First clinical application of cord blood mesenchymal stromal cells in children with multi-drug resistant nephrotic syndrome

Abstract

Background and objectives Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Design, setting, participants Prospective, open-label, single arm phase I–II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Results Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. Conclusions CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.

A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome

“…To the best of our knowledge, only 1 study on the safety and efficacy of MSC treatment was performed in an INS setting ( 19 ). Eleven children with multidrug-resistant NS, who had failed a median of 3 previous lines of therapy, completed 3 infusions at 0, 14, and 21 days of allogeneic cord blood–derived MSCs at 1.5 × 10 6 cells/kg and no infusion-related AE or toxicity was observed.…”

“…Most likely, this is due to the transient benefit of BM-MSC treatment, which was invariably followed within 12 months by disease relapse, with the consequent need for repeated courses of oral prednisone in all patients. To the best of our knowledge, only 1 study on the safety and efficacy of MSC treatment was performed in an INS setting (19). Eleven children with multidrug-resistant NS, who had failed a median of 3 previous lines of therapy, completed 3 infusions at 0, 14, and 21 days of allogeneic cord blood-derived MSCs at 1.5 × 10 6 cells/kg and no infusion-related AE or toxicity was observed.…”

“…Together, these data indicate that MSCs can suppress immune system activation by regulating cells of the adaptive and innate immune system. Therefore, the potential therapeutic role of MSCs has been tested in a variety of clinical settings, and several phase I and phase II studies have confirmed their safety with no adverse effects up to 1 year after treatment exposure ( 14 – 16 ) and suggested their effectiveness in a number of immune-mediated diseases, including glomerulopathies ( 12 , 17 – 19 ).…”

Novel therapeutic approaches for steroid-resistant nephrotic syndrome in paediatric patients: a comprehensive review

“…The results indicate that out of the 11 patients involved in the trial, 3 patients experienced either partial or total remission. 21…”

Clinical Prospect of Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles in Kidney Disease: Challenges and the Way Forward

“…Numerous studies have confirmed the beneficial effects of MSCs for the treatment of a variety of pathologies, including kidney diseases [ 19 , 20 , 21 , 22 , 23 , 24 ]. Nevertheless, in the MSC field, it became obvious that MSCs exert therapeutic functions via their secretome [ 25 , 26 , 27 , 28 ], and that the biologically active component of MSC secretome, i.e., extracellular vesicles (EVs), can be used in place of MSCs as potential therapeutics.…”