Effective and safe implementation of robot-assisted donor nephrectomy by experienced laparoscopic surgeons.

BACKGROUND: In June 2021, the first robot-assisted donor nephrectomy (RADN) was performed at the Leiden University Medical Center (LUMC), the Netherlands. The goal of this study was to investigate whether this procedure has been implemented safely and efficiently. METHODS: RADN was retrospectively compared to laparoscopic donor nephrectomy (LDN) performed during the same time period (June 2021 until November 2022). Patients were assigned to RADN depending on the availability of the da Vinci robot and surgical team. The studied endpoints were postoperative complications, operative time, estimated blood loss, warm ischemic time (WIT), and postoperative pain experience. For analysis, the Student's t-test and Chi-squared test were used for, respectively, continuous and categorical data. RESULTS: Forty RADN were compared to 63 LDN. Total insufflation time was significantly longer in RADN compared to LDN (188 min (169-214) versus 172 min (144-194); p = 0.02). Additionally, WIT was also found to be significantly higher in the robot-assisted group (04:54 min vs. 04:07 min; p < 0.01). No statistical differences were found in postoperative outcomes (eGFR of the recipient at 3-month follow-up, RADN 54.08 mL/min ±18.79 vs. LDN 56.41 mL/min ±16.82; p = 0.52), pain experience, and complication rate. CONCLUSION: RADN was safely and efficiently implemented at the LUMC. It's results were not inferior to laparoscopic donor nephrectomy. Operative time and warm ischemic times were longer in RADN. This may relate to a learning curve effect. No clinically relevant effect on postoperative outcomes was observed.

A nationwide assessment of hepatocellular adenoma resection: Indications and pathological discordance.

Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs < 50 mm compared to HCAs ≥ 50 mm. Changes in final postoperative diagnosis were assessed. We performed a retrospective study that included patients who underwent resection for (suspected) HCAs in the Netherlands from 2014 to 2019. Indication for resection was analyzed and stratified for small (<50 mm) and large (≥50 mm) tumors. Logistic regression analysis was performed on factors influencing change in tumor diagnosis. Out of 222 patients who underwent surgery, 44 (20%) patients had a tumor <50 mm. Median age was 46 (interquartile range [IQR], 33-56) years in patients with small tumors and 37 (IQR, 31-46) years in patients with large tumors ( p  = 0.016). Patients with small tumors were more frequently men (21% vs. 5%, p  = 0.002). Main indications for resection in patients with small tumors were suspicion of (pre)malignancy (55%), (previous) bleeding (14%), and male sex (11%). Patients with large tumors received operations because of tumor size >50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p  < 0.01), male sex (aOR, 3.7; p  = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p  = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis.

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL.

Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, one-third of patients experience refractory or relapsed disease. Studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) did not result in improved outcomes; however, L and O together may enhance natural killer-cell mediated antibody-dependent cellular toxicity when paired with CHOP. Here, we report on a phase 1b/2 study of 53 patients with newly diagnosed DLBCL who received 6 cycles of LO-CHOP. The end of treatment overall and complete response rates of the 50 evaluable patients were 98% and 90%, respectively. After a median follow-up of 4.5 years, the 4-year progression free and overall survival rates were 87.4% and 91.3%, respectively. Grade 3 to 4 adverse events were experienced by 70% of patients, including neutropenia (38%), thrombocytopenia (17%), fatigue (13%), and neutropenic fever (13%). Of the 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pretreatment ctDNA with cancer personalized profiling by deep sequencing, 24 (73%) were classifiable by the LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using phased variant enrichment and detection sequencing, 16/18 evaluable patients (89%) showed no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA. This trial has been registered at www.clinicaltrials.gov as NCT02529852.

Preclinical models versus clinical renal ischemia reperfusion injury: A systematic review based on metabolic signatures.

Despite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing toward a translational gap. Recently, two clinical studies on renal IR injury (manifested either as acute kidney injury or as delayed graft function) identified metabolic derailment as a key driver of renal IR injury. It was reasoned that these unambiguous metabolic findings enable direct alignment of clinical with preclinical data, thereby providing the opportunity to elaborate potential translational hurdles between preclinical research and the clinical context. A systematic review of studies that reported metabolic data in the context of renal IR was performed according to the PRISMA guidelines. The search (December 2020) identified 35 heterogeneous preclinical studies. The applied methodologies were compared, and metabolic outcomes were semi-quantified and aligned with the clinical data. This review identifies profound methodological challenges, such as the definition of IR injury, the follow-up time, and sampling techniques, as well as shortcomings in the reported metabolic information. In light of these findings, recommendations are provided in order to improve the translatability of preclinical models of renal IR injury.

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

Short Diagnosis-to-Treatment Interval Is Associated With Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma.

PURPOSE: Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias. PATIENTS AND METHODS: We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome. RESULTS: Short DTI was associated with advanced-stage disease (P < .001) and higher IPI (P < .001). We also found an inverse correlation between DTI and TMTV (RS = -0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels (P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI (P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2]). CONCLUSION: Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.

Liquid biopsy in lymphoma: Molecular methods and clinical applications.

In this article, we broadly review the application of cfDNA analysis to the diagnosis and management of lymphoma. We introduce the advantages of cfDNA measurement over conventional tissue biopsy and describe how cfDNA may be utilized for both genotyping and detection of minimal residual disease. First, we discuss genotyping, beginning with differences in identifying mutations from the blood plasma vs. from circulating cells. We review the technical distinctions between PCR- and NGS-based assays and describe two important applications of NGS-based cfDNA tests, namely the identification of resistance mutations and classification of disease subtype. We discuss difficulties in genotyping diseases with low burden of tumor cells and the application of cfDNA assays in these contexts. Second, we describe the utility of ctDNA measurement in assessing MRD. We cover recent advances in the assessment of pre-treatment disease burden as a prognostic biomarker, detection of molecular response to therapy, and early detection of relapsing disease. Third, we explore select emerging areas of research in ctDNA technologies that show promise in boosting the performance of existing ctDNA-based assays. These include cell-free DNA fragment structure analysis or 'fragmentomics', epigenetic modifications, and novel circulating analytes such as tumor-educated platelets and extracellular vesicular DNA. We also discuss alternative analytes to blood plasma for tumor detection, such as urine, saliva, and stool. Finally, we present a case that highlights potential applications of ctDNA approaches to the management of patients with lymphoma, while also defining important prerequisite advances before this can be fully realized. We close with a look to the future of cfDNA applications, outlining one potential timeline and path forward towards routine clinical application.

Improving outcomes for donation after circulatory death kidney transplantation: Science of the times.

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.

Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma.

PURPOSE: Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. PATIENTS AND METHODS: We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. RESULTS: Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. CONCLUSION: Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA.

Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures.

The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re-)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End-Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty-three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi-institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss.

Thirty Years of Pancreas Transplantation at Leiden University Medical Center: Long-term Follow-up in a Large Eurotransplant Center.

BACKGROUND: An overview of 30 years of pancreas transplantation at a high volume center. Analysis of patient survival- and graft survival-associated risk factors. METHODS: All pancreas transplantations performed in our center from January 1, 1984, till December 31, 2012, were evaluated. Covariates influencing pancreas graft survival were analyzed using both univariate and multivariate analysis and Kaplan-Meier analysis. RESULTS: In the study period, 349 pancreas transplantations were performed. With the introduction of modern induction therapy in 1999, 5-year patient survival improved to 92.0% (P = 0.003). Five-year pancreas graft survival improved to 80.3% (P = 0.026). Pancreas graft survival was influenced by left or right donor kidney, transplant type, local origin of procurement team, pancreas cold ischemia time, recipient cerebrovascular disease. Pancreas donor risk index increased to 1.39 over the years and pancreas donor risk index 1.24 or higher is a risk factor for graft survival (P = 0.007). CONCLUSIONS: This study has shown excellent results in patient and pancreas graft survivals after 30 years of pancreas transplantation in a high volume center. Different donor, transplant, and recipient related risk factors influence pancreas graft survival. Even with higher risk pancreas donors, good results can be achieved.

Donor pre-treatment in clinical kidney transplantation: a critical appraisal.

Kidney transplantation represents one of the medical achievements of the 20th century. However, its continued success is limited by the increasing shortage of donor grafts. As a result, more kidney grafts from marginal donors are being considered for transplantation, with concomitantly more initial graft injury and limited organ and patient survival. This has led to an increased need for interventions aiming to optimize and preserve graft quality. Interventions within the donor may protect against ischemia/reperfusion injury, and therefore, donor pre-treatment is a promising strategy to increase graft function and survival. During the last decade, diverse donor pre-treatment interventions have been explored in animal studies. Moreover, the first human trials concerning donor pre-treatment in kidney transplantation have provided encouraging results. Unfortunately, it remains difficult to determine how and where to intervene in the multifactorial and complex processes that affect the donor kidney. Moreover, ethical matters play a critical role in donor interventions, and pre-treatment should principally not have any potentially unfavorable effects on other organs to be transplanted or on the living donor. This review provides an overview of promising therapeutical strategies for donor pre-treatment in kidney transplantation and discusses the clinical trials that have been conducted thus far.

Bone marrow-derived mesenchymal stromal cells from patients with end-stage renal disease are suitable for autologous therapy.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive and reparative properties in vitro and in vivo. Although autologous bone marrow (BM)-derived MSCs are already clinically tested in transplant recipients, it is unclear whether these BM cells are affected by renal disease. We assessed whether renal failure affected the function and therapeutic potential of BM-MSCs. METHODS: MSCs from 10 adults with end-stage renal disease (ESRD) and 10 age-matched healthy controls were expanded from BM aspirates and tested for phenotype and functionality in vitro. RESULTS: MSCs from ESRD patients were >90% positive for CD73, CD90 and CD105 and negative for CD34 and CD45 and showed a similar morphology and differentiation capacity as MSCs from healthy controls. Of importance for their clinical utility, growth characteristics were similar in both groups, and sufficient numbers of MSCs were obtained within 4 weeks. Messenger RNA expression levels of self-renewal genes and factors involved in repair and inflammation were also comparable between both groups. Likewise, microRNA expression profiling showed a broad overlap between ESRD and healthy donor MSCs. ESRD MSCs displayed the same immunosuppressive capacities as healthy control MSCs, demonstrated by a similar dose-dependent inhibition of peripheral blood mononuclear cell proliferation, similar inhibition of proinflammatory cytokines tumor necrosis factor-α and interferon-γ production and a concomitant increase in the production of interleukin-10. CONCLUSIONS: Expanded BM-MSCs procured from ESRD patients and healthy controls are both phenotypically and functionally similar. These findings are important for the potential autologous clinical application of BM-MSCs in transplant recipients.

Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal.

AIMS: Ischemia/reperfusion (I/R) injury is a common clinical problem. Although the pathophysiological mechanisms underlying I/R injury are unclear, oxidative damage is considered a key factor in the initiation of I/R injury. Findings from preclinical studies consistently show that quenching reactive oxygen and nitrogen species (RONS), thus limiting oxidative damage, alleviates I/R injury. Results from clinical intervention studies on the other hand are largely inconclusive. In this study, we systematically evaluated the release of established biomarkers of oxidative and nitrosative damage during planned I/R of the kidney and heart in a wide range of clinical conditions. RESULTS: Sequential arteriovenous concentration differences allowed specific measurements over the reperfused organ in time. None of the biomarkers of oxidative and nitrosative damage (i.e., malondialdehyde, 15(S)-8-iso-prostaglandin F2α, nitrite, nitrate, and nitrotyrosine) were released upon reperfusion. Cumulative urinary measurements confirmed plasma findings. As of these negative findings, we tested for oxidative stress during I/R and found activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of oxidative stress signaling. INNOVATION: This comprehensive, clinical study evaluates the role of RONS in I/R injury in two different human organs (kidney and heart). Results show oxidative stress, but do not provide evidence for oxidative damage during early reperfusion, thereby challenging the prevailing paradigm on RONS-mediated I/R injury. CONCLUSION: Findings from this study suggest that the contribution of oxidative damage to human I/R may be less than commonly thought and propose a re-evaluation of the mechanism of I/R.

Interleukin-9 release from human kidney grafts and its potential protective role in renal ischemia/reperfusion injury.

OBJECTIVE AND DESIGN: The pathophysiology of ischemia/reperfusion (I/R) injury is dominated by an inflammatory response. In the identification of new therapeutic agents, the role of individual cytokines may be essential. Interleukin (IL)-9 is a pleiotropic cytokine recently identified to be involved in various immune responses. In this study, the role of IL-9 in renal I/R injury was assessed. METHODS: We performed repeated direct measurements of arteriovenous IL-9 concentration differences over the reperfused graft in human kidney transplantation. RESULTS: Substantial renal IL-9 release was observed from deceased donor kidneys (P = 0.006). In contrast, living donor kidneys, which have a more favourable clinical outcome, did not release IL-9 during early reperfusion (P = 0.78). Tissue expression of IL-9 did not change upon reperfusion in both living and deceased human donor kidneys. To assess the role of IL-9 in I/R injury, an experimental study comprising IL-9 inhibition in mice undergoing renal I/R was performed. Although there was no difference in kidney function, structural damage was significantly aggravated in anti-IL-9 treated mice. CONCLUSIONS: Deceased donor grafts show a substantial IL-9 release upon reperfusion in clinical kidney transplantation. However, inhibition of IL-9 aggravated kidney damage, suggesting a regulating or minor role of IL-9 in clinical I/R injury.

Mesenchymal stromal cells in renal ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in kidney transplantation. Renal I/R injury can lead to fibrosis and graft failure. Although the exact sequence of events in the pathophysiology of I/R injury remains unknown, the role of inflammation has become increasingly clear. In this perspective, mesenchymal stromal cells (MSCs) are under extensive investigation as potential therapy for I/R injury, since MSCs are able to exert immune regulatory and reparative effects. Various preclinical studies indicate the beneficial effects of MSCs in ameliorating renal injury and accelerating tissue repair. These versatile cells have been shown to migrate to sites of injury and to enhance repair by paracrine mechanisms instead of by differentiating and replacing the injured cells. The first phase I studies of MSCs in human renal I/R injury and kidney transplantation have been started, and results are awaited soon. In this review, preliminary results and opportunities of MSCs in human renal I/R injury are summarized. We might be heading towards a cell-based paradigm shift in the treatment of renal I/R injury.