Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.

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.

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.

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.

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.

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.

Disruption of clock gene expression in human colorectal liver metastases.

The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis.

Colorectal liver metastases with a disrupted circadian rhythm phase shift the peripheral clock in liver and kidney.

Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes (Rev-Erbα, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed.

Inflammatory genes in rat livers from cardiac- and brain death donors.

BACKGROUND: Liver transplantation (LT) is the only life-saving treatment for patients with end-stage liver disease. The increase in patients has prompted the use of not only donation after brain death (DBD) donors but also living donors (LD) and donation after cardiac death (DCD) donors. Donor-type affects early graft function and graft survival as evidenced by an increased risk of developing ischemic type biliary lesions and higher risk of graft loss in DCD as compared with those in DBD grafts. METHODS: Using a rat model, we used quantitative reverse transcription-polymerase chain reaction to examine expression levels of proinflammatory, cytoprotective, and injury genes and determined apoptosis in DCD and DBD livers at different time points after retrieval. RESULTS: After retrieval, early mediators of inflammation MCP-1, HMGB1, and toll-like receptor (TLR 4) were increased in DCD livers, whereas the proinflammatory genes interleukin 6, interleukin 1ß, tumor necrosis factor alpha, P-selectin, and E-selectin were massively upregulated in DBD compared with those in LD livers. HO-1 was increased in both postmortem groups. After cold ischemia, DCD livers showed increased levels of MCP-1, TLR4, and HMGB1, whereas expression of proinflammatory genes in DBD liver remained high. During 12 h of cold storage, expression levels remained stable except Hif-1α and HMGB1. DCD showed higher number of apoptotic cells compared with DBD livers. CONCLUSIONS: Compared with LD, DCD livers showed only mild upregulation of inflammatory markers, but increased levels of MCP-1, HMGB1, and TLR4, and more apoptotic cells. In contrast, DBD livers showed a massive inflammatory response. These differences in tissue injury and inflammatory response might be relevant for the outcome after LT.

Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma.

BACKGROUND: A reduction in skeletal muscle mass (sarcopenia) independently predicts poor survival in patients with hepatocellular carcinoma (HCC) undergoing treatment with curative intent. Whether this is due to an increased risk of recurrence and disease specific death, or due to an increased risk of postoperative morbidity and mortality is currently unclear. In this study, we investigate the association between sarcopenia and death in a cohort of HCC patients undergoing treatment with curative intent. METHODS: Patients undergoing surgical resection or radiofrequency ablation for lesions ≤ 3 cm between 2002 and 2013 were identified. Clinicopathological characteristics, CT-assessed sarcopenia and outcomes were analyzed. RESULTS: Among 90 patients, 52 (57.8%) were found to be sarcopenic. Sarcopenic patients had a limited overall survival (median: 33 months vs. non-sarcopenic median: 105 months; P = 0.002), but not disease-free survival. Sarcopenia was an independent predictor for overall survival in multivariate Cox-regression analysis (HR 3.756; P = 0.001). Major complications (32.7% vs. 13.2%, P = 0.033) and treatment-related mortality (17.3% vs. 2.6%, P = 0.029) were more frequent in sarcopenic patients. CONCLUSION: Sarcopenia impairs survival in patients with potentially curable hepatocellular carcinoma, mainly due to an increase in treatment-related mortality.

Ischemic postconditioning in human DCD kidney transplantation is feasible and appears safe.

Ischemic postconditioning may improve outcome after kidney transplantation. We performed a pilot study to assess feasibility and safety of ischemic postconditioning in human donation-after-circulatory-death kidney transplantation. Twenty patients were included. Primary outcome was rate of serious adverse events. Secondary outcomes were incidence of DGF and renal function at 3 months. Data were compared to a historical control group (n = 40). Furthermore, we performed a paired kidney analysis using the contralateral kidney (n = 11). Donor age and serum creatinine were higher in the experimental group compared with historical control: 57.7 (20-71) vs. 51.5 (24-74) years (P = 0.01) and 79 (40-156) µmol/l vs. 64 (25-115) µmol/l (P = 0.047). Postconditioning could be applied all times. One complication, a venous tear, occurred related to postconditioning. The experimental group experienced more DGF (85% vs. 63%) (P = 0.07). Serum creatinine at month 3 was 166 (109-331) µmol/l vs. 159 (81-279) µmol/l (P = 0.71). Paired kidney analysis showed no significant differences in DGF (72.2% vs. 54.5%, P = 0.66) and serum creatinine 199 (90-473) µmol/l vs. 184 (117-368) µmol/l (P = 0.76). This is the first report of applying IPoC in human kidney transplantation. Although IPoC is feasible and appears to be safe, no benefit in terms of reduced DGF or better renal function was observed (Dutch trial registry number NTR 3117).

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.

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.

Altered mitochondrial functioning induced by preoperative fasting may underlie protection against renal ischemia/reperfusion injury.

We reported previously that the robust protection against renal ischemia/reperfusion (I/R) injury in mice by fasting was largely initiated before the induction of renal I/R. In addition, we found that preoperative fasting downregulated the gene expression levels of complexes I, IV, and V of the mitochondrial oxidative phosphorylation (OXPHOS) system, while it did not change those of complexes II and III. Hence, we now investigated the effect of 3 days of fasting on the functioning of renal mitochondria in order to better understand our previous findings. Fasting did not affect mitochondrial density. Surprisingly, fasting significantly increased the protein expression of complex II of the mitochondrial OXPHOS system by 19%. Complex II-driven state 3 respiratory activity was significantly reduced by fasting (46%), which could be partially attributed to the significant decrease in the enzyme activity of complex II (16%). Fasting significantly inhibited Ca(2+) -dependent mitochondrial permeability transition pore opening that is directly linked to protection against renal I/R injury. The inhibition of the mitochondrial permeability transition pore did not involve the expression of the voltage-dependent anion channel by fasting. In conclusion, 3 days of fasting clearly induces the inhibition of complex II-driven mitochondrial respiration state 3 in part by decreasing the amount of functional complex II, and inhibits mitochondrial permeability transition pore opening. This might be a relevant sequence of events that could contribute to the protection of the kidney against I/R injury.

Relationship between the histological appearance of the portal vein and development of ischemic-type biliary lesions after liver transplantation.

Ischemic-type biliary lesions (ITBLs) are a major cause of morbidity after liver transplantation (LT). Their assumed underlying pathophysiological mechanism is ischemia/reperfusion injury of the biliary tree, in which the portal circulation has been proposed recently to have a role. The aim of this study was to investigate whether early histological changes, particularly in the portal vein, predispose patients to ITBLs. A case-control study of 22 LT recipients was performed through a retrospective assessment of more than 30 histological parameters in 44 intraoperative liver biopsy samples taken after cold ischemia (time 0) and portal reperfusion (time 1). Eleven grafts developed ITBLs requiring retransplantation (the ITBL group), and 11 matched controls had normally functioning grafts 11 years after LT on average (the non-ITBL group). Additionally, 11 liver biopsy samples from hemihepatectomies performed for metastases of colorectal cancer (CRC) were assessed similarly. Analyses showed no significant histological differences at time 0 between the ITBL and non-ITBL groups. However, the time 1 biopsy samples from the ITBL group showed smaller portal vein branches (PVBs) significantly more often than the samples from the non-ITBL group, which also showed persisting paraportal collateral vessels. Larger PVBs and paraportal collateral vessels were also found in the CRC group. A morphometric analysis confirmed these findings and showed that PVB measurements were significantly lower for the ITBL group at time 1 versus the ITBL group at time 0 and the non-ITBL and CRC groups (they were largest in the CRC group). Thus, the PVB dimensions decreased in the ITBL group in comparison with the time 0 biopsy samples, and they were significantly smaller at time 1 in comparison with the dimensions for the non-ITBL and CRC groups. In conclusion, a smaller PVB lumen size in postreperfusion biopsy samples from liver grafts, suggesting a relatively decreased portal blood flow, is associated with a higher incidence of ITBLs. These findings support recent clinical studies suggesting a possible pathophysiological role of portal blood flow in the oxygenation of the biliary tree after LT.

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.