Pre-transplant kidney quality evaluation using photoacoustic imaging during normothermic machine perfusion.

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 conclude that the presented technique has a high potential for supporting organ selection for kidney transplantation.

Safety and efficacy of kidney transplantation in patients with aortoiliac stenosis: a retrospective cohort study.

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 of life through kidney transplantation. However, for patients with TASC C/D stenosis, kidney transplantation improves quality of life without bringing survival benefits.

Real-time laser speckle contrast imaging measurement during normothermic machine perfusion in pretransplant kidney assessment.

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 perfusion can be visualized and semiquantified by LSCI. It provides a relative understanding of perfusion levels, allowing for a qualitative comparison between regions in the kidney. Dual-side LSCI measurements are of added value compared to single aspect measurement and renal function markers.

Rapamycin Does Not Act as a Dietary Restriction Mimetic in the Protection against Ischemia Reperfusion Injury.

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.

Bariatric surgery before and after kidney transplant: a propensity score-matched analysis.

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.

Therapeutic efficacy of extracellular vesicles to suppress allograft rejection in preclinical kidney transplantation models: A systematic review and meta-analysis.

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.

Additional Normothermic Machine Perfusion Versus Hypothermic Machine Perfusion in Suboptimal Donor Kidney Transplantation: Protocol of a Randomized, Controlled, Open-Label Trial.

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 help develop NMP as assessment tool for declined kidneys.

Effects of Morbid Obesity and Metabolic Syndrome on the Composition of Circulating Immune Subsets.

Morbid obesity is characterized by chronic, low-grade inflammation, which is associated with 'inflamm-aging'. The presence of metabolic syndrome (MetS) might accelerate this phenomenon of metaflammation. In this study, we assessed the effects of morbid obesity and MetS on the composition of a broad spectrum of immune cells present within the circulation. A total of 117 morbidly obese patients (MOP) without MetS (MetS-), 127 MOP with MetS (MetS+) and 55 lean controls (LC) were included in this study. Absolute numbers of T cell, B cell, NK cell and monocyte subsets were assessed within peripheral blood using flow cytometry. Both absolute cell numbers and proportion of cells were evaluated correcting for covariates age, body mass index and cytomegalovirus serostatus. Although the absolute number of circulating CD4+ T cells was increased in the MetS+ group, the CD4+ T cell composition was not influenced by MetS. The CD8+ T cell and B cell compartment contained more differentiated cells in the MOP, but was not affected by MetS. Even though the absolute numbers of NK cells and monocytes were increased in the MOP as compared to LC, there was no difference in proportions of NK and monocyte subsets between the three study groups. In conclusion, although absolute numbers of CD4+ and CD8+ T cells, B cells, NK cells and monocytes are increased in MOP, obesity-induced effects of the composition of the immune system are confined to a more differentiated phenotype of CD8+ T cells and B cells. These results were not affected by MetS.

Optimizing porcine donor kidney preservation with normothermic or hypothermic machine perfusion: A systematic review.

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.

Effects of Protein and Calorie Restriction on the Metabolism and Toxicity Profile of Irinotecan in Cancer Patients.

Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN-38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN-38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: -38.8%, P = 0.05 and SN-38: -13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0-24h ) with 7.1% (P = 0.04) compared with normal diet, whereas the SN-38 plasma AUC0-24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN-38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN-38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan.

Pre-Operative Fasting Provides Long Term Protection Against Chronic Renal Damage Induced by Ischaemia Reperfusion Injury in Wild Type and Aneurysm Prone Fibulin-4 Mice.

OBJECTIVE: Renal ischaemia reperfusion injury (IRI) is inevitable during open repair of pararenal aortic aneurysms. Pre-operative fasting potently increases resistance against IRI. The effect of fasting on IRI was examined in a hypomorphic Fibulin-4 mouse model (Fibulin-4+/R), which is predisposed to develop aortic aneurysms. METHODS: Wild type (WT) and Fibulin-4+/R mice were either fed ad libitum (AL) or fasted for two days before renal IRI induction by temporary clamping of the renal artery and vein of both kidneys. Six hours, 48 h, and seven days post-operatively, serum urea levels, renal histology, and mRNA expression levels of inflammatory and injury genes were determined to assess kidney function and damage. Additionally, matrix metalloproteinase activity in the kidney was assessed six months after IRI. RESULTS: Two days of fasting improved survival the first week after renal IRI in WT mice compared with AL fed mice. Short term AL fed Fibulin-4+/R mice showed improved survival and kidney function compared with AL fed WT mice, which could not be further enhanced by fasting. Both fasted WT and Fibulin-4+/R mice showed improved survival, kidney function and morphology compared with AL fed mice six months after renal IRI. Fibulin-4+/R kidneys of fasted mice showed reduced apoptosis together with increased matrix metalloprotease activity levels compared with AL fed Fibulin-4+/R mice, indicative of increased matrix remodelling. CONCLUSION: Fibulin-4+/R mice are naturally protected against the short-term, but not long-term, consequences of renal IRI. Pre-operative fasting protects against renal IRI and prevents (long-term) deterioration of kidney function and morphology in both WT and Fibulin-4+/R mice. These data suggest that pre-operative fasting may decrease renal damage in patients undergoing open abdominal aneurysm repair.

Protein and calorie restriction may improve outcomes in living kidney donors and kidney transplant recipients.

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.

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting.

BACKGROUND: Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue. EXPERIMENTAL APPROACH: Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses. KEY RESULTS: The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals. CONCLUSIONS: Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients.

Low Skeletal Muscle Density Is Associated with Early Death in Patients with Perihilar Cholangiocarcinoma Regardless of Subsequent Treatment.

BACKGROUND: Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. METHODS: Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. RESULTS: Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7-9.3) and high (HR 12.1, 95% CI 8.1-16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03-3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44-1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. CONCLUSION: A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death.

Estimated skeletal muscle mass and density values measured on computed tomography examinations in over 1000 living kidney donors.

BACKGROUND/OBJECTIVES: Currently, there are no widely accepted cut-off points to categorize patients as sarcopenic (low skeletal muscle mass) or myosteatotic based on computed tomography (CT) measurements. Moreover, little is known about skeletal muscle mass in healthy subjects, particularly in a Western-European population. SUBJECTS/METHODS: Skeletal muscle mass (skeletal muscle index, cm2/m2) and density (Hounsfield units, HU) at the level of the third lumbar vertebra were measured on contrast-enhanced CT images in live kidney donors with an age range of 18-86 years, who may be considered as healthy subjects, from 2010 to 2015. Differences between sex, body mass index (BMI), age groups, and American Society of Anesthesiologists (ASA) classification were assessed. Mann-Whitney U and Kruskal-Wallis tests were used to compare groups. RESULTS: Of the 1073 included patients, 499 (46.5%) were male and the median age and BMI were 51 years and 25.4 kg/m2, respectively. Male gender, increased age, and increased BMI were significantly associated with both skeletal muscle mass and density. Nomograms including these parameters were developed to calculate the estimated skeletal muscle mass and density of a healthy subject and the lower bound of the 90% prediction interval (p5) values were provided. CONCLUSIONS: Skeletal muscle density and mass were significantly associated with sex, age, and BMI in a large cohort of healthy Western-European subjects. The newly developed nomograms may be used to calculate the estimated healthy skeletal muscle mass for individuals in patient populations.

Caloric restriction is associated with preservation of muscle strength in experimental cancer cachexia.

Caloric restriction increases lifespan and healthspan, and limits age-associated muscle wasting. In this study, we investigate the impact of 30% caloric restriction (CR) in a murine cancer cachexia model. Forty CD2F1 mice were allocated as C26 tumor-bearing (TB) + ad libitum food intake (dietary reference intake [DRI]), TB CR, non-TB (NTB) CR, or NTB matched intake (MI). TB groups were inoculated subcutaneously with 0.5x106 C26 cells 14 days after initiating CR. Bodyweight, food intake, and grip-strength were recorded periodically. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected and weighed 3 weeks after tumor inoculation. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. At tumor inoculation, the mean body weight of TB CR was 88.6% of initial body weight and remained stable until sacrifice. TB DRI showed wasting before sacrifice. TB groups experienced muscle wasting compared with NTB MI. Grip-strength change was less severe in TB CR. Expression of MuRF1, Atrogin-1, and MyoD was similar between TB DRI and both CR groups. Expression of myogenin was increased in CR groups. In conclusion, caloric restriction limits loss of muscle strength but has no impact on muscle mass despite significant loss of body weight in an experimental cancer-associated cachexia model.

Cellular senescence as a therapeutic target to improve renal transplantation outcome.

Kidney transplants from aged donors are more vulnerable to ischemic injury, suffer more from delayed graft function and have a lower graft survival compared to kidneys from younger donors. On a cellular level, aging results in an increase in cells that are in a permanent cell cycle arrest, termed senescence, which secrete a range of pro-inflammatory cytokines and growth factors. Consequently, these senescent cells negatively influence the local milieu by causing inflammaging, and by reducing the regenerative capacity of the kidney. Moreover, the oxidative damage that is inflicted by ischemia-reperfusion injury during transplantation can induce senescence and accelerate aging. In this review, we describe recent developments in the understanding of the biology of aging that have led to the development of a new class of therapeutic agents aimed at eliminating senescent cells. These compounds have already shown to be able to restore tissue homeostasis in old mice, improve kidney function and general health- and lifespan. Use of these anti-senescence compounds holds great promise to improve the quality of marginal donor kidneys as well as to remove senescent cells induced by ischemia-reperfusion injury. Altogether, senescent cell removal may increase the donor pool, relieving the growing organ shortage and improve long-term transplantation outcome.

Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation-a retrospective study.

Low skeletal muscle mass (sarcopenia) is associated with increased morbidity and mortality in liver transplant candidates. We investigated the association between sarcopenia and hospital costs in patients listed for liver transplantation. Consecutive patients with cirrhosis listed for liver transplantation between 2007 and 2014 in a Eurotransplant centre were identified. The skeletal muscle index (SMI, cm2 /m2 ) was measured on CT performed within 90 days from waiting list placement. The lowest sex-spe cific quartile represented patients with sarcopenia. In total, 224 patients were included. Median time on the waiting list was 170 (IQR 47-306) days, and median MELD score was 16 (IQR 11-20). The median total hospital costs in patients with sarcopenia were €11 294 (IQR 3570-46 469) compared with €6878 (IQR 1305-20 683) in patients without sarcopenia (P = 0.008). In multivariable regression analysis, an incremental increase in SMI was significantly associated with a decrease in total costs (€455 per incremental SMI, 95% CI 11-900, P = 0.045), independent of the total time on the waiting list. In conclusion, sarcopenia is independently associated with increased health-related costs for patients on the waiting list for liver transplantation. Optimizing skeletal muscle mass may therefore lead to a decrease in hospital expenditure, in addition to greater health benefit for the transplant candidate.

Contrast-enhancement influences skeletal muscle density, but not skeletal muscle mass, measurements on computed tomography.

BACKGROUND & AIMS: Low skeletal muscle mass and density have recently been discovered as prognostic and predictive parameters to guide interventions in various populations, including cancer patients. The gold standard for body composition analysis in cancer patients is computed tomography (CT). To date, the effect of contrast-enhancement on muscle composition measurements has not been established. The aim of this study was to determine the effect of contrast-enhancement on skeletal muscle mass and density measurements on four-phase CT studies. DESIGN: In this observational study, two observers measured cross-sectional skeletal muscle area corrected for patients' height (skeletal muscle index [SMI]) and density (SMD) at the level of the third lumbar vertebra on 50 randomly selected CT examinations with unenhanced, arterial, and portal-venous phases. The levels of agreement between enhancement phases for SMI and SMD were calculated using intra-class correlation coefficients (ICCs). RESULTS: Mean SMI was 42.5 (±9.9) cm2/m2 on the unenhanced phase, compared with 42.8 (±9.9) and 43.6 (±9.9) cm2/m2 for the arterial and portal-venous phase, respectively (both p < 0.01). Mean SMD was lower for the unenhanced phase (30.9 ± 8.0 Hounsfield units [HU]) compared with the arterial (38.0 ± 9.9 HU) and portal-venous (38.7 ± 9.2 HU) phase (both p < 0.001). No significant difference was found between SMD in the portal-venous and arterial phase (p = 0.161). The ICCs were excellent (≥0.992) for all SMIs and for SMD between the contrast-enhanced phases (0.949). The ICCs for the unenhanced phase compared with the arterial (0.676) and portal-venous (0.665) phase were considered fair to good. CONCLUSIONS: Statistically significant differences in SMI were observed between different enhancement phases. However, further work is needed to assess the clinical relevance of these small differences. Contrast-enhancement strongly influenced SMD values. Studies using this measure should therefore use the portal-venous phase of contrast-enhanced CT examinations.

Low skeletal muscle mass is associated with increased hospital expenditure in patients undergoing cancer surgery of the alimentary tract.

BACKGROUND: Low skeletal muscle mass is associated with poor postoperative outcomes in cancer patients. Furthermore, it is associated with increased healthcare costs in the United States. We investigated its effect on hospital expenditure in a Western-European healthcare system, with universal access. METHODS: Skeletal muscle mass (assessed on CT) and costs were obtained for patients who underwent curative-intent abdominal cancer surgery. Low skeletal muscle mass was defined based on pre-established cut-offs. The relationship between low skeletal muscle mass and hospital costs was assessed using linear regression analysis and Mann-Whitney U-tests. RESULTS: 452 patients were included (median age 65, 61.5% males). Patients underwent surgery for colorectal cancer (38.9%), colorectal liver metastases (27.4%), primary liver tumours (23.2%), and pancreatic/periampullary cancer (10.4%). In total, 45.6% had sarcopenia. Median costs were €2,183 higher in patients with low compared with patients with high skeletal muscle mass (€17,144 versus €14,961; P<0.001). Hospital costs incrementally increased with lower sex-specific skeletal muscle mass quartiles (P = 0.029). After adjustment for confounders, low skeletal muscle mass was associated with a cost increase of €4,061 (P = 0.015). CONCLUSION: Low skeletal muscle mass was independently associated with increased hospital costs of about €4,000 per patient. Strategies to reduce skeletal muscle wasting could reduce hospital costs in an era of incremental healthcare costs and an increasingly ageing population.