Allogeneic adipose tissue-derived stem cells ELIXCYTE® in chronic kidney disease: A phase I study assessing safety and clinical feasibility

Cai-Mei Zheng, I-Jen Chiu, Yu-Wei Chen, Yung-Ho Hsu, Lie-Yee Hung, Mei-Yi Wu, Yuh-Feng Lin, Chia-Te Liao, Yi-Pei Hung, Chia-Chu Tsai, Yih-Giun Cherng, Mai-Szu Wu, Cai-Mei Zheng, I-Jen Chiu, Yu-Wei Chen, Yung-Ho Hsu, Lie-Yee Hung, Mei-Yi Wu, Yuh-Feng Lin, Chia-Te Liao, Yi-Pei Hung, Chia-Chu Tsai, Yih-Giun Cherng, Mai-Szu Wu

Abstract

The purpose of this phase I clinical trial is to assess the safety and tolerability of allogeneic adipose tissue-derived stem cells (ADSCs) among chronic kidney disease (CKD) patients. 12 eligible CKD patients with an estimated glomerular filtration rate (eGFR) of 15-44 ml/min/1.73 m2 received one dose of intravenous allogeneic ADSCs (ELIXCYTE® ), as 3 groups: 3 low dose (6.4 × 107 cells in total of 8 ml), 3 middle dose (19.2 × 107 cells in total of 24 ml) and 6 high dose (32.0 × 107 cells in total of 40 ml) of ELIXCYTE® and evaluated after 48 weeks. Primary endpoint was the safety profiles in terms of incidence of adverse events (AEs) and serious adverse event (SAE). Two subjects in high dose group experienced a total of 2 treatment-related AEs which are Grade 1 slow speech and Grade 1 bradyphrenia after the infusion. One subject in middle dose group experienced an SAE unlikely related to treatment, grade 2 proteinuria. No fatal AE was reported in this study. An increase in eGFR was observed in 7 out of 12 subjects (58%) at Week 24 and in 6 of 12 subjects (50%) by Week 48. By Week 24, an increase in eGFR by more than 20% among all CKD patients with baseline eGFR ≧ 30 ml/min/1.73 m2 as compared to only 2 subjects in baseline eGFR < 30 ml/min/1.73 m2 group. No significant reduction in proteinuria was noted among all subjects. This phase I trial demonstrated single-dose intravenous ELIXCYTE was well tolerated in moderate-to-severe CKD patients and its preliminary efficacy warrants future studies.

Trial registration: ClinicalTrials.gov NCT02933827.

Keywords: allogeneic adipose tissue-derived stem cells; chronic kidney disease; estimated glomerular filtration rate.

Conflict of interest statement

No potential conflict of interest was reported by the authors.

© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Subject disposition
FIGURE 2
FIGURE 2
eGFR changes from baseline vs. visit over 48 weeks in (A) all treated subjects; (B) baseline eGFR 

References

    1. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease – A systematic review and meta‐analysis. PLoS One. 2016;11(7):e0158765.
    1. Chapter 1: definition and classification of CKD. Kidney Int Suppl (2011). 2013;3(1):19‐62.
    1. Couser WG, Remuzzi G, Mendis S, et al. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258‐1270.
    1. Bradbury BD, Fissell RB, Albert JM, et al. Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Clin J Am Soc Nephrol. 2007;2(1):89‐99.
    1. Foley RN, Chen SC, Solid CA, et al. Early mortality in patients starting dialysis appears to go unregistered. Kidney Int. 2014;86(2):392‐398.
    1. Hickson LJ, El‐Zoghby ZM, Lorenz EC, et al. Patient survival after kidney transplantation: relationship to pretransplant cardiac troponin T levels. Am J Transplant. 2009;9(6):1354‐1361.
    1. Bieback K, Wuchter P, Besser D, et al. Mesenchymal stromal cells (MSCs): science and f(r)iction. J Mol Med. 2012;90(7):773‐782.
    1. Tang HJ, Tian ZG, Yang X, et al. Cell‐based therapies for experimental diabetic nephropathy: a systematic review and meta‐analysis. J Biol Regul Homeost Agents. 2016;30(4):1047‐1051.
    1. Papazova DA, Oosterhuis NR, Gremmels H, et al. Cell‐based therapies for experimental chronic kidney disease: a systematic review and meta‐analysis. Dis Model Mech. 2015;8(3):281‐293.
    1. Eirin A, Lerman LO. Mesenchymal stem cell treatment for chronic renal failure. Stem Cell Res Ther. 2014;5(4):83.
    1. Franquesa M, Herrero E, Torras J, et al. Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev. 2012;21(17):3125‐3135.
    1. Choi S, Park M, Kim J, et al. The role of mesenchymal stem cells in the functional improvement of chronic renal failure. Stem Cells Dev. 2009;18(3):521‐529.
    1. Ezquer FE, Ezquer ME, Parrau DB, et al. Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant. 2008;14(6):631‐640.
    1. Chen YT, Sun CK, Lin YC, et al. Adipose‐derived mesenchymal stem cell protects kidneys against ischemia‐reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 2011;9:51.
    1. Zhu XY, Urbieta‐Caceres V, Krier JD, et al. Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells. 2013;31(1):117‐125.
    1. Eirin A, Zhang X, Zhu XY, et al. Renal vein cytokine release as an index of renal parenchymal inflammation in chronic experimental renal artery stenosis. Nephrol Dial Transplant. 2014;29(2):274‐282.
    1. Eirin A, Zhu XY, Krier JD, et al. Adipose tissue‐derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30(5):1030‐1041.
    1. Ebrahimi B, Eirin A, Li Z, et al. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis. PLoS One. 2013;8(7):e67474.
    1. Donizetti‐Oliveira C, Semedo P, Burgos‐Silva M, et al. Adipose tissue‐derived stem cell treatment prevents renal disease progression. Cell Transplant. 2012;21(8):1727‐1741.
    1. Lee SR, Lee SH, Moon JY, et al. Repeated administration of bone marrow‐derived mesenchymal stem cells improved the protective effects on a remnant kidney model. Ren Fail. 2010;32(7):840‐848.
    1. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end‐stage renal failure. J Am Soc Nephrol. 2006;17(1):17‐25.
    1. Pleniceanu O, Harari‐Steinberg O, Dekel B. Concise review: kidney stem/progenitor cells: differentiate, sort out, or reprogram? Stem Cells. 2010;28(9):1649‐1660.
    1. Packham DK, Fraser IR, Kerr PG, et al. Allogeneic mesenchymal precursor cells (MPC) in diabetic nephropathy: a randomized, placebo‐controlled, dose escalation study. Ebiomedicine. 2016;12:263‐269.
    1. Gimble JM, Katz AJ, Bunnell BA. Adipose‐derived stem cells for regenerative medicine. Circ Res. 2007;100(9):1249‐1260.
    1. Gonzalez MA, Gonzalez‐Rey E, Rico L, et al. Adipose‐derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(3):978‐989.
    1. Gonzalez MA, Gonzalez‐Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells. Arthritis Rheum. 2009;60(4):1006‐1019.
    1. Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res. 2005;305(1):33‐41.
    1. Rehman J, Traktuev D, Li J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292‐1298.

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