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 30h presented a risk of graft failure near 40% higher than a patient with a cold ischemia time of 6h. 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.
Purpose of review
Grafted beta cells are lost because of recurrence of T1D and/or allograft rejection, two conditions diagnosed with pancreas graft biopsy, which is invasive and impossible in case of ...islet transplantation. This review synthetizes the current pathophysiological knowledge and discusses the interest of available immune biomarkers.
Recent findings
Despite the central role of auto-(recurrence of T1D) and allo-(T-cell mediated rejection) immune cellular responses, the latter are not directly monitored in routine. In striking contrast, there have been undisputable progresses in monitoring of auto and alloantibodies.
Summary
Except for pancreas recipients in whom anti-donor HLA antibodies can be directly responsible for antibody-mediated rejection, autoantibodies (and alloantibodies in islet recipients) have no direct pathogenic effect. However, their fluctuation offers a surrogate marker for the activation status of T cells (because antibody generation depends on T cells). This illustrates the necessity to understand the pathophysiology when interpreting a biomarker and selecting the appropriate treatment.
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.
There is extensive literature with comparisons between Anti-Thymocyte Globulin (ATG) and Basiliximab (BSX) as induction therapy in kidney transplant recipients. The purpose of our benchmarking study ...was to describe the consequences in terms of practices in 6 transplantation centers of a French prospective cohort.
We included adult patients who received a first or second kidney graft between 2013 and 2019 (n = 4157). We used logistic regressions to identify characteristics associated with the use of ATG or BSX.
Use of ATG between the centers ranged from 41% to 75%. We observed different factors associated with the treatment decision. Compared to a first transplant, performing a second graft was the only factor significantly associated with the choice of ATG in all centers. The AUC ranged from 0.67 to 0.91, indicating that the centers seemed to define their own rules. As a result, for patients with the same low immunological risk, the probability of receiving ATG varied from 7% to 36%. We stratified the analyses according to two periods, from 2013 to 2015 and from 2016 to 2019. A similar heterogeneity was observed, and in some cases ATG indications between the centers were inverted.
The heterogeneity of induction therapy practices did not decrease in France, even if the reated literature is prolific. This illustrates the necessity to improve the literature by using meta-analyses of recent studies stratified by graft and patient profiles.
Estimating glomerular filtration rate (GFR) is important for clinical management in kidney transplantation recipients (KTR). However, very few studies have evaluated the performance of the new GFR ...estimating equations (Lund-Malmö Revised-LMR, and Full Age Spectrum-FAS) in KTR.
GFR was estimated (eGFR) using CKD-EPI, MDRD, LMR, and FAS equations and compared to GFR measurement (mGFR) by reference methods (inuline urinary and iohexol plasma clearance) in 395 deceased-donor KTR without corticosteroids. The equations performance was assessed using bias (mean difference of eGFR and mGFR), precision (standard deviation of the difference), accuracy (concordance correlation coefficient-CCC), and agreements (total deviation index-TDI). The area under receiver operating characteristic curves (ROC) and the likelihood ratio for a positive result were calculated.
In the total population, the performance of the CKD-EPI, MDRD and FAS equations was significantly lower than the LMR equation regarding the mean 95%CI difference in bias (-2.0 -4.0; -1.5 versus 9.0 7.5; 10.0, 5.0 3.5; 6.0 and 10.0 8.5; 11.0 mL/min/1.73m2, P<0.005) and TDI (17.10 16.41; 17.88, 25.91 24.66; 27.16, 21.23 19.48; 23.13 and 25.84 24.16; 27.57, respectively). Concerning the CCC, all equation had poor agreement (<0.800) without statically difference between them. However, all equations had excellent area under the ROC curve (>0.900), and LMR equation had the best ability to correctly predict KTR with mGFR<45 mL/min/1.73 m2 (positive likelihood ratio: 8.87 5.79; 13.52).
Among a referral group of subjects KTR, LMR equation had the best mean bias and TDI, but with no significant superiority in other agreement tools. Caveat is required in the use and interpretation of PCr-based equations in this specific population.
Background
About 10–20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.
...Methods
We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.
Results
Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.
Conclusion
Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.
After the first year post transplantation, prognostic mortality scores in kidney transplant recipients can be useful for personalizing medical management. We developed a new prognostic score based on ...5 parameters and computable at 1-year post transplantation. The outcome was the time between the first anniversary of the transplantation and the patient's death with a functioning graft. Afterwards, we appraised the prognostic capacities of this score by estimating time-dependent Receiver Operating Characteristic (ROC) curves from two prospective and multicentric European cohorts: the DIVAT (Données Informatisées et VAlidées en Transplantation) cohort composed of patients transplanted between 2000 and 2012 in 6 French centers; and the STCS (Swiss Transplant Cohort Study) cohort composed of patients transplanted between 2008 and 2012 in 6 Swiss centers. We also compared the results with those of two existing scoring systems: one from Spain (Hernandez et al.) and one from the United States (the Recipient Risk Score, RRS, Baskin-Bey et al.). From the DIVAT validation cohort and for a prognostic time at 10 years, the new prognostic score (AUC = 0.78, 95%CI = 0.69, 0.85) seemed to present significantly higher prognostic capacities than the scoring system proposed by Hernandez et al. (p = 0.04) and tended to perform better than the initial RRS (p = 0.10). By using the Swiss cohort, the RRS and the the new prognostic score had comparable prognostic capacities at 4 years (AUC = 0.77 and 0.76 respectively, p = 0.31). In addition to the current available scores related to the risk to return in dialysis, we recommend to further study the use of the score we propose or the RRS for a more efficient personalized follow-up of kidney transplant recipients.
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.
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.
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.
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.
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.
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.
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.
This is the first report suggestive of CR in a face allotransplantation after immunosuppression minimization.
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