HTK-N as a new preservation solution for human kidney preservation: Results of a pilot randomized controlled clinical phase II trial in living donor transplantation.

BACKGROUND: HTK-N was developed based on the traditional HTK preservation solution, resulting in stronger protection against reactive oxygen species as well as better tolerance to hypothermia and ischemia. Aim of the present study was to compare HTK-N to HTK in clinical kidney transplantation demonstrating safety and non-inferiority. METHODS: We performed a randomized controlled single blinded clinical phase II trial in patients undergoing living donor kidney transplantation. After retroperitoneoscopic nephrectomy kidneys were either perfused and stored with classical HTK solution or the new HTK-N solution. Primary endpoint was the glomerular filtration rate (eGFR according to CKD EPI) 3 months after transplantation. Secondary endpoints included graft and patient survival beside others. RESULTS: The study included 42 patients, of which 22 were randomized in the HTK-N group and 20 in the HTK group. The primary end point showed a mean eGFR of 55.4 ± 14.0 ml/min/1.73 m2 in the HTK group compared to a GFR of 57.2 ± 16.7 ml/min/m2 in the HTK-N group (P = .72). Regarding secondary endpoints, there were no apparent differences. Posttransplant graft and patient survival was 100%. CONCLUSION: This study is the first clinical application of HTK-N for kidney preservation and demonstrates non-inferiority compared to HTK in the setting of living donor kidney transplantation.

[Angiomyolipoma of the liver-a case report and review of the literature]. / Angiomyolipom der Leber ­ Ein Fallbericht in Zusammenschau mit der Literatur.

We report the case of a 70-year-old female patient with an unclear liver mass after clinical and radiological evaluation. In histopathological evaluation, we diagnosed a hepatic angiomyolipoma, which is a rare entity and belongs to the perivascular epithelioid group of tumours (PEComa). In this report, we illustrate the typical histomorphology, immunohistochemical profile and molecular changes based on the case presentation and discuss and review the current literature on hepatic angiomyolipomas. In addition, typical differential diagnostic problems are highlighted.

Kidney transplantation with allografts from infant donors-Small organs, big value.

BACKGROUND: Although infant organ donors remain a rare source of organs for transplantation, technical challenges have resulted in increased rates of complications and inferior graft function. The aim of the present study was to investigate the outcomes of kidneys procured from juvenile and infant donors. PATIENTS AND METHODS: We evaluated all kidney transplants from deceased donors < 16 years of age performed at our center between 01/2008 and 08/2019. We defined three groups based on quartiles of donor body weight: <13 kg (infant donors), 13-40 kg (juvenile donors), and > 40 kg (standard criteria donors). Clinical characteristics and outcomes were compared between groups. RESULTS: Ninety-two transplants were included in this study. Out of 92 recipients, there were 32 (34.8%) adult and 60 (65.2%) pediatric patients. All groups demonstrated excellent graft function and survival on both short and long-term follow-up. 1-year, 3-year, and 5-year graft survival rates for the standard criteria donor group were 100%, 95.2%, and 88.4%, respectively, compared with 95.8% for infant and 95% for juvenile donors at all times (P = .79). eGFR at 5 years was 98.9 ± 5.5, 74.1 ± 6.2, and 81.6 ± 6.9 mL/min/1.73 m2 for infant, juvenile, and standard criteria donors, respectively (P < .01). CONCLUSION: Infant donor allografts can be transplanted with excellent long-term outcomes in both pediatric and adult recipients. Implanting them as single allografts onto pediatric candidates allows for the transplantation of two patients. As such, pediatric recipients should be prioritized for these donor organs.

Effect of oxygen concentration in anterograde liver persufflation on high energy phosphates and graft function after ischemic preservation.

Here we evaluate the potential of anterograde gaseous oxygen persufflation for graft reconditioning after extended storage times. Pig livers were retrieved and cold-stored in HTK solution for 16 h. Some grafts were subsequently subjected to anterograde gaseous oxygen persufflation via the portal vein for 2 h. Oxygen concentrations for persufflation were either 100% or 40%. The gas was insufflated at a pressure adjusted to 18 mmHg, a pressure required to see gas bubbles leaving at the hepatic vein. Gas flow required for adequate maintenance of persufflation pressure amounted to approx. 300 ml/min in both groups. Only the use of 100% oxygen resulted in a significant increase of end-ischemic tissue ATP and improved bile flow upon reperfusion. Brief anterograde oxygen persufflation can improve energetic status of ischemic livers prior to transplantation, but the use of pure oxygen and adequate gas flow seems necessary to improve ulterior graft function.

First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.

Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re-introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell-free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold-induced reperfusion injury or to evaluate graft performance.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Markers of Hippo-Pathway Activity in Tumor Forming Liver Lesions.

Hepatocellular Carcinoma (HCC) is a lethal cancer worldwide. Recently, the hippo signaling pathway has been implicated in tumorigenesis of HCC and other malignant tumors. Aim of the study was therefore to evaluate the hippo signaling pathway activity and its clinico-pathological associations and crosstalk in different tumor forming hepatocellular lesions (HCC, hepatocellular adenoma (HCA), focal nodular hyperplasia (FNH) and cirrhosis). A tissue micro array (TMA) from paired human tumorous and non-tumorous (NT) tissue samples of HCC (n = 92), HCA (n = 25), FNH (n = 28) and cirrhosis (n = 28; no NT) was constructed. The hippo-pathway related proteins of MST1/2, (nuclear(n)/cytoplasmic(c)) YAP and (phospho(p)) TAZ and interactors as Glypican3, RASSF1a, pAKT, pERK and pP70S6K were evaluated by immunohistochemistry (IHC). Proliferation was assessed by Ki67-IHC and apoptosis by TUNEL-technique. MST1/2- and nYAP-immunoreactivity was associated with lymph node status (p = 0.048, p = 0.001), higher grading (p = 0.012, p = 0.24) and unfavorable relapse-free survival (p = 0.004, p = 0.003). MST1/2, c/nYAP and pTAZ were significantly different between HCC/NT (p < 0.001, p = 0.029, p < 0.001, p < 0.001) and mono-/polyclonal hepatocellular lesions (HCC/HCA vs. FNH/cirrhosis; all p ≤ 0.001). Phospho-TAZ-negativity and nYAP-positivity were almost exclusively and MST1/2 exclusively detected in HCC. MST1/2 correlated with pP70S6K (p = 0.002), pERK (p = 0.042), RASSF1a-IRS (p = 0.002) and GPC3 (p < 0.001) and nYAP with GPC3 (p = 0.025), higher Ki67-indices (p = 0.016) and lower apoptosis rate (p = 0.078). MST1/2 and nYAP are unfavorable prognostic markers associated with an aggressive tumor-phenotype in HCC. Positive nYAP- and negative pTAZ-immunostaining were strong indicators of a monoclonal hepatocellular lesion. The unexpected findings for MST1/2 remain to be elucidated.

Liver steatosis in pre-transplant liver biopsies can be quantified rapidly and accurately by nuclear magnetic resonance analysis.

Donor livers marginally acceptable or acceptable according to extended criteria are more frequently transplanted due to the growing discrepancy between demand and availability of donor organs. One type of marginally acceptable graft is a steatotic donor liver, because it is more sensitive to ischemia-reperfusion injury. Thus, quantitative assessment of steatosis is crucial prior to liver transplantation. Extent of steatosis of 49 pre-reperfusion liver biopsies from patients who received orthotopic liver transplantation was assessed by three techniques: semi-quantitative histological evaluation, computerized histomorphometry, and NMR-based estimation of fat content. The findings were correlated to clinical data and to histological examination of corresponding post-reperfusion biopsies for quantification of ischemia-reperfusion injury. We found that values obtained through all three assessment methods were positively correlated. None of the values obtained by the three applied methods correlated with clinical outcome or extent of ischemia-reperfusion injury. Quantitative evaluation of steatosis by NMR yields results comparable to histological and morphometrical assessment. This technique is rapid (<5 min), accurately quantifies fat in donor livers, and provides results that can be used when evaluation by a pathologist is not available.

Liver transplantation in infants with biliary atresia: comparison of primary versus temporary abdominal closure.

INTRODUCTION: Biliary atresia (BA) is the most frequent disease leading to liver transplantation (LT) in infants. Since the patients often require transplantation before reaching a body weight of 10 kg, it is necessary to perform living-related or split liver transplantation by using a left lateral segment. However, this graft often exceeds a graft body weight ratio (GBWR) of 4. Because of the size mismatch and poor portal venous blood flow in most recipients, temporary abdominal closure is often favoured. The aim of the present study is to investigate the feasibility of primary abdominal closure in this group of extremely small infants undergoing LT. PATIENTS AND METHODS: All patients with the diagnosis of BA and a body weight ≤10 kg who underwent LT in our centre between January 2004 and December 2014 were included in this study. Patients who received primary abdominal closure at transplantation (group 1) were compared with those receiving temporary abdominal closure (group 2). The postoperative clinical and biochemical course was analysed. The outcome was determined and correlated with body and graft weight and the GBWR. RESULTS: Sixty-six LTs were performed in 57 patients in the study period (22 male, 35 female). Thirty-six patients received primary closure (group 1). Twenty-eight patients received temporary closure (group 2). Mean age at LT was 10 months (range 3-26) and mean GBWR 4.8 (range 2.9-9.3). A GBWR ≥4 occurred in 61.1 % in group 1 and in 60.9 % in group 2. There was no significant difference between both groups concerning body weight, graft weight or GBWR. Vascular thrombosis occurred in 8 patients (22 %) and 15 patients (42 %) in group 1 and in 10 patients (36 %) and 11 patients (39 %) in group 2, respectively. Six patients (17 %) of group 1 and five patients (18 %) of group 2 developed an intraabdominal infection postoperatively. After a mean follow-up of 4.6 years (range 1 month-11.1 years), patient and graft survival were 90.1 and 75 % in group 1 and 78.3 and 64.3 % in group 2, respectively. CONCLUSION: In our study, primary abdominal closure displays a similar outcome in comparison to temporary abdominal closure.

Kidney transplantation from deceased donors with elevated serum creatinine.

BACKGROUND: Elevated donor serum creatinine has been associated with inferior graft survival in kidney transplantation (KT). The aim of this study was to evaluate the impact of elevated donor serum creatinine on short and long-term outcomes and to determine possible ways to optimize the use of these organs. METHODS: All kidney transplants from 01-2000 to 12-2012 with donor creatinine ≥ 2 mg/dl were considered. Risk factors for delayed graft function (DGF) were explored with uni- and multivariate regression analyses. Donor and recipient data were analyzed with uni- and multivariate cox proportional hazard analyses. Graft and patient survival were calculated using the Kaplan-Meier method. RESULTS: Seventy-eight patients were considered. Median recipient age and waiting time on dialysis were 53 years and 5.1 years, respectively. After a median follow-up of 6.2 years, 63 patients are alive. 1, 3, and 5-year graft and patient survival rates were 92, 89, and 89 % and 96, 93, and 89 %, respectively. Serum creatinine level at procurement and recipient's dialysis time prior to KT were predictors of DGF in multivariate analysis (p = 0.0164 and p = 0.0101, respectively). Charlson comorbidity score retained statistical significance by multivariate regression analysis for graft survival (p = 0.0321). Recipient age (p = 0.0035) was predictive of patient survival by multivariate analysis. CONCLUSIONS: Satisfactory long-term kidney transplant outcomes in the setting of elevated donor serum creatinine ≥2 mg/dl can be achieved when donor creatinine is <3.5 mg/dl, and the recipient has low comorbidities, is under 56 years of age, and remains in dialysis prior to KT for <6.8 years.

One or 4 h of "in-house" reconditioning by machine perfusion after cold storage improve reperfusion parameters in porcine kidneys.

In-house machine perfusion after cold storage (hypothermic reconditioning) has been proposed as convenient tool to improve kidney graft function. This study investigated the role of machine perfusion duration for early reperfusion parameters in porcine kidneys. Kidney function after cold preservation (4 °C, 18 h) and subsequent reconditioning by one or 4 h of pulsatile, nonoxygenated hypothermic machine perfusion (HMP) was studied in an isolated kidney perfusion model in pigs (n = 6, respectively) and compared with simply cold-stored grafts (CS). Compared with CS alone, one or 4 h of subsequent HMP similarly and significantly improved renal flow and kidney function (clearance and sodium reabsorption) upon warm reperfusion, along with reduced perfusate concentrations of endothelin-1 and increased vascular release of nitric oxide. Molecular effects of HMP comprised a significant (vs CS) mRNA increase in the endothelial transcription factor KLF2 and lower expression of endothelin that were observed already at the end of one-hour HMP after CS. Reconditioning of cold-stored kidneys is possible, even if clinical logistics only permit one hour of therapy, while limited extension of the overall storage time by in-house machine perfusion might also allow for postponing of transplantation from night to early day work.

AST 17600 U/l after liver transplantation, what are you up to? - A case report.

BACKGROUND: Miscellaneous clinical classifications of liver function after liver transplantation are rested upon elevation of transaminases which represent damaging of hepatocytes and with it of the liver. CASE REPORT: We report the case of a 35-year-old man suffering from hepatocellular carcinoma in the setting of alcoholic liver cirrhosis. The patient underwent liver transplantation and developed an extreme peak of transaminases due to prolonged cold ischemia time and additional extended donor criteria. On the first postoperative day the laboratory results showed peak transaminases as follows: AST 17577 U/l and ALT 9884 U/l. Frequent ultrasound revealed no signs of vascular complications. In spite of the dramatically elevated transaminases the liver showed a good primary function and the patient was cardiopulmonary stable. The entire postoperative course was uneventful. We discharged the patient after three weeks in a very good general state of health, with normal laboratory values. CONCLUSIONS: Exclusive extreme elevation of transaminases after liver transplantation combined with adequate liver synthesis does not always require re-transplantation, if situation of the patient is stable. Nevertheless re-transplantation should be reconsidered in any case of clinical deterioration of the patient.

Optimized outcomes for renal allografts with cold ischemic times of 20 h or greater.

BACKGROUND: Prolonged cold ischemia time (CIT) has been associated with inferior graft survival in kidney transplantation (KT). The aim of this study was to evaluate the impact of prolonged CIT on short- and long-term outcomes and to determine the possible ways to optimize the use of these organs. METHODS: All kidney transplants from April 2001 to December 2010 with CIT ≥ 20 h were considered. Donor and recipient data were analyzed with uni- and multivariate Cox proportional hazard analyses. Graft and patient survival were calculated using the Kaplan-Meier method. RESULTS: One hundred and eighty-one patients were transplanted with 184 grafts. Median recipient age and waiting time on dialysis were 52.5 and 4.9 years, respectively. After a median follow-up of 4.9 years, 148 of 181 patients are alive, 143 of them with functioning grafts. One-, three, and five-year graft and patient survival rates were 90, 87, and 79 %, and 96, 91, and 85 %, respectively. Donor age (p < 0.0001), retransplantation (p = 0.0025), and induction therapy with interleukin-2 antagonists (p = 0.0487) were predictors of graft survival by univariate analysis. Donor age and retransplantation remained significant by multivariate analysis (p < 0.001 and p = 0.0046, respectively). Donor age (p = 0.0176) and creatinine level at 1-month post-KT (p = 0.0271) were predictors of patient survival by univariate analysis. Only donor age reached multivariate significance (p = 0.0464). The calculated donor age cut off was 60 years. CONCLUSIONS: Satisfactory long-term kidney transplant outcomes in the setting of CIT ≥ 20 h can be achieved with grafts from donors <60 years in first-time recipients. Induction therapy should preferably be with an interleukin-2 antagonist.

Fulminant septic shock due to Clostridium perfringens skin and soft tissue infection eight years after liver transplantation.

BACKGROUND: Bacterial and fungal infections are the main cause of death within the first year after liver transplantation. Clostridium perfringens is the most common germ causing gas gangrene. Infections with Clostridium perfringens may present in a variety of clinical manifestations, reaching from asymptomatic infections to massive intravascular haemolysis and multiple organ failure due to septic shock. CASE REPORT: We here report on a 55-year old male liver transplant patient suffering from skin and soft tissue infection eight years after liver transplantation. The patient was referred to our department from a community hospital. Upon admission in our department the infection had been ongoing for at least three days. Laboratory analyses demonstrated severe infection and impaired liver function. Tomogram and computed tomography scan of his right limb showed typical images of gas gangrene. The patient was immediately scheduled for surgical debridement. During surgery the patient developed septic shock with severe coagulopathy and died six hours after the operation due to uncontrolled septic shock. The histopathological and microbiologic work-up of the resected skin and soft tissue showed necrotic areas infiltrated with Clostridium perfringens. CONCLUSIONS: Even long-term survivors of liver transplantation are at major risk for life-threatening infections. The reported clinical scenario of Clostridium perfringens infection indicates the narrow therapeutic window. Clostridium perfringens should always be considered as a cause of infection in liver transplant patients.

Current concepts in transplant surgery: laparoscopic living donor of the kidney.

INTRODUCTION: Living donor kidney transplantation has emerged as an excellent alternative to cadaveric donation since, more than 50 years ago, the first live donor nephrectomy was successfully performed. OBJECTIVE: The basic idea of introducing laparoscopy in live donor nephrectomy was to obtain a potential reduction in incision-related morbidity with reduced pain and faster reconvalescence while providing at least the same level of operative security. This paper is focusing on technical aspects, outcome, results, and possible current concerns and advantages of laparoscopic living-related donor nephrectomy. CONCLUSION: According to our results and the results available in the literature, laparoscopic living donor nephrectomy is safe when performed with sufficient experience. Postoperative pain is less and recovery is significantly faster.