Triptolide capsule enables proteinuria reduction and renal stabilization in advanced alport syndrome beyond standard therapy

Alport syndrome (AS) is the most common inherited glomerular disease, yet therapeutic options remain extremely limited for patients with advanced chronic kidney disease (CKD), particularly those with estimated glomerular filtration rate (eGFR) below 45 mL·min−1·1.73 m−2. Standard renin-angiotensin-aldosterone system inhibitors (RASi) are often contraindicated or ineffective at this stage due to risks of hyperkalemia and further GFR decline.1 Although adjunctive agents such as sodium-glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists have shown promise,2-4 their use is similarly restricted by renal function thresholds, leaving a critical therapeutic gap for patients with advanced AS. Triptolide capsule, a Tripterygium wilfordii-derived formulation widely used in China for glomerular diseases,5 is not limited by renal function and has demonstrated proteinuria reduction in other nephropathies. However, its potential in advanced AS—a population with virtually no alternatives—remains unexplored. We conducted a retrospective, real-world study at Peking University First Hospital (IRB 2023Y385) involving 13 genetically confirmed adult patients with baseline eGFR ≤45 mL·min−1·1.73 m²−1 (Supplementary Methods). Participants received triptolide capsules 2–6 capsules/day, either as monotherapy (n = 3) due to RASi contraindications or as add-on therapy to stable RASi-based regimens (n = 10). The planned treatment duration with triptolide in this cohort was 3 months, after which therapy was discontinued in 11 of the 13 patients based on routine clinical practice and shared decision-making. Two patients, who met predefined safety criteria and wished to continue, remained on triptolide for up to 6 months under close monitoring. Detailed baseline clinical and genetic characteristics are provided in Supporting Information: Table S1. All concurrent medications and triptolide capsules dosages remain unchanged throughout the study period. Thirteen patients with CKD stage 3b or higher received triptolide capsules at individualized doses ranging from 2 to 6 capsules daily, administered in divided doses (twice or thrice daily). Ten patients continued stable RASi-based regimens (monotherapy or combination therapy with sodium-glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, or endothelin receptor antagonists), while three patients received triptolide capsules monotherapy due to RASi contraindications secondary to advanced renal impairment. Comprehensive patient characteristics, including molecular genetics and baseline clinical parameters, are detailed in Supporting Information: Table S1. All participants completed a 3-month follow-up period. The primary efficacy endpoint was change in 24-h urinary protein excretion from baseline. Secondary endpoints included changes in eGFR and safety parameters, with adverse events comprehensively monitored. Quantitative data are expressed as median (interquartile range [IQR]) and analyzed using the Wilcoxon signed‑rank test. A p‑value < 0.05 was considered statistically significant. A p-value < 0.05 was considered statistically significant. Statistical analyses and figure generation were performed using R version 4.3.3. After 3 months of triptolide capsules therapy, mean 24‑h urinary protein decreased by 32.9%, from 1.66 (IQR: 0.87, 3.36) to 0.98 (IQR: 0.63, 2.63) g/d, p = 0.003. Concurrently, mean eGFR improved by 10.2%, from 25.77 (IQR: 21.08, 29.49) to 26.17 (IQR: 23.74, 29.55) mL·min−1·1.73 m−2, p = 0.023 (Figure 1, Supporting Information: Table S1). Notably, improvements in proteinuria and eGFR were observed in both patients receiving RASi-based combination therapy (n = 10) and those treated with triptolide monotherapy (n = 3). The consistent reduction in urinary total protein across these two subsets indicates that the clinical benefit of triptolide in advanced AS may be preserved regardless of prior exposure to RASi-based regimens. Two patients followed for 6 months maintained reduced proteinuria and stable eGFR. Triptolide's mechanism focuses on stabilizing the podocyte cytoskeleton and mitigating secondary tubulointerstitial inflammation. By targeting these downstream inflammatory and structural pathways, it may help preserve residual nephron function in advanced disease. In contrast, investigational strategies such as gene therapy, anti-miR-21, or ACE2-related approaches primarily address the underlying genetic and molecular drivers but may have limited capacity to restore renal function once advanced glomerulosclerosis and interstitial fibrosis are established. The consistent reduction in urinary total protein across these two subsets indicates that the clinical benefit of triptolide in advanced AS may be preserved regardless of prior exposure to RASi‑based regimens. The safety profile was favorable. No severe adverse events occurred. Only two premenopausal women reported menstrual irregularity. While triptolide carries known risks of hepatotoxicity, myelosuppression, and reproductive toxicity, our cohort showed a manageable safety profile under individualized dosing and close monitoring (Supporting Information: Table S2). Consequently, triptolide serves as a vital, clinically accessible intervention to protect residual nephrons and slow progression in this late-stage population. Unlike previous studies focused on add-on therapy in earlier-stage AS, our cohort addresses the urgent unmet need in advanced stage. Triptolide capsules' dual benefits of proteinuria reduction and renal function stabilization demonstrate its promise as a bridge therapy for this high-risk population. The small sample size and retrospective design reflect the rarity of advanced AS and inherent challenges in recruiting patients with advanced CKD; the relatively short follow-up period permits only preliminary assessment of efficacy and safety. Nevertheless, these real-world data provide meaningful evidence for this special population and can serve as foundation for future larger, prospective, multi-center studies. Zhuo-ran Song and Na Li: Data collection; data analysis/interpretation; statistical analysis; wrote the manuscript. Yang Li: Data collection; curation. Hong Zhang: Supervision; mentorship. Xu-jie Zhou: Research idea; study design; revised the manuscript; project administration; supervision. We thank the participants and their families for their time and effort. This work was supported by National High Level Hospital Clinical Research Funding (Interdisciplinary Clinical Research Project of Peking University First Hospital, Grand/Award Number: 2024IR35, 2022CR41; China International Medical Foundation, Grand/Award Number: Z-2017-26-2202-2; Beijing Bethune Charitable Foundation, Grand/Award Number: YPZ-41. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest. This real-world, single-center observational study was conducted within the established Alport syndrome cohort at Peking University First Hospital under Institutional Review Board approval (2023Y385). The patients have given consent of their clinical information to be published in the journal. The data that support the findings of this study are available in the supplementary material of this article. The data used in this article are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.