Tacrolimus Concentration/Dose Ratio is Associated with Renal Function After Liver Transplantation.

BACKGROUND: The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment. MATERIAL AND METHODS: We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (<1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault. RESULTS: At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027). CONCLUSIONS: In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of <1.09 is associated with increased CNI nephrotoxicity in LTx recipients.

Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial.

AIMS: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS: Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS: Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

Complications after endoscopic sphincterotomy in liver transplant recipients: A retrospective single-centre study.

BACKGROUND AND STUDY AIMS: Biliary tract complications after liver transplantation are usually treated by endoscopic retrograde cholangiopancreatography. When biliary tract intervention is indicated, endoscopic sphincterotomy is often required. However, data regarding complication rates after endoscopic sphincterotomy in liver transplant recipients are limited. This study therefore investigated complication rates during the first 15 days after endoscopic sphincterotomy in liver transplant recipients. PATIENTS AND METHODS: This study retrospectively reviewed 157 consecutive liver transplant recipients who underwent endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy between January 1998 and August 2013 at the University Hospital of Münster, Germany. Complications that occurred within the first 15 days after the procedure were recorded, and complication rates were compared between patients who underwent conventional and precut endoscopic sphincterotomy. RESULTS: A total of 24 complications (15.2%) were recorded, including 9 cases (5.7%) of pancreatitis, 6 cases (3.8%) of bleeding, and 1 case (0.6%) of perforation. There were no procedure-related deaths. There were no significant differences in complication rates between the two sphincterotomy techniques. The rate of post-procedural pancreatitis decreased over time. CONCLUSION: Endoscopic sphincterotomy is a safe procedure in liver transplant recipients. The procedure-related complication rate is reasonable and most complications can be managed conservatively.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 µmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m(2) ) with cyclosporine, a difference of 10.5 ml/min/1.73 m(2) in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73 m(2) ) (P < 0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310).

Prognostic factors for kidney allograft survival in the Eurotransplant Senior Program.

BACKGROUND: The shortage of organ donors has led to the introduction of the Eurotransplant Senior Program (ESP) to optimize the allocation of kidneys from elderly donors by age-matching. In the face of a rapidly aging population, identification of prognostic factors for kidney allograft survival within the ESP population will be of enormous significance. MATERIAL AND METHODS: Donor and recipient data from 89 patients transplanted under the ESP protocol between 1999 and 2007 were retrospectively analyzed. Data were correlated with initial graft function, graft survival, acute rejection episodes, serum creatinine levels, glomerular filtration rates, and patient survival using univariate and multivariate analysis. Maximum follow-up was 5 years. RESULTS: Cold ischemia time (CIT) >16 hours, body mass index (BMI) ≥25 kg/m(2), and kidney re-transplantation were significant risk factors for delayed graft function (DGF). Odds ratio for primary non-function was significantly increased with prolonged CIT, BMI ≥25 kg/m(2), and duration of renal replacement therapy >69 months. CIT >15 h, DGF, and kidney re-transplantation were associated with poor graft survival (P<0.05). CONCLUSIONS: Risk reduction (e.g., aiming at CIT <15 h) and close surveillance of patients at risk appear to be crucial for allograft survival in the ESP.

Aorto-hepatic bypass in liver transplantation in the MELD-era: outcomes after supraceliac and infrarenal bypasses.

PURPOSE: Poor arterial inflow during orthotopic liver transplantation (OLT) may necessitate arterial revascularisation using aorto-hepatic bypasses with supraceliac (SC) or infrarenal (IR) allografts. This study compared both techniques focusing on the patients' preoperative conditions, postoperative graft/organ function, complications and survival. METHODS: Fifteen out of 114 OLT patients underwent revascularisation (7 IR/8 SC) between 2005 and 2008 and were included in the study. The patients' records were reviewed retrospectively. RESULTS: IR patients presented with a higher BMI, received more male donor organs and their reperfusion sequence was predominately portal venous (SC: primary arterial). SC patients presented a significantly worse preoperative creatinine clearance and a trend towards a higher MELD score. The postoperative graft/organ function, morbidity and mortality did not differ between the groups despite a trend towards a worse survival in the SC group. A deteriorated preoperative creatinine clearance and higher MELD score negatively impacted the survival. Postoperative bleeding episodes and major re-interventions also affected the outcome. CONCLUSIONS: We found no evidence for superiority of either bypass technique in our OLT patients. The trend toward a worse survival in SC patients was most likely caused by the worse preoperative conditions of these patients and highlights the importance of the impact of the MELD score on the outcome after OLT.

Liver transplantation versus supraselective transarterial chemoembolization in palliative patients with hepatocellular carcinoma exceeding the Milan Criteria - is it time for a more individual approach?

BACKGROUND: This study evaluated the effect of liver transplantation (LTX) and STACE on overall survival in palliative patients with HCC exceeding Milan criteria. MATERIAL AND METHODS: At a single center 63 HCC patients exceeding Milan criteria were retrospectively analyzed. Forty patients underwent STACE as palliative therapy modality and 23 palliative patients were scheduled for LTX. The primary endpoint was overall patient survival. Statistical analysis included Kaplan-Meier method, log rank, chi squared tests and Cox regression model for the identification of prognostic factors. RESULTS: There was no significant difference when comparing the 2 groups (LTX vs. no LTX) in terms of Child classification, co-morbidities, underlying disease, and sex. Overall survival was significantly prolonged after LTX was performed (p=0.012). In the Cox regression model, LTX (p=0.021), LTX <3Mo (p=0.047), CHILD stage (p=0.007), AFP (p=0.020), and tumor size of largest HCC nodule <40 mm (p=0.028) were independent prognostic factors for survival. CONCLUSIONS: Palliative patients beyond Milan have a significant survival benefit after they received early liver transplantation in comparison with STACE. The current approach to waiting list candidacy based on Milan criteria should be modified with a more individualized approach that considers age, AFP level, and tumor size.

Laparoscopic simulation training: Testing for skill acquisition and retention.

BACKGROUND: Simulation in laparoscopy leads to skill acquisition. Although many curricula for simulation training have been described, the nature of skill deterioration remains unclear. We evaluated skill acquisition and retention after laparoscopic simulation training. METHODS: Thirty-six novices in surgery (medical students) underwent a 5-day curriculum consisting of 9 skills of increasing complexity. Each subject underwent baseline and post-training evaluation after completion of the course. Skill retention testing was measured after 6 weeks (group 1; n = 18) and after 11 weeks (group 2; n = 18). Neither group had access to a training facility during this interval. Task completion was measured in time (s) with penalties for inaccurate performance. RESULTS: Comparison of the baseline and post-training values revealed a significant learning outcome for all exercises in both groups (P < .001). In group 1, skill retention testing found no significant decrease in skill level when compared to post-training values in all but 1 task (extracorporeal knot tying; P = .007). In group 2, differences between skill retention and post-training evaluation were observed for 5 of the 9 tasks (transfer task, positioning, loop tie, extracorporeal knot, and intracorporeal knot; P ≤ .05 for each). CONCLUSION: Basic laparoscopic skills can be learned successfully by novices in surgery using a compact curriculum. These skills are retained for at least 6 weeks. Eleven weeks after initial training, skill deterioration is likely, and therefore an opportunity for practice and repetition is desirable.

Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient.

The increasing demand for transplantation has led to consideration of liver grafts from donors exposed to hepatitis B virus (HBV). Six transplantations of liver grafts from hepatitis B surface antigen (HBsAg) positive donors have been reported; two recipients suffered from HBV/HDV (hepatitis Delta virus) coinfection and were followed up for 10-12 months. Here, we report a 56 months follow-up of a HBV/HDV-coinfected recipient of a HBsAg positive liver graft. Posttransplant combination prophylaxis consisted of hepatitis immunoglobulin, lamivudine and adefovir dipivoxil. HBsAg remained positive during stable posttransplant follow-up and subclinical HDV reinfection with low replication rate was detected at 1 month. Pegylated interferon therapy was introduced after documentation of histological evidence of mild chronic hepatitis, but without virological response after 48 weeks. Finally, antiviral treatment was switched to tenofovir disoproxil fumarate. More than 50 months posttransplant the recipient revealed clinical symptoms of decompensated liver cirrhosis and has been relisted for liver transplantation. In conclusion HBsAg positive liver grafts in HBsAg positive recipients with HDV coinfection may result in virological recurrence and rapid development of liver cirrhosis.

Acute antibody-mediated rejection in paediatric renal transplant recipients.

Acute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1-8 weeks. At follow-up, 14, 15 and 22 months' post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m(2) respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children.

A new technique for ureteral defect lesion reconstruction using an autologous vein graft and a biodegradable endoluminal stent.

PURPOSE: Ureteral defect lesions are severe complications caused by iatrogenic lesions or trauma. For ureteral defect lesions elaborate surgical intervention is needed, such as autotransplantation or ureteral replacement with small bowel. Thus, we developed a new technique for ureteral defect reconstruction in a pig model using an autologous vein graft splinted by an endoluminal biodegradable poly-L-lactic acid stent (Institute of Textile Technology and Process Engineering, Denkendorf, Germany). MATERIALS AND METHODS: In 42 pigs we removed the external jugular vein and used it as an autologous vein graft. After median laparotomy a 3 cm segment was resected from the proximal ureter and replaced by the vein with or without an endoluminal biodegradable poly-L-lactic acid stent. As controls, we used 14 pigs. We observed survival, kidney function, and neoureteral and kidney morphological changes for 7 days and for 6 months. RESULTS: After 6 months the stent material was completely broken down and the vein graft was relined with urothelium. It resembled native ureter with cytokeratin-7 positive columnar epithelium and newly formed capillaries in the ureteral wall. All animals had normal kidney function without renal pelvis congestion. CONCLUSIONS: This new technique for ureteral defect reconstruction using an autologous vein graft and a biodegradable endoluminal stent is feasible. It is an interesting alternative in the clinic due to the preservation of physiological urine passage and the antireflux mechanism.

Kidney-autotransplantation before radiotherapy: a case report.

BACKGROUND: A 28-year-old man suffering from a Ewing tumour arising from the 9th-11th ribs with infiltration of neuroforamina without distant metastases was planned to receive radiotherapy following primary intralesional surgery and induction chemotherapy. Due to pleural infiltration and effusion, a hemithorax irradiation with a sequential boost to the primary tumour site had to be administered. Different treatment planning variants failed to provide sufficient radiotherapy planning in view of target volume coverage and avoidance of organs at risk, especially due to high calculated radiation doses potentially compromising the left kidney. MATERIALS AND METHODS: To prevent left kidney organ exposure, an autotransplantation of the left kidney into the right fossa iliaca was performed. An infiltration of the kidney was initially excluded. RESULTS: Postoperatively, a renal scintigraphy showed a normal function of both kidneys allowing sufficient radiotherapy treatment planning. Target volume coverage was easily obtained using a combination of hemithorax irradiation and a sequential boost by an intensity-modulated-radiotherapy technique. CONCLUSION: In difficult individual treatment situations, surgical transpositions as well as organ autotransplantation might be useful in reducing radiotherapy organ dose levels.

Segmental resection of the duodenum for gastrointestinal stromal tumor (GIST).

BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. The biological appearance of these tumors reaches from small lesions with benign appearance to aggressive sarcomas. Only 3-5% of GISTs are localized in the duodenum. There is a controversy, if duodenal GISTs should be treated by a duodenopancreatectomy or by a limited resection of the duodenum. CASE PRESENTATION: A 29-year-old man presented with an acute upper gastrointestinal bleeding from a submucosal tumor located in the proximal part III of the duodenum, 3 cm distal of the papilla of Vater. After an emergency laparotomy with ligation of tumor-feeding vessels in a primary hospital, definitive surgical therapy was performed by partial resection of the duodenum with a duodenojejunostomy. Histology revealed a GIST with a diameter of 2.5 cm and <5 mitoses/50 high power fields, indicating a low risk of malignancy. Therefore no adjuvant therapy with Imatinib was initiated. CONCLUSION: GISTs of the duodenum are a rare cause of upper gastrointestinal bleeding. Partial resection of the duodenum is a warranted alternative to a duodenopancreatectomy, as this procedure has a lower operative morbidity, while providing comparable oncological results.

Exocrine drainage into the duodenum: a novel technique for pancreas transplantation.

Simultaneous pancreas-kidney transplantation is the treatment of choice for patients suffering from type 1 diabetes mellitus and end-stage renal failure secondary to diabetic nephropathy. Until 1995, about 90% of pancreas transplantations were performed with exocrine drainage into the bladder. Since then the proportion of pancreas transplants with enteric drainage increased steadily because of frequency of complications and long-term disadvantages of bladder drainage. However, the use of enteric drainage removes the opportunity to monitor pancreatic allograft function either by measuring urinary amylase or by carrying out biopsy via cystoscopy. We report a new technique of exocrine pancreatic drainage into the recipient duodenum. This modification places the pancreas graft including the duodenal anastomosis in a retroperitoneal location and, importantly, allows easy graft monitoring via gastroscopy.

Living donor of the kidney-open-video.

BACKGROUND AND AIMS: Living donor nephrectomy (LDN) has evolved a variety of different surgical techniques. Minimal invasive strategies were introduced to benefit the healthy donors. This paper attempts to identify the best possible practise in live kidney donation with special respect to donor safety. MATERIALS AND METHODS: We present a single-centre experience of 173 live kidney donations and describe the surgical technique of open retroperitoneal donation in detail and by video sequences. Additionally, the evidence for donor safety (mortality and morbidity) and the integrity of the graft function are reviewed, comparing different surgical techniques for LDN. RESULTS: Focussing on maximal donor safety, a retroperitoneal access seems mandatory. Very detailed informed consent, including the offer for different retrieval techniques, has led to a total of 163 open and 10 hand-assisted retroperitoneal live kidney donations at our institution. Published and own data reveal longer operating and warm ischaemic times for minimal invasive kidney removal when compared with open technique. Adequate perioperative analgesia (peridural catheter) provides comparable patient comfort, duration of hospital stay, complications and graft function although there are some procedure-associated risks for minimal invasive techniques. CONCLUSION: The special ethical situation of live donation necessitates maximal donor safety. Although open antero-lateral incision and retroperitoneal access does provide some inconveniences for the surgeon, we are convinced that this and the hand-assisted retroperitoneal approach are the only two options for LDN.

Sequence of reperfusion influences ischemia/reperfusion injury and primary graft function following porcine liver transplantation.

The impact of 3 different reperfusion sequences following orthotopic liver transplantation (OLT) in pigs were evaluated. The reperfusion technique commonly performed is primary portal in order to shorten warm ischemic times (WITs). Experimental and clinical data, usually comparing 2 out of 3 possible reperfusion sequences, provide controversial results. OLT was performed in 24 pigs randomized into 3 groups: primary arterial (A), simultaneous (SIM), and primary portal (P) reperfusion. Hemodynamics were continuously monitored and reperfusion injury and primary graft function were assessed by standard serum parameters, histopathological findings, immunohistochemistry for heme oxygenase 1 (HO-1), and heat shock protein 70 (HSP 70). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (gammaGT) following reperfusion were significantly increased for group A when compared to groups SIM and P. Hemodynamics showed significant differences after reperfusion compared to physiological data; differences in group comparisons were not significant. The bile production/100 g liver/hr was significantly higher for group SIM (1.15 mL) compared to group P (0.66 mL) and group A (0.62 mL). Histology and immunohistochemistry significantly correlated with functional results and outcome. Histological score was best for group SIM and worst for group A. HSP 70, being visualized mainly in the hepatocytes, showed higher expression for groups SIM and P. Inversely, HO-1, found in perisinusoidal cells, showed highest expression after primary arterial reperfusion. In conclusion, although associated with a 10-minute longer warm ischemic time, simultaneous reperfusion causes the least reperfusion injury with superior primary transplant function. Primary arterial reperfusion showed the worst overall outcome and highest degree of HO-1 expression.

Long-term follow-up of double kidney transplantation using a score for evaluation of marginal donors*.

To face the problem of organ shortage, marginal grafts from 36 donors which had been refused for single transplantation were used for double-kidney transplantation (D-KTX). The residual kidney function was evaluated by the Muenster double kidney score. In a 5-year period kidneys from 57 marginal donors were transferred to our center. According to the Muenster double kidney score, the kidneys were distributed to single, double or refusal of transplantation. Sixteen male and 20 female donors were used for D-KTX (70+/-9.3 years, range 53-86). Thirty-six recipients (23 male, 13 female; 60.5+/-6.9 years) were double-grafted within a mean cold ischemic time of 19.3+/-3.4 h. Immunosuppression varied according to human leukocyte antigen (HLA)-mismatch. Graft and patient survival was observed up to 5 years. Initial graft function rate was 69%. Two recipients had a primary nonfunction (5.5%) and nine recipients suffered from delayed graft function (DGF; 25%). One-, 2-, 3-year creatinine values were 1.6 +/- 0.5, 1.9 +/- 0.6 and 2.2 +/- 0.7 mg/dl, respectively. One-, 2-, 3-, 4- and 5-year function rate was 93.7%, 93.5%, 81.8%, 76.4% and 55%, respectively (n = 32, 31, 22, 17 and 9). Acute rejection rate was 19%. 4 grafts were lost to chronic rejection (months 22, 25, 28, 48). Six (16%) died in long-term follow-up because of pneumonia (n = 2), carcinoma of the lung (n = 1), cardial complications (n = 2) and multiorgan failure (n = 1). D-KTX is a safe way to face the problem of organ shortage. However, a score for preoperative evaluation of marginal kidneys for single, dual or refusal of transplantation is essential.