Discussion
atherosclerotic renal disease, acute tubular injury, toxic chemicals, fibrosis, disease stage, dehydration, renal disease, non-SVF-treated CKDu, nephropathy, atherosclerotic vascular renal disease, tubulointerstitial nephritis
CELLULAR INFILTRATE, DISEASE, FIBROSIS, INTERSTITIAL EDEMA, DEHYDRATION, RENAL DISEASE, NEPHROPATHY, HEAT, TUBULOINTERSTITIAL NEPHRITIS, PATHOLOGY
CKDu is an aggressive nephropathy of unknown etiology and is often fatal in resource-poor countries that have limited access to dialysis care. This first-in-human study shows that administration of adipose derived, autologous SVF cells via renal artery catheterization is feasible and safe. In addition, this study provides potential evidence that intra-arterial SVF treatment may result in improved kidney function over a sustained period of time, principally in early stages of the disease.Recent pathology studies suggest that CKDu begins with an acute insult to the kidney, potentially due to environmental causes (heat stress, dehydration, toxic chemicals), drugs, or infectious agents. The initial pathology in most patients who subsequently meet the criteria for CKDu reveals tubulointerstitial nephritis with varying degrees of acute tubular injury, interstitial edema, interstitial immune cellular infiltrates, and early fibrosis.The preliminary clinical results of this study appear to correlate with the above pathology studies, that is, the earlier CKDu patients (stages 3a and 3b) had a response to SVF that could reflect the known properties of SVF which include anti-inflammatory and anti-fibrotic properties, as well as the potential for tissue healing. These earlier stage patients had an increase in kidney volume which could be consistent with tissue healing and decreased fibrosis. They also demonstrated improved hilar RRI consistent with improved blood flow. Enhanced circulation could be related an increase in local formation of new blood vessels, perhaps in response to the known capability of MSC to produce and secrete vascular endothelial growth factor (VEGF). In contrast, the stages 4 and 5 patients had only a temporary improvement to the SVF therapy, consistent with a more “burnt-out” tissue state.Textor, Saad, and team looked at the safety, dose, and early evidence of efficacy of autologous Thus, the relevant physiologic mechanisms by which SVF might improve CKDu would seem to be aligned with the same mechanisms suggested by the beneficial treatment of atherosclerotic vascular renal disease by cultured adipose MSCs, that is, a decreased pro-inflammatory state, decreased fibrosis, and improved vascular flow. These changes in the underlying renal disease state are most likely due to the paracrine mediators released by the infused adipose stem/stromal cells upon infusion into the injured renal tissue. These findings from the cultured adipose MSC—atherosclerotic renal disease study are also relevant to the observations made in this study as to the degree of SVF treatment benefit seemed to be related to CKDu stage—if the kidneys are already significantly sclerotic, cell therapy is likely to be of limited benefit. An eGFR of 30 mL/minute/1.73 mThis study constitutes the first time that fresh, non-culture expanded, adipose-derived SVF has been used for the treatment of CKDu patients. This study has a number of limitations, principally a small sample size and lack of a randomized control group. Given the fatal nature of this disease, MINSA policy precludes invasive procedures with no clear potential for patient benefit. Therefore, 12 non-SVF-treated CKDu patients were selected for a historical comparison cohort, matched for age and disease stage, as a first-pass model to compare to the SVF-treated patients and to better evaluate safety and potential clinical utility. An additional limitation was the unavailability of kidney tissue to evaluate for pathophysiological changes before and after the intervention.Feasibility and safety were evaluated in this first-in-human study and insight was gained for future investigations as subjects with a wide spectrum of disease severity were evaluated. This study also provided evidence of potential clinical utility and for an effect size that will inform subsequent SVF clinical trials. MINSA has approved a subsequent study using a crossover design of single versus bilateral infusion such that all patients can have access to potential benefit while allowing for focus on the specific anatomic effects of SVF infusion. This follow-on study will have a larger number of patients, will concentrate on stages 3a and 3b disease, will use a standardized SVF treatment dose, and will include pre- and post-treatment histopathology.