Hypothermic machine perfusion can safely prolong cold ischemia time in deceased donor kidney transplantation. A retrospective analysis on postoperative morbidity and graft function.

In deceased donor kidney transplantation (KT), a prolonged cold ischemia time (CIT) is a negative prognostic factor for KT outcome, and the efficacy of hypothermic machine perfusion (HMP) in prolonging CIT without any additional hazard is highly debated. We conducted a retrospective study on a cohort of 154 single graft deceased donor KTs, in which a delayed HMP, after a preliminary period of static cold storage (SCS), was used to prolong CIT for logistic reasons. Primary outcomes were postoperative complications as well as 1 year graft survival and function. 73 cases (47.4%) were managed with HMP and planned KT, while 81 (52.6%) with SCS and urgent KT. The median CIT in HMP group and SCS group was 29 hour:57 minutes [27-31 hour:45 minutes] and 11 hour:25 minutes [9-14 hour:30 minutes], respectively (P < .001). The period of SCS in the HMP group was significantly shorter than in the SCS group (10 vs. 11 hour:25 minutes, P = .02) as well as the prevalence of expanded criteria donors was significantly higher (43.8% vs. 18.5%, P < .01). After propensity score matching for these two baseline characteristics, the HMP and SCS groups showed comparable outcomes in terms of delayed graft function, vascular, and urologic complications, infections, and episodes of graft rejection. At 1 year follow-up, serum creatinine levels were comparable between the groups. Therefore, the use of HMP to prolong the CIT and convert KT into a planned procedure seemed to have an adequate safety profile, with outcomes comparable to KT managed as an urgent procedure and a CIT nearly three time shorter.

Impact of kidney transplant morbidity on elderly recipients' outcomes.

BACKGROUND AND AIMS: Nowadays, advanced age does not represent an absolute contraindication to kidney transplantation (KT). However, aging is frequently associated with multiple comorbidities and lower performance status, making KT candidates less surgically fit. Limited data are available on the impact of KT morbidity on elderly recipients' outcomes. METHODS: Retrospective study on a single center cohort of 130 KT recipients over 65 years old, representing 16.2% of KT clinical series, during the period 2000-2018. Number and severity of comorbidities were evaluated with the Charlson Comorbidity index (CCI). RESULTS: The median age at transplantation was 67 [IQR66-71] years and median CCI was 5 [IQR4-6]. The prevalence of postoperative complications with a Clavien-Dindo (C-D) severity score > 2 was 29%. Increasing age did not predict KT morbidity in terms of C-D score > 2, infectious, respiratory, cardiologic, urologic or vascular complications, delayed graft function, symptomatic lymphocele, bleeding, acute or chronic rejection. Conversely, CCI score was a predictor of overall complications with C-D score > 2, cardiologic, respiratory and vascular complications, and bleeding. Among others, CCI score, post-KT cardiologic complications, C-D score > 2 were identified as significant predictors of both early mortality and graft loss in univariate analysis. Increasing recipient age did not correlate with graft loss risk and graft loss did not impact patient survival. C-D score > 2 was a predictor of poor survival even in multivariate analysis. CONCLUSIONS: Elderly recipients showed a significant vulnerability to KT morbidity which correlates with CCI. While graft loss did not impact recipient survival, severe postoperative complications (C-D > 2) were independently associated increased mortality.

Association between indocyanine green clearance test and ischemic type biliary lesions within one year after orthotopic liver transplantation.

BACKGROUND: Ischemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia-reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. OBJECTIVE: Our aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. METHODS: This retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. RESULTS: ITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77-0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: The findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.

Controlling Nutritional Status score does not predict patients' overall survival or hepatocellular carcinoma recurrence after deceased donor liver transplantation.

BACKGROUND: The Controlling Nutritional Status (CONUT) score is a newly developed laboratory-derived immunonutritional score which has been validated as prognostic marker for survival and tumor recurrence in surgically treated patients with various tumor types, including hepatocellular carcinoma (HCC). The aim of the present study was to test the CONUT score performance in HCC patients treated with liver transplantation (LT). METHODS: A retrospective study on a bi-centers cohort of 280 HCC patients submitted to LT between 2006 and 2017 was performed. Indication to LT was limited to Milan criteria or UCSF criteria, defined by preoperative imaging. RESULTS: Median pre-LT CONUT score was 5 (interquartile range 3-7). Overall patients' survival at 1, 3, and 5 years was 84%, 76.6%, and 68.3%, respectively. Multivariate analysis showed that HCC recurrence (hazard ratio [HR] = 1.987, P = .012] and pre-LT neutrophil to lymphocyte ratio (NLR) (HR = 1.064, P = .003) were independent risk factors for reduced survival. Cumulative incidence of HCC recurrence at 1, 3, and 5 years was 5.1%, 11.5%, and 15.5%, respectively. Pre-LT platelet-to-lymphocyte ratio (PLR) (subdistribution hazard ratio [SHR] = 1.086, P = .044], tumor max diameter (SHR = 1.695, P < .001), and bilobar tumor distribution (SHR = 6.892, P = .006) were independent risk factors for tumor recurrence. The CONUT score did not show any prognostic value. CONCLUSIONS: The CONUT score did not predict poor survival or tumor recurrence in LT recipients.

Early post-liver transplant surgical morbidity in HIV-infected recipients: risk factor for overall survival? A nationwide retrospective study.

The aim of the study was to analyse the risk factors for early surgical complications requiring relaparotomy and the related impact on overall survival (OS) in HIV-infected patients submitted to liver transplantation. Thus a retrospective investigation was conducted on a nationwide multicentre cohort of 157 HIV patients submitted to liver transplantation in six Italian Transplant Units between 2004 and 2014. An early relaparotomy was performed in 24.8% of cases and the underlying clinical causes were biliary leak (8.2%), bleeding (8.2%), intestinal perforation (4.5%) and suspect of vascular complications(3.8%). No differences in terms of prevalence for either overall or cause-specific early relaparotomies were noted when compared with a non-HIV control group, matched for MELD, recipient age, HCV-RNA positivity and HBV prevalence. While in the control group an early relaparotomy appeared a negative prognostic factor, such impact on OS was not noted in HIV recipients. Nonetheless increasing number of relaparotomies were associated with decreased survival. In multivariate analysis, preoperative refractory ascites and Roux-en-Y choledochojejunostomy reconstruction were significant risk factors for early relaparotomy. To conclude, in HIV liver transplanted patients, an increasing number of early relaparotomies because of surgical complications does negatively affect the OS. Preoperative refractory ascites reflecting a severe portal hypertension and a difficult biliary tract reconstruction requiring a Roux-en-Y choledochojejunostomy are associated with increased risk of early relaparotomy.

Are there any relations among transplant centre volume, surgical technique and anatomy for donor graft selection? Ten-year multicentric Italian experience on mini-invasive living donor nephrectomy.

BACKGROUND: Selection of the right or left living donor kidney for transplantation is influenced by many variables. In the present multi centric study including 21 Italian transplant centres, we evaluated whether centre volume or surgical technique may influence the selection process. METHODS: Intra- and perioperative donor data, donor kidney function, and recipient and graft survival were collected among 693 mini-invasive living donor nephrectomies performed from 2002 to 2014. Centre volume (LOW, 1-50 cases; HIGH, >50 cases) and surgical technique (FULL-LAP, full laparoscopic and robotic; HA-LAP, hand-assisted laparoscopy; MINI-OPEN, mini-lumbotomy) were correlated with selection of right or left donor kidney and with donor and recipient outcome. RESULTS: HIGH-volume centres retrieved a higher rate of donor right kidneys (29.3% versus 17.6%, P < 0.01) with single artery (83.1% versus 76.4%, P < 0.05) compared with LOW-volume centres. Surgical technique correlated significantly with rate of donor right kidney and presence of multiple arteries: MINI-OPEN (53% and 13%) versus HA-LAP (29% and 22%) versus FULL-LAP (11% and 23%), P < 0.001 and P < 0.05, respectively. All donors had an uneventful outcome; donor bleeding was more frequent in LOW-volume centres (4% versus 0.9%, P < 0.05). CONCLUSIONS: Centre volume and surgical technique influenced donor kidney side selection. Donor nephrectomy in LOW-volume centres was associated with higher risk of donor bleeding.

Multicenter italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients.

BACKGROUND: The aim of our work is to assess the clinical outcomes of liver transplantation (LT) for hepatocellular carcinoma (HCC) in HIV-coinfected patients. This is a multicenter study involving three Italian transplant centers in northern Italy: University of Modena, University of Bologna, and University of Udine. PATIENTS AND METHODS: We compared 30 HIV-positive patients affected by HCC who underwent LT with 125 HIV-uninfected patients who received the same treatment from September 2004 to June 2009. At listing, there were no differences between HIV-infected and -uninfected patients regarding HCC features. Patients outside the University of California, San Francisco criteria (UCSF) were considered eligible for LT if a down-staging program permitted a reduction of tumor burden. RESULTS: HIV-infected patients were younger, they were more frequently anti-HCV positive, and a higher number of HIV-infected patients presented a coinfection HBV-HCV. Pre-LT treatments (liver resection and or locoregional treatments) were similar between the two groups. Histological characteristics of the tumor were similar in patients with and without HIV infection. No differences were observed in terms of overall survival and HCC recurrence rates. CONCLUSION: LT for HCC is a feasible procedure and the presence of HIV does not particularly affect the post-LT outcome.

PO2 21% oxygenated hypothermic machine perfusion in kidney transplantation: Any clinical benefit?

BACKGROUND: In deceased donor kidney transplantation (KT), the use of hypothermic machine perfusion (HMP) has been acquiring the status of best practice in the pre-transplant management of kidney grafts. Two types of HMP are currently available, oxygenated HMP and non-oxygenated HMP. However, data on the real clinical impact of oxygenation on KT outcome are still heterogeneous. METHODS: Retrospective study on a cohort of 103 patients transplanted with a single kidney graft that was managed either with end-ischemic oxygenated (O2 group, Waves Machine, n = 51, 49.5%) or non-oxygenated HMP (no-O2 group, Life Port Kidney Transporter Machine, n = 52, 50.5%), during the period January 2016-December 2020. Oxygenation was performed at pO2 21%. RESULTS: The median cold ischemia time was 29 h:40 min [IQR 26 h:55 min-31 h:10 min] and the prevalence of grafts from extended criteria donors (ECD) was 46.7%, with a median kidney donor profile index (KDPI) of 72 [41-94]. The study groups were homogeneous in terms of recipient characteristics, ischemia times and donor characteristics. O2 and no-O2 groups showed comparable outcomes in terms of delayed graft function (O2 vs no-O2, 21.5% vs 25%, p = 0.58), vascular (0.2% vs 0.2%, p > 0.99) and urologic (13.7% vs 11.5%, p = 0.77) complications, and episodes of graft rejection (11.7% vs 7.7%, p = 0.52). At 1 year follow up, even creatinine serum levels were comparable between the groups (1.27 mg/dL [1.09 and 1.67] vs 1.4 mg/dL [1.9-1.78], p = 0.319), with similar post-transplant trend (p = 0.870). No significant benefit was either observed in ECD or KDPI > 60 subgroups, respectively. CONCLUSIONS: Oxygenation at pO2 21% during HMP seems not to significantly enhance the KT outcomes in terms of postoperative complications or graft function.

Current practice with grafts with multiple renal arteries in kidney transplantation: role of the methylene blue in the lower pole.

Kidneys with multiple renal arteries (MRAs) from different patches, may provide to the surgeon additional technical difficulties that make kidney transplants very challenging. MRAs have been largely debated over the years whether to be anastomosed or not due to the disappointing outcomes when it comes to inappropriate ligation or anastomosis.  Some authors empirically reassure that smaller branches can be safely ligated and dissected without intraoperative and postoperative complications or compromising the functional recovery of the graft. Literature is poor about the possible differences in the management of superior and inferior polar arteries. Inferior polar arteries represent a topic of great interest as they may also supply the proximal ureter. The aim of this article is to merge the current knowledge about the management of inferior polar arteries and to highlight if there is any role of the methylene blue dye (MB) in the study of the ureteral vascularization in kidney transplantation. MB can be considered a safe and simple tool of vascular perfusion assessment in kidney transplantation. By injecting the dye-solution into the inferior MRA hidden ureteral branches can be unmasked and guide the surgeon to preserve important vessels. In view of their fundamental role in the vascularization of the ureter, the lower polar arteries of the graft, should be invariably studied by MB. It provides an objective, simple and fast tool for the evaluation of the ureteral vascularization when injected through the inferior MRA of the graft.

Liver resection for noncolorectal and nonneuroendocrine metastases: results of a study on 56 patients at a single institution.

The usefulness of surgical treatment for hepatic metastases of noncolorectal nonneuroendocrine (NCRNNE) tumors is not yet clear due to the natural history of these tumors, their frequent systemic dissemination and their histological heterogeneity. The aim of this study was to evaluate the long-term outcome of patients who underwent liver resection for NCRNNE metastases. For this purpose we retrospectively analyzed 202 patients who underwent liver resection for metastasis between January 1989 and December 2006 at the Department of Surgery of the University Hospital of Udine. Fifty-six patients underwent liver resection because of NCRNNE metastases. The preoperative assessment was based on hepatic ultrasonography and CT scan; PET was used in a few patients. All patients had intraoperative liver ultrasonography to evaluate the lesions and to define the resection. Gender, age, primary tumor site (gastrointestinal or nongastrointestinal), synchronous or metachronous metastasis, unilobar or bilobar localization, number and diameter of the lesion(s), type of resection, margin status, positive lymph nodes in the hepatoduodenal ligament, and time between surgery and diagnosis of liver metastases were evaluated as possible prognostic factors for survival. Univariate analysis showed that the location of the primary tumor and the disease-free interval since the treatment of the primary tumor were positive predictive factors for longer survival. Multivariate analysis showed that the only independent significant factor was gastrointestinal versus nongastrointestinal origin. Demographic data, the synchronous or metachronous appearance of metastases, their unilobar or bilobar location, number and size, the type of resection, the resection margin status and the involvement of lymph nodes did not prove to be prognostic factors.

Early Graft Dysfunction Following Kidney Transplantation: Can Thermographic Imaging Play a Predictive Role?

The shortage of organs and the growing need for them over recent years have led to the adoption of less stringent donor acceptance criteria, resulting in the approval of marginal organs for transplant, especially from elderly donors. This implies a higher risk of graft dysfunction, a higher frequency of immunological and vascular complications, and shorter graft survival. Several strategies have been implemented in clinical practice to assess graft quality and suitability for transplantation. We have started to test the prospective intraoperative use of thermo-vision cameras during graft reperfusion. Images were acquired using the FLIR One Pro thermo-vision camera for android devices. We hypothesized that thermal images would give a better perspective about the quality of arterial perfusion and graft revascularization of the renal cortex. Thermo-vision cameras provide an easy-to-use, noninvasive, cost-effective tool for the global assessment of kidney graft cortical microcirculation in the immediate post-reperfusion period, providing additional data on the immediate viability and function of a graft.

Postoperative Trends and Prognostic Values of Inflammatory and Nutritional Biomarkers after Liver Transplantation for Hepatocellular Carcinoma.

Preoperative inflammatory biomarkers such as the Platelet-to-Lymphocyte Ratio (PLR) and the Neutrophil-to-Lymphocyte Ratio (NLR) strongly predict the outcome in surgically treated patients with hepatocellular carcinoma (HCC), while nutritional biomarkers such as the Controlling Nutritional Status (CONUT) and the Prognostic Nutritional Index (PNI) show an analogue prognostic value in hepatic resection (HR) but not in liver transplant (LT) cases. Data on the impact of LT on the inflammatory and nutritional/metabolic function are heterogeneous. Therefore, we investigated the post-LT trend of these biomarkers up to postoperative month (POM) 12 in 324 HCC patients treated with LT. Inflammatory biomarkers peaked in the early post-LT period but at POM 3 leveled off at values similar (NLR) or higher (PLR) than pre-LT ones. CONUT and PNI worsened in the early post-LT period, but at POM 3 they stabilized at significantly better values than pre-LT. In LT recipients with an overall survival >1 year and no evidence of early HCC recurrence, 1 year post-LT NLR and PNI independently predicted patient overall survival, while 1 year post-LT PLR independently predicted late tumor recurrence. In conclusion, at 1 year post-LT, the nutritional status of liver-transplanted HCC patients significantly improved while their inflammatory state tended to persist. Consequently, post-LT PLR and NLR maintained a prognostic value for LT outcome while post-LT CONUT and PNI acquired it.

Role for contrast-enhanced ultrasound in assessing complications after kidney transplant.

Kidney transplantation (KT) is an effective treatment for end-stage renal disease. Despite their rate has reduced over time, post-transplant complications still represent a major clinical problem because of the associated risk of graft failure and loss. Thus, post-KT complications should be diagnosed and treated promptly. Imaging plays a pivotal role in this setting. Grayscale ultrasound (US) with color Doppler analysis is the first-line imaging modality for assessing complications, although many findings lack specificity. When performed by experienced operators, contrast-enhanced US (CEUS) has been advocated as a safe and fast tool to improve the accuracy of US. Also, when performing CEUS there is potentially no need for further imaging, such as contrast-enhanced computed tomography or magnetic resonance imaging, which are often contraindicated in recipients with impaired renal function. This technique is also portable to patients' bedside, thus having the potential of maximizing the cost-effectiveness of the whole diagnostic process. Finally, the use of blood-pool contrast agents allows translating information on graft microvasculature into time-intensity curves, and in turn quantitative perfusion indexes. Quantitative analysis is under evaluation as a tool to diagnose rejection or other causes of graft dysfunction. In this paper, we review and illustrate the indications to CEUS in the post-KT setting, as well as the main CEUS findings that can help establishing the diagnosis and planning the most adequate treatment.

Predictive Value of Intraoperative Doppler Flowmetry for Delayed Graft Function in Kidney Transplantation: A Pilot Study.

BACKGROUND: The delayed graft function (DGF) in kidney transplantation (KT) is a risk factor for long-term poor graft survival. The pathogenesis is multifactorial but mainly related to an ischemia-reperfusion injury. However, the graft hemodynamics have been recently identified as a key aspect for early DGF risk assessment and potential therapeutic intervention. METHODS: A pilot study on 20 single kidney grafts from donor after brain death with intraoperative measurement of graft arterial flowmetry, 30 minutes after reperfusion. Exclusion criteria were grafts with multiple arteries or severe atherosclerosis of the recipient's external iliac artery. RESULTS: KT recipients with DGF (n = 4, 20%) were homogenous with controls (n = 16) in terms of cold ischemia time, donor age, recipients' hemodynamic parameters, renal artery, and recipients' external iliac artery diameters. Nonetheless, at transplant, the kidney grafts that developed DGF were characterized by a significantly higher renal artery resistive index (DGF vs no-DGF 0.96 ± 0.04 vs 0.77 ± 0.13, P = .02), as well as lower flow extraction rate (24.8% ± 11.8 vs 59.2% ± 21.1, P < .01). CONCLUSIONS: Intraoperative arterial graft flowmetry seems to be an effective tool to identify grafts at high risk of DGF.

Effects of Delayed Hypothermic Machine Perfusion on Kidney Grafts with a Preliminary Period of Static Cold Storage and a Total Cold Ischemia Time of Over 24 Hours.

BACKGROUND Hypothermic machine perfusion (HMP) appears to exert a reconditioning effect on the ischemic damage of kidney grafts. However, some concerns still remain about its real effectiveness when it is delayed after a preliminary period of static cold storage (SCS) or with prolonged overall cold ischemia time (CIT). MATERIAL AND METHODS The effect of HMP on hemodynamic, metabolic, histological and ultrastructural features of grafts was investigated in 21 single-kidney grafts treated with a delayed HMP after SCS and with a total CIT of over 24 h. RESULTS The mean CIT, SCS, and HMP times were 29 h, 12 h, and 18 h, respectively. Longer SCS was associated with higher vascular resistance and lower arterial flow. In the pre- vs. post-HMP comparison, a significant decrease in arterial resistances and increase of flow were recorded. The hemodynamic improvement was independent of HMP duration. The perfused grafts retained some metabolic activity, with a statistically significant decrease of pH, pO2, and glucose levels, and increase of lactates in the perfusion liquid, by the end of HMP. Longer SCS was associated with higher pH and greater pO2 decrease during HMP. Light microscopy and transmission electronic microscopy revealed no significant variations in nuclear, cytoplasmic, or ultrastructural damage. SCS, HMP, and CIT were not identified as risk factor for delayed graft function or rejection. CONCLUSIONS A delayed and extended HMP can recover the graft hemodynamic function, maintain some metabolic activity, and stabilize the accumulated ischemic damage due to a preliminary SCS.

Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients.

OBJECTIVES: The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections. METHODS: After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC. Biliary penetration of linezolid was calculated as the ratio between Cmin in bile and in plasma. Optimal theoretical pharmacodynamic exposure of linezolid against VRE in bile was defined as biliary Cmin>MIC90. RESULTS: C(min) of linezolid in bile achieved very high values at steady-state, which were significantly higher than in plasma (median of 21.77 versus 8.08 mg/L, P=0.021). The very high biliary penetration of linezolid (median value of 1.93; range 1.31-4.83) enabled achievement of optimal theoretical pharmacodynamic exposure against VRE in bile (Cmin>2 mg/L) on all of the occasions. CONCLUSIONS: These preliminary data suggest a potential role for linezolid in the treatment of cholangitis due to VRE in LTx patients. Obviously, further confirmatory data assessing also the AUC/MIC ratio of linezolid in bile are needed.