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Due to the shortage of kidneys donated for transplantation, surgeons are forced to use the organs with an elevated risk of poor function or even failure. Although the existing methods for pre-transplant quality evaluation have been validated over decades in population cohort studies across the world, new methods are needed as long as delayed graft function or failure in a kidney transplant occurs. In this study, we explored the potential of utilizing photoacoustic (PA) imaging during normothermic machine perfusion (NMP) as a means of evaluating kidney quality. We closely monitored twenty-two porcine kidneys using 3D PA imaging during a two-hour NMP session. Based on biochemical analyses of perfusate and produced urine, the kidneys were categorized into ‘non-functional’ and ‘functional’ groups. Our primary focus was to quantify oxygenation (sO2) within the kidney cortical layer of depths 2 mm, 4 mm, and 6 mm using two-wavelength PA imaging. Next, receiver operating characteristic (ROC) analysis was performed to determine an optimal cortical layer depth and time point for the quantification of sO2 to discriminate between functional and non-functional organs. Finally, for each depth, we assessed the correlation between sO2 and creatinine clearance (CrCl), oxygen consumption (VO2), and renal blood flow (RBF). We found that hypoxia of the renal cortex is associated with poor renal function. In addition, the determination of sO2 within the 2 mm depth of the renal cortex after 30 min of NMP effectively distinguishes between functional and non-functional kidneys. The non-functional kidneys can be detected with the sensitivity and specificity of 80% and 85% respectively, using the cut-off point of sO2 < 39%. Oxygenation significantly correlates with RBF and VO2 in all kidneys. In functional kidneys, sO2 correlated with CrCl, which is not the case for non-functional kidneys. We concl, Biomechanical Engineering

BACKGROUND: The impact of aortoiliac occlusive disease on kidney transplantation remains unclear. This study aims to investigate the clinical outcomes of kidney transplant patients with aortoiliac atherosclerotic stenosis. METHODS: Retrospective data from our transplant center were used to identify patients undergoing kidney transplantation between January 2010 and December 2020. Aortoiliac atherosclerotic stenosis was screened and stratified by the Trans-Atlantic Inter-Society Consensus (TASC) II classification. The primary outcome was patient survival. Secondary outcomes were 90-day mortality, death-censored graft survival, graft function, and arterial complications. Propensity score matching was used to match all patients in the stenosis group with patients without stenosis sharing similar characteristics. RESULTS: The analysis included 655 patients, 524 without stenosis and 131 with aortoiliac stenosis (95 with TASC A/B stenosis and 36 with TASC C/D stenosis). Recipient age [median (IQR), 66 (60-70) vs. 66 (59-71) years; P =0.47], sex [male: 87 (66%) vs. 355 (68%), P =0.85], and comorbidities were comparable between the stenosis and no-stenosis groups. Forty-six (35%) patients with stenosis were symptomatic. Patient survival was significantly lower in the stenosis group compared with the no-stenosis group (TASC A/B: 30.6% vs. no-stenosis: 44.1%, P =0.013; TASC C/D: 11.4% vs. no-stenosis: 44.1%, P <0.001). The incidence rates of artery dissection, lower extremity ischemia, and acute thrombosis were significantly higher in the stenosis group ( P <0.001). However, death-censored graft survival (TASC A/B: 73.6% vs. no-stenosis: 72.9%, P =0.62; TASC C/D: 58.1% vs. no-stenosis: 72.9%, P =0.16) and graft function were comparable between the groups. CONCLUSIONS: Aortoiliac atherosclerotic stenosis significantly impacts patient survival but not graft survival. Our analyses suggest that patients with TASC A/B stenosis have prolonged survival and enhanced quality

Objectives: Normothermic machine perfusion (NMP) provides a platform for pre-transplant kidney quality assessment that is essential for the use of marginal donor kidneys. Laser speckle contrast imaging (LSCI) presents distinct advantages as a real-time and noncontact imaging technique for measuring microcirculation. In this study, we aimed to assess the value of LSCI in visualizing renal cortical perfusion and investigate the additional value of dual-side LSCI measurements compared to single aspect measurement during NMP. Methods: Porcine kidneys were obtained from a slaughterhouse and then underwent NMP. LSCI was used to measure one-sided cortical perfusion in the first 100 min of NMP. Thereafter, the inferior renal artery branch was occluded to induce partial ischemia and LSCI measurements on both ventral and dorsal sides were performed.Results: LSCI fluxes correlated linearly with the renal blood flow (R2 = 0.90, p < 0.001). After renal artery branch occlusion, absence of renal cortical perfusion could be visualized and semiquantified by LSCI. The overall ischemic area percentage of the ventral and dorsal sides was comparable (median interquartile range [IQR], 38 [24−43]% vs. 29 [17−46]%, p = 0.43), but heterogenous patterns between the two aspects were observed. There was a significant difference in oxygen consumption (mean ± standard deviation [SD], 2.57 ± 0.63 vs. 1.83 ± 0.49 mLO2/min/100 g, p < 0.001), urine output (median [IQR], 1.3 [1.1−1.7] vs. 0.8 [0.6−1.3] mL/min, p < 0.05), lactate dehydrogenase (mean ± SD, 768 ± 370 vs. 905 ± 401 U/L, p < 0.05) and AST (mean ± SD, 352 ± 285 vs. 462 ± 383 U/L, p < 0.01) before and after renal artery occlusion, while no significant difference was found in creatinine clearance, fractional excretion of sodium, total sodium reabsorption and histological damage. Conclusions:LSCI fluxes correlated linearly with

Introduction: Short-term fasting protects against renal ischemia reperfusion injury (IRI). mTOR signaling is downregulated and may be involved in its protective effect. Rapamycin is considered a possible mimetic as it inhibits the mTOR pathway. This study examines the effect of rapamycin on renal IRI. Material and Methods: Mice were divided into four groups: ad libitum (AL), fasted (F), AL treated with rapamycin (AL+R), and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24 h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48 h after reperfusion. Oxidative stress resistance of human renal proximal tubular and human primary tubular epithelial cells after rapamycin treatment was determined. Results: All F and F+R mice survived the experiment. Although rapamycin substantially downregulated mTOR activity, survival in the AL+R group was similar to AL (10%). Renal regeneration was significantly reduced in AL+R but not in F+R. After IRI (48 h), pS6K/S6K ratio was lower in F, F+R, and AL+R groups compared to AL fed animals (p = 0.02). In vitro, rapamycin also significantly downregulated mTOR activity (p < 0.001) but did not protect against oxidative stress. Conclusion: Rapamycin pretreatment does not protect against renal IRI. Thus, protection against renal IRI by fasting is not exclusively mediated through inhibition of mTOR activity but may involve preservation of regenerative mechanisms despite mTOR downregulation. Therefore, rapamycin cannot be used as a dietary mimetic to protect against renal IRI.

Objectives: Normothermic machine perfusion (NMP) provides a platform for pre-transplant kidney quality assessment that is essential for the use of marginal donor kidneys. Laser speckle contrast imaging (LSCI) presents distinct advantages as a real-time and noncontact imaging technique for measuring microcirculation. In this study, we aimed to assess the value of LSCI in visualizing renal cortical perfusion and investigate the additional value of dual-side LSCI measurements compared to single aspect measurement during NMP. Methods: Porcine kidneys were obtained from a slaughterhouse and then underwent NMP. LSCI was used to measure one-sided cortical perfusion in the first 100 min of NMP. Thereafter, the inferior renal artery branch was occluded to induce partial ischemia and LSCI measurements on both ventral and dorsal sides were performed. Results: LSCI fluxes correlated linearly with the renal blood flow (R2 = 0.90, p < 0.001). After renal artery branch occlusion, absence of renal cortical perfusion could be visualized and semiquantified by LSCI. The overall ischemic area percentage of the ventral and dorsal sides was comparable (median interquartile range [IQR], 38 [24−43]% vs. 29 [17−46]%, p = 0.43), but heterogenous patterns between the two aspects were observed. There was a significant difference in oxygen consumption (mean ± standard deviation [SD], 2.57 ± 0.63 vs. 1.83 ± 0.49 mLO2/min/100 g, p < 0.001), urine output (median [IQR], 1.3 [1.1−1.7] vs. 0.8 [0.6−1.3] mL/min, p < 0.05), lactate dehydrogenase (mean ± SD, 768 ± 370 vs. 905 ± 401 U/L, p < 0.05) and AST (mean ± SD, 352 ± 285 vs. 462 ± 383 U/L, p < 0.01) before and after renal artery occlusion, while no significant difference was found in creatinine clearance, fractional excretion of sodium, total sodium reabsorption and histological damage. Conclusions: LSCI fluxes correlated linearly with renal blood flow during NMP. Renal cortical microcirculation and absent pe, Medical Instruments & Bio-Inspired Technology

Background: Obesity is becoming more prevalent in the end-stage renal disease population. Bariatric surgery (BS) is increasingly considered as an approach to become eligible for kidney transplant (KT) or reduce obesity-related morbidities. Objectives: To assess the short- and long-term outcomes of patients who underwent both BS and KT and to determine the optimal timing of BS. Methods: Patients who underwent both KT and BS between January 2000 and December 2020 were included and stratified according to the sequence of the 2 operations. The primary outcomes were patient and graft survival. The secondary outcomes were postoperative complications and efficacy of weight loss. Results: Twenty-two patients were included in the KT first group and 34 in the BS first group. Death-uncensored graft survival in the KT first group was significantly higher than in the BS first group (90.9% versus 71.4%, P = .009), without significant difference in patient survival and death-censored graft survival (100% versus 90.5%, P = .082; 90.9% versus 81.0%, P = .058). There was no significant difference in 1-year total weight loss (1-yr TWL: median [interquartile range {IQR}], 36.0 [28.0–42.0] kg versus 29.6 [21.5–40.6] kg, P = .424), 1-year percentage of excess weight loss (1-yr %EWL: median [IQR], 74.9 [54.1–99.0] versus 57.9 [47.5–79.4], P = .155), and the incidence of postoperative complications (36.4% versus 50.0%, P = .316) between the KT first and BS first groups. Conclusion: Both pre- and posttransplant BS are effective and safe. Different conditions of each transplant candidate should be considered in detail to determine the optimal timing of BS.

Background: Kidney transplantation is the optimal treatment of end-stage renal disease. Extracellular vesicles (EVs) have tremendous therapeutic potential, but their role in modulating immune responses in kidney transplantation remains unclear. Methods: We performed a systematic review and meta-analysis to investigate the therapeutic efficacy of EVs in preclinical kidney transplant models. Outcomes for meta-analysis were graft survival and renal function. Subgroup analysis was conducted between immune cell derived EVs (immune cell-EVs) and mesenchymal stromal cell derived EVs (MSC-EVs). Results: Seven studies published from 2013 to 2021 were included. The overall effects showed that EVs had a positive role in prolonging allograft survival (standardized mean difference (SMD) = 2.00; 95% confidence interval (CI), 0.79 to 3.21; P < 0.01; I2 = 94%), reducing serum creatinine (SCr) (SMD = -2.19; 95%CI, −3.35 to −1.04; P < 0.01; I2 = 93%) and blood urea nitrogen (BUN) concentrations (SMD = -1.69; 95%CI, −2.98 to −0.40; P = 0.01; I2 = 94%). Subgroup analyses indicated that only immune cell-EVs significantly prolonged graft survival and improve renal function but not MSC-EVs. Conclusions: EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs in prolonging graft survival and improving renal function. For interpretation of the outcomes, additional studies are needed to validate these findings.

INTRODUCTION: Ageing of the general population has led to an increase in the use of suboptimal kidneys from expanded criteria donation after brain death (ECD-DBD) and donation after circulatory death (DCD) donors. However, these kidneys have inferior graft outcomes and lower rates of immediate function. Normothermic machine perfusion (NMP) may improve outcomes of these suboptimal donor kidneys. Previous non-randomized studies have shown the safety of this technique and suggested its efficacy in improving the proportion of immediate functioning kidneys compared to static cold storage (SCS). However, its additional value to hypothermic machine perfusion (HMP), which has already been proved superior to SCS, has not yet been established.METHODS AND ANALYSIS: This single-center, open-label, randomized controlled trial aims to assess immediate kidney function after 120 minutes additional, end-ischemic NMP compared to HMP alone. Immediate kidney function is defined as no dialysis treatment in the first week after transplant. Eighty recipients on dialysis at the time of transplant who receive an ECD-DBD or DCD kidney graft are eligible for inclusion. In the NMP group, the donor kidney is taken of HMP upon arrival in the recipient hospital and thereafter put on NMP for 120 minutes at 37 degrees Celsius followed by transplantation. In the control group, donor kidneys stay on HMP until transplantation. The primary outcome is immediate kidney function.ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethical Committee of Erasmus Medical Center (2020-0366). Results of this study will be submitted to peer-reviewed journals.REGISTRATION: registered in clinicaltrials.gov (NCT04882254).HIGHLIGHTS: This is the first RCT to compare additional NMP to HMP alone.Extensive sampling will offer in-depth analysis of kidney physiology during NMP.This RCT may help identify biomarkers to predict clinical outcomes during NMP.Biomarkers can hel

We present an updated overview of the literature comparing normothermic with hypothermic machine perfusion in porcine kidneys. We conducted a systematic literature review in Embase, Medline Epub (Ovid), Cochrane Central, Web of Science, and Google Scholar on studies comparing normothermic (NMP) to hypothermic machine perfusion (HMP) in porcine kidneys. A meta-analysis was judged inappropriate because of heterogeneity in study design and perfusion methods. The quality of evidence of each included study was assessed. We included 8 studies. One out of 5 studies reported a significant difference in peak renal blood flow in favor of NMP. Oxygen consumption was significantly higher in NMP kidneys in 2 out of 5 studies. Peak creatinine clearance in NMP was significantly higher than that in HMP in 1 out of 6 studies. Two out of 4 studies reported a higher degree of epithelial vacuolation in kidneys receiving NMP over HMP. None of the studies found a significant difference between NMP and HMP in peak serum creatinine or graft survival after autotransplantation. The results need to be interpreted with caution in view of the diversity in perfusion protocols, the low quality of evidence, and the limited sample sizes.

BACKGROUND: Quercetin is a flavonoid with reported antioxidant, anti-inflammatory and anti-aging effects, and may limit muscle wasting in cancer cachexia. OBJECTIVE: To investigate the effect of quercetin on muscle wasting in the murine C26 cancer-cachexia model and assess the feasibility of non-invasive micro-CT analysis of skeletal muscle. MATERIALS AND METHODS: Custom CRM(P) diets supplemented with 250 mg/kg quercetin (Q) were obtained. Thirty CD2F1 mice were equally randomized to non-tumor-bearing (NTB), C26 tumor-bearing (TB), TB + Q. All groups started their allocated diet and underwent hindlimb micro-CT. Bodyweight, food intake, and grip-strength were recorded periodically. After 21 days, repeat micro-CT was performed. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. RESULTS: NTB and TB + Q gained 9.4% and 5.3% bodyweight respectively, TB lost 3.9%. Hind limb skeletal muscle volume remained stable for NTB and TB + Q, whereas TB decreased from 242.0 mm3 to 212.8 mm3. Mean GCM muscle weight was 175.2 mg (NTB), 171.3 mg (TB + Q) versus 125.5 mg (TB). A tendency towards decreased expression of atrogin-1 and MuRF1 was observed in TB + Q. CONCLUSION: Dietary quercetin supplementation limits bodyweight loss and muscle wasting in the C26-cancer-associated cachexia model.

Previously, we and others showed that dietary restriction protects against renal ischemia-reperfusion injury in animals. However, clinical translation of preoperative diets is scarce, and in the setting of kidney transplantation these data are lacking. In this pilot study, we investigated the effects of five days of a preoperative protein and caloric dietary restriction (PCR) diet in living kidney donors on the perioperative effects in donors, recipients and transplanted kidneys. Thirty-five kidney donors were randomized into either the PCR, 30% calorie and 80% protein reduction, or control group without restrictions. Adherence to the diet and kidney function in donors and their kidney recipients were analyzed. Perioperative kidney biopsies were taken in a selected group of transplanted kidneys for gene expression analysis. All donors adhered to the diet. From postoperative day 2 up until month 1, kidney function of donors was significantly better in the PCR-group. PCR-donor kidney recipients showed significantly improved kidney function and lower incidence of slow graft function and acute rejection. PCR inhibited cellular immune response pathways and activated stress-resistance signaling. These observations are the first to show that preoperative dietary restriction induces postoperative recovery benefits in humans and may be beneficial in clinical settings involving ischemia-reperfusion injury.