[Diagnosis and management of renal allograft rejection]. / Diagnostic et prise en charge thérapeutique du rejet en transplantation rénale.

Renal allograft rejection involves many mechanisms of innate and adaptive immunity, responsible for parenchymal inflammatory lesions that negatively impact the long-term outcomes of the renal allograft. The heterogeneous presentations of rejections in terms of clinical, biological and histological aspects make them difficult to manage in daily clinical practice. Indeed, current therapeutic strategies are disappointing in term of long-term outcomes, including graft survival. In this article, we will discuss the main effector mechanisms of rejection and their histological classification, as well as the existing treatments and those currently under evaluation.

: Le rejet du greffon rénal fait intervenir de nombreux mécanismes de l'immunité innée et adaptative, responsables de lésions inflammatoires parenchymateuses impactant négativement le devenir au long cours du greffon rénal. La grande hétérogénéité dans la présentation clinique, biologique et histologique des rejets de greffe en fait des entités difficiles à prendre en charge en pratique clinique quotidienne. En effet, les stratégies thérapeutiques actuelles montrent des résultats assez décevants pour le traitement des rejets, ce qui a comme conséquence une diminution significative de la survie des greffons. Nous aborderons dans cet article les principaux mécanismes effecteurs des rejets, leur classification histologique ainsi que les traitements existants et en cours de validation.

[18F]FDG PET/CT imaging disproves renal allograft acute rejection in kidney transplant recipients with acute kidney dysfunction: a validation cohort.

PURPOSE: [18F]FDG PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. METHODS: We prospectively performed 86 [18F]FDG PET/CT in 79 adult KTRs who underwent per-cause transplant biopsy for suspected AR. Biopsy-proven polyoma BK nephropathies (n = 7) were excluded. PET/CT was performed 192 ± 18 min after administration of 254.4 ± 30.4 MBq of [18F]FDG. The SUVmean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey's studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate "AR" from non-pathological ("normal" + "borderline") conditions. RESULTS: The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m2. Biopsies were categorized in 4 groups: "normal" (n = 54), "borderline" (n = 9), "AR" (n = 14), or "others" (n = 2). The median [min; max] mSUVmean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12], and 1.84 [1.57; 2.12] in "normal," "borderline," "AR," and "others" groups, respectively. ANOVA demonstrated a significant difference of mSUVmean among groups (F = 13.25, p < 0.0001). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively. CONCLUSION: [18F]FDG PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.

Fluorodeoxyglucose F(18) Positron Emission Tomography Coupled With Computed Tomography in Suspected Acute Renal Allograft Rejection.

Management of kidney transplant recipients (KTRs) with suspected acute rejection (AR) ultimately relies on kidney biopsy; however, noninvasive tests predicting nonrejection would help avoid unnecessary biopsy. AR involves recruitment of leukocytes avid for fluorodeoxyglucose F(18) ((18) F-FDG), thus (18) F-FDG positron emission tomography (PET) coupled with computed tomography (CT) may noninvasively distinguish nonrejection from AR. From January 2013 to February 2015, we prospectively performed 32 (18) F-FDG PET/CT scans in 31 adult KTRs with suspected AR who underwent transplant biopsy. Biopsies were categorized into four groups: normal (n = 8), borderline (n = 10), AR (n = 8), or other (n = 6, including 3 with polyoma BK nephropathy). Estimated GFR was comparable in all groups. PET/CT was performed 201 ± 18 minutes after administration of 3.2 ± 0.2 MBq/kg of (18) F-FDG, before any immunosuppression change. Mean standard uptake values (SUVs) of both upper and lower renal poles were measured. Mean SUVs reached 1.5 ± 0.2, 1.6 ± 0.3, 2.9 ± 0.8, and 2.2 ± 1.2 for the normal, borderline, AR, and other groups, respectively. One-way analysis of variance demonstrated a significant difference of mean SUVs among groups. A positive correlation between mean SUV and acute composite Banff score was found, with r(2) = 0.49. The area under the receiver operating characteristic curve was 0.93, with 100% sensitivity and 50% specificity using a mean SUV threshold of 1.6. In conclusion, (18) F-FDG PET/CT may help noninvasively prevent avoidable transplant biopsies in KTRs with suspected AR.

A more than 20% increase in deceased-donor organ procurement and transplantation activity after the use of donation after circulatory death.

BACKGROUND: Organ procurement and transplant activity from controlled donation after circulatory death (DCD) was evaluated over an 11-year period to determine whether this program influenced the transplant and donation after brain death (DBD) activities. MATERIAL AND METHODS: Deceased donor (DD) procurement and transplant data were prospectively collected in a local database for retrospective review. RESULTS: There was an increasing trend in the potential and actual DCD numbers over time. DCD accounted for 21.9% of the DD pool over 11 years, representing 23.7% and 24.2% of the DD kidney and liver pool, respectively. The DBD retrieval and transplant activity increased during the same time period. Mean conversion rate turning potential into effective DCD donors was 47.3%. Mean DCD donor age was 54.6 years (range, 3-83). Donors ≥60 years old made up 44.1% of the DCD pool. Among referred donors, reasons for nondonation were medical contraindications (33.7%) and family refusals (19%). Mean organ yield per DCD donor was 2.3 organs. Mean total procurement warm ischemia time was 19.5 minutes (range, 6-39). In 2012, 17 DCD and 37 DBD procurements were performed in the Liege region, which has slightly >1 million inhabitants. CONCLUSIONS: This DCD program implementation enlarged the DD pool and did not compromise the development of DBD programs. The potential DCD pool might be underused and seems to be a valuable organ donor source.

Delayed graft function does not harm the future of donation-after-cardiac death in kidney transplantation.

INTRODUCTION: Delayed graft function (DGF) occurs more frequently in kidney transplants from donation after cardiac death (DCD) than from donation after brain death (DBD). We investigated the effect of DGF on posttransplantation outcomes among grafts from controlled DCD kidneys. PATIENTS AND METHODS: This single-center retrospective study recruited 80 controlled DCD kidneys transplanted from January 2005 to December 2011. Mean patient follow-up was 28.5 months. RESULTS: There were no primary nonfunction grafts; the DGF rate was 35.5%. Overall graft survival rates between groups with versus without DGF were 92.4% and 95.2% at 1 year, 92.4% and 87.1% at 3 years, and 84.7% and 87.1% at 5 years, respectively (P = not significant (NS)). Patients with versus without DGF showed the same survival rates at the corresponding time 92.4% vs 97.2%, 92.4% vs 93.9%, and 84.7% vs 93.9% (P = NS). Estimated glomerular filtration rate was significantly lower in the DGF compared with the non-DGF group at hospital discharge (29 vs 42 mL/min; P = .00) and at 6 months posttransplantation (46 vs 52 mL/min; P = .04), but the difference disappeared thereafter: 47 vs 52 mL/min at 1 year, 50 vs 48 mL/min at 3 years, and 54 vs 53 mL/min at 5 years (P = NS). DGF did not increase the risk of an acute rejection episode (29.6% vs 30.6%; P = NS) or rate of surgical complications (33.3% vs 26.5%; P = NS). However, DGF prolonged significantly the length of hospitalization in the DGF versus the non- DGF group (18.9 vs 13 days; P = .00). Donor body mass index (BMI) ≥ 30 kg/m(2), recipient BMI ≥30 kg/m(2), and pretransplantation dialysis duration increased the risk of DGF upon multivariate logistic regression analysis. CONCLUSIONS: Apart from the longer hospital stay, DGF had no deleterious impact on the future of kidney allografts from controlled DCD, which showed comparable graft and patient survivals, renal function, rejection rates, and surgical complications as a group without DGF. Therefore, DGF should no longer be considered to be a medical barrier to the use of kidney grafts from controlled DCD.

Contribution of donors after cardiac death to the deceased donor pool: 2002 to 2009 University of Liege experience.

OBJECTIVE: In this study, we have evaluated the organ procurement and transplantation activity from donors after cardiac death (DCD) at our institution over an 8-year period. Our aim was to determine whether this program influenced transplantation programs, or donation after brain death (DBD) activity. METHODS: We prospectively collected our procurement and transplantation statistics in a database for retrospective review. RESULTS: We observed an increasing trend in potential and actual DCD number. The mean conversion rate turning potential into effective donors was 58.1%. DCD accounted for 16.6% of the deceased donor (DD) pool over 8 years. The mean age for effective DCD donors was 53.9 years (range, 3-79). Among the effective donors, 63.3% (n = 31) came from the transplant center and 36.7% (n = 18) were referred from collaborative hospitals. All donors were Maastricht III category. The number of kidney and liver transplants using DCD sources tended to increase. DCD kidney transplants represented 10.8% of the DD kidney pool and DCD liver transplants made up 13.9% of the DD liver pool over 8 years. The DBD program activity increased in the same time period. In 2009, 17 DCD and 33 DBD procurements were performed in a region with a little >1 million inhabitants. CONCLUSION: The establishment of a DCD program in our institution enlarged the donor pool and did not compromise the development of the DBD program. In our experience, DCD are a valuable source for abdominal organ transplantation.

Renal transplantation from living related donors: a single center experience in Viet Nam.

INTRODUCTION: End-stage renal disease is a major public health problem in Viet Nam. A cooperative project between the University of Liège, Belgium, and the University of Medicine Pham Ngoc Thach, Ho Chi Minh City, Viet Nam, has permitted the establishment of an autonomous program of renal transplantation from living-related donors at the Peoples' Hospital No 115. The aim of this paper was to report the primary results of the project and to draw conclusions for the future. PATIENTS AND METHODS: From January 2004 to July 2008, we performed 33 living-related renal transplantations. Mean ages of donors and recipients were 31.8 ± 9.5 and 41.6 ± 13.5 years, respectively. Laparoscopic nephrectomy was performed in 6 donors. The immunosuppressive regimen consisted of three drugs associated with induction therapy using anti-interleukin-2 receptor monoclonal antibody. RESULTS: The 33 donors are in good health at follow-up. Four developed major intra- or postoperative hemorrhage necessitating transfusion, with a surgical re-exploration in 1 donor. Wound infection occurred in 2 donors. Posttransplant recipient and graft survivals at 1 versus 3 years were 82% and 73% versus 82% and 65%, respectively. Eight recipients presented 13 biopsy-proven acute rejection episodes that were reversible in 7, but 1 patient lost his graft due to an irreversible rejection. Two recipients developed cancer. CONCLUSIONS: These initial results have encouraged us to continue the program of renal transplantation from living-related donors. However, they also pointed out the need to develop other donor sources.

Results of kidney transplantation from donors after cardiac death.

Confronting the organ donor shortage, many transplant centers around the world increasingly use donors after cardiac death (DCD). Over the past 20 years, follow-up studies in kidney recipients comparing DCD and donors after brain death (DBD) have shown comparable long-term graft function and survival. As a consequence, DCD programs should be continued and expanded, for these donors constitute a potential solution to the imbalance between the numbers of end-stage kidney disease patients on waiting lists versus available kidney grafts. DCD kidneys do not necessarily signify suboptimal grafts; they may merit to be allocated the same as DBD grafts.

[Monoclonal antibodies in renal transplantation]. / Les anticorps monoclonaux en transplantation rénale.

Renal transplantation is the best treatment for end-stage renal disease, but requires efficient immunosuppressive therapy. The latter has evolved over recent years with the development of more powerful drugs and of monoclonal antibodies with very specific target. The first monoclonal antibodies, acting against the interleukin 2 receptor, named basiliximab and daclizumab, have showed an excellent tolerance profile and efficacy to reduce acute graft rejection. However, in spite of these properties, the development of delayed graft function or the graft and patient survivals at 1 year were not modified by the use of such specific treatment. One potential advantage could yet be a decreasing need for corticosteroids and sometimes calcineurin inhibitors which could provide some long term benefits for the renal graft, but also the patient. Alemtuzumab, another monoclonal antibody, aimed at the membrane glycoprotein CD52, can also decrease the incidence of acute rejection and the depth of the required immunosuppressive therapy. Other antibodies are still in development with some interesting preliminary results which however demand confirmation in larger studies.

[Polyomavirus BK infection in renal transplant recipients]. / Infection à polyomavirus BK après transplantation renale.

Beside acute rejection or immunosuppressive therapy toxicity, infection by Polyomavirus BK, usually not aggressive in immunoactive patients, has emerged as an important factor affecting graft function in renal transplant recipients. Indeed, one of the most important complications of BK infection is nephropathy. Viral replication in the urinary tract as assessed by the presence of "decoy cells", or by a positive PCR for BK virus has been detected in up to half of the recipients but only 5% will present nephropathy which is usually the only sign. The most common risk factors for this emerging new cause are new immunosuppressive drugs and rejection episodes. The gold standard to diagnose BK nephropathy is immunohistochemical staining for large T antigen in graft biopsy specimens. Urine cytology examination and DNA BK PCR are used as a screening test. The prognosis in BK nephropathy has been considered to be poor. The early reduction of immunosuppression can improve the prognosis and perhaps also cidofovir or leflunomide use.

[Pancreas transplantation in the management of diabetes]. / La place de la transplantation pancréatique dans le traitement du diabète.

Pancreas transplantation has now become an established option in the treatment of diabetic complications. It normalizes glucose metabolism, prevents, stabilizes and improves the evolution of diabetes-associated lesions. Improvements in surgical procedure and in immunosuppression have better defined its indications. Combined kidney-pancreas transplantation appears today as the best treatment for the diabetic patient with end stage renal disease. Isolated pancreas transplantation is reserved to non-uremic patients with severe diabetic complications or with hyperlabile glycaemic control and severe impairment of quality of life.

Protein kinase- and staurosporine-dependent induction of neurite outgrowth and plasminogen activator activity in PC12 cells.

We analysed how interactions between protein kinase-dependent intracellular signalling pathways were implicated in the control of the production of tissue-type plasminogen activator (tPA) and the generation of neurite outgrowth by PC12 cells. To that aim, cells were treated with agents that interact with the trk receptor and with protein kinases A and C. Nerve growth factor induced only the formation of large neurites. The release of the protease and the production of short neurite outgrowth were found to be protein-kinase-A-dependent events that could be enhanced by simultaneous activation of protein kinase C with phorbol ester. At high concentration, staurosporine, a nonselective inhibitor of protein kinases, induced the production of short neurites and mimicked the protein-kinase-A-dependent effect on tPA release. Such a response was not observed with K-252a, an analogue of staurosporine devoid of neurite-outgrowth-promoting activity. The responses to protein kinase A stimulation and the addition of staurosporine, although similar, seemed to occur through an activation of distinct, yet interacting, signalling pathways. In conclusion, tPA release and large neurite outgrowth from PC12 cells are controlled by parallel, albeit interacting, pathways, suggesting that these two potentially antagonistic events in PC12 cell differentiation can be modulated in a concerted way or independently of each other, depending on the activity of several protein kinases.