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OBJECTIVE: To develop and validate an instrument for measuring knowledge and skills in evidence based medicine and to investigate whether short courses in evidence based medicine lead to a meaningful increase in knowledge and skills. DESIGN: Development and validation of an assessment instrument and before and after study. SETTING: Various postgraduate short courses in evidence based medicine in Germany. PARTICIPANTS: The instrument was validated with experts in evidence based medicine, postgraduate doctors, and medical students. The effect of courses was assessed by postgraduate doctors from medical and surgical backgrounds. INTERVENTION: Intensive 3 day courses in evidence based medicine delivered through tutor facilitated small groups. MAIN OUTCOME MEASURE: Increase in knowledge and skills. RESULTS: The questionnaire distinguished reliably between groups with different expertise in evidence based medicine. Experts attained a threefold higher average score than students. Postgraduates who had not attended a course performed better than students but significantly worse than experts. Knowledge and skills in evidence based medicine increased after the course by 57% (mean score before course 6.3 (SD 2.9) v 9.9 (SD 2.8), P

Background: Health care professionals worldwide attend courses and workshops to learn evidence-based medicine (EBM), but evidence regarding the impact of these educational interventions is conflicting and of low methodologic quality and lacks generalizability. Furthermore, little is known about determinants of success. We sought to measure the effect of EBM short courses and workshops on knowledge and to identify course and learner characteristics associated with knowledge acquisition. Methods: Health care professionals with varying expertise in EBM participated in an international, multicentre before– after study. The intervention consisted of short courses and workshops on EBM offered in diverse settings, formats and intensities. The primary outcome measure was the score on the Berlin Questionnaire, a validated instrument measuring EBM knowledge that the participants completed before and after the course. Results: A total of 15 centres participated in the study and 420 learners from North America and Europe completed the study. The baseline score across courses was 7.49 points (range 3.97–10.42 points) out of a possible 15 points. The average increase in score was 1.40 points (95% confidence interval 0.48–2.31 points), which corresponded with an effect size of 0.44 standard deviation units. Greater improvement in scores was associated (in order of greatest to least magnitude) with active participation required of the learners, a separate statistics session, fewer topics, less teaching time, fewer learners per tutor, larger overall course size and smaller group size. Clinicians and learners involved in medical publishing improved their score more than other types of learners; administrators and public health professionals improved their score less. Learners who perceived themselves to have an advanced knowledge of EBM and had prior experience as an EBM tutor also showed greater improvement than those who did not. Interpretation: EBM course organizers who wish to optimize knowledge gain should require learners to actively participate in the course and should consider focusing on a small number of topics, giving particular attention to statistical concepts.

Randomized controlled trials are essential for decision making and improving patient care. Although the number of published clinical trials in the field of transplantation is constantly rising, recent publications addressed problems of proper reporting of study results. Far too often, not even the key data (patient and graft survival, rejection rates, transplant relevant characteristics of the population, and details on the immunosuppressive therapy) were given. Good reporting should include primary and secondary outcomes, graft and patient survival, acute rejection rates (biopsy proven acute rejections and all treated), and clear accounting of the participant number throughout the different stages of a study. Several recent attempts (Consolidated Standards of Reporting Trials guidelines, submission of the study protocol, registry database) failed to improve or improved only partly the reporting quality. To improve reporting quality of randomized controlled trials in the future, we propose to use a comprehensive checklist with modified criteria of the Consolidated Standards of Reporting Trials guidelines to better reflect the special needs in the field of transplantation.

In earlier registry analyses, cyclosporine at doses of3 mg/kg/d at 1 year post-renal transplantation has been associated with significant graft loss or reduction in renal function. Improvements in cyclosporine formulation with increased bioavailability, plus the use of more efficient comedications, may now confer better outcomes. To determine the effect of the 1-year cyclosporine microemulsion (CsA-ME) dose on renal allograft function at 5 years, we analyzed data collected from 2889 patients with documented graft survival to year 5 in a prospective, multinational, observational study-Neoral MOST.Glomerular filtration rate (GFR) at year 1 was 63 +/- 20 mL/min and 59 +/- 22 mL/min at year 5. The multivariate analysis including year 1 CsA-ME dose as factor and GFR at 1 year as covariate revealed the most significant factors affecting GFR at year 5 were 1-year GFR, donor age60 years, and CsA-ME dose at 1 year. Risk factors associated with reduction in 5-year GFR (65 mL/min) included donor or recipient age60 years, delayed graft function, cadaveric donor, previous graft, and acute rejection. CsA-ME dose3 mg/kg/d was found to protect GFR. Analysis of GFR at each year posttransplantation (Wilcoxon model) found 1-year CsA-ME (cutoff 3 mg/kg/d) had a significant effect at each time point.Compared to higher doses, CsA-ME3 mg/kg/d at year 1 posttransplantation is associated with increased preservation of renal allograft function at year 5.

Background. Prevention of acute rejection still is an important endpoint in randomized controlled trials. Poor study reporting may create confusion and render decision-making difficult. The present study thoroughly analyses the presentation and definition of rejection in reports on large multicenter immunosuppressive trials published in the field of renal transplantation. Methods. Publications of large immunosuppression trials in kidney transplantation were identified by a predefined search strategy. The reported acute and biopsy-proven acute rejection (BPAR) episodes and additional information on number of patients recruited, publication year, impact factor, definition of acute rejection and the reporting of efficacy analyses were extracted. All reports were scanned for (a) at what point and (b) for which signs or reasons a biopsy was performed. Results. Eight of 41 (19.5%) papers investigating rejection rates reported a sufficient definition of acute rejection. Twenty-eight of 41 (68.3%) presented more than one rejection rate and were published in significantly higher impact journals. The absolute difference between clinical rejection and BPAR had a median of 6.5% and a wide range (0-16.9%). Efficaq/ analysis was presented in all but four (90.2%) reports. Thirteen of 35 (37.1%) papers did report the timing of the biopsies and 25 of 35 (71.4%) publications gave specifications of when a biopsy sample should be taken. Conclusions. The requirements of proper reporting of rejection episodes are not fulfilled in most of the publications and the use of many different terms for the description of rejection rates is confusing at present. Our comprehensive review clearly demonstrates the need for improved and standardized reporting of rejection episodes and we suggest to report both acute rejection and BPAR.

Background Long-term success of renal transplantation depends upon the quality of the donor organ, avoidance of peritransplant and early posttransplant damage (rejection), and optimal maintenance of graft function after the first 6-12 months. Glomerular filtration rate (GFR) at 1 year is a standard way to evaluate short-term success, whereas calculated GFR at 5 years gives a better appreciation of long-term outcomes. The objective of this study was to assess the effect of various demographic and transplant-related parameters on renal function via GFR at 1 year and 5 years post transplantation, using univariate and multivariate data analysis. Methods Data on 1-year GFR were available from 10,397 patients, whereas 2,889 patients provided data on both 1-year and 5-year GFR. All patients were enrolled in the Neoral Multinational Observational Study in Transplantation (Neoral-MOST), an ongoing, prospective, observational study of adult renal transplant recipients. Results One-year GFR was the most relevant predictor for 5-year GFR. In a multifactorial analysis (ANCOVA) using 1-year GFR as a continuous variable, the effects of several highly relevant parameters from univariate analysis (such as acute rejection and delayed graft function) on 5-year GFR appeared to be fully mediated by their influence on 1-year GFR, whereas immunological risk factors like HLA match or previous transplantation had an ongoing effect on graft function beyond year 1. Conclusions The findings of this study corroborate and augment data from previous registry surveys, and confirm the importance of observational studies in investigating the role of peritransplant parameters on long-term graft outcome.

Recent developments have proposed the cyclosporin (CsA) concentration at 2 h post-dose (C(2)) as the best single time-point predictor of the extent of CsA exposure and as the optimal basis for monitoring immunosuppressive therapy in renal transplant patients. The present study sought to validate the cornerstones of the current concept of C(2) monitoring.We assessed the predictive value, dose proportionality and intrapatient variability of C(2) levels in 41 de novo renal transplant recipients treated with CsA microemulsion, steroids, mycophenolate sodium and basiliximab.Patients with rejection and patients with CsA nephrotoxicity had lower C(2) (P = NS) and absorption (P0.05 for toxicity), while C(0) did not show any significant difference. Receiver operating characteristic analysis did not detect discriminative C(2) values as a predictor of rejection or toxicity. In a substantial number of patients (29%) we observed poor and/or slow absorption, with C(0)300 ng/ml and C(2) levels800 ng/ml during the first month and a high rate of complications in these patients (18% rejection, 64% toxicity). Absorption increased over the first month post-transplant. Analysis of dose changes indicated that C(2) levels are not dose-proportional. Intrapatient variability of C(2) was as high as that of C(0).C(2) levels do not predict rejection or toxicity. C(2) monitoring alone does not detect toxicity in poor and/or slow absorbers, who constitute a significant proportion of patients. Changes in absorption over time, high intrapatient variability and lack of dose proportionality constitute further limitations of the C(2) monitoring concept in the early post-transplant phase.

Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients.We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not. Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved.Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-kappaB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model.A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT1-receptor antibodies or from pharmacologic blockade of AT1 receptors.

Background. Most studies evaluating the impact of kidney donation on donors' quality of life (QOL) have limitations such as small cohort size, unmatched references, use of nonstandardized and nonvalidated questionnaires, or low response rates. Methods. We performed a study on donors' QOL that was designed to avoid these limitations. All available living renal donors in our department in the last 18 years were included in the study. QOL was assessed with two validated, standardized questionnaires (Short Form-36, Giessen Subjective Complaints List [Giessener Beschwerdebogen]-24) and compared with gender- and age-matched references. In addition, specific questions relating to kidney donation were asked. Results. The response rate (89.8%) is one of the highest reported for studies on QOL of living kidney donors. Most donors had an equal or better QOL than the healthy population. Donors' willingness to donate again (93.4%) or recommend living-donor kidney transplantation (92.4%) was high, irrespective of complications. A small number of donors experienced financial drawbacks or occupational disadvantages. Donors aged 31 to 40 years were found to be at risk of QOL deterioration after organ donation. Donor and recipient complications had a significant impact on donors' QOL. One third of the donors found that the psychologic care preceding and after kidney donation was insufficient. Conclusions. Our findings support the practice of living-donor kidney transplantation as a good means to meet the persisting organ shortage. Further effort must be put into minimizing donor and recipient complications. The specific demands of younger donors should be further elucidated. In addition to medical follow-up, living kidney donors should also be offered lifelong psychologic counseling.

Background. Genes determining the activity of the renin–angiotensin system (RAS) may be alloantigenindependent factors influencing kidney allograft function. We determined if gene polymorphisms of the RAS are associated with early and long-term posttransplantation graft dysfunction in 405 Caucasian kidney recipients with graft survivals of >2 years. Methods. We calculated the slopes of serum creatinine � 1 /year and urinary protein excretion/year to follow graft function over time. Subjects were genotyped for the deletion (D) polymorphism of the gene encoding angiotensin I-converting enzyme, the angiotensin II-receptor type1 gene 1166A-C polymorphism and the M235T polymorphism of the angiotensinogen gene. Results. The frequencies of factors predicting graft function were similar in patients with different genotypes. None of the polymorphisms influenced need for dialysis in the first week after transplantation, occurrence of at least one rejection episode, the slope of serum creatinine � 1 /year or the slope of urinary protein excretion/year. Results were independent of blood pressure or the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers or calcineurin inhibitors. The combination of genotypes did not influence the indicators of early and long-term graft dysfunction. Conclusions. Neither the investigated gene polymorphisms of the RAS in kidney allograft recipients nor their combinations have an impact on early and longterm graft dysfunction.

Background. Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican TM , RAD) is currently in clinical development to address this issue. Methods. The primary objective of this multicentre, randomized, double-blind, placebo-controlled, doseescalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus. Results. Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n ¼ 44) or placebo (n ¼ 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 10–19%); however, between-subject variability ranged from 34 to 60% for AUC and Cmax. Conclusions. These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.

The reporting quality of publications of clinical trials can affect the quality of clinical decision-making. We systematically assessed the quality of publications of large multicenter trials evaluating immunosuppressive regimens in de novo kidney transplantation. Study quality, reporting quality and accessibility of the results of 63 publications were assessed independently by three blinded investigators using an instrument combining the Jadad scale with a list of reporting quality items. Study quality was rated with an average of only 2.3 (range 1-5) on the Jadad scale. Unblinded studies were reported in 68.3% of publications and follow-up longer than 12 months was reported for only 13 out of 50 studies. The reviewed publications fulfilled an average of 69.1% of the reporting quality criteria. Fifty-four percent of publications did not report both treated and biopsy-proven rejections. Whether reported graft survival was censored for death could not be determined for 27% of publications. Only a few publications gave confidence intervals (CIs) or stated whether additional analyses were pre-specified. Even the largest trials of immunosuppression in kidney transplantation show considerable quality deficits in their design and publication. Additional efforts are required of investigators, editors and sponsors to achieve maximum study and reporting quality.

FTY720 is the first in a new class of immunomodulators—sphingosine 1-phosphate receptor (S1P-R) agonists. It is highly effective in prolonging allograft survival in preclinical models of transplantation. Furthermore, FTY720 acts synergistically with calcineurin inhibitors and proliferation inhibitors in these models, suggesting that use of FTY720 in combination with classical immunosuppressants may be a promising new option for transplant patients. Phase I studies conducted in stable renal transplant patients maintained on a cyclosporine (CsA)-based regimen have revealed a tolerable profile of FTY720 for transplant pharmacotherapy. The pharmacokinetics of FTY720 is characterized by linear dose-proportional exposure over a wide range of doses, only moderate interpatient variability, and a prolonged elimination half-life (t 1/2 89 to 157 hours). These factors suggest that FTY720 can be administered according to a simple once-daily schedule, without the need for blood-level monitoring or dose titration. The pharmacodynamics of FTY720 in humans are characterized by a significant reduction in peripheral blood count by up to 85%. In contrast to the nonspecific myelosuppressive effects of other immunosuppressants, this effect of FTY720 is specific for lymphocytes, with no effect observed on monocytes or granulocytes. In combination with CsA, FTY720 was well tolerated following single or multiple dosing, without any evidence of additional toxicities, indicating that FTY720 may be useful in the future design of more effective and less toxic regimens for prevention of graft rejection.

With the advent of cyclosporine (CsA) 20 years ago, graft survival increased considerably to more than 80% at 2 years posttransplant. The early formulation of CsA, Sandimmun, is effective in preventing organ rejection, although its absorption profile means it is subject to a high degree of variability. The development of a microemulsion formulation, Neoral, provided a therapy with superior efficacy in kidney, liver, and heart transplantation with an improved pharmacokinetic profile. Calcineurin inhibitors (CNIs), including CsA, have a narrow therapeutic range, so frequent blood measurements to control drug levels are required. Recent research has demonstrated that the measurement of blood CsA concentration at 2 hours postdosing—C 2 monitoring—has the potential to optimize efficacy and reduce the side effects associated with CNI use. In heart and de novo kidney transplantation, C 2 monitoring may help to further reduce the incidence of acute rejection, while in maintenance renal transplant recipients, C 2 monitoring can help to detect overexposure and thus allows safe dose reduction, which may improve blood pressure and renal function. C 2 monitoring thus facilitates a better balance between effective Neoral immunosuppression and unwanted side effects. Today, CsA remains the cornerstone of immunosuppression, and ongoing studies aim to further optimize patient management strategies with Neoral. With other trials evaluating the impact of Neoral in combination with newer therapies such as Certican, myfortic , and FTY720, the use of CsA in transplant recipients looks set to continue.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft function and survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering mycophenolic acid (MPA), developed with the objective of improving MPA-related upper GI adverse events. A pivotal, 12-month, phase III, randomized, multicenter, double-blind, double-dummy, parallel group study investigated whether stable renal transplant patients can be converted from MMF to EC-MPS therapy without compromising tolerability or efficacy. Stable renal transplant recipients received either MMF, 1000 mg b.i.d. (n=159), or EC-MPS, 720 mg b.i.d. (n=163), for 12 months. The incidence of GI adverse events was comparable between both treatment groups at 3 and 6 months, but there was a trend toward reduced severity of GI side effects in the EC-MPS group. There were fewer serious adverse events with EC-MPS and significantly fewer serious infections (P

An increase in waiting time for a cadaveric organs and a better graft-function, graft- and patient-survival with kidneys from a living donors have lead to an increase in living-donor renal transplantation in the therapy of end-stage renal disease. In Germany, with the implementation of a transplantation law in 1997 and due to improved surgical techniques (laparoscopy) the proportion of living renal donors has almost tripled during the last five years. The transplantation law also names the potential donors, including not only genetically related but also emotionally related donors. Inclusion criteria for living donation are age > 18 years, mental ability to give consent and an altruistic motivation (exclusion of financial benefits for the donor). If ABO blood group compatibility between donor and recipient is given and a cross match does not reveal immunologic obstacles a thorough medical and psychological examination must be performed with the potential donor. All risk factors for the donor beyond the actual operation must be excluded. Therefore all organ-systems have to be evaluated and risks for the donor as well as transferable pathologies and infections must be ruled out. International guidelines help to perform an efficient evaluation. Following organ donation the donor should be medically controlled as requested by law. Also, psychological counselling should be offered. The aim is to minimize risks for the single kidney and to recognize early potentially kidney damaging affections.

Background. Cyclosporin A (CyA) is a drug with a narrow therapeutic window and highly variable pharmacokinetics. Therapeutic drug monitoring is essential and conventionally has been guided by trough levels (C 0 ). Recent evidence indicates that a single blood concentration measurement 2 h after CyA administration (C 2 ) is a more accurate predictor of drug exposure and clinical events than determination of C 0 . To date, limited prospective data are available with respect to risks and benefits of C 2 monitoring in renal transplant recipients, and little experience exists with C 2 monitoring in maintenance patients. Methods. In 127 long-term renal allograft recipients, we determined C 2 levels in addition to conventional C 0 and observed clinical outcome over a period of 13.6 ± 3.1 months. To determine the precision of monitoring, we repeatedly determined C 0 and C 2 levels in 46 stable patients without dose change. Results. Clinical outcome was excellent (patient survival 100%, graft survival 97%), with only two borderline rejections, although C 2 levels (564 ± 186 ng/ml) were lower than recommended so far for maintenance patients. We found no significant differences in C 2 levels between patients with rejection and CyA toxicity. Receiver operating characteristic (ROC) analysis showed no prediction for risk of rejection, toxicity or infection by C 2 levels. Repeated determinations of both C 0 and C 2 levels in 46 patients revealed a high intra-patient variability. In these patients, the coefficient of variation for C 2 was only marginally better compared with C 0 . Conclusions. We conclude that in maintenance patients, C 2 concentrations between 500 and 600 ng/ml are well tolerated and provide effective and safe rejection prophylaxis. Although mean C 2 levels do not seem to be helpful in identifying patients at risk for rejection, they may be useful to detect over-immunosuppression and to improve long-term allograft survival further by reducing CyA nephrotoxicity.

The advent of new antidiabetic drugs is of special importance for diabetic patients with already impaired renal function since renal insufficiency is a relative or absolute contraindication for several of the established hypoglycemic drugs. Pioglitazone is a novel oral hypoglycemic agent that increases insulin responsiveness in target tissues. Pioglitazone and its active metabolites are excreted mainly via the liver. Drug exposure remains almost constant across a wide range of renal function since there is no accumulation of the drug or its active metabolites during repeated dosing in renal insufficiency. The pharmacokinetic properties of pioglitazone are ideally suited for patients with renal insufficiency. Although there are possible side effects (mainly fluid retention and weight gain and--very rarely--hepatotoxicity). Pioglitazone has a good safety profile in diabetic patients with impaired renal function.

Objective: Mycophenolate mofetil (MMF) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics, and despite the fact that in regard to the active metabolite, mycophenolic acid (MPA), there is a well-known association between the pharmacokinetic parameters and clinical outcome. Method: In order to determine the time course and the variability in cellular target of MPA after renal transplantation, we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy ( 1 g b.i.d.) for more than 1 year. The pharmacodynamic response was measured using inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells. MPA plasma concentrations were measured in parallel, IMPDH activity in 89 healthy blood donors was used as a control. Results: We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers (4.0 - 32.9 nmol/h/mg protein), in 8 patients on dialysis (5.3 - 18.9 nmol/h/mg protein) and in 8 renal transplant patients under long-term MMF treatment (2.3 - 14.4 nmol/h/mg protein). The mean AUC 0-12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF (62.2 ± 16.6 mg x h/ml) compared to dialysis patients receiving 1 g MMF for the first time (31.5 ± 15.6 mg x h/ml). Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response. Minimal IMPDH activity (1.62 ± 1.23 vs. 1.77 ± 1.49 nmol/h/mg protein) and maximal IMPDH inhibition (87.5 ± 0.08 vs. 77.4 ± 18.8%) during the dosing interval were similar. Conclusions: The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects.

Aims To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function.

Study objective: To determine the usefulness of high-resolution three-dimensional (3D) gadolinium-enhanced magnetic resonance venography (MRV) in the evaluation of central venous thrombo-occlusive disease of the chest. Design: Prospective study. Setting: University hospital. Patients: Sixteen consecutive patients with clinically suspected thrombosis of the superior vena cava, subclavian, brachiocephalic/innominate, internal jugular, or axillary veins. Thirteen patients had a neoplasm, two patients had a connective tissue disease, and one patient had a history of strenuous exercise. Twelve of 16 patients had prior central venous catheter placement. MRI was correlated with color-coded duplex sonography (CCDS) in 7 of 16 patients, digital subtraction angiography (DSA) in 3 of 16 patients, and CT in 2 of 16 patients. Intervention: Contrast-enhanced MRV was performed in a total of 20 examinations. A 3D data set (gradient echo; time to repeat, 4.6 ms; time to echo, 1.8 ms; flip angle, 30°; time of acquisition, 23 s; 512 matrix/64 partitions; slice thickness, 1.5 mm) was acquired in the arterial and venous phase. Overall image quality was assessed on a 5-point scale. The presence, site, and extent of thrombus, as well as presence of an intravascular device, were determined. Measurements and results: Overall image quality was rated very good (1 point) in 7 of 16 cases (44%) and good (2 points) in 9 of 16 cases (56%). Thrombus was detected in 16 of 16 patients, and complete extent of disease could be determined in 15 of 16 patients (94%). MRV did not miss any finding obtained by CCDS, DSA, or CT, and provided additional information in 6 of 16 examinations (38%). Conclusion: Contrast-enhanced MRV is a fast and reliable noninvasive procedure with excellent results regarding detection and determination of the extent of thrombo-occlusive disease of the chest veins. (CHEST 2001; 120:1570–1576)

Background. This survey was conducted to investigate similarities and differences in the diagnostic evaluation of adult candidates for cadaveric renal transplantation and the criteria for acceptance to the cadaveric renal transplant waiting-list in the European transplant centers. Methods. A questionnaire listing 45 diagnostic procedures (consultations of 9 specialties, 18 imaging techniques and 18 laboratory investigations), 45 medical conditions constituting possible reasons for exclusion from renal transplantation, and 10 properties characterizing the responding transplant center was sent to 214 European transplant centers. Results. A completed questionnaire was returned by 154 of 214 centers (72%). Significant disagreement (P

So far, the combined influence of donor age and recipient age on renal allograft survival has not been investigated sufficiently. In this retrospective single-centre study we analysed whether the influence of donor age and recipient age on renal allograft survival are dependent on each other.Data from 1269 cadaveric renal allograft transplantations were evaluated. Paediatric donors (15 years) and paediatric recipients (15 years) were excluded. Donors and recipients were divided by age: young donors (yd,/=55 years, n=1093), old donors (od,55 years, n=176), young recipients (yr,/=55 years, n=1058), and old recipients (or,55 years, n=211). Functional and actual long-term graft survival (8 years) within the four resulting groups was determined: yd/yr (n=926), yd/or (n=167), od/yr (n=132), and od/or (n=44).Univariate analysis showed that long-term graft survival of both, kidneys from young donors (functional, 66.1 vs 52.2%, P=0.004; actual, 53.3 vs 46.2%, P=0.065) and kidneys from old donors (functional, 68.7 vs 22.5%, P=0.07; actual, 57.1 vs 20.8%, P=0.15) was better in old recipients as compared to young recipients. Multivariate regression analysis revealed that actual graft survival of kidneys from old donors was significantly reduced in young recipients (od/yr) as compared to all other groups (P=0.001; RR, 1. 97; 95% CI, 1.32-2.94). In this group of patients, graft loss was mainly due to acute (33.7%) and chronic (24.0%) rejection.Transplantation of kidneys from 'old' donors into 'young' recipients should be avoided, and these kidneys should be given to age-matched recipients.

Fast and easy access to all relevant data is of most importance in medical diagnostics and therapy. Electronic patient records can fulfil these requirements much better than common paper-based records. This article describes the TBase2 system, an example of such an electronic patient record. It was developed in close cooperation with the Department of Nephrology at the university hospital Charite in Berlin. Due to its flexibility TBase2 can easily be adapted to the demands of other departments. Beside supporting the daily care for patients, TBase2 also gathers detailed data of high validity ideally suited for medical research.

Recent studies have implicated a variant of the angiotensin-converting enzyme gene (ACE), associated with increased activity of this enzyme, in the development and progression of diabetic nephropathy. This study provides a systematic review of all cross-sectional, case-control, and cohort studies in patients with insulin-dependent (IDDM) or non-insulin-dependent (NIDDM) diabetes mellitus of any race, examining the relationship between the ACE-insertion/deletion polymorphism and nephropathy. Nineteen studies in 21 populations published between 1994 and 1997 presenting data on 5336 patients were reviewed. Two investigators independently assessed the studies on methodologic quality, performance of study, and association between the ACE-insertion/deletion polymorphism and nephropathy. Separate analyses of the relationship between genotype and allele frequencies were performed for patients with IDDM and NIDDM by race, using Peto's odds ratio. In Caucasians with IDDM, pooling was not performed due to heterogeneity of the studies, but among the homogeneous studies, no association was detected. Likewise, no association was observed in Caucasian patients with NIDDM (odds ratio [OR], 1.10; 95% confidence interval [95% CI], 0.83 to 1.45). In Asian patients with NIDDM, the risk of nephropathy was increased in the presence of the DD or ID genotype (OR, 1.88; 95% CI, 1.42 to 2.85). Although this analysis fails to confirm an association between the ACE-insertion/deletion genotype and nephropathy in Caucasians with NIDDM or IDDM, a role for this genetic marker in Asian patients cannot be ruled out. However, due to methodologic limitations of individual studies, no definite conclusions can be drawn from this analysis. Clearly, more rigorous methodology needs to be applied in future studies.

This study examined the use of different definitions for acute rejection in recent large multicenter trials performed in America and Europe in order to assess whether systematic differences exist between both scientific cultures. We systematically selected recent publications on multicenter randomized controlled trials, investigating immunosuppressive regimens in de novo kidney transplant recipients. Publications included were classified according to the type of acute rejection reported: group 1 reported no or only one type of rejection rate (biopsy-proven or treated); group 2 reported information on both treated and biopsy-proven rates. Other potential factors (journal's impact-factor, study size) were compared within the subgroups. To determine the rates of treated but not biopsy-proven acute rejections, additional analyses were performed within subgroup 2. The reviewed publications were 24/44 (54.5%) European (E) and 20/44 (45.5%) American (A) origin. Eighteen of 44 publications reported no or only one type of rejection rate (group 1); 26 publications reported treated as well as biopsy-proven rates (group 2). Significantly more European publications reported both treated and biopsy-proven rates (E: 18/24 [75.0%] vs A: 8/20 [40.0%]; P = .019). Group 1 American papers were published in higher-ranked journals than European ones. The rate of blindly treated rejections did not differ significantly (A: 6.13% [range 0% to 12.8%] vs E: 8.43% [range 0% to 16.9%]) and the proportion of blindly treated rejections was slightly lower in American studies (A: 18.5% vs E: 26.5%). Our systematic review showed large discrepancies with a trend to report biopsy-proven rejection rates only in recent years.

Background Delayed graft function (DGF) is a common complication after renal transplantation, and may affect graft function. The aim of this analysis was to evaluate risk factors for DGF, as well as parameters and events influencing graft function after DGF. We analyzed data collected in an ongoing international, prospective; observational study, the Neoral-MOST (Multinational Observational Study in renal Transplantation), and included in the analysis all patients with cadaveric kidney transplants for whom renal function at 1 year posttransplantation was documented ( N = 8950). Logistic regression was used to evaluate the risk factors for DGF occurrence, and multifactorial analysis of variance (ANCOVA) to assess the relevance of different factors for GFR at 1 year. Results Higher donor age, longer CIT, male recipients, Caucasian recipients, high recipients body mass index, and PRA were all associated with a higher risk for DGF. Renal function of former DGF kidneys at 1 year was lower in kidneys of elder donors, or which had experienced rejection or CMV infection. Variations of the maintenance regimen at 1 year posttransplantation were not associated with better graft function. Multifactorial analysis showed donor age and acute rejection as significant independent factors. Conclusions Most factors increasing the risk for DGF or having a negative impact on renal function at 1 year in grafts with DGF are predetermined. Additional posttransplant damage by acute rejection was associated with further reductions in GFR. Preventing acute rejection is an important step in achieving optimal function of DGF grafts.

Endothelin (ET) A receptor antagonists have been shown to be beneficial in rat models of chronic kidney allograft dysfunction. We investigated urinary and plasma ET-1 (uET-1, pET-1) and BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble ET-converting enzyme (ECE) concentration in 310 adult Caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. All patients were on cyclosporine A- or FK506-based immunosuppression protocols. From all available measurements since transplantation, we calculated the slope of serum creatinine-1/year (slopeCrea) as a parameter for progression of chronic graft dysfunction, as well as the mean of serum creatinine (meanCrea) from most recent year before measurements as a parameter for actual graft function. The slope of urinary protein excretion/year (slopeProt) and mean of urinary protein concentration (meanProt) from most recent year was calculated analogue. uET-1 and uBigET-1 were adjusted for protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Blood and urine probes for measurements were always drawn immediately before morning dosage of immunosuppressants. There was no significant correlation of any measured component of the ET system with slopeCrea or slopeProt. MeanCrea (mg/dl) was significantly correlated with pBigET-1 (fmol/ml) and pET-1 (fmol/ml) (pBigET-1: r = 0.179, P = 0.001; pET-1: r = 0.161, P = 0.009). The other measured components of the ET systems were not significant correlated with meanCrea. In conclusion, the actual graft function is associated with elevated pET-1 and BigET-1 concentrations as it is well known from other forms of impaired kidney function. However, the actual concentration of ET-1, soluble ECE, and BigET-1 in urine and plasma in our study is not associated with parameters for progression of chronic graft dysfunction.

Plasma endothelin (ET)-1 concentrations have been shown to be elevated in patients receiving calcineurin-inhibitors (CI). We investigated urinary and plasma ET-1 (uET-1, pET-1), BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble endothelin-converting enzyme (ECE) concentrations in 381 adult caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. Blood and urine probes were always drawn immediately before morning dosage of immunosuppressants. Mean of urinary protein excretion (meanProt) and mean of serum creatinine (meanCrea) were calculated from all available measurements in the most recent year. uET-1 and uBigET-1 were adjusted for urinary protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Patients (n=310) were on a cyclosporine A or FK506 (CI-group) based immunosuppression protocol, and 71 patients were immunosuppressed without use of CI (nonCI group). Time since transplantation was similar in both groups (mean+/-S.D.; CI-group: 7.55+/-2.50; nonCI-group: 7.74+/-3.06 years, P=0.240) as well as meanCrea (mean+/-S.D.; CI-group: 1.97+/-1.34; nonCI-group: 1.77+/-1.29 mg/dl, P=0.326). pET-1 was significantly higher in the CI-group, compared with nonCI (mean+/-S.D.; 0.87+/-1.4 versus 0.56+/-0.76 fmol/ml, P=0.011). pBigET-1 was similar (mean+/-S.D.; 0.85+/-1.41 versus 0.70+/-1.21 fmol/ml, P=0.33). ECE concentrations were higher in the CI group (mean+/-S.D.; 14.30+/-18.02 versus 9.23+/-7.42 ng/ml, P=0.001). uET-1/meanProt and uBigET-1/meanProt concentration were similar in the CI-group compared with the nonCI-group (mean+/-S.D.; uET-1/meanProt: 15+/-24 versus 21+/-40 pmol/g, P=0.139; uBigET-1/meanProt: 34+/-55 versus 19+/-23pmol/g, P=0.248). pET-1 elevation in patients receiving CI might be more likely to be due to elevated conversion of pBig-ET-1 by more ECE, and not to higher concentrations of pBigET-1.

REFRACTORY rejection episodes are major causes of graft failure after renal transplantation. It is well known that late acute rejections have a poor long-term prognosis. Tacrolimus (FK) is an immunosuppressant agent that acts by inhibition of calcineurin activity, similar to cyclosporine A (CyA). It is used as a therapeutic alternative to CyA and is considered to be more potent than CyA. FK has also demonstrated efficacy as rescue therapy in patients who experience persistent acute rejection with CyA-based therapy. A corticosteroid-sparing effect has been demonstrated in several studies with FK, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of FK and CyA may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, CyA has a higher incidence of significant hypercholesterolaemia, hirsutism, and gingival hyperplasia, while FK has a higher incidence of diabetes mellitus, some types of neurotoxicity (eg, tremor, paraesthesia), diarrhea, and alopecia. Conversion from CyA to FK in ongoing allograft rejection after renal transplantation has been shown to be effective in the early posttransplant period ( 6 months after transplantation). However, tacrolimus rescue therapy was performed in only a small number of patients with late acute rejection or chronic rejection. In our institution, FK was introduced for rescue therapy in 27 renal transplant recipients with late rejection between 1994 and 1996. We analyzed the 5-year outcome of FK rescue therapy in these patients.

Obesity in transplant recipients is a frequent phenomenon but data from body composition analyses in long-term survivors are limited. Body composition and energy metabolism were studied in patients after liver (LTX) and kidney (KTX) transplantation and patients with liver cirrhosis (LCI) or on chronic hemodialysis (HD) and compared to healthy controls.In 42 patients 50.0 mo (median; range 17.1-100.6) after LTX and 30 patients 93.0 mo (31.2-180.1) after KTX as wells as in LCI (n = 39) or HD (n = 10) patients mid-arm muscle and fat area, body cell mass, and phase angle (bioimpedance analysis), and resting energy expenditure (indirect calorimetry, REE(CALO)) were measured.Obesity was more prevalent in LTX (17%) than LCI (3%) and in KTX (27%) than in HD (10%). In LTX and KTX, phase angle was higher than in end-stage disease (LTX 5.6° [4.1-7.2] versus LCI 4.4° [2.9-7.3], P0.001; KTX 5.9° [4.4-8.7] versus HD 4.3° [2.9-6.8]) but was lower in all patient groups than in controls (7.1°; 4.6-8.9; P0.001). In LCI and HD REE(CALO) was higher than predicted, while in LTX and KTX REE(CALO) was not different from predicted REE.Despite excellent graft function, many long-term LTX or KTX survivors exhibit a phenotype of sarcopenic obesity with increased fat but low muscle mass. This abnormal body composition is observed despite normalization of the hypermetabolism found in chronic disease and cannot be explained by overeating. The role of appropriate nutrition and physiotherapy after transplantation merits further investigation.

HE USE of information technology for the improvement of patient care by detecting and informing clinicians about key clinical events has already a long history with numerous successful examples in various areas of medicine. 1,2 Often the success of such systems depends on the feasibility of extracting exact rules from existing comprehensive domain knowledge. Thus the interpretation of laboratory results is wellsuited for support by computer systems if the cut-off between normal and critical values is known. Under this precondition the value of automated alerting systems for improving patient care is well-proven. 3,4 Unfortunately, some medical conditions make it impossible to define a normal range for those parameters that are essential in monitoring the respective condition. For kidney transplant recipients a serum creatinine within the “normal” range is not the norm but an exception. Meanwhile, despite ongoing efforts to develop other methods, serum creatinine remains the most important parameter for the assessment of renal graft function. 5‐7 A rise in serum creatinine corresponds to a deterioration in graft function. The attending physician has to recognize “significant” increases in serum creatinine that warrant further diagnostic measures to exclude or verify an underlying graft rejection which requires immediate therapy to prevent graft damage or loss. Whether a new measurement constitutes a rise can only be determined in relation to at least one previous measurement. Because each patient has an individual range of “usual” creatinine values with an individual size of the “usual” changes between consecutive measurements, the decision whether a rise in creatinine is “significant” still requires experience and intuition. Exact rules that define the properties of a “critical” sequence of creatinine values are not available because the pathophysiology of transplant rejection is still incompletely understood. Simple algorithms or rule-based expert systems are therefore not an option for the development of diagnostic decision support systems for this problem. Instead a technique that is capable of dealing with sequences (time series) of low-frequency measurements with unequal distances in between is required. Experience with assessment of time series already exists in other domains with applications ranging from stock prices over meteorological data to electrocardiograms. These applications work by pattern recognition (ie, a new time series is compared to stored patterns). But traditional algorithms for comparison of time series like Euclidian distance or arithmetic correlation are based on the assumption of equidistant measurements or equal length of the time series. Both assumptions are not met by laboratory results and moreover the measurements from blood sampes are usually rather infrequent. An approach that is not limited by these assumptions is dynamic time warping (DTW) that has been successfully applied to pattern recognition in time series. 8 One of its original application domains is speech recognition, where the matching of spoken words to word templates requires an algorithm that allows for different timing and pronunciation. The result of DTW can be seen as a “warping” of the time axis such that the distance between two time series becomes minimal with respect to a distance function. The cumulative value of this function yields a measure of distance or— because the two concepts are dual—similarity. When an incomplete domain theory prohibits the a priori definition of ideal patterns, it is still possible to compare new problems to historical cases. Case-based reasoning (CBR) is a promising approach with existing applications in a number of fields including medicine. 9 The idea is to mimic the human technique of problem-solving by analogy. To solve a new problem, the system retrieves similar stored cases and uses the solutions associated with these cases to generate a solution for the new problem. The cognitive adequacy to the human expert’s way of solving problems is one of the advantages of CBR in the medical domain. 9 The crucial task in the development of a CBR system is the definition of a similarity measure for the case retrieval. To our knowledge, so far no similarity measure for the comparison of courses of laboratory values by CBR has been established. We perform this study to evaluate whether DTW is a similarity measure that permits the application of CBR to time series of laboratory values, thus improving the assessment of creatinine courses in kidney transplant recipients.

Background Rejection still has a fundamental impact on patient and graft survivals after renal transplantation. Published studies vary widely in their reporting of biopsy-proven acute rejection (BPAR) and non-BPAR rates. We undertook a systematic search of existing publications for reasons explaining this difference. Additionally, we analyzed our own population, which has a clearly defined biopsy strategy, to further investigate the rate of non-BPAR in routine clinical practice. Methods From large, multicenter, randomized, controlled trials investigating immunosuppressive regimens in de novo kidney transplant recipients, we extracted the rates of all reported rejections (“total” rate) versus BPAR. Non-BPAR was defined as the difference between “total” and BPAR. Additional analyses were performed for potential influencing factors, such as year of publication, number, and mean age of patients recruited and impact factor of the journal at the time of publication. We scanned all de novo adult patients undergoing kidney transplantation in our center between 1996 and 2004 for rejection episodes during the first year. Results The median rate of non-BPAR within the first year in 27 papers was 7% (range, 0%– 16.9%). Similarly, the relative proportion of non-BPAR showed large differences. We could not identify potential influencing factors to explain the large variability. Among our population, 136/365 patients (37.3%) experienced acute rejection episodes, with BPAR diagnosed in 90/365 patients (24.7%), yielding an absolute 12.6% rate of non-BPAR. Conclusion Even centers with a well-defined biopsy strategy show a substantial proportion of non-BPAR episodes. Therefore, complete reporting of both BPAR and non-BPAR is important for the proper interpretation of study results.

Hepatitis B (HBV) and hepatitis C (HCV) virus infections are major risk factors affecting long-term morbidity and mortality after renal transplantation. Hepatitis prevalence is subject to geographical variations.To compare and analyze the geographical prevalence, risk factors and impact of HBV and HCV infection in multinational cohorts of renal transplant recipients.From 1989 - 2002, data on 12,856 kidney transplant recipients in 37 countries were collected within the prospective MOST (Multinational Observational Study in Transplantation). Subgroup analyses of hepatitis-related prevalence, risk factors and impact were conducted on patients whose HBV and HCV status was available at time of transplantation. Countries were substratified according to population prevalence ofor = 5% HBV oror = 10% HCV.The prevalence of HBV was 2.9%, of HCV 8.7% and of HBV together with HCV 0.4%. Risk factors for hepatitis infection in renal transplant recipients were long dialysis time, retransplantation and blood transfusions. At each study endpoint up to 5 years after transplantation, no significant differences in graft function were observed, although the 1-year acute rejection rate tended to be lower in HCV+ patients. At 5 years post-transplant, there were no differences between the subgroups and regions regarding infections, post-transplant diabetes mellitus or malignancies including PTLD.Overall, HCV infections are more prevalent than HBV. Despite large geographical differences in prevalence, HBV and HCV status did not appear to have a significant impact on renal graft function, infections, malignancies and post-transplant diabetes mellitus up to 5 years after renal transplantation throughout the MOST countries.

Summary Kidneys obtained from donors after cardiac death (DCD) are known to have higher rates of primary nonfunction and delayed graft function (DGF) than heart beating cadaveric donor (CAD) kidneys, but little is known about long-term function of DCD grafts that survive to 1 year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1 year, this study analyzed data collected from 326 DCD graft recipients and 340 CAD-matched controls enrolled in a prospective, multinational, observational study – Neoral®-MOST (Multinational Observational Study in Transplantation) (Novartis, Basel, Switzerland). No differences were found in the demographics or immunosuppression between the two groups. All patients received a Neoral®-based immunosuppressive regimen. Donors after cardiac death graft recipients had a higher incidence of DGF (40% vs. 27% CAD; P

Introduction. Mycophenolate mofetil (MMF) has greatly reduced the risk of acute rejection episodes (ARE) after renal transplantation, but dose reductions/withdrawals could jeopardize long-term results. Methods. The MOST database of de novo patients treated with MMF at month 1 and functioning grafts at month 12 were divided into 2 groups: groups 1, 2 g MMF at month 1 and month 12; and group 2, 2 g MMF at month 1 but MMF

To investigate possible interactions of the novel immunosuppressant everolimus with cyclosporine, a multicenter, randomized, double-blind, placebo-controlled, dose-escalating phase I study was performed. Everolimus regimens (0.75-10 mg/d) were administered for 28 days to stable renal allograft recipients receiving the microemulsion form of cyclosporine. Steady-state cyclosporine profiles were assessed at baseline on day 0 (cyclosporine alone) and on day 21 with everolimus on steady state. By day 21, mean dose-normalized cyclosporine AUC 0 - 1 2 increased by 15% in patients receiving placebo. In everolimus-treated patients, mean increases in cyclosporine AUC 0 - 1 2 ranged from 7% to 43%, which were not significantly different across all dosing cohorts including placebo. Linear regression of everolimus AUC on day 21 versus the increase in cyclosporine AUC 0 - 1 2 yielded a slope not significantly different from a horizontal line (P = ns). In conclusion, these results suggest that steady-state everolimus exposure over the wide range assessed in this study did not affect steady-state cyclosporine pharmacokinetics.

Introduction We collected data from kidney recipients with a functioning graft at German kidney transplant centers in order to analyze the efficacy of various cyclosporine (CsA)-based immunosuppressive strategies, the effects of different perioperative and maintenance regimens, and the impact of donor source on clinical outcome. Methods As part of the ongoing prospective Multinational Observational Study in Transplantation (MOST), data for both prospective and retrospective analysis were collected from kidney recipients over 18 years bearing a functioning graft that was transplanted at 21 German kidney transplant centers between 1987 and 2002. Results Data from 1223 renal graft recipients, including their CsA-based immunosuppressive regimens, were stratified as: 402 de novo patients (median 6.8 months posttransplant) and 821 patients on maintenance therapy (median 71 months posttransplant). Triple regimens with CsA + mycophenolate mofetil (MMF) + steroids (Ste) currently comprise the major perioperative immunosuppressive strategies in Germany (de novo 65%). IL-2 receptor antagonist (IL-2Ra) use is increasing (de novo 18%, maintenance 4%), while mono and dual regimen use de novo is declining (de novo 4%, maintenance 20%). Among 689 patients transplanted between 1987 and 2002 with outcome data, the mean incidence of acute rejection during the first posttransplant year was 21.6%. Rejection rates on initial therapy with CsA + MMF + Ste ± antibodies ( n = 517) averaged 17.8%. Conclusions Between 1987 and 2002, CsA-based immunosuppression combined with MMF and Ste became the most commonly used strategy for both initial and maintenance therapy after kidney transplantation in Germany, yielding the low acute rejection rates particularly when combined with IL-2Ra.

Most attempts to predict early kidney allograft loss are based on the patient and donor characteristics at baseline. We investigated how the early posttransplant creatinine course compares to baseline information in the prediction of kidney graft failure within the first 4 years after transplantation. Two approaches to create a prediction rule for early graft failure were evaluated. First, the whole data set was analysed using a decision-tree building software. The software, rpart, builds classification or regression models; the resulting models can be represented as binary trees. In the second approach, a Hill-Climbing algorithm was applied to define cut-off values for the median creatinine level and creatinine slope in the period between day 60 and 180 after transplantation. Of the 497 patients available for analysis, 52 (10.5%) experienced an early graft loss (graft loss within the first 4 years after transplantation). From the rpart algorithm, a single decision criterion emerged: Median creatinine value on days 60 to 180 higher than 3.1 mg/dL predicts early graft failure (accuracy 95.2% but sensitivity = 42.3%). In contrast, the Hill-Climbing algorithm delivered a cut-off of 1.8 mg/dL for the median creatinine level and a cut-off of 0.3 mg/dL per month for the creatinine slope (sensitivity = 69.5% and specificity 79.0%). Prediction rules based on median and slope of creatinine levels in the first half year after transplantation allow early identification of patients who are at risk of loosing their graft early after transplantation. These patients may benefit from therapeutic measures tailored for this high-risk setting.

The immune system undergoes a complex and continuous remodeling as the result of aging. These changes have a major impact on allorecognition and alloresponse. In addition, immunosuppression in the elderly is challenging as a consequence of an increased incidence of associated comorbidities and altered pharmacokinetics. Both advanced donor and recipient age should be considered independent risk factors for poor patient and graft survival rates, albeit acting in a synergistic manner. Consequently, modifications of the immune system because of aging may request an age-adapted allocation and immunosuppression in parallel with close patient monitoring. Interventions to selectively target changes associated with the senescence process seem to be promising therapeutic strategies to improve transplantation outcome. Here, we are going to review the immunologic changes associated with the aging process relevant for transplantation and their impact on immunosuppressive protocols, organ allocation policies, and transplantation outcome.

Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 ± 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61–0.89; p < 0.004). IMPDH activity above the cut-off value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Conclusion: Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.

Background. Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model. Methods. We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate. Results. A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P

Sirolimus (SRL) is an alternative to calcineurin inhibitors (CNI) in kidney transplant patients with chronic allograft dysfunction. Methods: 33 patients were converted to SRL receiving a single loading dose of 15 mg and initial maintenance dose of 5 mg/day. CNI was reduced by 50% on day 1 and tapered during 4–6 weeks after achieving SRL target (8–12 ng/ml). Concomitant immunosuppressive therapy remained unchanged. Results: Patient survival was 100% and graft survival was 85% after 1 year. Mean SRL dose decreased from 5 mg/day initially to 2.8 ± 1.3 mg/day. SRL dose-adjusted trough concentration did not change significantly over time. Dose-adjusted trough concentrations of CNI before conversion and of SRL after 1 year did not correlate. We observed no severe infections, however, one rejection Banff Ia occurred 7 months after conversion associated with subtherapeutic SRL trough concentration. Adverse events were anemia, dyslipidemia, epistaxis, stomatitis, and bronchiolitis obliterans which occurred mainly during the conversion phase. Conclusion: Overlapping conversion from CNI to SRL in chronic kidney transplant patients is possible and safe. However, further studies are necessary with shorter overlap and lower SRL loading and initial maintenance dose which might lead to a decrease in the high number of adverse events in the overlap phase.

Enteric-coated mycophenolate sodium (EC-MPS; myfortic, Novartis Pharma AG) is an advanced formulation delivering mycophenolic acid (MPA). EC-MPS was designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until reaching the small intestine. At a dose of 720 mg, EC-MPS exhibits equivalent MPA exposure (area under the concentration curve [AUC]) and maximal MPA concentration (C(max)) to mycophenolate mofetil (MMF; CellCept, Roche AG) 1000 mg. The time to maximal MPA concentration (T(max)) for EC-MPS is delayed relative to that for MMF, consistent with a functioning enteric coating. EC-MPS 720 mg b.i.d. has demonstrated therapeutic equivalence to MMF 1000 mg b.i.d. in renal transplant patients. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients. Furthermore, studies have confirmed that maintenance patients can be safely converted from MMF to EC-MPS with no compromise of efficacy or safety. EC-MPS therefore presents physicians and patients with a valid alternative MPA therapy with a comparable efficacy and safety profile to MMF.

Introduction. Laparoscopic living donor nephrectomy (LDN) offers multiple advantages to the donor. Since 1999 LDN has become the only surgical approach for living kidney donation in our department. To our knowledge a donor health-related quality of life (QoL) has not yet been performed with standardized and validated questionnaires to compare laparoscopic with open nephrectomy. We therefore performed a study with two questionnaires (SF-36/GBB-24) and one set of open questions for all donors in our department. Methods. Questionnaires were sent out to all donors between 1983 and 2001 with at least a 1-year follow-up. To exclude a bias a maximum response rate was sought; donors who did not answer were recontacted as well as their recipients or their physicians to motivate them for participation. Results. The response rate was (89.8%). Except for less limb pain in the laparoscopy group, no difference could be detected for donors QoL with respect to the surgical method. Willingness to donate again was not affected by the surgical method. Nevertheless if asked again today, most donors want laparoscopic kidney retrieval. Conclusions. Donors health-related QoL is not affected by the surgical method when queried retrospectively. Nevertheless, most donors today would favor laparoscopy, if they could chose again. How laparoscopy affects a reluctant donor to step forward must be determined in a prospective study.