Pål-Dag Line

Long-term risks for kidney donors

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Treatment Options in Hepatocellular Carcinoma Today

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. As over 90% of HCCs arise in cirrhotic livers preventive methods and surveillance policies have been adopted in most countries with high prevalence of hepatitis B or C infected people. Poor prognosis of HCC has shown some improvement during the last years. Targeted therapy with radiofrequency ablation (RFA), hepatic resection (HR), liver transplantation (LT), and transcatheter arterial chemoembolisation (TACE) seems to have an influence on this development. The heterogeneity of cirrhotic patients with HCC is still a big challenge. A patient with a small tumour in a cirrhotic liver may have a worse prognosis than a patient with a large tumor in a relatively preserved liver after “curative” HR. The choice of the treatment modality depends on the size and the number of tumours, the stage and the cause of cirrhosis and finally on the availability of various modalities in each centre.

Living donor kidney transplantation : The effects of donor age and gender on short-and long-term outcomes

Background. The influence of donor age and sex on acute rejection episodes and short- and long-term graft survival in living donor (LD) kidney transplantation has not been well characterized. Methods. This prospective cohort study includes 739 first time LD transplantations with median follow-up time of 55.1 months. Death censored graft survival according to donor age and sex was compared with Kaplan–Meier plots. Cox regression was performed to estimate the association between different risk factors and graft survival and acute rejection episodes. Results. Graft survival was not affected by donor age above 50 years as long as these recipients did not experience an early acute rejection episode. Acute rejection episodes increased in recipients of grafts from donors ≥65 years (P=0.009). Donor age ≥65, recipient age less than 50 years, human leukocyte antigen (HLA)-DR matching, and female donor gender were risk factors for early acute rejection episodes. In multivariate analysis donor age ≥65 years was a risk factor for graft loss in all time periods after transplantation. During the first 5 years after transplantation a steroid resistant rejection episode was an additional risk factor. More than 5 years after transplantation male donor gender was the only additional risk factor for graft loss. Conclusion. These results support the continued use of older male and female living donors who meet carefully constructed medical criteria and who are highly motivated to donate. Furthermore, donor age seems to be a more important predictor of graft loss than donor sex.

Liver transplantation for nonresectable liver metastases from colorectal cancer.

Objective:The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs). Background:Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated. Methods:In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy. Results:Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8–60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors. Conclusions:OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).

Morbidity and Mortality in 1022 Consecutive Living Donor Nephrectomies: Benefits of a Living Donor Registry

Background. We assessed postoperative complication rates in living donor nephrectomies (LDN) during the last decade (1997–2008). Methods. Postoperative complications were classified by the Clavien grading system. We defined Clavien grade more than or equal to 3 as major complications. A total of 1022 LDNs performed during the period 1997–2008 were included. Results. Median age at donation was 47.7 years (range 18.4–78.9), and mean body mass index was 25.4 (SD 3.2). There was no peri- or postoperative mortality. Laparoscopic nephrectomy was performed in 244 (23.9%) donors. Three of these needed surgical conversion. A total of 30 major (2.9%) and 184 (18%) minor complications were registered. There was a higher frequency of major complications in the laparoscopic group (4.1% vs. 2.6%), but the difference was not statistically significant. Twenty-three donors underwent early re-operations. Wound infection developed in 3.7% of donors. Increased risk was associated with body mass index more than 25 (OR 4.03; 95% CI 1.80, 9.04) and smoking (OR 4.38; 95% CI 2.30, 9.96). Significant perioperative bleeding occurred in 1.6%. There were seven cases of renal artery laceration. Increased risk for a combined endpoint of intraoperative incidents, major complications and significant bleeding were seen in relation to laparoscopic surgery (OR 2.63; 95% CI 1.33, 5.19). Conclusion. The risk of major complications related to LDN is low, but do represent a potential hazard to the donor. The special nature of LDN and the constantly evolving operative technique requires vigilant surveillance, by the use of national or supranational registries/databases.

Overall and cardiovascular mortality in Norwegian kidney donors compared to the background population

BACKGROUND There are concerns regarding potential long-term risks to the living kidney donor. Cardiovascular mortality has not been evaluated. The aim of this study was to assess overall and cardiovascular mortality in previous kidney donors compared with a general population sample. METHODS All live kidney donors in Norway in the period 1963-2007 were included. Controls matched 3:1 for age, gender and year of birth were provided by Statistics, Norway. Cause of death was retrieved from the death master file. Vital status as of 1 January 2010 was provided for all participants, and cause of death was available until 1 January 2008. Comparative survival analyses were performed by Kaplan-Meier curves and log-rank test. Age-stratified death rates were calculated and compared with a selected group with a health status hypothetically allowing donation. RESULTS There were 2269 living kidney donors in the study period. At donation, mean age was 47.6 + 12.6 years, 41.3% were male. Median observation time was 14.3 years. A total of 324 donors died during the study period. Causes of death were similar for donors and controls. By Kaplan-Meier analysis, overall and cardiovascular mortality was lower for previous kidney donors than for matched controls (P < 0.001 and P = 0.004, respectively). Age-stratified death rates were elevated for the oldest group of donors. CONCLUSIONS Overall and cardiovascular mortality results are partially reassuring. However, the seemingly elevated mortality rate among the oldest donors requires further study.

Microdialysis Monitoring of Liver Grafts by Metabolic Parameters, Cytokine Production, and Complement Activation

Introduction. The outcome of liver transplantation is steadily improving. Still there is need for earlier detection of complications like hepatic artery thrombosis and rejection. The aim of this study was to explore whether microdialysis with a 100-kDa cutoff filter could be used to monitor local inflammation after liver transplantation. Methods. Twenty patients undergoing liver transplantations were observed for 1 week posttransplant. Microdialysis catheters were introduced in each liver lobe subcutaneously and metabolic parameters (glucose, pyruvate, glycerol, and lactate), cytokines (interleukin [IL]-6, IL-8, monocyte chemottractic protein-1, and inducible protein [IP]-10), and complement activation (C5a) were measured. Results. Fourteen patients experienced an uneventful course, judged clinically by ultrasound Doppler and by metabolic markers including lactate and the ischemia indicator lactate-to-pyruvate ratio. All patients with uneventful course had a consistent rise in IP-10 from 200 to 3000 pg/mL after transplantation, whereas the other cytokines stayed low. Two patients with rejection showed a selective increase in IL-8 and C5a, starting 2 to 4 days before alanine transferase increased, reaching 10- to 50-fold increase compared with baseline levels, and decreased rapidly after start of antirejection therapy. C5a concentration was substantially increased in these two patients at the time of transplantation. A third patient developed a hepatic artery thrombosis and rejection and showed a rapid rise in intrahepatic lactate and a complex inflammatory pattern. Conclusion. Microdialysis using a 100-kDa filter is a promising way of monitoring the inflammatory reaction after liver transplantation. Increase in IP-10 reflects a normal pathophysiologic response posttransplant, whereas IL-8 and C5a were increased only in patients with rejection.

Automated determination of free mycophenolic acid and its glucuronide in plasma from renal allograft recipients.

Mycophenolic acid, the active moiety of mycophenolate mofetil, inhibits the enzyme inosine monophosphate dehydrogenase. The main metabolite, mycophenolic acid glucuronide, has no immunosuppressive effect. Reported protein bindings are 97% for mycophenolic acid and 82% for mycophenolic acid glucuronide. Considerable intraindividual and interindividual variability in mycophenolic acid pharmacokinetics has been observed. Data on the variability of mycophenolic acid free fraction in plasma are sparse but may be relevant when discussing whether therapeutic drug monitoring of this drug is warranted. The authors describe a fully automated method for the determination of free concentrations by dialysis across a membrane followed by concentration of the dialysate on a trace enrichment column and liquid chromatography. Total concentrations are measured by protein precipitation and direct injection on the trace enrichment column. Plasma concentrations as low as 6 ng/mL free mycophenolic acid and 1 &mgr;g/mL free mycophenolic acid glucuronide can be measured with between-day coefficient of variation less than 15% and 6%, respectively. Stability testing confirmed that plasma samples could be stored for 14 days at 4°C or −20°C and at room temperature for approximately 12 hours without significant changes in free concentrations. Predose total and free concentrations of mycophenolic acid and mycophenolic acid glucuronide were determined in 27 samples from stable renal allograft recipients treated with mycophenolate mofetil, cyclosporin, and steroids. Total concentrations ranged from 0.57 to 16.2 &mgr;g/mL mycophenolic acid and 36 to 199 &mgr;g/mL mycophenolic acid glucuronide. Free concentrations ranged from 13 to 210 ng/mL mycophenolic acid and 8 to 58 &mgr;g/mL mycophenolic acid glucuronide. The method presented here has been successfully applied to measure free mycophenolic acid and free mycophenolic acid glucuronide in clinical samples. Further investigations may provide important data to support the identification of principles and target ranges for the monitoring of mycophenolic acid in the immunosuppressive therapy of organ transplant recipients.

Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982–2013

Abstract Aim and background. The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. Materials and methods. The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. Results. Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004–2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. Conclusion. The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Intraoperative prediction of ischaemic injury of the bowel: A comparison of laser Doppler flowmetry and tissue oximetry to histological analysis

Intraoperative diagnosis of inadequate colonic perfusion would contribute to prevention of ischaemic colitis after abdominal aortic reconstructions. The aim of this study was to evaluate laser Doppler flowmetry (LDF) and tissue oximetry (TpO2) as predictors of the development of bowel necrosis. Devascularised loops of colon and ileum in anaesthetised pigs were divided into 10-20 mm segments and measurements of laser Doppler flux and TpO2 were performed in each segment. After 7 h of ischaemia the segments were resected for histological and biochemical analysis. In 65 colonic and 58 ileal segments a significantly lower flux was found in segments with necrosis of greater than or equal to 30% of the mucosal thickness compared to segments with necrosis of less than or equal to 10% (p less than 0.01). The discriminant flux value was 50 perfusion units, confirming a previous clinical study. The specificity was 0.96 and the sensitivity 0.94. Flux was inversely correlated to tissue lactate concentration. Significantly lower TpO2 was found in 19 colonic segments with necrosis of greater than or equal to 30% of mucosa compared to 19 colonic segments with necrosis of less than or equal to 10% (p less than 0.01). Using a discriminant value of 5kPa, a specificity of 0.79, and a sensitivity of 0.95 were calculated. In 27 ileum segments no significant difference in TpO2 between different histological groups was found (p greater than 0.30). The results show that LDF and TpO2 can predict ischaemic injury of the colon, and LDF also of the small bowel.