Weight gain in long-term survivors of kidney or liver transplantation--another paradigm of sarcopenic obesity?

OBJECTIVE: 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. METHODS: 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. RESULTS: 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], P < 0.001; 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; P < 0.001). In LCI and HD REE(CALO) was higher than predicted, while in LTX and KTX REE(CALO) was not different from predicted REE. CONCLUSIONS: 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.

Determinants of knowledge gain in evidence-based medicine short courses: an international assessment.

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.

Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria.

The aim was to evaluate long-term graft survival and function after conversion to sirolimus (SRL) for chronic calcineurin inhibitor (CNI) toxicity and the predictive value of baseline proteinuria. This is a follow-up conversion study of 59 renal transplant patients with deteriorating graft function and histologic signs of CNI toxicity. Previously, baseline proteinuria <800 mg/day was identified as a short-term predictor for successful conversion. Follow-up was 5.3 +/- 0.8 (3.7-6.8) years. Patient survival was 88%, graft survival 38%. Creatinine clearance at the last follow-up was 33.7 +/- 14 ml/min, proteinuria 826 +/- 860mg/day. Baseline proteinuria <800 mg/day was associated with better graft survival. In a cox analysis including proteinuria >800 mg, glomerular filtration rate, age at conversion, chronic Banff score at conversion and time after transplantation at conversion, higher proteinuria was associated with a relative risk of graft loss of 3.98. Prognosis of chronic allograft dysfunction is poor. However, conversion to SRL remains an option for patients with low baseline proteinuria, which can slow down deterioration of graft function during a follow-up period of up to 5 years.

Follow-up after renal transplantation with organs from donors after cardiac death.

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 < 0.001). One year glomerular filtration rate (GFR) and GFR-decline after 1 year were similar in DCD and CAD recipients (GFR 56 ml/min DCD vs. 59 ml/min CAD; GFR-decline -1.3 ml/min DCD vs. -1.4 ml/min CAD; P = not significant). Multifactorial analyses confirmed that GFR at 1 year was significantly influenced by donor age and gender, DGF, and acute rejection; however, DCD status was not an independent risk factor in cyclosporine-treated patients with grafts that had functioned for at least 1 year.

Reporting of rejection after renal transplantation in large immunosuppressive trials: biopsy-proven, clinical, presumed, or treated rejection?

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%). Efficacy 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.

Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant.

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.

Influence of everolimus on steady-state pharmacokinetics of cyclosporine in maintenance renal transplant patients.

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 AUC0-12 increased by 15% in patients receiving placebo. In everolimus-treated patients, mean increases in cyclosporine AUC0-12 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 AUC0-12 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.

Limitations of C2 monitoring in renal transplant recipients.

BACKGROUND: 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. METHODS: 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. RESULTS: Patients with rejection and patients with CsA nephrotoxicity had lower C(2) (P = NS) and absorption (P<0.05 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) levels <800 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). CONCLUSIONS: 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.

Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.

BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Age and immune response in organ transplantation.

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.

Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation.

UNLABELLED: 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.

Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction.

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long-term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12-15 mg SRL once, then 4-5 mg/day, target trough level 8-12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1-2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 +/- 0.75 to 2.22 +/- 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 +/- 1.02 to 4.44 +/- 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 +/- 516 vs. 1532 +/- 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 +/- 0.5 vs. 1.9 +/- 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 +/- 0.7 vs. 1.7 +/- 0.7; p = 0.048) and number of acute rejections before conversion (0.73 +/- 0.69 vs. 1.27 +/- 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.

No association between renin-angiotensin system gene polymorphisms and early and long-term allograft dysfunction in kidney transplant recipients.

BACKGROUND: Genes determining the activity of the renin-angiotensin system (RAS) may be alloantigen-independent factors influencing kidney allograft function. We determined if gene polymorphisms of the RAS are associated with early and long-term post-transplantation 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 long-term graft dysfunction.

Integrating an evidence-based medicine rotation into an internal medicine residency program.

PURPOSE: To measure the impact of a resident focused evidence-based medicine (EBM) educational intervention on EBM knowledge of residents and students, to assess its feasibility, and to evaluate residents' attitudes regarding this rotation. METHOD: In 2002, based on the EBM user and EBM practitioner model, the authors designed the EBM elective rotation and conducted a controlled trial of its implementation in the internal medicine residency program in three teaching hospitals affiliated with the University at Buffalo, New York. The intervention group (one hospital, 17 medical students and residents) received a multifaceted intervention. In the control group (two hospitals, 23 medical students and residents), there was no curriculum change. The effectiveness in a pre- and post-test was assessed using the English version of the Berlin Questionnaire. A survey of all internal medicine residents (n = 119) was conducted to evaluate their attitudes toward the EBM elective rotation. RESULTS: In the intervention group, knowledge improved slightly, but not significantly (.71 on a scale ranging from 0-15 on the Berlin questionnaire, p =.3). The mean score in the control group decreased significantly (1.65, p =.005). The difference in change scores between the two groups was significant even after adjustment for covariates (2.52, p =.006). Residents (response rate 83%) had positive attitudes regarding the rotation. CONCLUSION: An EBM elective rotation was successfully integrated into a residency program. This multifaceted educational approach with an "on-the-ward" EBM resident, may improve the EBM knowledge and skills of targeted students and residents.

Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients.

BACKGROUND: Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican, RAD) is currently in clinical development to address this issue. METHODS: The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating 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 = 44) or placebo (n = 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 C(max). 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.

Sirolimus dosage during and after conversion from calcineurin inhibitor therapy to sirolimus in chronic kidney transplant patients.

UNLABELLED: 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.

Review of the immunosuppressant enteric-coated mycophenolate sodium.

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.

Reports of large immunosuppression trials in kidney transplantation: room for improvement.

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.