Jinwei Wang

Key Points: Serum proteomics on the basis of the Therapeutic Evaluation of Steroids in IgA Nephropathy Global trial revealed glucocorticoid-modulated proteins in IgA nephropathy. Complement and endothelial injury modules persisted despite glucocorticoid treatment, suggesting complementary therapeutic targets. Leptin and C1QTNF5 improved prediction of glucocorticoid efficacy and may guide therapeutic decisions. Background: Glucocorticoids remain an important anti-inflammatory therapy for IgA nephropathy but are associated with substantial treatment-related adverse effects, highlighting the urgent need for early prediction of treatment efficacy. We hypothesized that randomized controlled trial–based serum proteomic profiling could delineate glucocorticoid-modulated proteins and more accurately stratify patients likely to benefit from glucocorticoid therapy. Methods: We performed proteomic analyses of samples from the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) trial, in which patients with IgA nephropathy were randomized to receive methylprednisolone or placebo. Four hundred seventy-nine longitudinal serum samples from 241 Chinese participants collected at baseline and at 6 and 12 months were analyzed. Linear mixed-effect models were used to identify glucocorticoid-modulated proteins and pathways in the methylprednisolone group relative to placebo. Cox proportional hazards and penalized ridge regression models were used to prioritize proteins and develop a prediction model for therapeutic efficacy. The candidate proteins were further validated by ELISA. Results: Among more than 1500 detected proteins, 302 were glucocorticoid modulated and enriched in pathways of cytoskeletal stabilization and immunometabolism. Notably, pathways associated with long-term eGFR decline, such as complement activation and endothelial injury, were not modulated by glucocorticoids. Among the glucocorticoid-modulated proteins, Cox proportional hazards and penalized ridge regression models identified those whose baseline levels improved prediction of treatment efficacy compared with clinical variables alone. ELISA was used to validate selected candidate proteins leptin and C1QTNF5. The prediction model incorporating these two proteins significantly outperformed the traditional clinical model in predicting glucocorticoid efficacy (5-year area under the curve, 0.85 [95% confidence interval, 0.72 to 0.88] versus 0.80 [95% confidence interval, 0.78 to 0.91]). Conclusions: Data from this randomized trial–based proteomic study helped delineate glucocorticoid-modulated proteins and pathways and identified robust protein biomarkers that enabled stratification of patients likely to benefit from glucocorticoid therapy.

Background: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare renal disorder for which prospective controlled treatment evidence is limited. Clone-directed therapies targeting plasma cells or B cells are increasingly used, but comparative prospective data are lacking. Methods: This single-center, open-label, pilot RCT aimed to evaluate the feasibility and preliminary efficacy of plasma cell-targeted therapy (bortezomib-cyclophosphamide-dexamethasone, BCD) versus B-cell-targeted therapy (rituximab, RTX). Twenty eligible patients were randomized (1:1) to receive either six cycles of BCD or 4 weekly doses of RTX at 375 mg/m². In patients with B-cell reconstitution >5/μl, a 500 mg RTX booster dose was administered at 6 months according to the prespecified protocol. The primary efficacy endpoint was overall renal response at 12 months. Changes in proteinuria, serum albumin and estimated glomerular filtration rate were also assessed at 6 and 12 months as secondary outcomes. Safety outcomes included infections and hematologic toxicity. Results: Baseline characteristics were generally comparable between groups. The median age was 57 years, and mean proteinuria 4.1 ± 3.1 g/d. In the primary intention-to-treat analysis (n = 20), the primary outcome of overall renal response at 12 months was observed in 60% (6/10) of patients in the BCD group and 70% (7/10) in the RTX group (P = 1.0). Treatment failure occurred in two patients in the BCD group and none in the RTX group. At 6 months, complete response occurred in five patients in the BCD group and three patients in the RTX group. Both groups showed reductions in proteinuria and improvements in serum albumin over 12 months. A transient decline in estimated glomerular filtration rate was observed in the BCD group at 6 months and recovered by 12 months. Safety profiles were manageable, with one serious adverse event, pneumonia, in the BCD group. Conclusion: Both BCD and RTX were associated with renal responses in this exploratory pilot trial of PGNMID. Given the small sample size, open-label design, and differences in treatment exposure structure, these findings are hypothesis-generating. Larger multicenter studies with longer follow-up are needed to define optimal therapy for PGNMID.

BACKGROUND: Vascular calcification and osteoporosis often co-occur during postmenopause, end-stage renal disease, advancing age, and diabetes, leading to increased mortality and significant challenges in therapy. FAM19A5 (family with sequence similarity 19 [chemokine (C-C motif)-like], member A5), as a novel protective adipokine, has been identified to suppress postinjury neointima formation. However, the involvement of adipose-derived FAM19A5 in vascular calcification and osteoporosis remains unclear. METHODS: A cross-sectional study was conducted to assess the relationship among circulating FAM19A5, coronary artery calcification, and osteoporosis. Adipose-specific FAM19A5 transgenic mice and AAV8 (adeno-associated virus serum type 8)-adipo-shFAM19A5 were employed to study gain or loss of function of FAM19A5 in 2 distinct mouse models: ovariectomy followed by Vitamin D3 overload (OVX-VitD3) and adenine diet. Calcium assays, micro-CT, Western blot, RT-qPCR, luciferase reporter assays, and ChIP-qPCR were performed to clarify the phenotype and elucidate the molecular mechanisms. Finally, administration of AAV8-adipoq-FAM19A5 and S1PR2 (sphingosine 1-phosphate receptor 2) global knockout mice was used to investigate their therapeutic effects. RESULTS: Circulating FAM19A5 was negatively correlated with coronary artery calcification and osteoporosis in patients and mouse models. Adipose-specific FAM19A5 transgenic mice exhibited milder aortic calcification and preserved bone mass via S1PR2 in both OVX-VitD3 and adenine diet models. Although adipose-specific knockdown of FAM19A5 aggravates aortic calcification and bone mass loss. Interestingly, FAM19A5 mitigated vascular smooth muscle cells’ calcification by activating S1PR2-Gi-PKA signaling and promoted mice osteoblasts differentiation by triggering S1PR2-Gq-PKCδ (protein kinase C delta isoform) signaling. Finally, administration of AAV8-adipoq-FAM19A5 effectively rescued vascular calcification and osteoporosis, but exerted no beneficial effects in S1PR2 knockout mice. CONCLUSIONS: Adipose-derived FAM19A5 plays an essential role in orchestrating vascular calcification and osteoporosis through the selective activation of S1PR2. Our findings provide novel insight into the previously unexplored role of adipose tissue in maintaining vascular-bone homeostasis. FAM19A5-S1PR2 may be considered as a potential therapeutic strategy for vascular calcification and osteoporosis.

Acute kidney injury (AKI) is a common hospital-acquired condition linked to oxidative stress and poor outcomes. Bilirubin exerts dual, level-dependent effects, acting as an antioxidant within mildly elevated levels yet becoming cytotoxic when markedly elevated. While moderate bilirubin elevation shows long-term kidney benefits, its association with AKI remains unclear. This retrospective cohort study included adult patients admitted between 2018 - 2020 with total bilirubin (TBIL) below 1.5 times the upper limit of normal (<30 μmol/L). The primary outcome was in-hospital AKI, defined by the Kidney Disease: Improving Global Outcomes criteria. Patients were stratified into high and low TBIL groups based on the median. Restricted cubic splines examined potential nonlinear relationships between TBIL and AKI. Cox regression assessed the association of TBIL as a continuous variable with in-hospital AKI and mortality. Subgroup analyses included age, sex, diabetes mellitus, white blood cell count, abnormal liver function, direct/indirect bilirubin ratio, and serum albumin. Among 29,261 hospitalized patients, in-hospital AKI occurred in 785 patients (2.68%). Unadjusted analysis revealed a U-shaped relationship between TBIL and AKI risk (P-overall = 0.004, P-nonlinear = 0.002), whereas the nonlinear component was attenuated after multivariable adjustment (P-overall = 0.001, P-nonlinear = 0.09). Multivariable Cox regression showed higher TBIL levels were independently associated with increased risks of in-hospital AKI (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.06–1.22) and mortality (HR 1.26, 95% CI 1.02–1.54). Results were consistent across all subgroups. Higher TBIL levels, even within the normal to mildly elevated range, were independently associated with increased risks of in-hospital AKI and mortality. The online version contains supplementary material available at 10.1186/s12882-026-04968-0.

Key Points: Proteinuria responses to endothelin receptor antagonists and sodium-glucose cotransporter 2 inhibitors were not correlated. Ambrisentan-henagliflozin combination therapy reduced proteinuria similarly to ambrisentan monotherapy but exceeded henagliflozin alone. Combination therapy resulted in markedly less fluid retention and weight gain compared with endothelin receptor antagonist monotherapy. Background: 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. Methods: This open-label randomized crossover trial enrolled adults with IgA nephropathy, eGFR >30 ml/min per 1.73 m ² , 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/d, henagliflozin 10 mg/d, and combination), each for 4 weeks followed by a 4-week washout. Primary end point was correlation between treatments in 24-hour UPCR changes. Secondary end points included eGFR change. Safety end points included fluid retention (body weight change). Results: Sixty-five patients were enrolled, with a mean baseline eGFR of 69 ml/min per 1.73 m ² (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). The mean reduction in eGFR from baseline was −4.7 ml/min per 1.73 m ² (95% CI, −6.9 to −2.6) with combination therapy, which was significantly greater than with ambrisentan (−0.5 ml/min per 1.73 m ² ; 95% CI, −2.8 to 1.9) but comparable with henagliflozin (−3.5 ml/min per 1.73 m ² ; 95% CI, −5.8 to −1.2). Less fluid retention occurred with combination treatment versus ambrisentan alone. Conclusions: Combining an ERA with an SGLT2 inhibitor further reduced proteinuria versus SGLT2 inhibitor alone, with less fluid retention than ERA alone. Clinical Trial registry name and registration number: Chinese Clinical Trial Registry (ChiCTR2400080435).

Key Points: The presence of cellular segmental sclerosis and crescents predicts a favorable response to glucocorticoid therapy in patients with IgA nephropathy. Glucocorticoid therapy was associated with lower risk of kidney failure across histologic subtypes, with the greatest benefit in cellular segmental sclerosis. The study highlights that there is a need for further subclassification of segmental sclerosis lesions that may guide therapeutic decisions. Background: The Oxford Classification is widely accepted as a histopathology tool to predict kidney outcomes in IgA nephropathy. However, it remains unclear whether the mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores can predict therapeutic response. This study aims to determine the predictive value of mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores on the efficacy of glucocorticoid therapy using the Therapeutic Effects of Steroids in IgA Nephropathy Global trial. Methods: Three hundred and seventy-nine Chinese participants were enrolled in the Therapeutic Effects of Steroids in IgA Nephropathy Global trial, of whom 279 had kidney biopsy slides available for central pathology review. The primary outcomes were a composite of ≥40% reduction in eGFR, kidney failure, or death due to kidney disease. Multivariable Cox regression analysis was used to determine the effects of glucocorticoid therapy across pathologic subgroups, and the interaction between glucocorticoid therapy and pathology scores was evaluated. Results: Among 279 participants selected for this study, the median (interquartile range) time from kidney biopsy to randomization was 4 (3–7) months. The median (interquartile range) follow-up was 4.7 (3.0–6.4) and 5.1 (3.1–6.8) years for the placebo and glucocorticoid-treated group. Glucocorticoid therapy showed benefits across all histologic subtypes. Participants with crescents (C1/C2) showed a trend toward greater benefit from glucocorticoid therapy (C1/2: hazard ratio [HR], 0.05 [95% confidence interval (CI), 0.008 to 0.3]; C0: HR, 0.6 [95% CI, 0.4 to 0.9]; P for interaction = 0.4). Participants with hypercellularity within segmental sclerosis lesions (cellular segmental sclerosis) demonstrated a significant reduction in the risk of kidney failure compared with those without (HR, 0.2 [95% CI, 0.07 to 0.4] versus HR, 0.6 [95% CI, 0.4 to 1.0]; P for interaction = 0.03). Analysis of local pathologists' scores of all 379 Chinese participants demonstrated a significantly greater benefit from glucocorticoid therapy in participants with crescents (C0: HR, 0.7 [95% CI, 0.4 to 1.2]; C1: HR, 0.3 [95% CI, 0.2 to 0.6]; C2: HR, 0.2 [95% CI, 0.08 to 0.7]; P for interaction = 0.05). Conclusions: The presence of crescents and cellular segmental sclerosis in patients with IgA nephropathy was associated with a favorable response to glucocorticoid therapy.

Early prediction of acute kidney injury (AKI) may provide a crucial opportunity for AKI prevention. To date, no prediction model targeting AKI among general hospitalized patients in developing countries has been published. Here we show a simple, real-time, interpretable AKI prediction model for general hospitalized patients developed from a large tertiary hospital in China, which has been validated across five independent, geographically distinct, different tiered hospitals. The model containing 20 readily available variables demonstrates consistent, high levels of predictive discrimination in validation cohort, with AUCs for serum creatinine-based AKI and severe AKI within 48 h ranging from 0.74–0.85 and 0.83–0.90 for transported models and from 0.81–0.90 and 0.88–0.95 for refitted models, respectively. With optimal probability cutoffs, the refitted model could predict AKI at a median of 72 (24–198) hours in advance in internal validation, and 54–90 h in advance in external validation. Broad application of the model in the future may provide an effective, convenient and cost-effective approach for AKI prevention.