[How many potential organ donors are there really? : Retrospective analysis of why determination of irreversible loss of brain function was not performed in deceased patients with relevant brain damage]. / Wie viele potenzielle Organspender gibt es wirklich? : Retrospektive Analyse zu nichterfolgter Diagnostik des irreversiblen Hirnfunktionsausfalls bei verstorbenen Patienten mit relevanter Hirnschädigung.

BACKGROUND: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out. OBJECTIVE: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors. METHOD: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage. RESULTS: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed. CONCLUSION: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment.

Cost-effectiveness of hypothermic machine preservation versus static cold storage in renal transplantation.

Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short- and long-term cost-effectiveness. Three hundred thirty-six consecutive kidney pairs were included, one of which was assigned to MP and one to CS. The economic evaluation combined the short-term results based on the empirical data from the study with a Markov model with a 10-year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long-term survival, quality of life, and long-term costs were derived from literature. The short-term evaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of $86,750 per life-year gained in favor of MP. The corresponding incremental cost-utility ratio was minus $496,223 per quality-adjusted life-year (QALY) gained. We conclude that life-years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS.

The Eurotransplant donor risk index in liver transplantation: ET-DRI.

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. From 5723 patients follow-up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET-DRI). Concordance-index calculation shows this ET-DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET-DRI for risk indication and possibly for allocation purposes within the Eurotrans-plant region.

The influence of laboratory-induced MELD score differences on liver allocation: more reality than myth.

BACKGROUND: Liver allocation in Eurotransplant (ET) is based on the MELD score. Interlaboratory MELD score differences in INR and creatinine determination have been reported. The clinical implication of this observation has not been demonstrated. METHODS: MELD scores were calculated in 66 patients with liver cirrhosis using bilirubin, creatinine, and INR analyzed in six liver transplant centers. Based on allocation results of ET, patients transplanted from December 2006 to June 2007 were divided according to MELD score in four groups. For each group, the influence of the match MELD on the probability of receiving a transplant was studied (Cox proportional hazards model). RESULTS: Laboratory-dependent significant differences in MELD score were demonstrated. Cox proportional hazards model showed a significant association between MELD score and the probability of organ allocation. The unadjusted hazard ratio for receiving a liver transplant was significantly different between group 2 and group 4 (group 2: MELD 19-24; group 4: MELD > 30). CONCLUSION: Laboratory-dependent significant differences in MELD score were observed between the six transplant centers. We demonstrated a significant association between the MELD score and the probability of organ allocation. The observed interlaboratory variation might yield a significant difference in organ allocation in patients with high MELD scores.

The prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys.

Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been prospectively validated. Prospectively collected RR values of 302 machine-perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1-year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 38.1 [1.56-934]; p = 0.026) [corrected] but the predictive value of RR was low, reflected by a c-statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1-year graft failure (hazard ratio 12.33 [1.11-136.85]; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand-alone quality assessment tool cannot be used to predict outcome with sufficient precision.

Considerations for patients awaiting heart transplantation.

The aim of this study is to provide a description of patients on the waiting list for heart transplants in Germany; the focus is on comparing the era after implementation of the new transplant law with the former era. This study used data from the Eurotransplant registry. The population consisted of all patients who registered for heart transplantation in Germany between January 1990 and May 2009. Patients were followed up to the earliest of the following events: heart transplantation, death, or end of the observation period. The actual mortality rates were calculated using a competing risk methodology. The proportion of patients on the waiting list aged 65 years or older has increased from 1.9 % in 1990 to 8.3 % in 1997, 7.8 % in 2000 and 12.6 % on December 31, 2008. The 1-year waiting list mortality rate, expressed as the proportion of patients who die within 1 year after being listed for heart transplantation decreased in the period 2001-2009 compared to the period 1991-2000. Patients registered in the period from 1991-2000 had a 25.9 % chance of dying prior to heart transplantation compared to 18.9 % for patients who were registered in the years 2001-2009. In the registration period 1981-1990, a transplant candidate had a 64.3 % chance of undergoing heart transplantation within the first year after being listed, while for patients who were registered in the period 2001-2009 this probability has been reduced to 40.2 %. Despite the fact that patient profiles have worsened and access to transplantation decreased, mortality rates of patients on the heart transplant waiting list have decreased. These data show that treatment of patients with advanced heart disease has improved in Germany.

[Amendments to the Transplantation Act and impact on the donor situation in Germany]. / Änderungen im Transplantationsgesetz und Auswirkungen auf das Spenderaufkommen in Deutschland.

In Germany, the scarcity of donor organs has persisted over decades and reached an historical low point in the year 2017. A thorough analysis of the causes revealed structural deficits in the identification and registration of possible donors as one of the central reasons for the low donation rate. This prompted the political authorities to act and resulted in two new laws, which led to a modification of the German Transplantation Act. On 1 April 2019, the Act on Improvement of the Cooperation and the Structural Framework for Organ Donation came into force. This Act strengthens the role of the transplant coordinators in the harvesting hospitals and establishes adequate reimbursement of the organ donation-related costs in the harvesting hospitals. Furthermore, it fosters the cooperation of the transplant coordinators with the German organ procurement organization. On 16 January 2020, the existing opt-in legislation was modified. While the general principle of the opt-in legislation stayed unchanged, different measures were introduced that aim to repeatedly inform all citizens about organ donation and thereby motivate them to make a decision on organ donation. In order to enable a reliable and transparent documentation an organ donor registry will be established. The practical implementation of the various measures of both Acts is supported by a multi-institutional collaborative initiative plan for organ donation. The legal regulations and their practical implementation are depicted in detail.

[Organ donation : Update 2019]. / Organspende : Update 2019.

The number of organ donors in Germany has been falling since 2010. In 2017, it reached its lowest level in 20 years with 797 organ donors. With 9.7 organ donors per million inhabitants, Germany lags far behind other European countries. The development of the donor numbers has long been an issue of concern for the Deutsche Stiftung Organtransplantation (DSO). Together with the donor hospitals, DSO has carried out extensive analyses on the possible causes. Though causes are multiple and complex, one important lever for improving the situation is seen in better detection and consistent reporting of possible organ donors. This is considered the best way to meet the patient's desire regarding organ donation. With reference to the dramatic development, DSO calls for a broad social debate and a joint initiative involving medical associations, contractors, patient associations and policymakers. Getting organ donation back on track in Germany for the benefit of patients on the waiting lists can only be achieved by a joint effort.

[Donor liver histology : Joint recommendations of the DGP, DTG and DSO]. / Histologische Diagnostik bei Spenderlebern : Gemeinsame Empfehlungen von DGP, DTG und DSO.

BACKGROUND: The indications, implementation and reporting of liver biopsies for deceased organ donation are not mandatory or regulated. Reliable data on outcome quality and prognostic relevance are therefore not available. Defined standards are thus required to enable meaningful studies and to ensure high data quality of a national transplantation registry. OBJECTIVE: Presentation of a synopsis of available studies and literature-based recommendations. RESULTS AND CONCLUSION: Against the background of an organ shortage and a growing number of older donors, pretransplantation liver histology is of significant relevance to guide clinical decision making. With the joint recommendations of the German Transplantation Society (DTG), the German Society of Pathology (DGP) and the German Organ Transplantation Foundation (DSO) standardized procedures are defined for the first time.

How to recognize a suitable pancreas donor: a Eurotransplant study of preprocurement factors.

INTRODUCTION: Because of the increasing demand for pancreas transplantation, more marginal donors are offered to Eurotransplant. The aim of this study was to validate a donor quality score that would facilitate recognition of a suitable pancreas donor among all reported donors. MATERIALS AND METHODS: We analyzed all 3180 consecutively reported pancreas donors for the period between January 1, 2002 and June 30, 2005 and determined the influence of the preprocurement pancreas suitability score (P-PASS) on the acceptance of a pancreas. We defined a range and point weight for each variable based on clinical expertise and known literature. RESULTS: Multiple regression analysis using pancreas acceptance as an outcome variable identified P-PASS > or = 17 as a significant cutoff point (P < .001). Pancreata from donors with P-PASS > or = 17 were three times more likely to be refused. CONCLUSION: The donor score can help in screening for potential pancreas donors, where an ideal donor has a P-PASS < 17. Our data demonstrate that consideration of a combination of preprocurement factors can help identify a suitable pancreas donor. Therefore, we recommend that a pancreas donor score be calculated for each potential pancreas donor, and all donors with a P-PASS < 17 should be considered for pancreas donation.

[Model for end-stage liver disease. New basis of allocation for liver transplantations]. / Model for end-stage liver disease. Neue Grundlage der Allokation für die Lebertransplantation.

In December 2006 the allocation of livers from deceased donors in Germany and several other Eurotransplant countries was reset. The previous allocation system relied on CTP score to assess the need of transplantation, but it also assigned to waiting time a prominent role in prioritization. That system was replaced by the primarily urgency-oriented model of end-stage liver disease (MELD) allocation system. First experience with this classification in the U.S.A. shows that MELD scores are able to identify the urgency of liver transplantation correctly in most types of liver disease. Due to the MELD-based allocation, the growing waiting time and waiting-list mortality could be counteracted. At the same time it became evident however that MELD scores do not reflect mortality on the waiting list or thus the urgency for all types of liver diseases. Therefore the new allocation system introduced in the Eurotransplant countries contains standardized and flexible exceptions for these diseases. In addition the new allocation rules were created as a learning system. Repeated "fine tuning" of the allocation process based on continuous monitoring of daily allocation practice and clinical studies aim at just and effective distribution of the precious and limited supply of donor organs.

C0h/C2h monitoring of the pharmacodynamics of cyclosporin plus mycophenolate mofetil in human heart transplant recipients.

UNLABELLED: Pharmacokinetic (PK) parameters like C2h have improved efficacy of immunosuppressive therapy. However, drug interactions, toxicities, and individual differences to drug effects still remain challenging. Therefore, this study was designed to assess pharmacodynamic (PD) effects of the combination cyclosporin (CsA) plus mycophenolate mofetil (MMF) on lymphocyte functions in peripheral blood of stable heart transplant recipients (HTx) using our established FACS assays. METHODS: Blood from 25 HTx patients was drawn before (C0h) and 2 hours after dosing (C2h). CsA and mycophenolic acid (MPA) concentrations were measured by EMIT. FACS assessed expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and T-cell activation (CD25, CD95). RESULTS: Evening doses of CsA (25/50/75 or 100 mg) and MMF (250/500 or 1000 mg) produced C0h levels as follows: CsA, 162 +/- 12 ng/mL; MPA, 1.7 +/- 0.2 mg/L. Morning doses of CsA (50/75 or 100 mg) and MMF (250/500/1000 or 1500 mg) produced C2h-levels as follows: CsA, 589 +/- 56 ng/mL and MPA, 7.4 +/- 1.3 mg/L. PD effects at C0h/C2h (% expression +/- SEM, all P < .05) were IL-2, 18 +/- 3/10 +/- 2; TNF-alpha, 12 +/- 2/7 +/- 1; PCNA, 8 +/- 1/5 +/- 1; CD25, 26 +/- 4/13 +/- 2; CD95, 23 +/- 4/11 +/- 2). Correlations (r2) at time point C2h between inhibition of lymphocyte functions (PD) with drug concentrations (PK) and with drug doses were CsA-PK, 0.71 to 0.91; MMF-PK, 0.55 to 0.76; CsA-dose, 0.73 to 0.87; MMF-dose, 0.61 to 0.80. CONCLUSION: For the first time, the immunosuppressive effects of the combination CsA plus MMF were quantified in whole blood of human HTx at different time points. PD assays may offer the opportunity to optimize clinical immunosuppressive drug therapy.

Pharmacodynamic monitoring of the conversion of cyclosporine to tacrolimus in heart and lung transplant recipients.

OBJECTIVE: Conversion from cyclosporine (CsA) to tacrolimus (TRL) remains challenging in the daily routine due to individual variations in blood concentrations (pharmacokinetics, PK), pharmacodynamics (PD) and in interactions on plasma mycophenolic acid (MPA) concentrations. Therefore, we used our PD assays of lymphocyte function to monitor the conversion of CsA to TRL in heart (HTx) and lung (LTx) transplant recipients. METHODS: Patients (six HTx, two LTx) were converted from CsA to TRL because of gingival hyperplasia. All patients were treated with 6 mg BID TRL 24 hours after the last CsA dose and received mycophenolate mofetil BID cotherapy. PK measurements of CsA, TRL, and MPA were done by EMIT. Expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and activation (CD25) was assessed by FACS. RESULTS: TRL concentrations increased from day 1 to 3, but did not alter MPA concentrations, which were comparably high to MPA concentrations in combination with CsA (day 0). Compared to CsA therapy, increased TRL concentrations did not further inhibit PCNA expression, inhibited CD25 expression less on days 1 and 2 and equally high on day 3, but inhibited expression of IL-2 and TNF-alpha significantly higher on days 2 and 3 (P < .05). CONCLUSION: This study shows that monitoring PD of lymphocyte functions after conversion from CsA to TRL in HTx and LTx recipients revealed differences of inhibition of lymphocyte functions. Monitoring PD of lymphocyte function may provide insights in drug interactions of immunosuppressive combination therapy and may help to tailor immunosuppression to avoid toxicity and to enhance efficacy.

Angiographic, intravascular ultrasound and functional findings early after orthotopic heart transplantation.

Accelerated graft atherosclerosis is responsible for increased mortality and morbidity among heart transplant recipients. The aim of this in-vivo study was to evaluate coronary atherosclerotic vessel alterations and endothelial function. Seventeen patients (14 males; mean age 49.3 years; range 24 to 69) were studied an average of 11 weeks (range 5 to 21) after heart transplantation because of coronary artery disease (n = 8), dilative cardiomyopathy (n = 7), mitral valve replacement (n = 1) and left atrial metastases of a leiomyosarcoma (n = 1). Mean age of the donor hearts (9 males) was 29 years (range 12 to 55). All recipients underwent biplane ventriculography and coronary angiography. In this study population, a total of 120 coronary segments (main stem, 21; left anterior descending artery, 85; circumflex artery, 14) were analyzed by intravascular ultrasound (20 MHz, 3.5F). In 13 patients, acetylcholine was infused into the proximal left anterior descending artery (10(-8) to 10(-5) M) to evaluate vasomotion within this segment. Regional contraction abnormalities were documented in 2 patients. Nine segments angiographically showed non-critical stenoses (5 patients). Intravascular ultrasound detected 52 cross-sectional areas with a three-layer pattern indicating intimal thickening. Mean circumferential extension of intimal proliferation was 192 degrees, mean intimal thickness 0.35 mm. Only 5 segments of the sonographically pathological cross-sectional areas showed angiographical evidence of atherosclerotic lesions. Intracoronary administration of acetylcholine at doses of 10(-8) and 10(-7) M resulted in vasoconstriction of the examined coronary segment in only 2 patients; the intracoronary application of acetylcholine at doses of 10(-6) and 10(-5) M revealed coronary vasoconstriction in 10 of the total of 13 patients. Using intravascular ultrasound, coronary artery lesions in heart transplant recipients can already be depicted at a very early stage. The abnormal response to acetylcholine in most of the heart recipients is independent of the extent of atherosclerotic vessel abnormalities documented by ultrasound or angiography.

Clinical and invasive 7-month follow-up of a patient with a synthetic coronary graft.

The PossisR polytetrafluoroethylene Permaflow is a synthetic coronary graft which incorporates a Venturi resistor and which is anastomosed to the superior vena cava. Multiple anastomoses to the coronary vessels can be established in sequence until the graft is finally connected to the aorta. This aortocaval fistula enables permanent flow within the synthetic graft. We present the post-operative clinical and invasive findings of a 69-year-old female patient with a PossisR coronary graft. Follow-up angiography 3 and 7 months post-operatively showed patency of both coronary anastomoses and sufficient run-off to the native vessel segments. The left-right shunt induced by the graft was hemodynamically insignificant. Left ventricular function had improved significantly. 30 MHz intravascular ultrasound of the proximal part of the PossisR graft did not show an extra inner layer at the luminal side of the synthetic graft wall, so that relevant intimal thickening could be excluded after an interval of 7 months post implantation. Using an intravascular imaging technique, focal atherosclerotic lesions or thrombotic graft wall alterations could also be ruled out.

Significance of cardiogenic mixing in dog lungs.

Single-breath washout of two inert gases (He and SF6) in anesthetized mechanically ventilated dogs in normal conditions with the heart beating and during reversible heart arrest revealed no effects attributable to the action of the beating heart. It is concluded that in the conditions of the experiments convective mixing by the cardiac action played an insignificant role in promoting intrapulmonary mixing and transport.

Is the heart preadapted to hypoxia? Evidence from fractal dynamics of heartbeat interval fluctuations at high altitude (5,050 m).

The dynamics of heartbeat interval time series over large time scales were studied by a modified random walk analysis introduced recently as Detrended Fluctuation Analysis. In this analysis, the intrinsic fractal long-range power-law correlation properties of beat-to-beat fluctuations generated by the dynamical system (i.e., cardiac rhythm generator), after decomposition from extrinsic uncorrelated sources, can be quantified by the scaling exponent (alpha) which, in healthy subjects, for time scales of approximately 10(4) beats is approximately 1.0. The effects of chronic hypoxia were determined from serial heartbeat interval time series of digitized twenty-four-hour ambulatory ECGs recorded in nine healthy subjects (mean age thirty-four years old) at sea level and during a sojourn at 5,050 m for thirty-four days (EvK2-CNR Pyramid Laboratory, Sagarmatha National Park, Nepal). The group averaged alpha exponent (+/- SD) was 0.99 +/- 0.04 (range 0.93-1.04). Longitudinal assessment of alpha in individual subjects did not reveal any effect of exposure to chronic high altitude hypoxia. The finding of alpha approximately 1 indicating scale-invariant long-range power-law correlations (1/f noise) of heartbeat fluctuations would reflect a genuinely self-similar fractal process that typically generates fluctuations on a wide range of time scales. Lack of a characteristic time scale along with the absence of any effect from exposure to chronic hypoxia on scaling properties suggests that the neuroautonomic cardiac control system is preadapted to hypoxia which helps prevent excessive mode-locking (error tolerance) that would restrict its functional responsiveness (plasticity) to hypoxic or other physiological stimuli.