotherapy in patients with type II diabetes mellitus and chronic kidney disease.

Alport syndrome is a hereditary nephropathy caused by pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes, encoding type IV collagen chains that are essential for glomerular basement membrane integrity. The missense pathogenic variant p.Gly407Arg in COL4A3 has been reported in Portuguese families, but detailed phenotypic characterization remains limited. This study aimed to describe the renal and extra-renal manifestations and identify predictors of renal outcomes in a cohort of patients carrying the COL4A3 p.Gly407Arg variant. We conducted a retrospective observational study including 62 patients from 25 families followed at a tertiary nephrology center in northern Portugal between 2007 and 2025 with genetically confirmed Autosomal Dominant Alport syndrome due to monoallelic COL4A3 p.Gly407Arg pathogenic variant. Demographic, clinical, laboratory, audiologic, and ophthalmologic data were analyzed. Renal events were defined as incident kidney failure, estimated Glomerular Filtration Rate (eGFR) <15 mL/min/1.73 m2, or eGFR ≥30% decline from baseline sustained over time. Changes in eGFR over time were analyzed using a univariate linear mixed effects model. At diagnosis, 98% of patients presented with microscopic hematuria, and 53% had proteinuria (urinary protein-creatinine ratio (UPCR) 240mg/g, IQR 9-840). The mean eGFR was 94 ± 32 mL/min/1.73m2. Mean follow-up time in the study (from the initiation of clinical observation until the occurrence of the event or the end of follow-up) was 4.72 years (IQR 2.43-8.43). During a median follow-up of 4.72 years, 16 patients (26%) developed renal events, with 5 (8%) initiating KRT at a mean age of 58 (range 45-66) years. The mean renal survival was 67 years (63-72). Proteinuria ≥500mg/g was significantly associated with faster eGFR decline (p < 0.001) and a higher risk of renal events (imputed as a time-varying variable, HR 1.03, 95% CI 1.001-1.059, p= 0.04). Hearing loss occurred in 34% of patients and ocular changes in 18% of the patients evaluated. Patients carrying monoallelic COL4A3 p.Gly407Arg pathogenic variant exhibit variable phenotypic expression, with proteinuria representing the strongest predictor of renal function decline.

WCN26-5044 UROMODULIN PROFILE AS AN INNOVATIVE MARKER OF EARLY TUBULAR DYSFUNCTION AND CKD PROGRESSION

Empirical comparison of iodine excretion estimated from spot urine samples with measured 24-hour urinary iodine excretion in healthy adults.

Lupus Nephritis (LN) is one of the most common complications of systemic lupus erythematosus. Recent primary studies have stated the superiority of adding voclosporin to standard treatment regimens in reducing proteinuria in LN patients. In this meta-analysis, we evaluate the safety and efficacy of combining voclosporin in patients with LN. We searched PubMed, Embase, Scopus, and Web of Science on February 25, 2025, to identify randomized controlled trials (RCTs) that compared the use of voclosporin with standard treatment versus placebo. The Cochrane ROB 2.0 tool was used to assess the quality of the included studies. Cumulative hazard ratio (HR) and risk ratio (RR) with their corresponding 95% confidence intervals (CI) were calculated using R and RevMan software. 770 patients with LN were included in the three RCTs, with a mean age of 33.01(SD, 9.94) years. Voclosporin significantly achieved a higher reduction of the urine protein-to-creatinine ratio (UPCR) below 50% of its baseline value [HR: 1.97, 95% CI 1.66 to 2.35, log-rank p < 0.001], and below 0.5 g/g [HR: 1.84, 95% CI 1.43 to 2.37, log-rank p < 0.001] compared to placebo. There were higher complete and partial response rates at 6 months and 12 months in the voclosporin group, respectively. The overall adverse events and treatment-related serious adverse events significantly increased in the voclosporin group, which increases the clinical concerns of using voclosporin in LN patients. This analysis highlights the superior efficacy outcomes of voclosporin in inducing LN remission and reducing proteinuria. However, the risk of adverse effects was higher when voclosporin was used. Larger primary studies are needed to explore its exact safety profile.

Patients with chronic kidney disease often exhibit impaired brain function; however, the differences between those with non-diabetic kidney disease (non-DKD) and diabetic kidney disease (DKD) remain poorly understood. This study aimed to investigate alterations in resting-state brain activity in patients with non-DKD and DKD. Thirty non-DKD patients, thirty DKD patients, and twenty-nine healthy controls underwent laboratory examinations and resting-state functional magnetic resonance imaging (rs-fMRI). The brain activity was analyzed using the amplitude of low-frequency fluctuations (ALFF) and seed-based functional connectivity (FC), and correlations between laboratory indicators and FC were examined. Both non-DKD and DKD groups exhibited reduced ALFF in several brain regions, including the bilateral putamen, alongside elevated ALFF in the left middle occipital gyrus. Seed-based FC analysis revealed decreased connectivity between bilateral putamen and several regions, including decreased FC between the left putamen and left caudate. Compared with the non-DKD group, the DKD group demonstrated reduced ALFF in the left putamen and right precuneus, along with decreased FC between the right putamen and right thalamus. Several biomarkers, including urinary protein-to-creatinine ratio (UPCR), C-reactive protein (CRP), and hemoglobin (HGB), were associated with observed FC alterations. Our findings indicate that DKD patients exhibit distinct patterns of brain activity compared to non-DKD patients, with the putamen potentially acting as a key neural target in the progression of CKD. These functional alterations correlate closely with systemic status, suggesting a significant role in the pathogenesis of neural impairment. Our results may enhance the understanding of neural functional alterations and the underlying mechanisms in non-DKD and DKD patients.

WCN26-8170 Urine protein–creatinine ratio response at 12 months in patients with immunoglobulin A nephropathy receiving nefecon vs placebo: Analysis of NefIgArd trial data

Placental DNA methylation at thyroid hormone-related genes mediates the association between prenatal exposure to bisphenol analogues and increased offspring obesity risk.

Objective: To investigate the effect of initial periodontal therapy on renal function related indicators in patients with chronic kidney disease (CKD) and periodontitis, with a special focus on evaluating the improvement in proteinuria and hematuria. Methods: This superiority randomized controlled trial involved 200 patients with CKD and periodontitis, recruited from May 2024 to January 2025 at the department of nephrology and referred to the department of stomatology at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, who were randomly assigned (1∶1) to either the intervention group (n=100) or the control group (n=100) using a computer-generated random sequence. The intervention group received standardized initial periodontal therapy, while the control group received only oral hygiene instruction. Blood and urine samples were collected from both groups at baseline and at 1, 3 and 6 months post-treatment to measure indicators including estimated glomerular filtration rate (eGFR), serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), bicarbonate (HCO3-), cystatin C (CysC), urinary albumin-to-creatinine ratio (UACR), urinary protein-to-creatinine ratio (UPCR), urinary creatinine (UCR), urinary microalbumin (UMA), urinary total protein (UTP), urinary red blood cell count (URBC), and dipstick results for hematuria and proteinuria. Statistical analysis followed the intention-to-treat (ITT) principle, with missing data handled by multiple imputation (MI) and analyzed using linear mixed models (LMM). P values were adjusted for multiple comparisons using the Bonferroni correction. Results: Baseline characteristics, including age, sex, body mass index (BMI), primary disease distribution, and renal laboratory parameters, were well-balanced between the two groups (P>0.05). At the 6-month primary endpoint, UACR in the intervention group was significantly better than that in the control group, with a between-group geometric mean ratio (GMR) of 0.105 (95%CI: 0.076-0.145, P<0.001). For secondary endpoints at 6 months, eGFR was significantly higher in the intervention group than in the control group, with a mean difference (MD) of 8.019 (95%CI: 4.784-11.254, P<0.001). The between-group GMRs for URBC and UPCR were 0.291 (95%CI: 0.203-0.419, P<0.001) and 0.216 (95%CI: 0.172-0.271, P<0.001), respectively. In addition, the between-group GMR of CysC at 6 months was 0.750 (95%CI: 0.681-0.827, P<0.001). No statistically significant between-group differences were observed for BUN, Scr, UA, or HCO3-during the study period (all P>0.05). Conclusions: This study demonstrates that initial periodontal therapy can effectively reduce proteinuria and hematuria in patients with CKD and periodontitis. It also has a positive impact on increasing eGFR and decreasing CysC. These findings suggest that periodontal health management could serve as a valuable adjunctive strategy in the comprehensive management of patients with CKD.

Diabetic kidney disease (DKD) is a major contributor to end-stage renal disease (ESRD) in diabetic patients. Early identification of high-risk individuals and predictive modeling can aid in improving outcomes. The development of a practical nomogram model for ESRD risk stratification is critical for guiding clinical decision-making in DKD populations. This retrospective single-center study included 250 patients diagnosed with diabetic nephropathy (DN) between January 2017 and October 2019. Patients were followed for 5 years and classified into ESRD and non-ESRD groups. Baseline variables were analyzed using univariate and multivariate logistic regression to identify independent risk factors. A nomogram was developed based on key predictors. Internal validation was performed via the bootstrap method (1,000 resamples), and external validation used an independent cohort of 85 DN patients from January to June 2020. The nomogram was designed to provide clinicians with a visual tool for individualized risk assessment. Of the 230 eligible patients, 78 (33.91%) developed ESRD. Systolic blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), serum creatinine (Scr), estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (UPCR) were identified as independent predictors (p < 0.05). The nomogram incorporating these variables showed strong performance: internal AUC = 0.836 (95% CI: 0.787 - 0.886); external AUC = 0.828 (95% CI: 0.775 - 0.881). Calibration curves and Hosmer-Lemeshow goodness-of-fit test (HLGFT) confirmed good model fit and predictive accuracy. The model's simplicity and discriminative power make it suitable for routine clinical use. The nomogram model based on six baseline variables demonstrates high predictive value for ESRD progression in DKD patients and may guide early risk assessment and personalized management. This tool enables clinicians to designate high-risk patients efficiently, facilitating timely interventions to delay ESRD onset.

Human exposure to current-use and legacy pesticides in Chile remains largely understudied. In this pilot study, we collected silicone wristbands and urine samples to characterize pesticide exposure, assess between-matrix correlations, and identify potential exposure determinants. A total of 43 male agricultural workers enrolled in the Maule Cohort (MAUCO) were recruited in 2023. Participants wore wristbands for 8-11 days. A spot urine sample was collected upon wristband retrieval at the end of the sampling period (July-August 2023). We analyzed 20 pesticides on wristbands and 10 urinary pesticide biomarkers using GC-MS/MS and LC-MS/MS targeted methods. We estimated univariable associations between concentrations in both sampling matrices and individual demographic and behavioral factors collected via questionnaires. Participants (42-64 years) reported a median of 25 years in agricultural work, yet only 37% reported prior pesticide training. Among the frequently detected analytes (>80% detection frequency), we found significant and positive correlations between chlorpyrifos, cis-permethrin, and trans-permethrin, and their corresponding urinary metabolites (rs = 0.34-0.53; p < 0.05). When stratified by job title, the strongest correlations were found among field workers (rs = 0.49-0.71; p < 0.05). Field re-entry work was a significant determinant across both matrices, highlighting a potential modifiable exposure pathway. Silicone wristbands provide a complementary noninvasive method to estimate personal pesticide exposure, offering insights into critical exposure patterns in under-resourced settings.

Metal exposures are increasingly recognized as a major risk factor for chronic diseases, yet very few prior studies have comprehensively characterized metal concentrations in the Caribbean. This study characterized urinary metal concentrations and their associations with demographic characteristics and other lifestyle factors among middle-aged and older Tobagonian adults. We quantified urinary concentrations of 18 metals and metalloids (referred to here as "metals") in 896 adults from a subsample of the Tobago Health Study, including 466 men and 430 women. Morning spot urine samples were collected from men in 2014-2016, and from women in 2019-2020. Metal concentrations were compared to studies of adults from other populations. Metal exposure risk factors included demographics, body composition, and lifestyle, including diet. We used sex-stratified partial least squares (PLS) regression to identify risk factors associated with metal concentrations. Twelve metals including arsenic (As), barium (Ba), cadmium (Cd), cobalt (Co), cesium (Cs), copper (Cu), molybdenum (Mo), lead (Pb), tin (Sn), thallium (Tl), uranium (U) and zinc (Zn) were detected in >87% of participants in both men and women. Compared to other populations, Zn and Tl concentrations were higher among Tobagonian men and women. We observed distinct urinary metal concentration patterns among men and women that varied by age, education, body composition and lifestyle factors. A mix of non-modifiable and modifiable risk factors associated with urinary metal concentrations were identified. These findings can inform future studies to identify vulnerable populations and tailor public health messaging to reduce exposure risk. Future research is needed to understand sex differences and how these exposures may contribute to adverse health outcomes. This study provides the first comprehensive characterization of urinary metal concentrations among middle-aged and older adults in Tobago, identifying both modifiable and non-modifiable factors associated with exposure. Twelve metals, including arsenic, cadmium, lead, and thallium, were detected in most participants, with some concentrations exceeding those reported in other populations. Distinct urinary metal concentration patterns that varied by demographics and lifestyle factors were observed among men and women. The exposure profiles of adults from Tobago can inform targeted public health strategies and lay the groundwork for future research on the health impacts of metal exposures in this understudied population.

Patients with IgA nephropathy and proteinuria are at risk of kidney failure despite use of guideline recommended renin-angiotensin system and sodium-glucose cotransporter 2 inhibition. Atrasentan reduces proteinuria in IgA nephropathy, but its efficacy as adjunct to renin-angiotensin system and sodium-glucose cotransporter 2 inhibition has not been rigorously tested. Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy treated with renin-angiotensin system and sodium-glucose cotransporter 2 inhibitors. Atrasentan, a highly selective endothelin-A receptor antagonist, is approved for proteinuria reduction in adults with IgA nephropathy. Renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are guideline recommended, yet the additional benefit of atrasentan has not been rigorously determined. We performed a randomized, double-blind, placebo-controlled crossover study of atrasentan in adults with IgA nephropathy, eGFR ≥30 ml/min per 1.73 m2, and urinary protein >0.5 g/d while on maximal, stable RASi and SGLT2i. Participants were randomized 1:1 to either sequence AB or sequence BA (0.75 mg atrasentan [A] once daily during period 1 and matching placebo [B] during period 2 or vice versa), with a 12-week washout period in between. The primary end point was the change in urinary protein-to-creatinine ratio (UPCR) to week 12. The secondary end point was the change in UPCR to week 24. Safety end points included the type, incidence, severity, seriousness, and relatedness of adverse events (AEs). We recruited 54 participants with mean age 48 years (SD 12), 43% female, mean eGFR 63 ml/min per 1.73 m2 (SD 22), and median UPCR 1.0 g/g (Q1-Q3, 0.7-1.4). Treatment with atrasentan versus placebo resulted in a difference in geometric mean percentage change in UPCR at week 12 of -25.3% (95% confidence interval, -36.8 to -11.7; P < 0.001). The treatment difference in UPCR between atrasentan versus placebo during treatment period 2 at week 24 was -26.4% (95% confidence interval, -45.8 to -0.0). There was one unrelated serious adverse event. Fluid retention events were uncommon, and none required hospitalization. There were no study drug discontinuations due to treatment-related adverse events and no deaths. Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy and proteinuria ≥0.5 g/d treated with RASi and SGLT2i therapy. Atrasentan was well tolerated, and no new safety signals emerged. NCT05834738.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. A Proliferation-Inducing Ligand (APRIL) plays a critical role in the development and progression of IgAN. This study aimed to evaluate the efficacy and safety of sibeprenlimab, an APRIL receptor antagonist, in IgAN patients. A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library from database inception to November 30, 2025. Randomized controlled trials (RCTs) were identified. Literature quality was assessed using the Cochrane Risk of Bias 2 tool. Data were analyzed using RevMan 5.4. Two high-quality, multi-center, double-blinded RCTs involving 665 primary IgAN patients were included. Compared with the control group, the sibeprenlimab group showed a greater percentage reduction in urine protein-to-creatinine ratio (UPCR) (MD -48.35, 95% CI -62.00 to -34.69, P < 0.00001), a lower proportion of patients experiencing hematuria (OR 0.11, 95% CI 0.06 to 0.20, P < 0.00001), a lower least-squares mean change in estimated glomerular filtration rate (eGFR) (MD 6.11, 95% CI 2.06 to 10.16, P = 0.003), and a marked decrease in circulating galactose-deficient IgA1 (Gd-IgA1) and serum APRIL levels (mean reductions of 66.0% and 95.8%, respectively). Although the overall incidence of adverse events was comparable (OR 0.90, 95% CI 0.39 to 2.09, P = 0.80), the sibeprenlimab group experienced a greater reduction in serum IgG, IgA, and IgM levels than the control group (mean reductions of 35.0%, 66.5%, and 74.8%, respectively). Current limited but robust evidence suggests that sibeprenlimab is effective in reducing proteinuria and hematuria, lowering circulating Gd-IgA1 and serum APRIL levels, and slowing the decline in eGFR in IgAN patients. Although sibeprenlimab exhibits an overall favorable safety profile, it may be associated with reductions in serum IgG, IgA, and IgM levels. Not applicable.