Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Operational tolerance in kidney transplantation and associated biomarkers.

In the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients - i.e. patients who maintain allograft function in the absence of immunosuppression - are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, non-antigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective - identifying tolerant patients, enabling tolerance trials - as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.

Thrombophilic factors do not predict outcomes in renal transplant recipients under prophylactic acetylsalicylic acid.

A cohort of recipients of renal transplant after 2000 (N=310) was prospectively screened on the day of transplantation and 1 month later for a panel of 11 thrombophilic factors to assess their effect on posttransplant outcomes. All patients received prophylactic acetylsalicylic acid, started before transplantation. The rate of thromboembolic events or acute rejection episodes during the first posttransplant year (primary composite endpoint) was 16.7% among patients free of thrombophilic factor (N=60) and 17.2% in those with >or=1 thrombophilic factor (N=250) (p>0.99). The incidence of the primary endpoint was similar among patients free of thrombophilic factors and those with >or=2 (N=135), or >or=3 (N=53) factors (16.3% and 15.1% respectively; p=1) and in patients who remained thrombophilic at 1 month (15.7%; p=0.84). None of the individual thrombophilic factor present at the day of transplantation was associated with the primary endpoint. The incidence of cardiovascular events at 1-year, serum creatinine at 1-year, 4-year actuarial graft and patient survival were not influenced by the presence of >or=1 thrombophilic factor at baseline (p=NS). In conclusion, the presence of thrombophilic factors does not influence thromboembolic events, acute rejection, graft or patient survival in patients transplanted after 2000 and receiving prophylactic acetylsalicylic acid.

[Experience about more than 2000 renal transplantations at the university of Brussels]. / A propos de 2000 greffes rénales a l'U.L.B.: le parcours d'un patient transplanté rénal en 2007.

Since 1965, more than 2000 renal transplantations (including more than 100 living-donor transplantations) have been performed at the University of Brussels. An end-stage renal disease patient candidate to renal transplantation will be therefore followed from his enrolment on the waiting list to the long-term post-transplant period. Improvement in the outcome of renal transplantation is achieved due to better knowledge in many fields of medicine, such as immunology, infectious disease, metabolic diseases (hyperlipemia, diabetes mellitus), pharmacology, use of immunosuppressive regimen, a more adequate cardiovascular prevention and treatment. If the best results were achieved with kidneys from living donors, the graft survival rate at the University of Brussels was nearly 80% for the last period (2000-2006). Unfortunately, renal transplantation cannot cure certain comorbid conditions and even may promote them: infectious diseases, neoplasia, metabolic disorders (e.a diabetes mellitus, hyperlipemia). Many efforts have to be done to develop less toxic and more immune selective therapeutic strategies. Living donation and extension of the pool of cadaveric donors will reduce the length of time spent on the waiting list and will significantly impact on mortality and morbidity after kidney transplantation.

Conversion from tacrolimus to cyclosporin is associated with a significant improvement of glucose metabolism in patients with new-onset diabetes mellitus after renal transplantation.

BACKGROUND: The incidence of new-onset posttransplant diabetes mellitus (PTDM) is increased in renal transplant patients treated with tacrolimus. METHODS: We retrospectively analyzed fasting plasma glucose and HbA1c levels as well as the dose of glucose-lowering agents in 34 renal transplant patients converted from tacrolimus to cyclosporine (CsA) for PTDM. Diabetes was defined according to current guidelines as repeated fasting plasma glucose (FPG) levels > or =126 mg/dL. RESULTS: At conversion, 11 patients received insulin, 5 received oral agents, and 18 had no glucose-lowering therapy. Fasting plasma glucose levels decreased from 146 +/- 64 mg/dL at conversion to 111 +/- 26 mg/dL at 3 months and 104 +/- 21 mg/dL at 12 months (P < .001). HbA1c levels decreased from 6.8 +/- 0.8% at conversion to 6.0 +/- 0.6% at 12 months (P = .001). Insulin was stopped in 3, the dose reduced in 7, and remained stable in 1 of the patients. The average daily insulin dose among these patients was reduced from 31 +/- 17 units at conversion to 13 +/- 12 units at 12 months (P < .05). There was no significant change in the number of patients treated with oral glucose-lowering agents. Diabetes reversed (fasting plasma glucose < or = 125 mg/dL without glucose-lowering therapy) in 44% (95% confidence interval, 23% to 64%) of patients during the first year after conversion (P < .001). Graft function, blood pressure, and lipid levels remained stable after conversion but the proportion of patients receiving lipid-lowering therapy increased from 18% to 49% (P < .01). CONCLUSIONS: Conversion from tacrolimus to CsA for PTDM was associated with a marked improvement in glucose metabolism and frequent reversal of diabetes.

The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature.

In order to clarify the role of mitomycin (MMC) in the treatment of NSCLC, we performed a systematic review of the literature and qualitatively assessed the selected studies using the ELCWP and Chalmers scales. 5 trials (202 patients) assessed the activity of MMC as single-agent chemotherapy in NSCLC. The overall response rate was 25% (95% Cl 19-31). In 10 randomized phase III trials (1769 patients), we studied the role of MMC in combination therapy. A meta-analysis, based on the available published data, failed to show any survival advantage of the MMC containing regimens (hazard ratio = 0.95; 95% Cl 0.83-1.10). Finally, 4 eligible trials (139 patients) assessed the activity of MMC regimens as salvage therapy, 3 in combination with vindesine and one with cisplatin and vinblastine. The overall response rate for the MMC-vindesine regimen was 10.5% (95% Cl 1.7-19.4). In conclusion, MMC is an active drug for NSCLC but does not improve survival when combined with other active drugs, particularly cisplatin. Its use for salvage therapy appears to be associated with marginal activity only.

Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis.

The role of the anti-apoptotic protein Bcl-2 in lung cancer remains controversial. In order to clarify its impact on survival in small and non-small cell lung cancer (NSCLC), we performed a systematic review of the literature. Trials were selected for further analysis if they provided an independent assessment of Bcl-2 in lung cancer and reported analysis of survival data according to Bcl-2 status. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a quality scale designed by the European Lung Cancer Working Party (including study design, laboratory methods and analysis). Of 28 studies, 11 identified Bcl-2 expression as a favourable prognostic factor and three linked it with poor prognosis; 14 trials were not significant. No differences in scoring measurement were detected between the studies, except that significantly higher scores were found in the trials with the largest sample sizes. Assessments of methodology and of laboratory technique were made independently of the conclusion of the trials. A total of 25 trials, comprising 3370 patients, provided sufficient information for the meta-analysis. The studies were categorised according to histology, disease stage and laboratory technique. The combined hazard ratio (HR) suggested that a positive Bcl-2 status has a favourable impact on survival: 0.70 (95% confidence interval 0.57-0.86) in seven studies on stages I-II NSCLC; 0.50 (0.39-0.65) in eight studies on surgically resected NSCLC; 0.91 (0.76-1.10) in six studies on any stage NSCLC; 0.57 (0.41-0.78) in five studies on squamous cell cancer; 0.75 (0.61-0.93) and 0.71 (0.61-0.83) respectively for five studies detecting Bcl-2 by immunohistochemistry with Ab clone 100 and for 13 studies assessing Bcl-2 with Ab clone 124; 0.92 (0.73-1.16) for four studies on small cell lung cancer; 1.26 (0.58-2.72) for three studies on neuroendocrine tumours. In NSCLC, Bcl-2 expression was associated with a better prognosis. The data on Bcl-2 expression in small cell lung cancer were insufficient to assess its prognostic value.