Clinical Research in Renal Transplantation: A Bibliometric Perspective on a Half-century of Innovation and Progress.

BACKGROUND: Groundbreaking biomedical research has transformed renal transplantation (RT) into a widespread clinical procedure that represents the mainstay of treatment for end-stage kidney failure today. Here, we aimed to provide a comprehensive bibliometric perspective on the last half-century of innovation in clinical RT. METHODS: The Web of Science Core Collection was used for a comprehensive screening yielding 123 303 research items during a 50-y period (January 1973-October 2022). The final data set of the 200 most-cited articles was selected on the basis of a citation-based strategy aiming to minimize bias. RESULTS: Studies on clinical and immunological outcomes (n = 63 and 48), registry-based epi research (n = 38), and randomized controlled trials (n = 35) dominated the data set. Lead US authors have signed 110 of 200 articles. The overall level of evidence was high, with 84% of level1 and -2 reports. Highest numbers of these articles were published in New England Journal of Medicine , Transplantation , and American Journal of Transplantation. Increasing trend was observed in the number of female authors in the postmillennial era (26% versus 7%). CONCLUSIONS: This study highlights important trends in RT research of the past half-century. This bibliometric perspective identifies the most intensively researched areas and shift of research interests over time; however, it also describes important imbalances in distribution of academic prolificacy based on topic, geographical aspects, and gender.

Controversy Over Liver Transplantation or Resection for Neuroendocrine Liver Metastasis: Tumor Biology Cuts the Deal.

BACKGROUND: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute. METHODS: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics. RESULTS: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria. CONCLUSIONS: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT.

Oxygenated End-Hypothermic Machine Perfusion in Expanded Criteria Donor Kidney Transplant: A Randomized Clinical Trial.

Importance: Continuous hypothermic machine perfusion during organ preservation has a beneficial effect on graft function and survival in kidney transplant when compared with static cold storage (SCS). Objective: To compare the effect of short-term oxygenated hypothermic machine perfusion preservation (end-HMPo2) after SCS vs SCS alone on 1-year graft survival in expanded criteria donor kidneys from donors who are brain dead. Design, Setting, and Participants: In a prospective, randomized, multicenter trial, kidneys from expanded criteria donors were randomized to either SCS alone or SCS followed by end-HMPo2 prior to implantation with a minimum machine perfusion time of 120 minutes. Kidneys were randomized between January 2015 and May 2018, and analysis began May 2019. Analysis was intention to treat. Interventions: On randomization and before implantation, deceased donor kidneys were either kept on SCS or placed on HMPo2. Main Outcome and Measures: Primary end point was 1-year graft survival, with delayed graft function, primary nonfunction, acute rejection, estimated glomerular filtration rate, and patient survival as secondary end points. Results: Centers in 5 European countries randomized 305 kidneys (median [range] donor age, 64 [50-84] years), of which 262 kidneys (127 [48.5%] in the end-HMPo2 group vs 135 [51.5%] in the SCS group) were successfully transplanted. Median (range) cold ischemia time was 13.2 (5.1-28.7) hours in the end-HMPo2 group and 12.9 (4-29.2) hours in the SCS group; median (range) duration in the end-HMPo2 group was 4.7 (0.8-17.1) hours. One-year graft survival was 92.1% (n = 117) in the end-HMPo2 group vs 93.3% (n = 126) in the SCS group (95% CI, -7.5 to 5.1; P = .71). The secondary end point analysis showed no significant between-group differences for delayed graft function, primary nonfunction, estimated glomerular filtration rate, and acute rejection. Conclusions and Relevance: Reconditioning of expanded criteria donor kidneys from donors who are brain dead using end-HMPo2 after SCS does not improve graft survival or function compared with SCS alone. This study is underpowered owing to the high overall graft survival rate, limiting interpretation. Trial Registration: isrctn.org Identifier: ISRCTN63852508.

Intraoperative use of transit time flow measurement improves patency of newly created radiocephalic arteriovenous fistulas in patients requiring hemodialysis.

BACKGROUND: The autologous arteriovenous fistula is the primary choice to establish hemodialysis access without high failure rates. Intraoperative ultrasound flow measurements of newly created autologous arteriovenous fistulas represent a possibility of quality control and may therefore be a tool to assess their functionality. The aim of our study was to correlate intraoperative blood flow with access patency. METHODS: Between March 2012 and March 2015, intraoperative transit time flow measurements were collected on 89 patients. Measurements were performed 5-10 min after the creation of a standardized anastomosis using 3-6 mm flow probes. To examine the correlation between intraoperative blood flow and access patency, groups of patients with high (> 200 mL/min) versus low flow (< 200 mL/min) were enrolled. Patients were assessed clinically and with ultrasound every 3 months. Data were analyzed retrospectively. RESULTS: In the current short-term follow-up, including 89 patients (age 62 ± 3 years), 61 (68.5%) of the autologous arteriovenous fistulas were currently being used in an observation period ranging from 3 months to 3 years (mean observation period 546 ± 95 days) postoperatively. The intraoperative blood flow in patients with functioning autologous arteriovenous fistula (78) was significantly higher than that of patients without functioning autologous arteriovenous fistulas (407 ± 25 vs 252 ± 42 mL/min, respectively; p < 0.005) (11). CONCLUSION: The intraoperative measurement of blood flow is a useful tool to predict the outcome of maturation in autologous arteriovenous fistula. With this method, technical problems can be detected and corrected intraoperatively. Routine implementation of intraoperative flow measurements has to be examined by prospective controlled trials.

SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients.

BACKGROUND: The impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT. MATERIALS AND METHODS: The feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3' untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs). RESULTS: Of all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48-23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers. CONCLUSION: Our results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.

Risk Factors for High Mortality on the Liver Transplant Waiting List in Times of Organ Shortage: A Single-Center Analysis.

BACKGROUND Germany has the highest rate of patients dying or becoming unfit for transplant while waitlisted within the Eurotransplant region. Therefore, the aim of the current study was to analyze mortality as well as risk factors for mortality of candidates listed for liver transplantation at our center. MATERIAL AND METHODS Between 01/2011 and 12/2013, 481 adult patients were listed for primary liver transplantation (LT) at a single German center. Clinical and laboratory parameters were prospectively collected and retrospectively analyzed by univariable and multivariable logistic regression and Cox proportional hazards. RESULTS The mean model for end-stage liver disease (MELD) score of all liver transplant waitlist registrants (52.4 years, 60.1% male) was 16.9 (±10.2) at time of listing, with 10% of the listed patients having a MELD score of >32. After waitlisting, 133 (27.7%) candidates died within the follow-up period. Three-month-survival after listing for transplantation was 89% for patients ultimately receiving LT vs. 71.2% that did not receive LT (p<0.001). Multivariable analysis identified clinical parameters such as ICU treatment, preceding abdominal surgery, variceal bleeding, and ascites, as well as hydropic decompensation, as independent risk factors for waitlist mortality. CONCLUSIONS Consideration of independent risk factors of mortality within the MELD-based allocation system potentially improves assessment of individual urgency and might improve utilization of available organs.

Promyelocytic leukemia protein deficiency leads to spontaneous formation of liver tumors in hepatitis C virus transgenic mice.

Persistent infection with hepatitis C virus (HCV) is a known risk factor for the development of hepatocellular carcinoma (HCC). The lack of the tumor suppressor promyelocytic leukemia protein (PML) in combination with HCV fosters hepatocarcinogenesis via induction of HCC using diethylnitrosamine (DEN) in a rodent model. However, the spontaneous development of malignant lesions in PML-deficient mice with an HCV-transgene (HCVtg ) has not been investigated thus far. We crossed PML-deficient mice with HCV transgene expressing mice and observed the animals for a period of 12 months. Livers were examined macroscopically and histologically. Gene expression analysis was performed on these samples, and compared with expression of selected genes in human samples of patients undergoing liver transplantation for HCC. In vitro studies were performed in order to analyze the selected pathways. Genetic depletion of PML in combination with HCVtg coincided with an increased hepatocyte proliferation, resulting in development of HCCs in 40% of the PML-deficient livers. No tumor development was observed in mice with either the PML-knockout (PML-/- ) or HCVtg alone. Gene expression profiling uncovered pathways involved in cell proliferation, such as NLRP12 and RASFF6. These findings were verified in samples from human livers of patients undergoing liver transplantation for HCC. Further in vitro studies confirmed that lack of PML, NLRP12, and RASFF6 leads to increased cell proliferation. The lack of PML in combination with HCV is associated with increased cell proliferation, fostering tumor development in the liver. Our data demonstrate that PML acts as an important tumor suppressor in HCV-dependent liver pathology.