Novel Cellular Immunotherapy in Refractory Membranous Nephropathy: A First-in-Human Trial of Human Umbilical Cord Blood-Derived Mononuclear Cells

(Objective) The clinical value of human umbilical cord blood mononuclear cells (hUCBMNCs) in chronic kidney disease and acute renal failure has been confirmed. This study further explores the clinical efficacy and safety of hUCBMNCs in the treatment of refractory membranous nephropathy (MN), and observes the changes in clinical indicators and lymphocyte subsets in patients with refractory MN who have had poor long-term follow-up results with the classic treatment regimen after receiving hUCBMNCs. (Methods) Eight patients with refractory MN diagnosed at Taian Central Hospital in Shandong Province from January 2022 to March 2024 were enrolled. All eight patients had received the classic treatment regimen for MN with poor results. They were then treated with intravenous infusion of hUCBMNCs (a course of treatment consisting of three intravenous infusions of 2.00×10^8 (100 ml) units of hUCB-MNCs, with a 1-week interval between each infusion. Individual patients with BMI > 30 received an additional intravenous infusion of 2.00×10^8 (100 ml) units of hUCB-MNCs). The clinical manifestations and ancillary examination results of the patients were collected. The therapeutic effects and disease outcomes were observed at short-term follow-up (1 week, 2 weeks, and 4 weeks after treatment) and long-term follow-up (12 weeks after treatment). (Results) During the short-term follow-up, 7 patients experienced varying degrees of clinical improvement during the treatment process, while 1 patient showed no response to the treatment. The 24-hour urinary protein excretion and concentration were significantly improved during the treatment (P＜0.05). The maximum reduction in 24-hour urinary protein excretion was 46%-79%. The serum albumin levels increased in 75% of the patients, and the levels of CD3 ⁺ 4 ⁺ 8 ⁺ lymphocytes were elevated (P＜0.05). By the end of the long-term follow-up, 5 patients had significant improvements in 24-hour urinary protein excretion and concentration (P＜0.05), 2 patients showed no response to the treatment, and 1 patient withdrew from the long-term follow-up. The effective rate of treatment was 71%. The reduction in 24-hour urinary protein excretion in the 5 patients ranged from 17% to 76%, with 1 patient achieving complete remission (CR) and 3 patients achieving partial remission (PR). The levels of serum B lymphocytes and NK lymphocytes were increased compared to before the treatment (P＜0.05), and all patients experienced an improvement in fatigue symptoms. (Conclusion) hUCBMNCs can significantly reduce the 24-hour urinary protein excretion and concentration, increase the serum albumin levels, and improve the condition and symptoms of patients with refractory MN through immune regulation and immune system reconstruction. Improvement can be observed immediately after the first treatment, with a rapid onset of action, no need for an accumulation dose, few adverse reactions, and high safety.