Cell Therapies in Diabetic Kidney Disease: Is It Time for Clinical Translation?

We followed with interest the report by Perico et al. on the next-generation human bone marrow-derived, antibody-purified (CD362+) population of next-generation bone marrow–derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) that preserves renal function (evaluated by eGFR estimated by the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease equations not by measured GFR) in people with progressive diabetic kidney disease.1 Mesenchymal stromal cells have emerged as potential candidates for cell-based therapies to modulate the immune response and repair tissues after injury.2 Immunologic profiling provided that ORBCEL-M preserves circulating regulatory T cells, lowers natural killer T cells, and stabilizes inflammatory monocyte subsets.1 We appreciated that their findings shed light on the research of cell-based therapies for patients with diabetic kidney disease. However, after reading this article, we would like to highlight some important issues in this study. First, we found that the article lacked descriptions of the kidney biopsy. According to previous research results, although renal lesions in patients with type II diabetes manifest in a quite heterogeneous fashion,3 histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR. Therefore, we thought the authors should have stated this in the article. The authors could further determine and compare the degree of renal lesions in different patients through kidney biopsy. These efforts will contribute to the credibility of their findings. Second, we observed that critical information, such as the hypoglycemic drugs, especially novel hypoglycemic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogs, were ignored. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogs had potential kidney protective effects, and the lack of this information might threaten the reproducibility of this study. Moreover, a previous multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled trial assessing a single intravenous infusion of allogeneic mesenchymal precursor cells or placebo in adults with diabetic nephropathy with an eGFR of 20–50 ml/min per 1.73 m2 indicated that mesenchymal precursor cell infusion stabilized or improved eGFR and measured GFR at week 12 without adverse events. However, we could find no measured GFR benefit in Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM). Not come singly but in pairs. A previous retrospective cohort study found that autologous adipose-derived mesenchymal stem cells significantly improved high-density lipoprotein, low-density lipoprotein, and remnant-like particle cholesterol levels.4 We could find no changes in total cholesterol and triglycerides in NEPHSTROM. Fourth, the wide range of baseline urine albumin-to-creatinine ratio as well as immune and inflammatory profiles in a small number of patients complicated the assessment of changes within and between groups in these parameters. In addition, multiple exploratory statistical analyses cannot rule out the possibility of type 1 errors. Finally, a small sample size is suitable for a 1b/2a trial, it cannot rule out rarer safety events. Although there were no immune-related adverse events, the authors have not reinfused patients with cells from the same donor to confirm the lack of sensitization. In conclusion, the authors documented the safety and tolerability of a single infusion of lowest dose ORBCEL-M in patients with diabetic kidney disease. However, further investigation of ORBCEL-M in diabetic kidney disease in appropriately sized and powered studies of longer duration, including periodic dosing and optimal dose and frequency, is urgently needed.