Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the United States: A Comparison of International Transplant Practices and Outcomes.

BACKGROUND: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. METHODS: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. RESULTS: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. CONCLUSIONS: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.

Predictive value of mixed antigen screen beads in pre-transplant assessment of HLA immunization in solid organ transplant recipients.

Pre-transplant serum screening of anti-HLA antibodies is recommended for solid organ transplantations. Many laboratories use the less expensive bead-based screening assay as the main technique and, if positive, turn to single-antigen beads (SAB). We studied the correlations between these two immunoassays. We re-analyzed the raw data of the two assays in 3030 first organ transplant recipients, explored with the two tests. We performed a ROC curve analysis of the screening ratio to predict a positive SAB assay. The AUC were 0.72 and 0.64 for class I and class II. The optimal thresholds of screening ratios were 3.28 (class I) and 2.11 (class II). Whatever the class, the negative predictive value was low, around 40%, with 36% of discordant sera, as defined by negative screening and positive SAB. Testing class I discordant sera on acid-treated SAB showed that 54% of antibodies reacted against denatured HLA molecules. However, these screening-negative sera may contain donor-specific antibodies in 13.9% and 28.7% of cases for class I and class II, respectively, involved in antibody-mediated rejection with the same frequency as non-discordant sera. Given the low predictive value of screening, both assays should be performed at least once on the same serum before transplantation.

Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance.

IMPORTANCE: Approximately 3500 donated kidneys are discarded in the United States each year, drawing concern from Medicare and advocacy groups. OBJECTIVE: To estimate the effects of more aggressive allograft acceptance practices on the donor pool and allograft survival for the population of US wait-listed kidney transplant candidates. DESIGN, SETTING, AND PARTICIPANTS: A nationwide study using validated registries from the United States and France comprising comprehensive cohorts of deceased donors with organs offered to kidney transplant centers between January 1, 2004, and December 31, 2014. Data were analyzed between September 1, 2018, and April 5, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was kidney allograft discard. The secondary outcome was allograft failure after transplantation. We used logistic regression to model organ acceptance and discard practices in both countries. We then quantified using computer simulation models the number of kidneys discarded in the United States that a more aggressive system would have instead used for transplantation. Finally, based on actual survival data, we quantified the additional years of allograft life that a redesigned US system would have saved. FINDINGS: In the United States, 156 089 kidneys were recovered from deceased donors between 2004 and 2014, of which 128 102 were transplanted, and 27 987 (17.9%) were discarded. In France, among the 29 984 kidneys recovered between 2004 and 2014, 27 252 were transplanted, and 2732 (9.1%, P < .001 vs United States) were discarded. The mean (SD) age of kidneys transplanted in the United States was 36.51 (17.02) years vs 50.91 (17.34) years in France (P < .001). Kidney quality showed little change in the United States over time (mean [SD] kidney donor risk index [KDRI], 1.30 [0.48] in 2004 vs 1.32 [0.46] in 2014), whereas a steadily rising KDRI in France reflected a temporal trend of more aggressive organ use (mean [SD] KDRI, 1.37 [0.47] in 2004 vs 1.74 [0.72] in 2014; P < .001). We applied the French-based allocation model to the population of US deceased donor kidneys and found that 17 435 (62%) of kidneys discarded in the United States would have instead been transplanted under the French system. We further determined that a redesigned system with more aggressive organ acceptance practices would generate an additional 132 445 allograft life-years in the United States over the 10-year observation period. CONCLUSIONS AND RELEVANCE: Greater acceptance of kidneys from deceased donors who are older and have more comorbidities could provide major survival benefits to the population of US wait-listed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03723668.

GFR Assessment of Living Kidney Donors Candidates.

Living kidney donation provides the best outcomes (survival, cost, and quality of life) of all renal replacement modalities. Living kidney donors, on the other hand, are at the increased risk of end-stage kidney disease (ESKD) after donation compared with healthy nondonors for multiple possible reasons. Extensive predonation screening is required to assess eligibility for donation to avoid the rejection of suitable candidates and minimize acceptance of donors with increased risk of ESKD. The association between the lower predonation glomerular filtration rate (GFR) and increased ESKD risk in donors highlights the relevance of GFR assessment for living kidney donor candidates. However, the method to evaluate GFR is still debated, and the thresholds of acceptable predonation GFR vary across guidelines. All guidelines favor GFR measurement with an exogenous tracer over estimated GFR, but only the British Transplant Society guidelines mandates it. While the Kidney Disease Improving Global Outcomes Group guidelines advocates for age-independent GFR thresholds, most other guidelines propose various age-dependent GFR thresholds with resulting profound differences in assessment of donor suitability between guidelines. Many important questions are not addressed by any guidelines, including the approach to discordant GFR measurement and estimated GFR results, the use of method-specific GFR thresholds and thresholds dependent on comorbidities or race. Further data are required exploring the associations between these variables and the course of postdonation GFR. Last, GFR evaluation studies conducted in approved donors and not in those initially presenting as potential candidates are questionable regarding their suitability for potential donor evaluation.

The Association Between Fibroblast Growth Factor 23 and Renal Transplantation Outcome Is Modified by Follow-up Duration and Glomerular Filtration Rate Assessment Method.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) could contribute to cardiovascular morbidity in chronic kidney disease. In studies of kidney transplant recipients, a high circulating level of FGF23 has been associated with death and graft loss independently of estimated glomerular filtration rate (GFR). Whether FGF23 is associated with adverse outcomes in the early posttransplantation period is unknown. METHODS: We analyzed a cohort of 845 kidney transplant recipients in stable condition who had GFR measured in the first years after transplantation with a median follow-up of 71 months. RESULTS: A high FGF23 concentration was associated with death or graft loss in univariate analysis, but this association was lost after adjustment for measured GFR. In contrast, FGF23 remained significantly associated with the composite outcome when estimated GFR was substituted for measured GFR. We also observed that follow-up duration modified the association between FGF23 and outcome. Although FGF23 was not associated with any endpoint in the full duration of the study, we found an independent association between FGF23 and the incidence of graft loss within the 4 years after FGF23 measurement. We did not find an association between FGF23 levels and left ventricular mass in a subgroup of 227 patients who had echocardiography performed within 3 months of FGF23 measurement. DISCUSSION: This study demonstrates that FGF23 measured during the first year after transplantation is not an independent predictor of death and graft loss and is not associated with left ventricular hypertrophy in the posttransplantation period. It further unveils important factors modifying the association between FGF23 and outcome in this population.

PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial.

BACKGROUND: In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk. METHODS: We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019. DISCUSSION: The main expected benefits of this study are i) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii) the reduction of chance losses related to ATG under-prescription, iii) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy. TRIAL REGISTRATION: The study was registered in the Clinical Trials Registry (# NCT02056938, February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014).

[Living donors for kidney transplantation: ethical and legal challenges]. / La transplantation rénale à partir de donneurs vivants: enjeux éthiques et juridiques.

Living donor kidney transplantation has developed very heterogeneously worldwide despite excellent results and without taking into account the context of global organ shortage. Such a heterogeneity highlights persistent ethical issues, whereas organ trafficking is emerging as an organized transplant tourism reinforcing the need for strong national legal frameworks. Despite its powerful regulation system, which ensures standardization, transparency and accountability of support for donation, France remains reluctant to enlarge the circle of legal donors, whereas it would be the first step to give a greater role to living organ donation.

What is the relevance of systematic aorto-femoral Doppler ultrasound in the preoperative assessment of patients awaiting first kidney transplantation: a monocentric prospective study.

BACKGROUND: The purpose of our study was to study the relevance of a systematic aorto-femoral colour Doppler ultrasound (DUS) in the evaluation of first renal transplant receivers. METHODS: We prospectively studied 100 consecutive first renal transplant (RT) receivers. All patients had a preoperative physical examination with a careful vascular system evaluation including assessment of risk factors and colour DUS of aortic, iliac and femoral arteries. Renal transplantation was planned in the right iliac fossa with end-to-lateral vascular anastomoses. Clinical parameters, DUS results, operative and post-operative parameters at 3 months were compared according to the vascular assessment. RESULTS: Among the 84 patients presenting with a normal preoperative physical arterial examination, 12 patients (14.3%) had an abnormal DUS, revealing atherosclerotic arteries, but no case of arterial stenosis. Among the 16 patients with abnormal physical arterial examination, 10 patients (62.5%) had abnormal DUS, including 4 cases of iliac stenosis. In 3 of the 16 patients (18.8%), DUS revealed right iliac artery stenosis requiring a modification in the surgical procedure. No additional vascular procedure was reported in the case of normal preoperative vascular examination. No technical problems during arterial anastomosis and no post-transplantation arterial complications were reported. In multivariate analysis, abnormal physical examination was the most significant risk factor of atherosclerotic infiltration in DUS. CONCLUSION: The abnormality of arterial physical examination is the best clinical predictor of abnormal DUS in preoperative assessment of renal transplant receivers. However, the low sensitivity and positive predictive value of the physical examination do not support the conclusion that DUS can be avoided in patients with normal arterial physical examination. Nevertheless, in the case of arterial physical abnormality, 'for case' DUS is critical and helps in the surgical strategy in approximately 20% of cases.

The cost-effectiveness of prophylaxis with valaciclovir in the management of cytomegalovirus after renal transplantation.

Prophylaxis-based antiviral treatment and intensive monitoring followed by pre-emptive antiviral treatment are both commonly used management strategies to reduce risk of cytomegalovirus (CMV) infection following renal transplantation. This study employed a decision-model approach using published efficacy data and information from a recent survey of French clinical practice to consider the relative costs and outcomes associated with CMV prevention strategies for high-risk patient groups. The cost per case of treating tissue invasive and symptomatic CMV disease was estimated at euro 15,431 and euro 10,852, respectively. In the highest infection-risk patient group (positive donor with no previous CMV history) prophylactic oral valaciclovir was shown to avoid the greatest number of CMV disease cases (35 cases per 100 transplanted patients) and reduced the overall CMV-related costs per transplanted patient by around 14% over a'wait-and-treat' baseline strategy. In contrast, intensive monitoring and preemptive treatment resulted in a much higher cost per transplanted patient. This analysis suggests that prophylactic treatment remains the most cost-effective approach to the management of CMV in renal-transplanted patients. Further comparative studies between prophylactic and pre-emptive treatment would be a valuable addition to the current evidence based on CMV prevention.

Benefit-risk assessment of ciclosporin withdrawal in renal transplant recipients.

Ciclosporin is associated with significant toxicity, including nephrotoxicity, and with an increased risk of cardiovascular events. Many attempts have been made to wean patients from ciclosporin. Before the availability of new immunosuppressive drugs, the acute rejection rate observed after ciclosporin withdrawal did not permit the widespread use of withdrawal regimens even though meta-analysis did not show that they adversely affected patient or graft survival. Nevertheless, maintenance therapy with azathioprine and corticosteroids has not become routine practice. The introduction of mycophenolate mofetil and subsequently sirolimus has increased the number of clinical studies of the effects of ciclosporin withdrawal. In stable patients, this withdrawal is associated with a small but significant increase in the incidence of acute rejection episodes. Declining renal function and other forms of ciclosporin-related toxicity have improved. However, this improvement was also observed when ciclosporin was only reduced (and not withdrawn), which did not increase the risk of acute rejection. More precise definition of the patients who could benefit from ciclosporin-withdrawal may help to optimise the immunosuppressive regimen in this setting. In patients with chronic allograft deterioration, ciclosporin withdrawal together with mycophenolate mofetil introduction has been shown to improve renal function significantly in many small studies, and a large prospective randomised study. For the time being, ciclosporin withdrawal is a good therapeutic option for patients with declining renal function and signs of chronic ciclosporin nephrotoxicity on renal biopsy. Finally, recent preliminary studies have reported the results of complete avoidance of calcineurin inhibitors after renal transplantation. These results are promising as regards the incidence of acute rejection, renal function and safety, but need confirmation in larger trials with a longer follow-up. Nevertheless, it has become clear that the concept of an immunosuppressive regimen with little or no nephrotoxicity after renal transplantation is more and more important and plays a crucial part in tailoring immunosuppression to the needs of specific patient populations.

Prevalence and management of anemia in renal transplant recipients: a European survey.

The TRansplant European Survey on Anemia Management (TRESAM) documented the prevalence and management of anemia in kidney transplant recipients. Data from 72 transplant centers in 16 countries were screened, involving 4263 patients who had received transplants 6 months, 1, 3 or 5 years earlier. The mean age of transplant recipients was 45.5 years at transplantation. The most common etiology was chronic glomerulonephritis. The most common comorbidities were coronary artery disease, hepatitis B/C, and type 2 diabetes. The mean hemoglobin levels before transplantation were significantly higher in the more recently transplanted recipients. At enrollment, 38.6% of patients were found to be anemic. Of the 8.5% of patients who were considered severely anemic, only 17.8% were treated with epoetin. There was a strong association between hemoglobin and graft function; of the 904 patients with serum creatinine > 2 mg/dL, 60.1% were anemic, vs. 29.0% of those with serum creatinine

The economic value of valacyclovir prophylaxis in transplantation.

Cytomegalovirus (CMV) infection and disease, with its extensive direct and indirect consequences, adds considerably to the cost of patient management in both solid organ and bone marrow transplantation. Antiviral prophylaxis for CMV infection can offer cost advantages over preemptive therapy and "wait-and-treat" approaches. Valacyclovir has demonstrated efficacy for CMV prophylaxis in renal, heart, and bone marrow transplantation and is cost-effective when compared with placebo in renal transplant recipients at high risk of CMV infection. In reducing CMV infection and disease, valacyclovir prophylaxis appears to be associated with reductions in indirect effects of CMV (acute graft rejection, other opportunistic infections) and, if these effects are considered, the potential exists for even greater savings to be made with valacyclovir therapy. Benefits of valacyclovir in transplantation extend beyond CMV to other herpesviruses and may be increased in some clinical situations by prolonging prophylaxis beyond 3 months.