Low incidence of coronary angiography in the evaluation process of the potential heart donor.

INTRODUCTION: We investigated the practice of coronary angiography (CA) on donor hearts. PATIENTS AND METHODS: Between January 1, 2000, and December 31, 2010, all reported organ donors aged <66 years were analyzed retrospectively. Donor charts were evaluated regarding a performed CA, its outcome, the timing of CA during the evaluation process, and reasons for organ refusal. The percentage of positive CA studies in organ donors aged ≥45 years was also evaluated. RESULTS: Of 292 reported organ donors, 152 organ donor hearts were declined (group 1), and 140 hearts (group 2) were transplanted. Of the 152 declined hearts, 91 hearts were found not suitable for organ offer, and 61 were not successfully allocated or were refused by Eurotransplant. CA was conducted in 17 organ donors (5.8%). In 6 donors, a previous CA was reported (all had pathologic findings), and in 11 donors, a donor CA was performed, indicating 4 pathologic and 7 negative findings (54.5% of the hearts evaluated by donor CA were transplanted). No complication or delay of the donation process was reportedly related to donor CA. CONCLUSIONS: Special emphasis and implementation of recommendations for CA to be part of the evaluation of donor organs seem necessary.

Socio-economic effects and cost saving potential of remote patient monitoring (SAVE-HM trial).

OBJECTIVE: In the SAVE-trial we evaluated the safety, reliability and improvements of patient management using the BIOTRONIK Home Monitoring®-System (HM) in pacemaker (PM) and implanted cardioverter defibrillator (ICD) patients. DESIGN: 115 PM (Module A) and 36 ICD-patients (Module B) were recruited 3 months after implantation. PATIENTS: 65 patients in Module A were randomised to HM-OFF and had one scheduled outpatient clinic follow-up(FU) per year, whereas patients randomised to HM-ON were equipped with the mobile transmitter and discharged without any further scheduled in-office FU. In Module B 18 patients were randomised to HM-OFF and followed by standard outpatient clinic controls every 6 months; 18 patients were randomised to HM-ON receiving remote monitoring plus one outpatient clinic visit per year; unscheduled follow-ups were performed when necessary. RESULTS: The average follow-up period was 17.1 ± 9.2 months in Module A and 26.3 ± 8.6 months in Module B. In both modules, the number of FUs per year was significantly reduced (Module A HM-ON 0.29 ± 0.6 FUs/year vs HM-OFF 0.53 ± 0.5 FUs/year; p b 0.001; Module B HM-ON 0.87 ± 0.25 vs HM-OFF 1.73 ± 0.53 FU/year,p b 0.001). Cost analysis was significantly lower in the HM-ON group compared to the HM-OFF group (18.0 ± 41.3 and 22.4 ± 26.9 € respectively; p b 0.003). 93% of the unscheduled visits in Module B were clinically indicated,whereas 55% of the routine FUs were classified as clinically unnecessary. CONCLUSION: Remote home monitoring of pacemaker and ICD devices was safe, reduced overall hospital visits, and detected events that mandated unscheduled visits.

Establishing a donation after cardiac death model in pigs.

INTRODUCTION: Due to the lack of human donors, several strategies have sought to expand the organ pool. Efforts to characterize donation after cardiac death (DCD) have included studies of cell viability, histological and immunohistochemical changes, and oxidative stress, which is known to negatively impact graft survival. A large animal model would be useful for these inquiries. Therefore, we sought to establish a DCD animal model in pigs. METHODS: We simulated non-heart-beating donation Maastricht II and III conditions in 24 pigs. Cardiac fibrillation was induced using 9-V direct current. After various times of ventricular fibrillation (1-10 minutes) with no mechanical and/or medical treatment to achieve cardiac output, reanimation was performed for 30 minutes prior to multiorgan donation. Then, a neurological status was performed. Blood samples were obtained at defined times tissue samples were stored in liquid nitrogen and subsequently embedded in paraffin and subjected to further analysis. RESULTS: We established a DCD pig model in our laboratory by inducing cardiac fibrillation. Up to now, only DCD donation according to the Maastricht criteria II and III has been performed, but establishing all Maastricht criteria of DCDs seems to be feasible. CONCLUSION: A DCD model in pigs enables us to characterize organ quality more precisely as well as evaluate amelioration of storage conditions and donor treatments in a large-animal model.

Serum albumin, subjective global assessment, body mass index and the bioimpedance analysis in the assessment of malnutrition in patients up to 15 years after liver transplantation.

BACKGROUND: The subjective global assessment (SGA) or the body mass index (BMI) is used to determine the nutritional state after LTX. Bioelectrical impedance analysis (BIA) is used as tool to determine body composition by nutritional care professionals. METHODS: BIA, SGA, BMI, and serum albumin (SA) levels were performed to assess malnutrition following liver transplantation. BIA measurement was used as reference standard to determine existing malnutrition. A phase angle (PA) <5 was used to define potentially existing chronic disease-related malnutrition as a standard. All other measured parameters were compared with respect to their prognostic accuracy regarding the prediction of malnutrition as compared to the mentioned standard. RESULTS: Seventy-one recipients (51 men, 20 women) were included. Median age was 58, weight 77 kg, BMI 26 kg/m(2) , PA 4.1°, and SA 4.3 g/dL. According to the Nutritional Risk Screening 2002, 9.4% (6/71), to BMI 15.4% (11/71), to SA 30.9% (22/71), and to BIA 36.5% (28/71) of the patients were malnourished. PA did not correlate with BMI or NA, there was a significant correlation with SA (p = 0.001). Univariate analysis revealed SA as independent predictor for malnutrition. ROC analysis for all parameters revealed a significantly (p < 0.05) better area under the receiver operating characteristic curve for SA (0.812) than for BMI (0.603) for the prediction of malnutrition. CONCLUSION: SGA or BMI calculation alone does not suffice to evaluate the nutritional status. SA seems to play a crucial role in the prediction of severe disease-related malnutrition in this special patient cohort.

Attitude toward xenotransplantation of patients prior and after human organ transplantation.

Xenotransplantation is a potential strategy to overcome the shortage of human donor organs. As this technique has a major medical and psychological impact on patients and their family and friends, the attitude of patients currently waiting for organ transplantation is important. Therefore, we conducted a survey on the attitude toward xenotransplantation of patients on the waiting list and already transplanted patients. Patients received detailed information before being asked to fill in the questionnaire. We found that 65% would accept xenotransplantation, irrespective of gender, education level or if the patients were on the waiting list or already transplanted. The most common concern was transmission of diseases or genetic material, followed by psychological concerns and ethical issues. More patients had a positive attitude toward accepting cell or tissue transplantation when compared to whole organs. Pig pancreas islet cell transplantation is generally well accepted, patients with diabetes mellitus show even higher acceptance rates than patients without diabetes. In conclusion, xenotransplantation seems to be well accepted in patients who are potential future candidates for organ transplantation. Informing patients about the current status of research tended to decrease acceptance rates slightly.

Lessons learned with noninvasive cardiac monitoring for acute rejection.

INTRODUCTION: Computerized Heart Allograft Rejection Monitoring (CHARM), used for noninvasive rejection monitoring in heart transplant recipients, is based on the analysis of ventricular evoked response (VER) signals. This study evaluated the prognostic validity of the TslewC, a parameter extrapolated from the VER. METHODS: During orthotopic heart transplantation (OHT) 2 unipolar, fractally coated, screw-in leads implanted epimyocardially were connected to a telemetric pacemaker. Recordings of IEGMs were performed routinely at hospital and at outpatient visits. Data processing yielded trend curves. TslewC was calculated from the tangent of VER. One hundred five patients divided into survivors and nonsurvivors, were compared using a two-tailed Student's t test. RESULTS: In the final follow-up a significant lower TslewC was observed among patients in the nonsurvivor compared with the other group (P<.001). Tests to find an optimal prognostic threshold of the TslewC yielded the value of 26 mV. CONCLUSION: TslewC functioned as a prognostic factor after OHT. Further studies must provide a prognostic threshold to avoid patient visits all 4 weeks. Patients would only have to be admitted to the hospital if the TslewC was under this prognostic threshold.

Morphological and functional characterization of a pancreatic beta-cell line microencapsulated in sodium cellulose sulfate/poly(diallyldimethylammonium chloride).

BACKGROUND: Late diabetic complications cannot be prevented totally by current antidiabetic strategies. Therefore, new therapeutic concepts of insulin replacement such as pancreas transplantation are evolving. Due to the shortage of human donor organs, transplantation of microencapsulated xenogeneic pancreatic islet cells has attracted considerable attention. Sodium cellulose sulfate/poly(diallyldimethylammonium chloride) (NaCS/PDADMAC) is a material with favorable biogenic properties that has been used for microencapsulation of various cell types. However, there are no data on the suitability of NaCS/PDADMAC for microencapsulation of pancreatic beta-cells. MATERIAL AND METHODS: Cell growth and viability of NaCS/PDADMAC-microencapsulated HIT-T15 cells, an immortalized hamster pancreatic beta-cell line, were assessed using a dimethylthiazol-diphenyltetrazoliumbromide (MTT)-based cell growth determination kit and apoptosis was detected by antibodies against activated caspase 3. Glucose-dependent insulin secretion was assessed with ELISA and the uptake of glucose was measured using fluorescence-labeled glucose. RESULTS: Statistical analysis revealed no differences in glucose-dependent cell proliferation, insulin secretion and glucose uptake between non-microencapsulated and microencapsulated HIT-T15 cells. Stimulation of HIT-T15 cells with glucose (100 mg/ml) resulted in a biphasic insulin secretion response. CONCLUSION: Microencapsulation of HIT-T15 cells in NaCS/PDADMAC does not influence cell proliferation, insulin secretion and glucose uptake. Our results indicate that NaCS/PDADMAC is well suited for microencapsulation of pancreatic beta-cells.

The impact of overweight on the development of diabetes after heart transplantation.

BACKGROUND: Overweight is defined with a body mass index (BMI) >25. A BMI >25 is known as an independent risk factor for increased morbidity and mortality. The influence of an increased BMI on the development of diabetes and on survival after heart transplantation (HTX) was investigated. METHODS: A total of 137 patients (116 men, 21 women), who underwent HTX at our Department from 1986 to 2002, were included in the study. For group stratification, the pre-operative BMI values were taken (group I: BMI 25). Groups were compared for primary disease, age and sex, development of renal failure, development of diabetes, and survival. The probability of survival and the freedom-from-diabetes interval were calculated by the use of Kaplan-Meier method. RESULTS: No significant differences between groups I and II were found concerning primary disease, age and sex, and occurrence of renal failure. There was a tendency towards increased survival (p = 0.18) in group I. Patients of group II developed diabetes after HTX more frequently than those of group I (p < 0.001). Cox regression revealed that pre-operative BMI >25 is a highly significant independent risk factor for post-operative development of diabetes mellitus (DM) (p < 0.001). CONCLUSION: Overweight prior to HTX appears to negatively influence long-term survival after HTX, although this difference did not reach statistical significance. Pre-operative overweight is a significant and independent risk factor for the development of post-transplant diabetes.

Initial experiences with a telemedicine framework for remote pacemaker follow-up.

According to international guidelines implanted cardiac pacemakers (PM) have to be checked periodically to ensure that they are working correctly. To spare a significant number of patients the burden of traveling to specialized PM clinics a telemedicine framework has been developed prototypically. A mobile, personal digital assistant (PDA) based PM follow-up unit provides the caregiver at the point-of-care with the necessary infrastructure to perform a basic PM follow-up examination remotely. In case of detected malfunction of the PM the patient is ordered to the hospital for further examination. The system has been evaluated in a clinical pilot trial on 44 patients with a total of 23 different PM models from 8 different manufacturers. The initial results indicate the potential of the concept to work as an efficient, manufacturer independent screening method with the ultimate goal to increase the safety, quality and efficiency of PM therapy.

Porcine islet cells microencapsulated in sodium cellulose sulfate.

One hundred fifty million people suffer from diabetes mellitus worldwide. Modern exogenous insulin therapy cannot prevent late complications. Islet cell transplantation could be a sufficient therapeutic option but the shortage of human organs limits this option. The use of xenogeneic porcine islet cells may also be a viable alternative. One way to manage hyperacute rejection is by the protection of xenogeneic cells from the immune system by microencapsulation. In this study sodium cellulose sulfate (NaCS) was evaluated as a material for encapsulation. An insulin-producing cell line (HIT-T15) was established in our laboratory. Glucose-dependent insulin production and cell growth were monitored. Cells were encapsulated with NaCS by Austrianova, Vienna. The insulin production and mitosis rate were examined. Cell growth and insulin production by HIT-T15 cells affected the glucose levels in the nutrient solution. Cell viability and glucose-dependent insulin production were not influenced by NaCS. Encapsulation with NaCS is feasible and it could be shown that the material is permeable to nutrients and metabolic side products. The encapsulated cells are able to detect the glucose concentration in the nutrient solution and to react in a proper way by producing insulin. Encapsulation with NaCS, which is more biocompatible and less immunogenic than other materials, seems to be a promising method for immunoisolation of porcine beta cells for xenotransplantation to replace the endocrine pancreas in a physiologic way.

Late acute cardiac allograft rejection: new therapeutic options?

BACKGROUND: Late acute cellular rejection is associated with decreased survival and the development of CAV. Among new immunosuppressive drugs introduced into clinical practice, everolimus, has been shown to be safe in cardiac transplantation. We report our experience with everolimus in heart transplant recipients who developed late acute cellular cardiac rejection. METHODS: Patients with a history of previous rejection episodes who experienced cardiac rejection were switched to an everolimus, cyclosporine, and steroid immunosuppressive regimen. All patients had already received statins and antihypertensive medications. Everolimus, cyclosporine trough levels, and laboratory values were controlled monthly. Drug administration was adapted to an everolimus trough level between 3 and 8 ng/mL, mean maintenance dosage was 0.25 to 1.5 mg twice a day. Death, safety, side effects, biopsy-proven acute rejection episodes, laboratory values, and blood levels were evaluated retrospectively. RESULTS: Four cardiac allograft recipients (two male, two female), at a median of 1473.25 days post-orthotopic heart transplantation (oHTx) (range = 65 to 3045), received 1 to 1.5 mg everolimus per day. Over a follow-up period of at least 2 month (range = 2 to 10) the mortality was 0%. The drug was well tolerated; no acute cellular rejection greater than grade 1a (ISHLT grading) was observed after 2 months. In one patient increased cholesterol values and in two others, elevated triglyceride levels were seen, but were controlled with increased statin therapy. No obvious increased creatinine values were seen with everolimus. CONCLUSION: In conclusion, conversion to an everolimus-based immunosuppressive regimen after late cardiac rejection is safe and effective; no major side effects were observed.

Nonnephrotoxic immunosuppression in patients after liver transplantation.

INTRODUCTION: Calcineurin inhibitor (CI)-associated renal impairment and renal failure after liver transplantation has been recognized since the early days of its use. Various strategies have been used to prevent or slow down the progression of renal dysfunction in liver transplant recipients, but did not succeed. In this report, we describe the course of renal function of 58 stable liver transplant recipients and compared 2 groups with different immunosuppressive protocols. METHODS: In the study group, 22 patients at various intervals from liver transplantation were included. The immunosuppressive therapy consisted of Sirolimus (SRL). Additional all patients except 2 received Mycophenolate Mofetil (MMF) and 14 of them also received Tacrolimus. Patients of the control group (36 patients) had an immunosuppressive therapy with calcineurin inhibitors. Patients were monitored for creatinine monthly and creatinine clearance (CCr) every sixth month. Risk factors for renal dysfunction were evaluated. RESULTS: After introduction of SRL in patients with renal impairment and after a mean follow-up time of 12 (2-26) months, there was a decrease of 28.3% in mean creatinine and of 41.8% in mean urea. We observed an improvement of renal function in all patients initially after introduction of SRL. In the control group, in comparison to preoperative levels, there was an increase of 27.5% in mean creatinine and of 13.3% in mean urea after a mean follow-up time of 3.6 years with CI therapy. CONCLUSION: The results of our retrospective study showed that with SRL renal impairment could be stopped and renal function could be improved. We suggest administering immunosuppressive therapy with SRL in combination with low dose Tacrolimus and/or MMF for patients with renal impairment.

Center experience in liver transplantation (LTX): management of dermal side effects caused by sirolimus.

INTRODUCTION: Sirolimus improves post transplant maintenance therapy in LTX. Dermal side effects causing pain and discomfort can limit patients' compliance. The package insert mentions such skin disorders as acne and rash. One case of sirolimus-induced leucocytoclastic vasculitis is reported in the literature. METHODS: From July 1998 to October 2003, Sirolimus was implemented in the immunosuppressive protocol in 23 out of 60 liver recipients. Sirolimus target levels are between 3 and <10 ng/dl. Combination with a calcineurinblocker and/or MMF (mycophenolate mofetil) depending on liver function and creatinine is standard. Weekly patient monitoring in the first month after discharge included physical examination, blood samples and immunosuppresant trough levels. Biopsies were taken from untypical efflorescences. RESULTS: Three patients with non-specific effloresces were reported: one with leucocytoclastic vasculitis and one with exfoliate forearm dermatitis required change of medication while one perivascular lymphocytic eosinophilic dermatitis subsided after dose reduction. In three cases of mouth ulcer, trough levels exceeded 10 ng/dl and in six patients acne diminished after dose reduction. Eighteen out of 23 patients are still receiving sirolimus. Reasons for removal from the study were incompliance and incompatibility. Two patients died. DISCUSSION: Immunosuppressants inevitably produce side effects in TX recipients. The positive management of troublesome side effects contributes importantly to compliance and patient survival.

Improving the rate of organ donation.

BACKGROUND: Organ shortage is a major problem in transplantation. Many potential donors are still lost due to a lack of information and communication. Many transplantation centers report a major donor increase after introducing new donor policies. The aim of this study was to evaluate in retrospective fashion a new donor policy in our region. METHODS: For the past 10 years all reported donors from intensive care units (ICUs) in our region were evaluated. Our new policy had 2 main steps: accepting more marginal grafts and using a transplantation representative. The goal was the improved communication with ICUs to support physicians involved in donor care. A public information program was also implemented. RESULTS: In the first year, numbers of donors obviously improved (+60.5%) and remained stable the following year. The mean donor age increased to 41.56 years. The donor pool showed mainly an improved kidney-donation rate (+53%) with also an increase in multiorgan donation (+37%). One year posttransplantation survival was not negatively influenced by this donor pool. As expected, transplantation activities increased notably, particularly liver transplantation (+31.11%) but also kidney transplantation (+26.73%). DISCUSSION: Many donors are lost because physicians in charge of brain dead patients are not fully informed about modified donation criteria. The reason for this is a lack of information and communication by transplantation units. Improved surgical techniques and better preoperative, intraoperative, and postoperative treatment have yielded better results with marginal grafts. Immediate graft function in recipients of suboptimal grafts may be delayed, but without a significantly negative impact on patient and graft survival. Because the age of organ recipients is steadily increasing with fewer contraindications for transplants, more organs will be needed.

Experiences in liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Beside surgical resection, orthotopic liver transplantation (OLT) is not only effective but also the only potentially curable treatment in selected cases of small tumors. We report our experience in 11 male patients transplanted for HCC from August 1998 to July 2002. Selection criteria for OLT were unresectability of the hepatic tumor and severity of the underlying liver disease. The tumor diagnosis was confirmed by histology, imaging techniques, and tumor markers. All patients received an orthotopic liver allograft using a modified piggyback technique. Six of the 11 patients are alive; one died due to acute rejection and four died from recurrent disease. In all four patients with recurrent disease, vascular invasion was shown histologically, whereas only one patient without evidence of recurrence showed vascular invasion. To prevent recurrence after OLT the immunosuppressive regime was adjusted to the underlying disease by early cessation of prednisolone and reduction in the long-term exposure to immunosuppressive drugs. Patients were screened for recurrence by ultrasound and computed tomography. Recurrent HCC were treated symptomatically. OLT is an effective treatment for subgroups of patients with HCC. It might be possible to downstage the liver tumor by chemoembolization and/or radiofrequency ablation and allow the patients to wait for a suitable donor. After OLT the early withdrawal of prednisolone and the reduction of other immunosuppression is feasible. In conclusion, OLT can be a potentially curative therapy for HCC.

Occurance of apoptosis during ischemia in porcine pancreas islet cells.

PURPOSE: Pancreas islet transplantation is a potential treatment of diabetes mellitus and porcine organs provide an easily available source of cells. Unfortunately quality and quantity of isolated islets are still not satisfactory. Apoptosis occurs in freshly isolated islets and plays a significant role in early graft loss. We evaluated the influence of four storage solutions on porcine pancreas islets. METHOD: After warm ischemia of 15-20 minutes 12 organs were stored in 4 cold preservation solutions: Histidine-Tryptophan-Ketoglutarate solution (HTK), Hank's buffered saline solution (HBSS), University of Wisconsin (UW) solution and Ringer-Lactate (R). After cold ischemia for 100 minutes, organs were fixed in 3% formalin. Apoptotic cells were counted on hematocylin-eosin stainings. RESULTS: Most apoptotic cells were found in organs stored in R. Low numbers were found in the other groups. The difference between organs stored in R and organs stored in UW, HTK, or HBSS was highly significant. No significant difference could be found between UW, HTK and HBSS. CONCLUSION: Cold and warm ischemia of the pancreas seems to induce apoptosis in islet cells. Preservation solutions cause less apoptosis than electrolyte solution. No significant differences could be found among the preservation solutions.

Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation.

Osteoprotegerin (OPG) is an antiresorptive cytokine and a key regulator of osteoclastogenesis and activity. Since OPG is downregulated by glucocorticoids and cyclosporine A in vitro we examined whether immunosuppressive therapy would play a role in the development of transplantation osteoporosis. We enrolled 57 cardiac transplant recipients (median time since transplantation, 3.2 years (1.1-11.5 years)) in this cross-sectional study. Standardized spinal X-rays as well as hip bone density measurements were performed in all patients. Serum OPG was determined using a commercially available ELISA. Vertebral fractures were present in 56% of the patients. Bone densities of all femoral neck subregions were correlated to serum OPG concentrations (r values between 0.40 and 0.48, all P < 0.005). Multiple regression analysis revealed OPG levels to be independently correlated to femoral neck Z scores (r = 0.49, P = 0.002). After adjustment for age, BMI, neck Z score, renal function, and months since transplantation, serum OPG was the only significant predictor of prevalent vertebral fractures (P = 0.001). In a separate 6-month prospective study of 14 heart transplant recipients receiving calcium and vitamin D serum OPG levels fell by 41% (P = 0.0004) after 3 months and 47% (P = 0.0001) after 6 months following cardiac transplantation. Bone loss at the lumbar spine and femoral neck after 6 months was correlated to the decrease in serum OPG at 6 months (r = 0.82, P < 0.0001, and r = 0.60, P = 0.02, respectively) as well as 3 months after cardiac transplantation (r = 0.65, P = 0.01, and r = 0.69, P = 0.006, respectively). Serum OPG alone accounted for 67% of the variance of lumbar spine bone density changes over the first 6 months posttransplantation. We conclude that serum OPG levels decline consistently in all patients following initiation of immunosuppressive therapy and are independently correlated with changes in bone density. We hypothesize that OPG plays a major role in the development of transplantation osteoporosis.