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

We thank Drs. Chen and Liang1 for their very relevant comments on our manuscript.2 In regard to kidney biopsies, we agree that analysis of pathologic abnormalities could have allowed us to definitively exclude patients with nondiabetic CKD3 and might further strengthen the between-group comparisons. However, as described, histologic diagnosis was not a trial inclusion criterion, and only 1 of 16 enrolled participants had a prior kidney biopsy (which confirmed diabetic nephropathy). In our discussions during the design of the trial, we concluded that (1) the risk of performing a biopsy as part of the study protocol could not be justified and (2) the frequency of prior biopsy confirmation of diabetic nephropathy among patients attending our three clinical sites was too low to support adequate enrollment. We believe that other trial inclusion criteria, such as the presence of abnormal albuminuria and lack of clinical features suspicious for non–diabetes-associated CKD, minimized the likelihood that some enrolled patients had kidney diseases distinct from diabetic kidney disease and are consistent with many other therapeutic trials in diabetic kidney disease. Regarding the lack of information on newer hypoglycaemic drugs, we have documented that only 1 of 16 participants was prescribed a sodium-glucose cotransporter 2 inhibitor at the time of randomization. We now also clarify that four participants in the placebo group and three in the ORBCEL-M group were prescribed a DPP4 inhibitor or glucagon-like peptide-1 receptor agonist at the time of enrollment. We recognize that protocolized inclusion of such agents and/or focusing on participants unable to tolerate them will be critical issues for future cell therapy trial designs. In relation to the effects of mesenchymal stromal cell (MSC) therapy on the rate of decline of GFR, we believe that our results are generally consistent with those previously reported for allogeneic mesenchymal precursor cells during a shorter follow-up period.4 In Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) cohort 1, the rate of decline of measured GFR was numerically but not significantly lower for recipients of ORBCEL-M compared with placebo over 18 months of follow-up, while similar trends for eGFR were statistically significance. For lipid parameters, the lack of significant changes after MSC therapy was unsurprising to us in this prospectively followed, placebo-controlled clinical trial cohort and likely reflects that the trial participants had good, stable lipid control at the time of enrollment. Finally, although our findings document the safety and tolerability and confirm low potential for this MSC-based cell therapy to sensitize recipients, we acknowledge that the small sample size of NEPHSTROM provides only preliminary evidence of its potential renoprotective and immune modulatory/anti-inflammatory effects. Thus, we fully agree with Chen and Liang that the larger numbers of participants and incorporation of other design features will be necessary to validate these findings in future trials.