Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice.

(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.

Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation.

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naïve and transplanted young versus aged kidneys revealed that naïve aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8+ T cells produced more IFNγ than their young counterparts. Senescent renal CD8+ T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a+ CXCR6+ NK cells was documented in aged naïve kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFNγ, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFNγ and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft.

Feasibility of robotic-assisted pancreatic resection in patients with previous minor abdominal surgeries: a single-center experience of the first three years.

BACKGROUND: Robotic-assisted pancreatic surgery is limited to specialized high-volume centers and selected patient cohorts. Especially for patients with a history of previous abdominal surgeries, the standard procedure remains open surgery due to the fear of complications caused by abdominal adhesions. METHODS: Clinical data of all consecutive patients undergoing robotic-assisted pancreatic surgery using the daVinci Xi system (Intuitive Surgical) at our center (Department of Surgery, Universitätsmedizin Berlin, Germany) were collected prospectively and further analyzed from October 2017 to October 2020. Prior abdominal surgeries were specified according to the surgical approach and localization. In univariate and multivariate analysis, baseline and perioperative parameters of patients with a history of prior abdominal surgeries (PS) were compared to those of patients with no history of prior abdominal surgeries (NPS). RESULTS: Out of 131 patients undergoing robotic-assisted pancreatic surgery, 62 (47%) had a history of abdominal surgery. Previous procedures included most often appendectomy (32%) followed by gynecological surgery (29%) and cholecystectomy (27%). 24% of PS had received multiple surgeries prior to the robotic-assisted pancreatic resections. Baseline characteristics and comorbidities were comparable between the groups. We did not detect differences in the duration of surgery (262 min), conversion rates (10%), and postoperative complications between NPS and PS. Postoperative pancreatic fistula (POPF), postpancreatectomy hemorrhage (PPH), and in-house mortality showed no significant differences between the two groups. Multivariate analysis revealed male sex and high BMI as a potential predictive factor for severe postoperative complications. Other characteristics like the type of pancreatic resection, ASA, and underlying malignancy showed no difference in the multivariable analysis. CONCLUSIONS: We propose robotic-assisted pancreatic surgery to be safe and feasible for patients with a history of minor prior abdominal surgery. Hence, each patient should individually be evaluated for a minimally invasive approach regardless of a history of previous operations.

Body Mass Index Thresholds and the Use of Bariatric Surgery in the Field of Kidney Transplantation in Germany.

BACKGROUND: Obesity in the recipient is linked to inferior transplant outcome. Consequently, access to kidney transplantation (KT) is often restricted by body mass index (BMI) thresholds. Bariatric surgery (BS) has been established as a superior treatment for obesity compared to conservative measures, but it is unclear whether it is beneficial for patients on the waiting list. METHODS: A national survey consisting of 16 questions was sent to all heads of German KT centers. Current situation of KT candidates with obesity and the status of BS were queried. RESULTS: Center response rate was 100%. Obesity in KT candidates was considered an important issue (96.1%; n = 49/51) and 68.6% (n = 35/51) of departments responded to use absolute BMI thresholds for KT waiting list access with ≥ 35 kg/m2 (45.1%; n = 23/51) as the most common threshold. BS was considered an appropriate weight loss therapy (92.2%; n = 47/51), in particular before KT (88.2%; n = 45/51). Sleeve gastrectomy was the most favored procedure (77.1%; n = 37/51). Twenty-one (41.2%) departments responded to evaluate KT candidates with obesity by default but only 11 (21.6%) had experience with ≥ n = 5 transplants after BS. Concerns against BS were malabsorption of immunosuppressive therapy (39.2%; n = 20/51), perioperative morbidity (17.6%; n = 9/51), and malnutrition (13.7%; n = 7/51). CONCLUSIONS: Obesity is potentially limiting access for KT. Despite commonly used BMI limits, only few German centers consider BS for obesity treatment in KT candidates by default. A national multicenter study is desired by nearly all heads of German transplant centers to prospectively assess the potentials, risks, and safety of BS in KT waitlisted patients.

Hepatic artery reconstruction using an operating microscope in pediatric liver transplantation-Is it worth the effort?

INTRODUCTION: In pediatric liver transplantation (pLT), hepatic artery thrombosis (HAT) is associated with inferior transplant outcome. Hepatic artery reconstruction (HAR) using an operating microscope (OM) is considered to reduce the incidence of HAT. METHODS: HAR using an OM was compared to a historic cohort using surgical loupes (SL) in pLT performed between 2009 and 2020. Primary endpoint was the occurrence of HAT. Secondary endpoints were 1-year patient and graft survival determined by Kaplan-Meier analysis and complications. Multivariate analysis was used to identify independent risk factors for HAT and adverse events. RESULTS: A total of 79 pLTs were performed [30 (38.0%) living donations; 49 (62.0%) postmortem donations] divided into 23 (29.1%) segment 2/3, 32 (40.5%) left lobe, 4 (5.1%) extended right lobe, and 20 (25.3%) full-size grafts. One-year patient and graft survival were both 95.2% in the OM group versus 86.2% and 77.8% in the SL group (p = .276 and p = .077). HAT rate was 0% in the OM group versus 24.1% in the SL group (p = .013). One-year patient and graft survival were 64.3% and 35.7% in patient with HAT, compared to 93.9% and 92.8% in patients with no HAT (both p < .001). Multivariate analysis revealed HAR with SL (p = .022) and deceased donor liver transplantation (DDLT) (p = .014) as independent risk factors for HAT. The occurrence of HAT was independently associated with the need for retransplantation (p < .001) and biliary leakage (p = .045). CONCLUSION: In pLT, the use of an OM is significantly associated to reduce HAT rate, biliary complications, and graft loss and outweighs the disadvantages of delayed arterial perfusion and prolonged warm ischemia time (WIT).

Expression of MICA in Zero Hour Biopsies Predicts Graft Survival After Liver Transplantation.

In search for novel biomarkers to assess graft quality, we investigated whether defined candidate genes are predictive for outcome after liver transplantation (LT). Zero-hour liver biopsies were obtained from 88 livers. Gene expression of selected candidate markers was analyzed and correlated with clinical parameters as well as short and long-term outcomes post LT. Whereas both, the calculated Eurotransplant Donor-Risk-Index and the donor body mass index, had either a poor or no predictive value concerning serum levels indicative for liver function (ALT, AST, GGT, bilirubin) after 6 months, chronological donor age was weakly predictive for serum bilirubin (AUC=0.67). In contrast, the major histcompatibility complex class I related chain A (MICA) mRNA expression demonstrated a high predictive value for serum liver function parameters revealing an inverse correlation (e.g. for ALT: 3 months p=0.0332; 6 months p=0.007, 12 months 0.0256, 24 months p=0.0098, 36 months, p=0.0153) and proved significant also in a multivariate regression model. Importantly, high expression of MICA mRNA revealed to be associated with prolonged graft survival (p=0.024; log rank test) after 10 years of observation, whereas low expression was associated with the occurrence of death in patients with transplant related mortality (p=0.031). Given the observed correlation with short and long-term graft function, we suggest MICA as a biomarker for pre-transplant graft evaluation.

Transplantation programs facing lack of empirical evidence on SARS-CoV-2 vaccination: A society recommendation consensus update.

BACKGROUND: Since phase III trials for the most prominent vaccines excluded immunocompromised or immunosuppressed patients, data on safety and efficacy of SARS-CoV-2 vaccines for recipients of solid organ transplantations are scarce. AIMS: Our study offers a synthesis of expert opinions aligned with available data addressing key questions of the clinical management of SARS-CoV-2 vaccinations for transplant patients. METHOD: An online research was performed retrieving available recommendations by national and international transplantation organizations and state institutions on SARS-CoV2 vaccination management for transplant recipients. RESULTS: Eleven key statements were identified from recommendations by 18 national and international societies, and consensus for the individual statements was evaluated by means of the Society Recommendation Consensus score. The highest consensus level (SRC A) was found for prioritized access to vaccination for transplant patients despite anticipation of a weakened immune response. All currently authorized vaccines can be considered safe for transplant patients (SRC A). The handling of immunosuppressive medication, the timely management of vaccines, and other aspects were aligned with available expert opinions. CONCLUSION: Expert consensus can be determined for crucial aspects of the implementation of SARS-CoV-2 vaccination programs. We hereby offer a tool for immediate decision-making until empirical data becomes available.

Perioperative Perfusion of Allografts with Anti-Human T-lymphocyte Globulin Does Not Improve Outcome Post Liver Transplantation-A Randomized Placebo-Controlled Trial.

Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on the results of perioperative ATLG perfusion in a randomized, single-blinded, placebo-controlled, feasibility trial (RCT) involving 30 liver recipients (LTx). Organs were randomly assigned for perfusion with ATLG/Grafalon® (AP) (n = 16) or saline only (control perfusion = CP) (n = 14) prior to implantation. The primary endpoint was defined as graft function reflected by aspartate transaminase (AST) values at day 7 post-transplantation (post-tx). With respect to the primary endpoint, no significant differences in AST levels were shown in the intervention group at day 7 (AP: 53.0 ± 21.3 mg/dL, CP: 59.7 ± 59.2 mg/dL, p = 0.686). Similarly, exploratory analysis of secondary clinical outcomes (e.g., patient survival) and treatment-specific adverse events revealed no differences between the study groups. Among liver transplant recipients, pre-operative organ perfusion with ATLG did not improve short-term outcomes, compared to those who received placebo perfusion. However, ATLG perfusion of liver grafts was proven to be a safe procedure without the occurrence of relevant adverse events.

Thoracic Surgery in the COVID-19 Pandemic: A Novel Approach to Reach Guideline Consensus.

The COVID-19 pandemic challenges international and national healthcare systems. In the field of thoracic surgery, procedures may be deferred due to mandatory constraints of the access to diagnostics, staff and follow-up facilities. There is a lack of prospective data on the management of benign and malignant thoracic conditions in the pandemic. Therefore, we derived recommendations from 14 thoracic societies to address key questions on the topic of COVID-19 in the field of thoracic surgery. Respective recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found to temporarily suspend non-critical elective procedures or procedures for benign conditions and to prioritize patients with symptomatic or advanced cancer. Prior to hospitalization, patients should be screened for respiratory symptoms indicating possible COVID-19 infection and most societies recommended to screen all patients for COVID-19 prior to admission. There was a weak consensus on the usage of serology tests and CT scans for COVID-19 diagnostics. Nearly all societies suggested to postpone elective procedures in patients with suspected or confirmed COVID-19 and recommended constant reevaluation of these patients. Additionally, we summarized recommendations focusing on precautions in the theater and the management of chest drains. This study provides a novel approach to informed guidance for thoracic surgeons during the COVID-19 pandemic in the absence of scientific evidence-based data.

[COVID-19 Pandemic in Germany: The Current Situation in Thoracic Surgery]. / COVID-19-Pandemie in Deutschland: Die aktuelle Lage in der Thoraxchirurgie.

BACKGROUND: The new COVID-19 pandemic has an impact on routine thoracic surgery. Various concepts and recommendations are being pursued to protect patients and hospital staff. However, the implementation of these recommendations may depend on the existing infrastructure, local conditions and in-house procedural instructions. MATERIAL AND METHOD: Between 11th May and 26th May 2020, an anonymous online survey on the topic of COVID-19 was conducted among thoracic surgeons in Germany. The survey consisted of 16 questions on the local COVID-19 case numbers, protective measures, procedural instructions and treatment concepts. The results were summarised, descriptively analysed and discussed. RESULTS: The response rate of 42.6% (n = 66), included replies from 23 (34.8%) specialised hospitals, 18 (27.3%) maximum care hospitals and 14 (21.2%) university clinics. COVID-19-positive patients were treated in 65 (99%) clinics and 37.9% of the clinics also performed surgery on COVID-19-positive patients. Nasopharyngeal swabs were the main instrument for COVID-19 patient testing (in 95.4% of the clinics). Test results influenced decisions on treatment in 71.2% of the clinics. In 59.1% of clinics, safety equipment was supplemented with FFP2 masks and eye protection during thoracic surgeries due to the COVID-19 pandemic. DISCUSSION: Almost all thoracic surgeons reported that they had treated patients with COVID-19 and half of them also had performed surgery on COVID-19-positive patients. The applied procedural instructions as well as the effects of COVID-19 on treatment decisions and patient-doctor contact differed between the reporting clinics.

Treatment of Anti-HLA Donor-Specific Antibodies Results in Increased Infectious Complications and Impairs Survival after Liver Transplantation.

Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 December 2015 were examined. Recipients < 18 years, living donor-, combined, high-urgency-, and re-transplantations were excluded. Out of 510 LTs, 113 DSA-positive cases were propensity score-matched with DSA-negative cases based on the components of the Balance of Risk score. One-, three-, and five-year survival after LT were 74.3% in DSA-positive vs. 84.8% (p = 0.053) in DSA-negative recipients, 71.8% vs. 71.5% (p = 0.821), and 69.3% vs. 64.9% (p = 0.818), respectively. Rejection therapy was more often applied to DSA-positive recipients (n = 77 (68.1%) vs. 37 (32.7%) in the control group, p < 0.001). At one year after LT, 9.7% of DSA-positive patients died due to sepsis compared to 1.8% in the DSA-negative group (p = 0.046). The remaining causes of death were comparable in both groups (cardiovascular 6.2% vs. 8.0%; p = 0.692; hepatic 3.5% vs. 2.7%, p = 0.788; malignancy 3.5% vs. 2.7%, p = 0.788). DSA seem to have an indirect effect on the outcome of adult LTs, impacting decision-making in post-transplant immunosuppression and rejection therapies and ultimately increasing mortality due to infectious complications.

[Living donor kidney transplantation]. / Nierentransplantation durch Lebendspende.

BACKGROUND: Due to the discrepancy between the increasing need of kidneys for transplantation and the continuously low numbers of brain dead donors, the possibility of living donor kidney transplantation is gaining importance. OBJECTIVE: The indications and evaluation of donors in living donor kidney transplantation were investigated. MATERIAL AND METHODS: The statistics of the German Organ Transplantation Foundation (DSO) were evaluated. The fundamental references in the literature and expert opinions are discussed. RESULTS AND CONCLUSION: Living donor kidney transplantation is an excellent option for patients with end-stage kidney failure. A thorough evaluation of potential donors and their aftercare is indispensable. There is a great potential to expand the living donor programs.

Outcome after pediatric liver transplantation for staged abdominal wall closure with use of biological mesh-Study with long-term follow-up.

Abdominal wall closure after pediatric liver transplantation (pLT) in infants may be hampered by graft-to-recipient size discrepancy. Herein, we describe the use of a porcine dermal collagen acellular graft (PDCG) as a biological mesh (BM) for abdominal wall closure in pLT recipients. Patients <2 years of age, who underwent pLT from 2011 to 2014, were analyzed, divided into definite abdominal wall closure with and without implantation of a BM. Primary end-point was the occurrence of postoperative abdominal wall infection. Secondary end-points included 1- and 5-year patient and graft survival and the development of abdominal wall hernia. In five out of 21 pLT recipients (23.8%), direct abdominal wall closure was achieved, whereas 16 recipients (76.2%) received a BM. BM removal was necessary in one patient (6.3%) due to abdominal wall infection, whereas no abdominal wall infection occurred in the no-BM group. No significant differences between the two groups were observed for 1- and 5-year patient and graft survival. Two late abdominal wall hernias were observed in the BM group vs none in the no-BM group. Definite abdominal wall closure with a BM after pLT is feasible and safe when direct closure cannot be achieved with comparable postoperative patient and graft survival rates.

Perioperative Pleural Drainage in Liver Transplantation: A Retrospective Analysis from a High-Volume Liver Transplant Center.

BACKGROUND Pleural effusions represent a common complication after liver transplantation (LT) and chest drain (CD) placement is frequently necessary. MATERIAL AND METHODS In this retrospective cohort study, adult LT recipients between 2009 and 2016 were analyzed for pleural effusion formation and its treatment within the first 10 postoperative days. The aim of the study was to compare different settings of CD placement with regard to intervention-related complications. RESULTS Overall, 597 patients met the inclusion criteria, of which 361 patients (60.5%) received at least 1 CD within the study period. Patients with a MELD >25 were more frequently affected (75.7% versus 56.0%, P<0.001). Typically, CDs were placed in the intensive care unit (ICU) (66.8%) or in the operating room (14.1% during LT, 11.5% in the context of reoperations). In total, 97.0% of the patients received a right-sided CD, presumably caused by local irritations. Approximately one-third (35.4%) of ICU-patients required pre-interventional optimization of coagulation. Of the 361 patients receiving a CD, 15 patients (4.2%) suffered a post-interventional hemorrhage and 6 patients (1.4%) had a pneumothorax requiring further treatment. Less complications were observed when the CD was performed in the operating room compared to the ICU: 1 out 127 patients (0.8%) versus 20 out of 332 patients (6.0%); P=0.016. CONCLUSIONS CD placement occurring in the operating room was associated with fewer complications in contrast to placement occurring in the ICU. Planned CD placement in the course of surgery might be favorable in high-risk patients.

Effects of expanded allocation programmes and organ and recipient quality metrics on transplant-related costs in kidney transplantation - an institutional analysis.

Expansions of donor pools have a controversial impact on healthcare expenditures. The aim of this study was to investigate the emerging costs of expanded criteria donor (ECD) kidney transplantations (KT) and to identify independent risk factors for increased transplant-related costs. We present a retrospective explorative analysis of hospital costs and reimbursements of KTs performed between 2012 and 2016 in a German university hospital. A total of 174 KTs were examined, including 92 (52.9%) ECD organ transplantations. The ECD group comprised 43 (24.7%) 'old-for-old' transplantations. Median healthcare costs were 19 570€ (IQR 18 735-27 405€) in the standard criteria donor (SCD) group versus 25 478€ (IQR 19 957-29 634€) in the ECD group (+30%; P = 0.076). 'Old-for-old' transplantations showed the highest healthcare expenditures [26 702€ (19 570-33 940€)]. Irrespective of the allocation group, transplant-related costs increased significantly in obese (+6221€; P = 0.009) and elderly recipients (+6717€; P = 0.019), in warm ischaemia time exceeding 30 min (+3212€; P = 0.009) and in kidneys with DGF or surgical complications (+8976€ and +10 624€; both P < 0.001). Transplantation of ECD organs is associated with incremental costs, especially in elderly and obese recipients. A critical patient selection, treatment of obesity before KT and keeping warm ischaemia times short seem to be crucial, in order to achieve a cost-effective KT regardless of the allocation group.

Prospective Assessment of Liver Function by an Enzymatic Liver Function Test to Estimate Short-Term Survival in Patients with Liver Cirrhosis.

BACKGROUND: MELD attempts to objectively predict the risk of mortality of patients with liver cirrhosis and is commonly used to prioritize organ allocation. Despite the usefulness of the MELD, updated metrics could further improve the accuracy of estimates of survival. AIMS: To assess and compare the prognostic ability of an enzymatic 13C-based liver function test (LiMAx) and distinct markers of liver function to predict 3-month mortality of patients with chronic liver failure. METHODS: We prospectively investigated liver function of 268 chronic liver failure patients without hepatocellular carcinoma. Primary study endpoint was liver-related death within 3 months of follow-up. Prognostic values were calculated using Cox proportional hazards and logistic regression analysis. RESULTS: The Cox proportional hazard model indicated that LiMAx (p < 0.001) and serum creatinine values (p < 0.001) were the significant parameters independently associated with the risk of liver failure-related death. Logistic regression analysis revealed LiMAx and serum creatinine to be independent predictors of mortality. Areas under the receiver-operating characteristic curves for MELD (0.86 [0.80-0.92]) and for a combined score of LiMAx and serum creatinine (0.83 [0.76-0.90]) were comparable. CONCLUSIONS: Apart from serum creatinine levels, enzymatic liver function measured by LiMAx was found to be an independent predictor of short-term mortality risk in patients with liver cirrhosis. A risk score combining both determinants allows reliable prediction of short-term prognosis considering actual organ function. Trial Registration Number (German Clinical Trials Register) # DRKS00000614.

Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts.

It has already been shown that neutralization of the activating NK cell receptor NKG2D in combination with co-stimulation blockade prolongs graft survival of vascularized transplants. In order to clarify the underlying cellular mechanisms, we transplanted complete MHC-disparate BALB/c-derived cardiac grafts into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1-/- ). Although median survival was 8 days for both recipient groups, we detected already at day 5 posttransplantation significantly greater intragraft frequencies of NKp46+ NK cells in Klrk1-/- recipients than in wildtypes. This was followed by a significantly greater infiltration of CD4+ , but a lesser infiltration of CD8+ T cell frequencies. Contrary to published observations, co-stimulation blockade with CTLA4-Ig resulted in a significant acceleration of cardiac rejection by Klrk1-/- recipients, and this result was confirmed by applying a neutralizing antibody against NKG2D to wildtypes. In both experimental setups, grafts derived from Klrk1-/- recipients were characterized by significantly higher levels of interferon-γ mRNA, and both CD4+ and CD8+ T cells displayed a greater capacity for degranulation and interferon-γ production. In summary, our results clearly illustrate that NKG2D expression in the recipient is important for cardiac allograft survival, thus supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance.

Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation.

BACKGROUND: Clinical data suggest that iron disturbances deleteriously affect graft survival after heart transplantation (HTx), but immunological mechanisms underlying this phenomenon have not yet been elucidated. METHODS: To identify the mechanistic influence of iron in a murine model of HTx, fully allogeneic BALB/c donor organs were transplanted into iron-overloaded or iron-deficient C57BL/6 mice, and recipients were analyzed for functional and immunological parameters. RESULTS: After HTx, iron overload accelerated acute rejection as observed by shortened graft survival (HTx vs HTx + iron; p = 0.01), elevated rejection score (p < 0.01), and induction of troponin T (p < 0.01). Compared with controls, allografts and recipient spleens derived from iron-overloaded recipients were characterized by a pronounced graft infiltration of CD4+ T cells (p < 0.01), CD3-NKp46+ natural killer cells (p < 0.05), and reduced frequencies of regulatory T cells (p < 0.01). This was accompanied by lower mRNA expression levels of anti-inflammatory cytokines, including interleukin-10, transforming graft factor-ß, and Foxp3. Cardiac allograft survival was further tested under co-stimulation blockade (CTLA4-Ig) showing that naïve grafts transplanted into iron-overloaded recipients illustrated restricted graft outcome compared with wild types (p = 0.0051), which was rescued after treatment with the iron chelator deferoxamine. Iron deficiency (ID) also resulted in enhanced intragraft infiltration of inflammatory cells and accelerated rejection in the acute setting (HTx vs HTx + ID; p = 0.02) and after co-stimulation blockade (p = 0.0059). CONCLUSIONS: We provide novel insights into the understanding of disturbances in iron homeostasis and their consequences after HTX, allowing novel insights regarding improvements in personalized immunosuppression to prolong allograft survival.

Identification of the activating cytotoxicity receptor NKG2D as a senescence marker in zero-hour kidney biopsies is indicative for clinical outcome.

The definition of biological donor organ age rather than chronological age seems obvious for the establishment of a valid pre-transplant risk assessment. Therefore, we studied gene expression for candidate markers in 60 zero-hour kidney biopsies. Compared with 29 younger donors under age 55, 31 elderly donors age 55 and older had significant mRNA expression for immunoproteasome subunits (PSMB8, PSMB9 and PSMB10), HLA-DRB, and transcripts of the activating cytotoxicity receptor NKG2D. Gene expression was validated in an independent donor cohort consisting of 37 kidneys from donors 30 years and under (Group I), 75 kidneys from donors age 31-54 years (Group II) and 75 kidneys from donors age 55 and older (Group III). Significant gene induction was confirmed in kidneys from Group III for PSMB9 and PSMB10. Strikingly, transcripts of NKG2D had the significantly highest gene induction in Group III versus Group II and Group I. Similar results were obtained for CDKN2A, but not for telomere length. Both NKG2D and CDKN2A mRNA expression were significantly correlated with creatinine levels at 24 months after transplantation. Univariate regression analysis showed significant predictive power regarding graft function at 6 and 12 months for NKG2D and CDKN2A. However, only NKG2D remained significantly predictive in the multivariate model at 12 months. Thus, our results reveal novel candidate markers in aged renal allografts, which could be helpful in the assessment of organ quality.