http://www.annalsoftransplantation.comTable of contents Volume 13, 2008 Number 3.en-usCopyright 2008 by the Annals of Transplantationhttp://www.annalsoftransplantation.com/rssIndexCopernicus Journal Management System RSS GENERATORwebmaster@www.annalsoftransplantation.com (ADM)Mon, 08 Sep 2008 10:25:56 ESThttp://www.annalsoftransplantation.com/abstracted.php?icid=868531&level=5The combination of synergistic drugs is the main strategy to prevent early acute rejection and to provide long-term effective rejection prophylaxis. Evaluation of drug concentrations to guide drug dosing is routinely established for calcineurin-inhibitors CNIs and mTOR inhibitors. Arguments in favour of therapeutic drug-monitoring TDM are the large inter-patient variability of many immunosuppressants with their potential for severe toxicity and drug-to-drug interactions. The manuscript discusses several confounding factors, which influence the appropriate therapeutic window. These include decreasing risk of rejection over time, cumulative risk for toxicity with time, and the synergistic potential of combination immunosuppressive therapy with respect to efficacy and shared toxicities. In addition, a long list of donor and recipient characteristics have a direct or indirect effect on the therapeutic window, but have not been evaluated in rigorous, prospective trials. Unfortunately, only a very small number of adequately powered, prospective randomized trials evaluate different therapeutic windows for immunosuppressants or even the utility of TDM at all. Other problems of TDM include the inherent variability of absorption and drug levels and a suboptimal correlation between pharmacokinetic surrogate parameters and drug exposure for most drugs. Drugs with a high intra-patient day-to-day variability may be less suited for TDM compared to drugs with a high inter-patient, but low intra-patient variability. Furthermore it is not known whether the same parameter is suitable for controlling efficacy as well toxicity. With cumulative overexposure the effect of time might be more far more important than a specific level at a given time point and provides another fundamental dimension. A new approach of TDM, classified as pharmacodynamic (PD) drug monitoring, which directly reflects the drug’s biological effects has been proposed to better assess the individual state of immunosuppression, however difficult test systems and lack of prospective trials limit this approach currently. Future studies have to take these considerations into account in order to better guide immunosuppression towards a more individualized therapy, which remains an important goal in transplant medicine. Klemens Budde, Petra Glander Review articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868531&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868532&level=5With the emergence of more immunosuppressive drug combinations in transplantation, the number and complexity of drug interactions have increased and constitute a growing challenge for clinicians. Especially, clinically relevant immunosuppressive drug interactions require prompt identification, intensified monitoring of drug concentrations and adequate dosing responses. The drug interaction whereby cyclosporine, as opposed to tacrolimus, inhibits the enterohepatic (re)circulation of mycophenolic acid and its inactive MPAG metabolite, will result in significantly lower dose-corrected MPA concentrations in cyclosporine-treated patients which in turn will lead to early clinical MPA underexposure in 50% of patients receiving 2 grams of MMF per day. Also, when reducing or withdrawing cyclosporine or switching to tacrolimus as alternative calcineurin-inhibitor and vice versa, this important drug interactions needs to be taken into consideration. The combination of cyclosporine and the proliferation signal inhibitors (PSI) sirolimus and everolimus, requires dose reductions of both drugs because of a well-established synergistic drug interaction which will lead to increased nephrotoxicity when left unadjusted. Despite the observations that clinically important drug interactions between PSI and tacrolimus are apparently lacking, switching between calcineurin-inhibitors in renal recipients requires intensified monitoring of PSI concentrations. Finally, when corticosteroid doses are substantially reduced or completely withdrawn from a tacrolimus-based immunosuppressive regimen, a moderate increase of tacrolimus concentrations will ensue, albeit without any clearly described clinical consequences. More attention for clinically relevant immunosuppressive drug interactions is warranted in this era of tailor-made transplantation medicine whereby an increasing number of immunosuppressive drug combinations are, not uniquely, but rather sequentially used during the life course of a transplanted organ. Dirk R. Kuypers Review articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868532&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868533&level=5Background: Patients with acute massive pulmonary embolus have a high mortality even with treatment. For patients in whom thrombolytic intervention is contraindicated, surgical pulmonary embolectomy is a viable option. Case Report: We present a patient who, four months after kidney transplantation, developed acute massive PE with cardiac arrest. He underwent surgical pulmonary embolectomy and was discharged two weeks later, with preservation of renal allograft function and long-term survival. Conclusions: While the mortality risk of surgical embolectomy is high, survival has been greatly improved by the use of cardiopulmonary bypass. Early diagnosis and initiation of aggressive treatment is vital to achieving successful outcomes in patients who would otherwise be unsalvageable. Patrick P. McHugh, Thomas D. Johnston, Roberto Gedaly, Hoonbae Jeon, Dinesh Ranjan Case reporthttp://www.annalsoftransplantation.com/abstracted.php?icid=868533&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868534&level=5Background: Despite observed huge progress in understanding the immunological basis of transplantation and the development of new immunosuppressive agents that have signifi cantly improved both -- the patient and graft survival, still the kidney donation from live volunteers remains the most consistent factor which affects the long-term survival. The conventional, open method of donor nephrectomy is associated with signifi cant surgical trauma. The laparoscopic live-donor nephrectomy (LDN) is the alternative for open approach. Case Report: We present our experience of the case of laparoscopic removal of the kidney from a living donor. We applied retroperitoneoscopic access, the operation time was 210 minutes. Kidney was implanted shortly after LDN and its immediate function was observed. We have observed no serious postoperative complications either in donor or recipient. Conclusions: We hope that this successful initial case of LDN will have a positive effect on cooperation between transplantologists and urologists, and on rate of kidney donation in Poland. Marcin Słojewski, Tomasz Śluzar, Adam Gołąb, Jerzy Chłodny, Samir Zeair, Krzysztof Dziewanowski, Marek Umiński, Andrzej Sikorski Case reporthttp://www.annalsoftransplantation.com/abstracted.php?icid=868534&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868535&level=5Background: We have found no study conducted economic issues on patient outcomes after heart transplantation (HTx) in China for further development. Material/Methods: From May 2004 to February 2006, there were 10 transplants performed in 9 male patients in our center: 1 heart lung recipient and 8 heart recipient. Among them, 7 lacked health insurance and 2 had insurance. Results: Their ages were between 24 years and 43 years (mean 39 years). The number of hospitalizations, number of days in hospital per admission, number of emergency room visits and mean left ventricular ejection fraction (LVEF) in the year before operation were 5.5, 54, 8.1 and 0.19 respectively. After operation, these figures decreased significantly to 1.7 (P<0.05), 18 (P<0.05), 1.1 (P<0.05) and 0.70 (P<0.05) respectively. During the follow up of 370~930d, one of the 9 patients who lacked health insurance died of acute rejection due to stopping mycophenolate mofetil (MMF) 7 months after operation and the heart lung recipient who also lacked health insurance died of pulmonary infection 1 year later. All patients who lacked health insurance experience emotional distress. Conclusions: HTx is a good treatment for selected patients with end-stage heart failure (ESHF) and future research is to be expected in the fields of insurance coverage to improve the quality of life and the Chinese transplant group should be commended for their courageous work in the treatment of end stage heart disease under challenging circumstances. Ji-ming Sha, Yi-qin Tao, Dao-hang Li, Hai-feng Hu Mon, 8 Sep 2008 10:25 ESTOriginal articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868535&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868536&level=5Background: Several factors influence ischemic/reperfusion injury in simultaneous pancreas-kidney transplantation (SPKT). Per-operative period is full of intense changes in systemic parameters related to pancreatic reperfusion (PR). This work aims to study these changes evaluating fluid reposition, need of vasopressors and other related factors. Material/Methods: Sixteen SPKT enduring patients mean age 32.4±4.76 had metabolic, electrolyte and hemodynamic data evaluated and compared at three times. Arterial blood gases, glucose, hematocrit; Na, K; MAP, HR and PAP were monitored after skin incision (T1), before and after PR (T2-T3). Fluid reposition, vasopressors, endocrine graft recovery and other related factors as donors, grafts, surgery team and receptors were also considered. Results: Glucose, PaO2, PaCO2 and electrolytes didn’t vary along the times. From T1v.T2 there was significant metabolic acidosis; T2v.T3 identified tachycardia and pulmonary hypertension; T1v.T3 confirmed metabolic acidosis, hemodilution and arterial hypotension. Use of crystalloids (8500±2909.75 mL), colloids (647.05±492.59 mL), human albumin (8.57±2.44 U), fresh frozen plasma (1.06±1.91 U), platelets (1.86±4.16 U) and red packed cells (5.75±3.25 U), needs of noradrenalin and dobutamin: 37,5% and 6,25%. Endocrine graft recovery median was 4.15 h. Related factors to donor’s: 25.43±8.14 years, BMI 23.24±1.66, serum creatinine 1.1±0.47mg/dl, hemodynamically stable and trauma as cause of 50% donors brain death; graft storage: cold ischemia time (CIT) median of 12.5 h; surgery team: warm ischemia time (WIT) median of 60min; receptors: ASA4, type 1 diabetes mellitus and end stage renal disease medias of 18.87±5.64 and 2±1.3 years. Conclusions: Our experience confirmed the intense instability related in literature caused by PR in SPKT. Adriana de Castro Carvalho Faria, Eduardo Costa Teixeira, Felipe Oliveira de Faria, José Marcus Raso Eulálio, Louis Barrucand, Nubia Verçosa Original articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868536&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868537&level=5Background: Survival after orthotopic liver transplantation (OLT) for primary biliary cirrhosis (PBC) is excellent. In order to define the optimal time point for OLT, the Mayo risk score (MRS) was developed and a score of 7.8 was identified for transplantation. However, in reality most recipients are in a bad condition with a MRS above 7.8. So far it is still unknown if a higher score is associated with more complications after OLT perioperatively and in a long-term follow-up. Therefore, this study was designed to investigate the association of the MRS score with postoperative survival and complications. Material/Methods: Between 1989 and 2006, 115 patients were transplanted for histologically proven PBC at the Charité Campus Virchow Clinic. In 98 of these patients, MRS data was available and retrospectively analyzed. Median age of 87 women and 11 men was 54 years (25 to 66 years). Results: The median follow-up after liver transplantation was 109 months (0.5–205 months). Actuarial patient survival after 5, 10 and 15 years was 90%, 88%, and 83%. Calculated survival by MRS without transplantation after 1, 5 and 7 years was 20%, 2% and 1% for these patients. Twelve patients (12%) died and histological recurrence of PBC was detected in 14 patients (14%). Seven patients underwent retransplantation (7%) and 58 patients developed an acute rejection episode (59%). Mean MRS was in all patients 9.54±1.35 and did not differ between patients with lethal course, retransplantations, PBC recurrence, rejection episodes and duration of hospital stay. Classification of all patients into a low (<8.5), middle (8.5–10) and high MRS score (>10) did not show a significant difference in long-term survival. Univariate analysis for identifying the level of MRS as risk for death, PBC-recurrence, retransplantation, acute rejection episodes and hospital stay only showed a significant increased risk for acute rejection episodes (1 episode = 0.04; 2 episodes = 0.01) for patients with a MRS above 8.5. Conclusions: The Mayo risk score is an approved mathematical model predicting survival in non-transplanted patients suffering from PBC. However, the score did not predict the course of our liver transplanted patients in a long-term follow-up. We could not demonstrate a reduced patient survival at a median MRS of 9.4 and about 10.0. Therefore, it is, from our point of view, questionable if the optimal time point for OLT is still 7.8. Dietmar A. Jacob, Marcus Bahra, Sven C. Schmidt, Guido Schumacher, Andreas Weimann, Peter Neuhaus, Ulf P. Neumann Original articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868537&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868538&level=5Background: The objectives of this study were: to assess and compare the antibody responses of renal allograft recipients and dialysis patients to pneumococcal vaccination. Material/Methods: 14 stable dialysis patients as well as 37 kidney transplant recipients were eligible for inclusion in this trial. Participated patients receive a single 0.5-mL of 23-valent vaccine Pneumovax® administered intramuscularly in the upper extremities. The efficacy of vaccination was evaluated by measuring the antibody response to the whole vaccine. Sera were obtained prior to vaccination and 4 weeks, 6 months and 1 year after the vaccination. Results: Prior to vaccination, mean IgG and IgG2 titers were equivalent in Dx and KTx patients (p>0.1 in both). Four weeks after vaccination, 49 out of 51 participated patients (96%) represented an increase in their anti pneumococcal IgG levels (mean 99±66) compared to 48 out of 51 (94%) for month 6 (mean 90±59), and 38 out of 45 (85%) for the first year after vaccination (mean 73±69). KTx patients kept significantly more serum IgG2 levels at months 6 and 12 after vaccination (p=0.001, p=0.03, respectively; Table 1). Mean IgG values for month 6 was 9±41 units lesser than month 1 post vaccination serum IgG levels. Conclusions: We found that patients with renal failure on hemodialysis and kidney transplantation well respond to immunization by anti pneumococcal vaccination. But, they rapidly loss their serum antibody levels during the one year after vaccination. Specifying protective levels for serum IgG and IgG2 levels in these patients would help us to more precisely follow these patients and to consider a revaccination when they failed to save the protective serum antibody level. Vahid Pourfarziani, Mohammad Bagher Ramezani, Saeed Taheri, Morteza Izadi, Behzad Einollahi Original articlehttp://www.annalsoftransplantation.com/abstracted.php?icid=868538&level=5http://www.annalsoftransplantation.com/abstracted.php?icid=868539&level=5I read the valuable paper titled “Transplantation research output by Muslim Nations: Current status, trends and future outlook” by Nourbala et al [1] in the previous issue of Annals of Tansplantation with great interest. Bibliometry is a fundamental part for research policy making, while we lack it in the field of transplantation [2]. On the other hand, the point that appeals to me was the peak of publication from Iran in 2007, with 120 papers in comparison with 33 in 2006, which means a 260% increase in only one year. However, the authors predicted a drastic drop of publications by the Iranian scientists in the field by 2008. They related this conclusion to the irregularity in trend of publications in the previous years. Unfortunately, I have to agree with them and would like to emphasize a reason of this instability: the weakness in the link between clinicians and professional research assistant teams and networks, which was experienced lately by a newly developed transplantation research center in our country. In 2006, just a year before the abovementioned peak, an innovative decision was made by the research deputy of Baqyiatallah University of Medical Sciences (BMSU) at the same time of developing a new research center, namely the Nephrology Urology Research Center (NURC). They invited a research assistant team to join their research center (the model and outputs of this link have been described elsewhere [3,4]). As a result, a group of professional research assistants joined the outstanding professors, a phenomenon not well developed in our country, whereas using the research assistants who are hard working and motivated is a well known process in many academic institutes worldwide. Although this connection led to the publication of at least 40 of the 2007 papers on transplantation by a single research center, unfortunately, it could not remain stable. The unstable nature of these cooperative plans shifts these professional research assistant teams to other fields each year, which may create a peak in another fields; nonetheless, the resultant achievements will be temporary. Limiting regulations and lack of support continues to preclude a persistent network that would be beneficial for both parts. Many professional individuals, groups and even institutes working in the private sector such as Dr. Taheri Medical Research Group (see the affiliations in the discussed article), Farzan institute, Medicine and Health Promotion Institute [www.mhpinstitute.ir], and Scientific Writing Network (SWN) [www.swn.ir] are suffering from a very unstable situation in their financial relation with health organizations. The most dominant part of the problem is the traditional thought by research directors and policy makers that the research funds should be paid for research conduction costs but not its publication expenditures. Direct financial support of publication and writing assistance is currently limited in Iran. Consequently, the final product of research grants may be just a “final report” stocked in library shelves. This means we are selecting to be perished not published. I believe that the benefit of the link between research organizations and professional research assistants, which is well known in some countries, has not been well understood in our country. Why are we unable to do so? I can only hope for a better view of research directors and policy makers in our country in the future. References: 1. Nourbala MH, Taheri S, Habibi R et al: “Transplantation” research output by Muslim Nations: Current status, trends and future outlook. Ann Transplant, 2008; 13(2): 21–27 2. Aslani J, Khedmat H, Assari S et al: Transplantation research in Iran: a bibliometric study. Transplant Proc, 2007; 39(4): 788–89 3. Einollahi B, Bahaeloo-Horeh S, Assari S, Ghanei M: Kidney Transplantation Society Tries to Answer Its Questions through a link between Scientists and Young Researchers. Saudi J Kidney Dis Transpl, Accepted 4. Ghanei M, Saadat SH, Bahaeloo-Horeh S et al: Facilitating medical research for a group of young Iranian physicians: does it decrease the risk of brain drain? IJME, 2008; Accepted Shervin Assari Mon, 8 Sep 2008 10:25 ESTLetter/Correspondencehttp://www.annalsoftransplantation.com/abstracted.php?icid=868539&level=5