Investigated the safety of intra-renal arterial transfusion of autologous CD34+ cells and time courses of creatinine levels, endothelial dysfunction biomarkers and micro-RNAs in chronic kidney disease patients-phase I clinical trial

Abstract

This was a phase I clinical trial to investigate the safety of autologous peripheral-blood-derived CD34+ cell therapy for patients with chronic kidney disease (CKD-treatment) (i.e., at Stages III and IV). Between November 2014 and October 2015, a total of 10 study patients were prospectively enrolled into this phase I trial. Patients who failed to enroll into the trial in the initial state of eligibility assessment were served as CKD-control group (n = 9). The health-control group was composed of 10 volunteers for the purposes of comparing (1) circulation level of endothelial progenitor cells (EPCs), (2) angiogenesis ability, and (3) anti-apoptotic miRNAs between healthy subjects and CKD patients. CD34+ cells (5.0 × 107) were transfused into right-renal artery after subcutaneous G-CSF injection (5μg/kg/twice a day for 4 days). Circulating EPC number, angiogenesis capacity (i.e., Matrigel assay) and anti-apoptotic miRNAs (miR-374a-5p/miR-19a-3p/ miR-106b-5p/miR-26b-5p/ miR-20a-5p) were significantly lower in CKD patients than in healthy subjects (all p < 0.001). Flow-cytometric analysis of renal-vein blood samplings (i.e., at 0/5/10/30 mins after cell transfusion) showed the EPC level was significantly progressively increased (p < 0.001). Procedural safety was 100% with all patients uneventfully discharged and one-year survival rate was 100%. The paired-t test showed serum creatinine maintained the same level between the baseline and at the end of one-year follow-up (all p > 0.4), whereas the net increase between initial and final creatinine level was higher in CKD-control than in CKD-treatment. In conclusion, CD34+ cell therapy was safe and maintained the renal function in stationary state at the end of study period.

Intravenous administration of iPS‐MSCSPIONs mobilized into CKD parenchyma and effectively preserved residual renal function in CKD rat

“…The most important finding in the present study was that, as compared with CKD only, intravenous administration of iPS‐MSCs significantly preserved residual renal function (ie reduced the levels of creatinine/BUN and the ratio of urine creatinine to urine protein) and reduced the kidney injury score (ie HE, stain pathological findings). Our findings corroborate those of previous studies . Additionally, the cellular expressions of podocyte components (ie ZO‐1, synaptopodin) and endothelial cell surface marker (ie CD31 + ) were preserved, whereas renal tubular injury biomarker (ie KIM‐1) was substantially reduced in CKD animals treated by iPS‐MSCs than in CKD only animals.…”

“…The fate and final destination of intravenous administration of stem cells for treatment of chronic phase of ischaemic‐related organ dysfunction, including in the setting of CKD, have not been fully investigated. This raises questions why some investigators in clinical trials tend towards intra‐arterial administration of stem cells into ischaemic organs for improving ischaemia‐related organ dysfunction, even though intra‐arterial administration of stem cells is more invasive than intravenous administration . The novel finding in the present study was that, using MRI examination, we precisely identified that intravenously administered iPS‐MSC SPIONs (ie iron‐labelled iPS‐MSCs) settled in kidney parenchyma of CKD, but not in healthy, kidney, highlighting that a chronically dysfunctional organ can capture stem cells for tissue/organ repair and regeneration.…”

“…This raises questions why some investigators in clinical trials tend towards intra-arterial administration of stem cells into ischaemic organs for improving ischaemia-related organ dysfunction, even though intra-arterial administration of stem cells is more invasive than intravenous administration. 23,32,33 The novel finding in the present study was that, using MRI examination, we precisely identified that intravenously administered iPS-MSC SPIONs (ie iron-labelled iPS-MSCs) settled in kidney parenchyma of CKD, but not in healthy, kidney, highlighting that a chronically dysfunctional organ can capture stem cells for tissue/organ repair and regeneration. Accordingly, our data provide important and clinically supportive information for intravenous administration (ie an alternative route) of stem cell therapy.…”

“…Numerous data have emphasized the therapeutic impact of stem cells on improving ischaemic-related organ dysfunction. 18,[20][21][22][23][24] The most important finding in the present study was that, as compared with CKD only, intravenous administration of iPS-MSCs significantly preserved residual renal function (ie reduced the levels of creatinine/ BUN and the ratio of urine creatinine to urine protein) and reduced the kidney injury score (ie HE, stain pathological findings). Our findings corroborate those of previous studies.…”

“…Interestingly, pre-clinical and clinical studies 18,[20][21][22][23][24] have shown that therapy with mesenchymal stem cells (MSCs)/endothelial progenitor cells (EPCs) for CKD is safe and preserves residual renal function in the setting of CKD. Recently, human induced pluripotent stem cell (iPSC)-derived MSCs have been shown to exhibit multiple paracrine actions for organ repair and regeneration because of the strong capacity of self-renewal and differentiation into most somatic cell lineages.…”