Fanny Buron

Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation

Although cold ischemia time has been widely studied in renal transplantation area, there is no consensus on its precise relationship with the transplantation outcomes. To study this, we sampled data from 3839 adult recipients of a first heart-beating deceased donor kidney transplanted between 2000 and 2011 within the French observational multicentric prospective DIVAT cohort. A Cox model was used to assess the relationship between cold ischemia time and death-censored graft survival or patient survival by using piecewise log-linear function. There was a significant proportional increase in the risk of graft failure for each additional hour of cold ischemia time (hazard ratio, 1.013). As an example, a patient who received a kidney with a cold ischemia time of 30 h presented a risk of graft failure near 40% higher than a patient with a cold ischemia time of 6 h. Moreover, we found that the risk of death also proportionally increased for each additional hour of cold ischemia time (hazard ratio, 1.018). Thus, every additional hour of cold ischemia time must be taken into account in order to increase graft and patient survival. These findings are of practical clinical interest, as cold ischemia time is among one of the main modifiable pre-transplantation risk factors that can be minimized by improved management of the peri-transplantation period.

Estimating glomerular filtration rate in kidney transplant recipients: performance over time of four creatinine-based formulas.

Background. The management of kidney transplant recipients requires accurate estimate of glomerular filtration rate (GFR). This study aims at evaluating the performance of four creatinine-based formulas for estimating the GFR (estimated GFR) in this population. Methods. Performances of Cockcroft and Gault formula, Modification of Diet in Renal Disease (MDRD) simplified formula, Chronic Kidney Disease Epidemiology Collaboration formula, and Nankivell formula were assessed compared with inulin clearance taken as the gold standard for measuring GFR (measured GFR). Performances were assessed using the first measurements of GFR obtained in 1249 subjects. How estimated GFR tracks changes in measured GFR over time since transplantation in those patients with repeated measures was also assessed. Results. The MDRD formula provided the best estimate of GFR with a mean bias of −0.5 mL/min/1.73 m2, a standard deviation of bias of 12 mL/min/1.73 m2, and a 30% accuracy at 85%. The MDRD formula also seemed to provide the best performance for estimating GFR, irrespective of age, stage of renal failure, and in people whose body mass index was more than 18.5 kg/m2. This robustness is important in clinical practice. The performance of the four formulas was not modified by the posttransplant period. Conclusion. Even if 30% accuracy was suboptimal in the Kidney Disease Outcomes Quality Initiative guidelines, our results, obtained in a large number of patients, lead us to recommend using the MDRD formula to monitor GFR in kidney transplant recipients.

Human Mesenchymal Stem Cells and Immunosuppressive Drug Interactions in Allogeneic Responses: An In Vitro Study Using Human Cells

OBJECTIVES The use of mesenchymal stem cells (MSC), which display immunosuppressive activity, seems to be a promising therapeutic approach in solid organ transplantation. However, little is known about their interactions with immunosuppressive drugs. The objective of this study was to assess these interactions in allogeneic responses. METHODS We studied the effects on alloimmune responses in mixed lymphocyte reactions of MSC plus five agents-cyclosporine, tacrolimus, rapamycin, mycophenolate acid (MPA), and dexamethasone (DEX). RESULTS Human MSC isolated from bone marrow were characterized by their phenotype and their ability to differentiate into adipocytes or osteoblastes. MSC plus the agents inhibited allogeneic lymphocyte proliferation in a dose-dependent manner. Calcineurin inhibitors and rapamycin antagonized the inhibitory effect of MSC, whereas MPA promoted it and DXM did not modify it. CONCLUSION MPA seems to be the best immunosuppressant to associated with MSC for transplanted patients.

Clinicopathological Findings of Chronic Rejection in a Face Grafted Patient

Background Skin chronic rejection (CR) in vascularized composite allotransplantation has not been included in the Banff classification yet. We report a face-transplant patient who developed cutaneous clinicopathologic changes suggestive of CR. Methods The recipient was a 27-year-old man with severe disfigurement of the lower face due to a pyrotechnic explosion. He received a facial allograft, including mandible, cheeks, lips, and chin, in November 2009. Immunosuppression included antithymocyte globulins and bone-marrow infusion then steroids, tacrolimus, and mycophenolate mofetil. Results During the first posttransplant year the acute rejection episodes were characterized by reversible oedema and erythema of the graft. Subsequently, the patient developed primary asymptomatic Epstein-Barr virus (EBV) infection, followed by EBV+ B-cell lymphoma and hepatic EBV-associated posttransplant smooth muscle tumors; therefore, the immunosuppressive treatment was greatly reduced. Since the second posttransplant year, the allografted facial skin became progressively sclerotic and presented pigmented macules on a background of hypopigmentation and teleangiectasias, resulting in a poikilodermatous aspect. Skin biopsies showed epidermal atrophy, basal cell vacuolization, and diffuse dermal sclerosis in the absence of significant dermal cell infiltration. The dermal capillaries showed thickened walls and narrowed lumina, whereas the large vessels did not show significant alterations. Neither donor-specific antibodies nor vascular Cd4 deposits were detected. A dysfunction of the graft functions occurred. It was evidenced by a decrease in mouth opening and modification of some phonemes although lip closure was still possible allowing food intake. Conclusions This is the first report suggestive of CR in a face allotransplantation after immunosuppression minimization.

A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors

Delayed graft function (DGF) is a common complication in kidney transplantation and is known to be correlated with short- and long-term graft outcomes. Here we explored the possibility of developing a simple tool that could predict with good confidence the occurrence of DGF and could be helpful in current clinical practice. We built a score, tentatively called DGFS, from a French multicenter and prospective cohort of 1844 adult recipients of deceased donor kidneys collected since 2007, and computerized in the Données Informatisées et VAlidées en Transplantation databank. Only five explicative variables (cold ischemia time, donor age, donor serum creatinine, recipient body mass index, and induction therapy) contributed significantly to the DGF prediction. These were associated with a good predictive capacity (area under the ROC curve at 0.73). The DGFS calculation is facilitated by an application available on smartphones, tablets, or computers at www.divat.fr/en/online-calculators/dgfs. The DGFS should allow the simple classification of patients according to their DGF risk at the time of transplantation, and thus allow tailored-specific management or therapeutic strategies.

Pancreas retransplantation: a second chance for diabetic patients?

BACKGROUND If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome. METHODS Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated. RESULTS Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years). CONCLUSION Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.Background If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome. Methods Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated. Results Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years). Conclusion Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

Background The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. Methods 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. Results 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. Conclusions Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Influence of anemia on patient and graft survival after renal transplantation: results from the French DIVAT cohort.

Background and Objectives Contradictory results are reported concerning the influence of anemia on patient and graft survival after renal transplantation. Assuming that level of renal function and anemia are strongly correlated, posttransplantation anemia (PTA) may have a different impact depending on the stage of chronic kidney disease (CKD). Methods This study is a retrospective multicenter analysis using the DIVAT French database. The prevalence, risk factors, and influence of 12-month PTA (World Health Organization’s definition) on patient and graft survival were analyzed according to CKD stage (Modification of Diet in Renal Disease equation). Results The prevalence of 12-month PTA in our cohort of 4217 patients was 41.1%. Multivariate analysis demonstrated that worse renal function, donor age, period of transplantation, induction therapy, and mTOR inhibitors were significant risk factors for PTA. Posttransplantation anemia was a significant risk factor for all-cause mortality in CKD stages 1 to 2T (hazard ratio, 2.39; 95% confidence interval, 1.99–4.40) and 3T (hazard ratio, 1.52; 95% confidence interval, 1.08–2.15) and for cardiovascular mortality only on CKD stages 1T and 2T. In renal transplant recipients with CKD stages 4 to 5T, patient and graft survival were similar in patients with versus without anemia. Graft survival was not influenced by PTA, whatever the CKD stage. Conclusions Posttransplantation anemia is associated with decreased patient survival only in CKD stages 1T, 2T, and 3T. Posttransplantation anemia has no influence on graft survival regardless of CKD stage.

Advagraf®, a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts

The efficacy and safety of tacrolimus twice‐a‐day (BID) and once‐a‐day (QD) formulations are similar. However, the available information regarding the initiation and management of tacrolimus QD is sparse and practical information is lacking. A panel of French experts extensively reviewed the available literature on tacrolimus pharmacokinetics, clinical efficacy, and safety in kidney transplantation and, based on their own day‐to‐day experience, provided the practitioners with practical guidelines for the daily use and management of tacrolimus QD in de novo initiation or early conversion.

Mesenchymal stem cell and immunosuppressive drug interactions.

The authors declare no conflict of interest. The authors thank Eddie Takahashi for the English translation. Address correspondence to: Prof. Georges Mourad, M.D., Department of Nephrology and Transplantation, University of Montpellier, Hôpital Lapeyronie 191, Avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 05, France. E-mail: g-mourad@chu-montpellier.fr Received 5 November 2008. Revision requested 30 January 2009. Accepted 5 March 2009. Copyright