Efficacy and Safety of Human Bone Marrow-Derived Mesenchymal Stem Cells according to Injection Route and Dose in a Chronic Kidney Disease Rat Model.

Background and Objectives: We compared the efficacy and safety of human bone marrow-derived mesenchymal stem cells (hBMSC), delivered at different doses and via different injection routes in an animal model of chronic kidney disease. Methods and Results: A total of ninety 12-week-old rats underwent 5/6 nephrectomy and randomized among nine groups: sham, renal artery control (RA-C), tail vein control (TV-C), renal artery low dose (RA-LD) (0.5×106 cells), renal artery moderate dose (RA-MD) (1.0×106 cells), renal artery high dose (RA-HD) (2.0×106 cells), tail vein low dose (TV-LD) (0.5×106 cells), tail vein moderate dose (TV-MD) (1.0×106 cells), and tail vein high dose (TV-HD) (2.0×106 cells). Renal function and mortality of rats were evaluated after hBMSC injection. Serum blood urea nitrogen was significantly lower in the TV-HD group at 2 weeks (p<0.01), 16 weeks (p<0.05), and 24 weeks (p<0.01) than in the TV-C group, as determined by one-way ANOVA. Serum creatinine was significantly lower in the TV-HD group at 24 weeks (p<0.05). At 8 weeks, creatinine clearance was significantly higher in the TV-MD and TV-HD groups (p<0.01, p<0.05) than in the TV-C group. In the safety evaluation, we observed no significant difference among the groups. Conclusions: Our findings confirm the efficacy and safety of high dose (2×106 cells) injection of hBMSC via the tail vein.

Therapeutic Effect of Three-Dimensional Cultured Adipose-Derived Stem Cell-Conditioned Medium in Renal Ischemia-Reperfusion Injury.

Background and Objectives: We evaluated the effect of adipose-derived stem cell-derived conditioned medium (ADSC-CM) on the renal function of rats with renal ischemia-reperfusion injury (IRI)-induced acute kidney injury. Methods and Results: Forty male Sprague-Dawley rats were randomly divided into four groups: sham, nephrectomy control, IRI control, ADSC-CM. The ADSC-CM was prepared using the three-dimensional spheroid culture system and injected into renal parenchyme. The renal function of the rats was evaluated 28 days before and 1, 2, 3, 4, 7, and 14 days after surgical procedures. The rats were sacrificed 14 days after surgical procedures, and kidney tissues were collected for histological examination. The renal parenchymal injection of ADSC-CM significantly reduced the serum blood urea nitrogen and creatinine levels compared with the IRI control group on days 1, 2, 3, and 4 after IRI. The renal parenchymal injection of ADSC-CM significantly increased the level of creatinine clearance compared with the IRI control group 1 day after IRI. Collagen content was significantly lower in the ADSC-CM group than in the IRI control group in the cortex and medulla. Apoptosis was significantly decreased, and proliferation was significantly increased in the ADSC-CM group compared to the IRI control group in the cortex and medulla. The expressions of anti-oxidative makers were higher in the ADSC-CM group than in the IRI control group in the cortex and medulla. Conclusions: The renal function was effectively rescued through the renal parenchymal injection of ADSC-CM prepared using a three-dimensional spheroid culture system.

Comparison of Stromal Vascular Fraction and Adipose-Derived Stem Cells for Protection of Renal Function in a Rodent Model of Ischemic Acute Kidney Injury.

Aims: Few studies have compared the use of different cell types derived from adipose tissue or the optimal route for efficient and safe cell delivery in ischemic acute kidney injury (AKI). We compared the abilities of stromal vascular fraction (SVF) and adipose-derived stem cells (ADSC), injected via three different routes, to protect renal function in a rodent model of ischemic AKI. Methods: Ninety male Sprague-Dawley rats were randomly divided into 9 groups: sham, nephrectomy control, AKI control, transaortic renal arterial SVF injection, renal parenchymal SVF injection, tail venous SVF injection, transaortic renal arterial ADSC injection, renal parenchymal ADSC injection, and tail venous ADSC injection groups. Their renal function was assessed 4 days before and 1, 2, 3, 4, 7, and 14 days after surgical procedures to induce ischemic AKI. The histomorphometric studies were performed 14 days after surgical procedures. Results: Renal parenchymal injection of SVF notably reduced the level of serum blood urea nitrogen and creatinine elevation compared to the AKI control group. Renal parenchymal injection of SVF notably reduced the level of creatinine clearance decrease. In addition, collagen content was lower in the renal parenchymal SVF injection group, and fibrosis was reduced. Apoptosis was reduced in the renal parenchymal SVF injection group, and proliferation was increased. The expression levels of antioxidative markers such as glutathione reductase and peroxidase were higher in the renal parenchymal SVF injection group. Conclusions: Our findings suggest that renal function is protected from ischemic AKI through renal parenchymal injection of SVF, which has enhanced antifibrotic, antiapoptotic, and antioxidative effects.

Solo-surgeon pure laparoscopic donor nephrectomy using passive camera holder: IDEAL stage 2a study.

BACKGROUND: Solo-surgery can be defined as a practice of a surgeon operating alone using a camera holder, without other surgical members except for a scrub nurse. This study was designed to evaluate the feasibility and safety of solo-surgeon pure laparoscopic donor nephrectomy. METHODS: The study protocol was approved by the Institutional Review Board of Asan Medical Center, Seoul, Korea. The brief study protocol was registered on the Clinical Research Information Service site of the Korea Centers for Disease Control and Prevention. Candidates fulfilling all inclusion and exclusion criteria were enrolled in the clinical trial and underwent solo-surgeon pure laparoscopic donor nephrectomy. The feasibility was assessed by the proportion of subjects who could undergo solo-surgeon pure laparoscopic donor nephrectomy without difficulty. The perioperative complications were identified to assess the safety of solo-surgeon pure laparoscopic donor nephrectomy. RESULTS: Of the 47 potential candidates from November 2018 to August 2019, 40 were enrolled in the clinical trial and seven excluded due to declining participation. The feasibility of solo-surgeon pure laparoscopic donor nephrectomy was 100%, without an occasion of any difficulty requiring conversion to the human assisted pure laparoscopic donor nephrectomy. Fourteen intraoperative complications occurred in 10 patients. The most common intraoperative complication was spleen injury. Two of three cases classified as the Satava classification grade II were due to the incomplete stapling of endoscopic stapler. Seventy-eight postoperative complications occurred in 34 patients. The most common postoperative complication was nausea/vomiting and followed by aspartate aminotransferase/alanine aminotransferase elevation. Most postoperative complication was independent of the solo-surgery itself. CONCLUSIONS: Solo-surgeon pure laparoscopic donor nephrectomy using passive camera holder is technically feasible. In terms of safety, it is necessary to adjust the scope of surgery performed alone. Trial Registration CRIS, KCT0003458. Registered 30/01/2019, Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/15868 .

Therapeutic Effect of Human Mesenchymal Stem Cell-Conditioned Medium on Erectile Dysfunction.

PURPOSE: Owing to the safety and cost effectiveness of conditioned medium (CM), its therapeutic effects have attracted significant attention from many researchers. To date, numerous studies have been conducted on CM; however, little has been done with regard to erectile dysfunction (ED). In this research, the potential of human mesenchymal stem cell-derived CM (MSC-CM) for the treatment of ED was investigated. MATERIALS AND METHODS: A high concentration of MSC-CM was prepared through 3D spheroid culturing with bone marrow-derived MSCs and cut-off filtering. The composition of CM was analyzed using biochemical assays, and the effect of the preparation process on the quality of CM was investigated. The therapeutic effects of MSC-CM were evaluated through animal studies using a cavernous nerve (CN) injury rat model. RESULTS: 3D spheroid culturing afforded a 278-fold increase in the total protein content of CM, as compared to that from 2D cultures; the protein concentration increased by 19 times on increasing the centrifugation time for cut-off filtering. Biochemical assays indicated that the CM contains various types of angiogenic, neurotrophic, and anti-inflammatory factors. Histological assay results showed that MSC-CM has angio- and neuro-trophic effect in a CN injury rat model in vivo, and these therapeutic effects appear in a dose-dependent manner. CONCLUSIONS: The experimental results confirmed the therapeutic effect of MSC-CM in healing damaged cavernosal tissue and restoring erectile function. These results successfully demonstrated that MSC-CM has significant potential for the treatment of ED.

Pure laparoscopic donor nephrectomy without routine drainage does not increase postoperative morbidity.

PURPOSE: We aimed to define the feasibility of the omission of routine insertion of a drain after pure laparoscopic donor nephrectomy (PLDN). We compared the outcomes between those with and without routine drain insertion. MATERIALS AND METHODS: From July 2014 to October 2018, 178 PLDN were consecutively performed by a single surgeon. Since October 2016, we stopped routine insertion of a drain after PLDN. Thus, the former 80 drained routinely were defined as the Drainage group and the latter 98 were defined as the Non-drainage group. One patient drained non-routinely in the Non-drainage group was excluded from the final analysis. Operative and convalescence parameters and intra- and postoperative complications were compared between the groups. Intra- and postoperative complications within 90 days of surgery were graded using the Satava and Clavien-Dindo classifications, respectively. RESULTS: Baseline characteristics were similar between the groups, except for concomitant surgery, American Society of Anesthesiologists score, and preoperative glomerular filtration rate. All operative and convalescence parameters were similar between the groups, except for postoperative glomerular filtration rate. The rates of overall intra- (22.5% versus 28.9%, p=0.337) and postoperative (62.5% versus 59.8%, p=0.713) complications were similar between the groups. The rates of potentially drain-related postoperative complications were also similar between the groups (36.3% versus 33.0%, p=0.650). Two patients per group suffered from major drain-related complications (2.5% versus 2.1%). CONCLUSIONS: PLDN without routine drainage can be performed safely without an increase in postoperative morbidity.

Hypoxic Preconditioned Mesenchymal Stromal Cell Therapy in a Rat Model of Renal Ischemia-reperfusion Injury: Development of Optimal Protocol to Potentiate Therapeutic Efficacy.

Although previous and ongoing clinical studies have used stromal cells during renal ischemia-reperfusion injury (IRI), there is little consensus regarding the optimal protocol. We aimed to optimize the protocol for hypoxic preconditioned human bone marrow-derived mesenchymal stromal cell (HP-hBMSC) therapy in a rat model of renal IRI. We determined the optimal injection route (renal arterial, renal parenchymal, and tail venous injection), dose (low-dose: 1×106, moderate-dose: 2×106, and high-dose: 4×106), and injection period (pre-, concurrent-, and post-IRI). During optimal injection route study, renal arterial injections significantly reduced the decreasing glomerular filtration rate (GFR), as compared to GFRs for the IRI control group, 2 and 4 days after IRI. Therapeutic effects and histological recoveries were the greatest in the group receiving renal arterial injections. During the dose finding study, high-dose injections significantly reduced the decreasing GFR, as compared to GFRs for the IRI control group, 3 days after IRI. Therapeutic effects and histological recoveries were the greatest in the high-dose injection group. While determining the optimal injection timing study, concurrent-IRI injection reduced elevated serum creatinine levels, as compared to those of the IRI control group, 1 day after IRI. Pre-IRI injection significantly reduced the decreasing GFR, as compared with GFRs for the IRI control group, 1 day after IRI. Therapeutic effects and histological recoveries were the greatest in the concurrent-IRI group. In conclusion, the concurrent-IRI administration of a high dose of HP-hBMSC via the renal artery leads to an optimal recovery of renal function after renal IRI.